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1. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Author

Kunkle, Brian W, Grenier-Boley, Benjamin, Sims, Rebecca, Bis, Joshua C, Damotte, Vincent, Naj, Adam C, Boland, Anne, Vronskaya, Maria, van der Lee, Sven J, Amlie-Wolf, Alexandre, Bellenguez, Céline, Frizatti, Aura, Chouraki, Vincent, Martin, Eden R, Sleegers, Kristel, Badarinarayan, Nandini, Jakobsdottir, Johanna, Hamilton-Nelson, Kara L, Moreno-Grau, Sonia, Olaso, Robert, Raybould, Rachel, Chen, Yuning, Kuzma, Amanda B, Hiltunen, Mikko, Morgan, Taniesha, Ahmad, Shahzad, Vardarajan, Badri N, Epelbaum, Jacques, Hoffmann, Per, Boada, Merce, Beecham, Gary W, Garnier, Jean-Guillaume, Harold, Denise, Fitzpatrick, Annette L, Valladares, Otto, Moutet, Marie-Laure, Gerrish, Amy, Smith, Albert V, Qu, Liming, Bacq, Delphine, Denning, Nicola, Jian, Xueqiu, Zhao, Yi, Del Zompo, Maria, Fox, Nick C, Choi, Seung-Hoan, Mateo, Ignacio, Hughes, Joseph T, Adams, Hieab H, Malamon, John, Sanchez-Garcia, Florentino, Patel, Yogen, Brody, Jennifer A, Dombroski, Beth A, Naranjo, Maria Candida Deniz, Daniilidou, Makrina, Eiriksdottir, Gudny, Mukherjee, Shubhabrata, Wallon, David, Uphill, James, Aspelund, Thor, Cantwell, Laura B, Garzia, Fabienne, Galimberti, Daniela, Hofer, Edith, Butkiewicz, Mariusz, Fin, Bertrand, Scarpini, Elio, Sarnowski, Chloe, Bush, Will S, Meslage, Stéphane, Kornhuber, Johannes, White, Charles C, Song, Yuenjoo, Barber, Robert C, Engelborghs, Sebastiaan, Sordon, Sabrina, Voijnovic, Dina, Adams, Perrie M, Vandenberghe, Rik, Mayhaus, Manuel, Cupples, L Adrienne, Albert, Marilyn S, De Deyn, Peter P, Gu, Wei, Himali, Jayanadra J, Beekly, Duane, Squassina, Alessio, Hartmann, Annette M, Orellana, Adelina, Blacker, Deborah, Rodriguez-Rodriguez, Eloy, Lovestone, Simon, Garcia, Melissa E, Doody, Rachelle S, Munoz-Fernadez, Carmen, Sussams, Rebecca, Lin, Honghuang, Fairchild, Thomas J, and Benito, Yolanda A

Subjects
Biochemistry and Cell Biology, Genetics, Biological Sciences, Neurodegenerative, Dementia, Alzheimer's Disease, Aging, Prevention, Brain Disorders, Neurosciences, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Neurological, Aged, Alzheimer Disease, Amyloid beta-Peptides, Case-Control Studies, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Testing, Genome-Wide Association Study, Haplotypes, Humans, Immunity, Lipid Metabolism, Lipids, Male, tau Proteins, Alzheimer Disease Genetics Consortium (ADGC), European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES), Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Published
2019

2. Severity dependent distribution of impairments in PSP and CBS: Interactive visualizations

Author

Brittain, Claire, McCarthy, Andrew, Irizarry, Michael C, McDermott, Dana, Biglan, Kevin, Höglinger, Günter U, Lorenzl, Stefan, del Ser, Teodoro, Boxer, Adam L, Group, The AL-108-231 Study, Williams, David, Lafontaine, Anne Louise, Marras, Connie, Jog, Mandar, Panisset, Michael, Lang, Anthony, Parker, Lesley, Stewart, Alistair J, Corvol, Jean-Christophe, Azulay, Jean-Philippe, Couratier, Philippe, Mollenhauer, Brit, Ludolph, Albert, Benecke, Reiner, Hoglinger, Gunter, Lipp, Axel, Reichmann, Heinz, Woitalla, Dirk, Chan, Dennis, Zermansky, Adam, Burn, David, Lees, Andrew, Gozes, Illana, Boxer, Adam, Miller, Bruce L, Lobach, Iryna V, Roberson, Erik, Honig, Lawrence, Zamrini, Edward, Pahwa, Rajesh, Bordelon, Yvette, Driver-Dunkley, Erika, Lessig, Stephanie, Lew, Mark, Womack, Kyle, Boeve, Brad, Ferrara, Joseph, Hillis, Argyle, Kaufer, Daniel, Kumar, Rajeev, Xie, Tao, Gunzler, Steven, Zesiewicz, Theresa, Dayalu, Praveen, Golbe, Lawrence, Grossman, Murray, Jankovic, Joseph, McGinnis, Scott, Santiago, Anthony, Tuite, Paul, Isaacson, Stuart, Leegwater-Kim, Julie, Litvan, Irene, Knopman, David S, Schneider, Lon S, Doody, Rachelle S, Golbe, Lawrence I, Roberson, Erik D, Koestler, Mary, Jack, Clifford R, Van Deerlin, Viviana, Randolph, Christopher, Whitaker, Steve, Hirman, Joe, Gold, Michael, Morimoto, Bruce H, investigators, The PROPSPERA, G, Georg Nuebling, Hensler, Mira, Paul, Sabine, Zwergal, Andreas, 4RNTI-1authors, Heuer, Hilary W, Tartaglia, Maria C, McGinnis, Scott M, Dickerson, Bradford C, Kornak, John, Schuff, Norbert, Rabinovici, Gil D, Rosen, Howard J, Investigators, Tau Restoration on PSP, Gómez, JC, Tijero, B, Berganzo, K, de Yebenes, J Garc'ıa, Sendón, JL Lopez, and Garcia, G

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Trials and Supportive Activities, Rare Diseases, Neurodegenerative, Aging, Acquired Cognitive Impairment, Clinical Research, Dementia, Frontotemporal Dementia (FTD), Health Disparities, Alzheimer's Disease Related Dementias (ADRD), 4.2 Evaluation of markers and technologies, Neurological, Aged, Aged, 80 and over, Basal Ganglia Diseases, Data Visualization, Disease Progression, Female, Humans, Male, Middle Aged, Models, Neurological, Neurodegenerative Diseases, Prognosis, Severity of Illness Index, Supranuclear Palsy, Progressive, Syndrome, Corticobasal syndrome, Progressive supranuclear palsy, PSP rating scale, Interactive visualizations, Predictive models, AL-108-231 Study Group, PROPSPERA investigators, 4RNTI-1authors, Tau Restoration on PSP (TAUROS) Investigators, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences, Biological psychology
Abstract

BackgroundProgressive supranuclear palsy (PSP) -Richardson's Syndrome and Corticobasal Syndrome (CBS) are the two classic clinical syndromes associated with underlying four repeat (4R) tau pathology. The PSP Rating Scale is a commonly used assessment in PSP clinical trials; there is an increasing interest in designing combined 4R tauopathy clinical trials involving both CBS and PSP.ObjectivesTo determine contributions of each domain of the PSP Rating Scale to overall severity and characterize the probable sequence of clinical progression of PSP as compared to CBS.MethodsMulticenter clinical trial and natural history study data were analyzed from 545 patients with PSP and 49 with CBS. Proportional odds models were applied to model normalized cross-sectional PSP Rating Scale, estimating the probability that a patient would experience impairment in each domain using the PSP Rating Scale total score as the index of overall disease severity.ResultsThe earliest symptom domain to demonstrate impairment in PSP patients was most likely to be Ocular Motor, followed jointly by Gait/Midline and Daily Activities, then Limb Motor and Mentation, and finally Bulbar. For CBS, Limb Motor manifested first and ocular showed less probability of impairment throughout the disease spectrum. An online tool to visualize predicted disease progression was developed to predict relative disability on each subscale per overall disease severity.ConclusionThe PSP Rating Scale captures disease severity in both PSP and CBS. Modelling how domains change in relation to one other at varying disease severities may facilitate detection of therapeutic effects in future clinical trials.

Published
2019

3. CSF neurofilament light chain and phosphorylated tau 181 predict disease progression in PSP

Author

Rojas, Julio C, Bang, Jee, Lobach, Iryna V, Tsai, Richard M, Rabinovici, Gil D, Miller, Bruce L, Boxer, Adam L, Williams, David, Lafontaine, Anne Louise, Marras, Connie, Jog, Mandar, Panisset, Michael, Lang, Anthony, Parker, Lesley, Stewart, Alistair J, Corvol, Jean-Christophe, Azulay, Jean-Philippe, Couratier, Philippe, Mollenhauer, Brit, Lorenzl, Stefan, Ludolph, Albert, Benecke, Reiner, Hoglinger, Gunter, Lipp, Axel, Reichmann, Heinz, Woitalla, Dirk, Chan, Dennis, Zermansky, Adam, Burn, David, Lees, Andrew, Gozes, Illana, Boxer, Adam, Roberson, Erik, Honig, Lawrence, Zamrini, Edward, Pahwa, Rajesh, Bordelon, Yvette, Driver-Dunkley, Erika, Lessig, Stephanie, Lew, Mark, Womack, Kyle, Boeve, Brad, Ferrara, Joseph, Hillis, Argyle, Kaufer, Daniel, Kumar, Rajeev, Xie, Tao, Gunzler, Steven, Zesiewicz, Theresa, Dayalu, Praveen, Golbe, Lawrence, Grossman, Murray, Jankovic, Joseph, McGinnis, Scott, Santiago, Anthony, Tuite, Paul, Isaacson, Stuart, Leegwater-Kim, Julie, Litvan, Irene, Knopman, David S, Schneider, Lon S, Doody, Rachelle S, Koestler, Mary, Jack, Clifford R, Van Deerlin, Viviana, Randolph, Christopher, Whitaker, Steve, Hirman, Joe, Gold, Michael, and Morimoto, Bruce H

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Aging, Alzheimer's Disease, Neurodegenerative, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Dementia, Neurological, Aged, Amyloid beta-Peptides, Biomarkers, Brain, Central Nervous System Agents, Disease Progression, Double-Blind Method, Female, Humans, Longitudinal Studies, Male, Neurofilament Proteins, Oligopeptides, Peptide Fragments, Phosphorylation, Prognosis, Severity of Illness Index, Supranuclear Palsy, Progressive, tau Proteins, AL-108-231 Investigators, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo determine the ability of CSF biomarkers to predict disease progression in progressive supranuclear palsy (PSP).MethodsWe compared the ability of baseline CSF β-amyloid1-42, tau, phosphorylated tau 181 (p-tau), and neurofilament light chain (NfL) concentrations, measured by INNO-BIA AlzBio3 or ELISA, to predict 52-week changes in clinical (PSP Rating Scale [PSPRS] and Schwab and England Activities of Daily Living [SEADL]), neuropsychological, and regional brain volumes on MRI using linear mixed effects models controlled for age, sex, and baseline disease severity, and Fisher F density curves to compare effect sizes in 50 patients with PSP. Similar analyses were done using plasma NfL measured by single molecule arrays in 141 patients.ResultsHigher CSF NfL concentration predicted more rapid decline (biomarker × time interaction) over 52 weeks in PSPRS (p = 0.004, false discovery rate-corrected) and SEADL (p = 0.008), whereas lower baseline CSF p-tau predicted faster decline on PSPRS (p = 0.004). Higher CSF tau concentrations predicted faster decline by SEADL (p = 0.004). The CSF NfL/p-tau ratio was superior for predicting change in PSPRS, compared to p-tau (p = 0.003) or NfL (p = 0.001) alone. Higher NfL concentrations in CSF or blood were associated with greater superior cerebellar peduncle atrophy (fixed effect, p ≤ 0.029 and 0.008, respectively).ConclusionsBoth CSF p-tau and NfL correlate with disease severity and rate of disease progression in PSP. The inverse correlation of p-tau with disease severity suggests a potentially different mechanism of tau pathology in PSP as compared to Alzheimer disease.

Published
2018

4. Transethnic genome‐wide scan identifies novel Alzheimer's disease loci

Author

Jun, Gyungah R, Chung, Jaeyoon, Mez, Jesse, Barber, Robert, Beecham, Gary W, Bennett, David A, Buxbaum, Joseph D, Byrd, Goldie S, Carrasquillo, Minerva M, Crane, Paul K, Cruchaga, Carlos, De Jager, Philip, Ertekin‐Taner, Nilufer, Evans, Denis, Fallin, M Danielle, Foroud, Tatiana M, Friedland, Robert P, Goate, Alison M, Graff‐Radford, Neill R, Hendrie, Hugh, Hall, Kathleen S, Hamilton‐Nelson, Kara L, Inzelberg, Rivka, Kamboh, M Ilyas, Kauwe, John SK, Kukull, Walter A, Kunkle, Brian W, Kuwano, Ryozo, Larson, Eric B, Logue, Mark W, Manly, Jennifer J, Martin, Eden R, Montine, Thomas J, Mukherjee, Shubhabrata, Naj, Adam, Reiman, Eric M, Reitz, Christiane, Sherva, Richard, St. George‐Hyslop, Peter H, Thornton, Timothy, Younkin, Steven G, Vardarajan, Badri N, Wang, Li‐San, Wendlund, Jens R, Winslow, Ashley R, Adams, Perrie M, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Barmada, Michjael M, Barnes, Lisa L, Beach, Thomas G, Becker, James T, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Cairns, Nigel J, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cribbs, David H, Crocco, Elizabeth A, De Jager, Philip L, DeCarli, Charles, DeKosky, Steven T, Demirci, F Yesim, Dick, Malcolm, Dickson, Dennis W, Doody, Rachelle S, Duara, Ranjan, Faber, Kelley M, Fairchild, Thomas J, Fallon, Kenneth B, Farlow, Martin R, Ferris, Steven, Frosch, Matthew P, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Glass, Jonathan D, Green, Robert C, and Growdon, John H

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Genetics, Dementia, Alzheimer's Disease, Aging, Prevention, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Apolipoprotein E4, GTPase-Activating Proteins, Genetic Predisposition to Disease, Genome-Wide Association Study, Heparin-binding EGF-like Growth Factor, Humans, Membrane Glycoproteins, Molecular Chaperones, NFI Transcription Factors, Peroxisomal Bifunctional Enzyme, Polymorphism, Single Nucleotide, Receptors, GABA, Alzheimer's Disease Genetics Consortium, APOE interaction, Alzheimer's disease, Genome-wide association, Transethnic, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionGenetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.MethodsWe conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.ResultsGenome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P

Published
2017

5. Progression of brain atrophy in PSP and CBS over 6 months and 1 year

Author

Dutt, Shubir, Binney, Richard J, Heuer, Hilary W, Luong, Phi, Attygalle, Suneth, Bhatt, Priyanka, Marx, Gabe A, Elofson, Jonathan, Tartaglia, Maria C, Litvan, Irene, McGinnis, Scott M, Dickerson, Bradford C, Kornak, John, Waltzman, Dana, Voltarelli, Lisa, Schuff, Norbert, Rabinovici, Gil D, Kramer, Joel H, Jack, Clifford R, Miller, Bruce L, Rosen, Howard J, Boxer, Adam L, Williams, David, Lafontaine, Anne Louise, Marras, Connie, Jog, Mandar, Panisset, Michael, Lang, Anthony, Parker, Lesley, Stewart, Alistair J, Corvol, Jean-Christophe, Azulay, Jean-Philippe, Couratier, Philippe, Mollenhauer, Brit, Lorenzl, Stefan, Ludolph, Albert, Benecke, Reiner, Hoglinger, Gunter, Lipp, Axel, Reichmann, Heinz, Woitalla, Dirk, Chan, Dennis, Zermansky, Adam, Burn, David, Lees, Andrew, Gozes, Illana, Boxer, Adam, Lobach, Iryna V, Roberson, Erik, Honig, Lawrence, Zamrini, Edward, Pahwa, Rajesh, Bordelon, Yvette, Driver-Dunkley, Erika, Lessig, Stephanie, Lew, Mark, Womack, Kyle, Boeve, Brad, Ferrara, Joseph, Hillis, Argyle, Kaufer, Daniel, Kumar, Rajeev, Xie, Tao, Gunzler, Steven, Zesiewicz, Theresa, Dayalu, Praveen, Golbe, Lawrence, Grossman, Murray, Jankovic, Joseph, McGinnis, Scott, Santiago, Anthony, Tuite, Paul, Isaacson, Stuart, Leegwater-Kim, Julie, Knopman, David S, Schneider, Lon S, Doody, Rachelle S, Koestler, Mary, Van Deerlin, Viviana, Randolph, Christopher, Whitaker, Steve, Hirman, Joe, Gold, Michael, Morimoto, and , Bruce H

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Biomedical Imaging, Aging, Rare Diseases, Alzheimer's Disease, Clinical Research, Neurosciences, Brain Disorders, Acquired Cognitive Impairment, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, 2.1 Biological and endogenous factors, Aetiology, Neurological, Aged, Atrophy, Basal Ganglia, Cerebral Cortex, Disease Progression, Female, Follow-Up Studies, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Statistics, Nonparametric, Supranuclear Palsy, Progressive, AL-108-231 investigators, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo examine the utility and reliability of volumetric MRI in measuring disease progression in the 4 repeat tauopathies, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), to support clinical development of new tau-directed therapeutic agents.MethodsSix- and 12-month changes in regional MRI volumes and PSP Rating Scale scores were examined in 55 patients with PSP and 33 patients with CBS (78% amyloid PET negative) compared to 30 normal controls from a multicenter natural history study. Longitudinal voxel-based morphometric analyses identified patterns of volume loss, and region-of-interest analyses examined rates of volume loss in brainstem (midbrain, pons, superior cerebellar peduncle), cortical, and subcortical regions based on previously validated atlases. Results were compared to those in a replication cohort of 226 patients with PSP with MRI data from the AL-108-231 clinical trial.ResultsPatients with CBS exhibited greater baseline atrophy and greater longitudinal atrophy rates in cortical and basal ganglia regions than patients with PSP; however, midbrain and pontine atrophy rates were similar. Voxel-wise analyses showed distinct patterns of regional longitudinal atrophy in each group as compared to normal controls. The midbrain/pons volumetric ratio differed between diagnoses but remained stable over time. In both patient groups, brainstem atrophy rates were correlated with disease progression measured using the PSP Rating Scale.ConclusionsVolume loss is quantifiable over a period of 6 months in CBS and PSP. Future clinical trials may be able to combine CBS and PSP to measure therapeutic effects.

Published
2016

6. Predicting disease progression in progressive supranuclear palsy in multicenter clinical trials.

Author

Bang, Jee, Lobach, Iryna V, Lang, Anthony E, Grossman, Murray, Knopman, David S, Miller, Bruce L, Schneider, Lon S, Doody, Rachelle S, Lees, Andrew, Gold, Michael, Morimoto, Bruce H, Boxer, Adam L, and AL-108-231 Investigators

Subjects
AL-108-231 Investigators, Humans, Supranuclear Palsy, Progressive, Disease Progression, Magnetic Resonance Imaging, Prognosis, Middle Aged, Patient Dropouts, Female, Male, Clinical Trials as Topic, Multicenter Studies as Topic, Outcome Assessment, Health Care, Clinical trial methodology, Progressive supranuclear palsy, Neurosciences, Clinical Trials and Supportive Activities, Clinical Research, Mental Health, Neurological, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

IntroductionClinical and MRI measurements can track disease progression in PSP, but many have not been extensively evaluated in multicenter clinical trials. We identified optimal measures to capture clinical decline and predict disease progression in multicenter PSP trials.MethodsLongitudinal clinical rating scales, neuropsychological test scores, and volumetric MRI data from an international, phase 2/3 clinical trial of davunetide for PSP (intent to treat population, n = 303) were used to identify measurements with largest effect size, strongest correlation with clinical change, and best ability to predict dropout or clinical decline over one year as measured by PSP Rating Scale (PSPRS).ResultsBaseline cognition as measured by Repeatable Battery for Assessing Neuropsychological Status (RBANS) was associated with attrition, but had only a small effect. PSPRS and Clinical Global Impression (CGI) had the largest effect size for measuring change. Annual change in CGI, RBANS, color trails, and MRI midbrain and ventricular volumes were most strongly correlated with annual PSPRS and had the largest effect sizes for detecting annual change. At baseline, shorter disease duration, more severe depression, and lower performance on RBANS and executive function tests were associated with faster worsening of the PSPRS in completers. With dropouts included, SEADL, RBANS, and executive function tests had significant effect on PSPRS trajectory of change.ConclusionBaseline cognitive status and mood influence the rate of disease progression in PSP. Multiple clinical, neuropsychological, and volumetric MRI measurements are sensitive to change over one year in PSP and appropriate for use in multicenter clinical trials.

Published
2016

7. Accelerating rates of cognitive decline and imaging markers associated with &bgr;-amyloid pathology

Author

Insel, Philip S, Mattsson, Niklas, Mackin, R Scott, Schöll, Michael, Nosheny, Rachel L, Tosun, Duygu, Donohue, Michael C, Aisen, Paul S, Jagust, William J, Weiner, Michael W, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R, Jagust, William, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Liu, Enchi, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, JQ, Shaw, Les, Lee, Virginia MY, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, and Griffith, Randall

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Acquired Cognitive Impairment, Dementia, Neurodegenerative, Biomedical Imaging, Brain Disorders, Aging, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Neurological, Aged, Amyloid beta-Peptides, Aniline Compounds, Atrophy, Biomarkers, Brain, Cognition, Cognitive Dysfunction, Disease Progression, Ethylene Glycols, Female, Fluorodeoxyglucose F18, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Mental Status Schedule, Neuropsychological Tests, Peptide Fragments, Positron-Emission Tomography, Radiopharmaceuticals, Regression Analysis, Alzheimer's Disease Neuroimaging Initiative, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo estimate points along the spectrum of β-amyloid pathology at which rates of change of several measures of neuronal injury and cognitive decline begin to accelerate.MethodsIn 460 patients with mild cognitive impairment (MCI), we estimated the points at which rates of florbetapir PET, fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to baseline CSF Aβ42. Points of initial acceleration in rates of decline were estimated using mixed-effects regression.ResultsRates of neuronal injury and cognitive and even functional decline accelerate substantially before the conventional threshold for amyloid positivity, with rates of florbetapir PET and FDG PET accelerating early. Temporal lobe atrophy rates also accelerate prior to the threshold, but not before the acceleration of cognitive and functional decline.ConclusionsA considerable proportion of patients with MCI would not meet inclusion criteria for a trial using the current threshold for amyloid positivity, even though on average, they are experiencing cognitive/functional decline associated with prethreshold levels of CSF Aβ42. Future trials in early Alzheimer disease might consider revising the criteria regarding β-amyloid thresholds to include the range of amyloid associated with the first signs of accelerating rates of decline.

Published
2016

8. Assessment of the genetic variance of late-onset Alzheimer's disease

Author

Ridge, Perry G, Hoyt, Kaitlyn B, Boehme, Kevin, Mukherjee, Shubhabrata, Crane, Paul K, Haines, Jonathan L, Mayeux, Richard, Farrer, Lindsay A, Pericak-Vance, Margaret A, Schellenberg, Gerard D, Kauwe, John SK, Consortium, Alzheimer's Disease Genetics, Adams, Perrie M, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barber, Robert C, Barmada, Michael M, Barnes, Lisa L, Barral, Sandra, Beach, Thomas G, Becker, James T, Beecham, Gary W, Beekly, Duane, Bennett, David A, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Burns, Jeffrey M, Buxbaum, Joseph D, Cairns, Nigel J, Cantwell, Laura B, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carrasquillo, Minerva M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cribbs, David H, Crocco, Elizabeth A, Cruchaga, Carlos, De Jager, Philip L, DeCarli, Charles, Demirci, F Yesim, Dick, Malcolm, Dickson, Dennis W, Doody, Rachelle S, Duara, Ranjan, Ertekin-Taner, Nilufer, Evans, Denis A, Faber, Kelley M, Fairchild, Thomas J, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Frosch, Matthew P, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Goate, Alison M, Graff-Radford, Neill R, Green, Robert C, Growdon, John H, Hakonarson, Hakon, Hamilton, Ronald L, Hamilton-Nelson, Kara L, Hardy, John, Harrell, Lindy E, Honig, Lawrence S, Huebinger, Ryan M, Huentelman, Matthew J, Hulette, Christine M, Hyman, Bradley T, Jarvik, Gail P, Jicha, Gregory A, Jin, Lee-Way, Jun, Gyungah, Kamboh, M Ilyas, Karydas, Anna, Katz, Mindy J, Kaye, Jeffrey A, Kim, Ronald, and Kowall, Neil W

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Genetics, Acquired Cognitive Impairment, Aging, Human Genome, Dementia, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer's Disease, 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Protein Precursor, Datasets as Topic, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Membrane Glycoproteins, Netrin Receptors, Polymorphism, Single Nucleotide, Receptors, Cell Surface, Receptors, Immunologic, Risk, Alzheimer's Disease Genetics Consortium, Alzheimer's disease, Genetic variance, Clinical Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Alzheimer's disease (AD) is a complex genetic disorder with no effective treatments. More than 20 common markers have been identified, which are associated with AD. Recently, several rare variants have been identified in Amyloid Precursor Protein (APP), Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Unc-5 Netrin Receptor C (UNC5C) that affect risk for AD. Despite the many successes, the genetic architecture of AD remains unsolved. We used Genome-wide Complex Trait Analysis to (1) estimate phenotypic variance explained by genetics; (2) calculate genetic variance explained by known AD single nucleotide polymorphisms (SNPs); and (3) identify the genomic locations of variation that explain the remaining unexplained genetic variance. In total, 53.24% of phenotypic variance is explained by genetics, but known AD SNPs only explain 30.62% of the genetic variance. Of the unexplained genetic variance, approximately 41% is explained by unknown SNPs in regions adjacent to known AD SNPs, and the remaining unexplained genetic variance outside these regions.

Published
2016

9. Better verbal memory in women than men in MCI despite similar levels of hippocampal atrophy

Author

Sundermann, Erin E, Biegon, Anat, Rubin, Leah H, Lipton, Richard B, Mowrey, Wenzhu, Landau, Susan, Maki, Pauline M, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R, Jagust, William, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Liu, Enchi, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, JQ, Shaw, Les, Lee, Virginia MY, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, and Mitsis, Effie

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Prevention, Aging, Behavioral and Social Science, Clinical Research, Alzheimer's Disease, Brain Disorders, Acquired Cognitive Impairment, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Trials and Supportive Activities, Dementia, 2.1 Biological and endogenous factors, Aetiology, Neurological, Aged, Aged, 80 and over, Atrophy, Cognitive Dysfunction, Cross-Sectional Studies, Female, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Memory, Middle Aged, Sex Characteristics, Verbal Learning, Alzheimer's Disease Neuroimaging Initiative, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo examine sex differences in the relationship between clinical symptoms related to Alzheimer disease (AD) (verbal memory deficits) and neurodegeneration (hippocampal volume/intracranial volume ratio [HpVR]) across AD stages.MethodsThe sample included 379 healthy participants, 694 participants with amnestic mild cognitive impairment (aMCI), and 235 participants with AD and dementia from the Alzheimer's Disease Neuroimaging Initiative who completed the Rey Auditory Verbal Learning Test (RAVLT). Cross-sectional analyses were conducted using linear regression to examine the interaction between sex and HpVR on RAVLT across and within diagnostic groups adjusting for age, education, and APOE ε4 status.ResultsAcross groups, there were significant sex × HpVR interactions for immediate and delayed recall (p < 0.01). Women outperformed men among individuals with moderate to larger HpVR, but not among individuals with smaller HpVR. In diagnosis-stratified analyses, the HpVR × sex interaction was significant in the aMCI group, but not in the control or AD dementia groups, for immediate and delayed recall (p < 0.01). Among controls, women outperformed men on both outcomes irrespective of HpVR (p < 0.001). In AD dementia, better RAVLT performance was independently associated with female sex (immediate, p = 0.04) and larger HpVR (delayed, p = 0.001).ConclusionWomen showed an advantage in verbal memory despite evidence of moderate hippocampal atrophy. This advantage may represent a sex-specific form of cognitive reserve delaying verbal memory decline until more advanced disease stages.

Published
2016

10. Periventricular hyperintensities are associated with elevated cerebral amyloid

Author

Marnane, Michael, Al-Jawadi, Osama O, Mortazavi, Shervin, Pogorzelec, Kathleen J, Wang, Bing Wei, Feldman, Howard H, Hsiung, Ging-Yuek R, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R, Jagust, William, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Liu, Enchi, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, JQ, Shaw, Les, Lee, Virginia MY, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, and Mitsis, Effie

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Aging, Clinical Research, Alzheimer's Disease, Neurosciences, Brain Disorders, Acquired Cognitive Impairment, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Aged, Aged, 80 and over, Amyloid beta-Peptides, Biomarkers, Cerebral Ventricles, Cognitive Dysfunction, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Positron-Emission Tomography, Prospective Studies, Alzheimer's Disease Neuroimaging Initiative, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo investigate the association between periventricular white mater hyperintensities (PVWMH) and biomarkers of elevated cerebral β-amyloid (Aβ) in the Alzheimer's Disease Neuroimaging Initiative, a large prospective multicenter observational study.MethodsThe burden of frontal, parietal, and occipital PVWMH on 3T fluid-attenuated inversion recovery MRI was evaluated in 698 cognitively normal participants and participants with mild cognitive impairment (MCI) using a novel semiquantitative visual rating scale. Results were correlated with CSF-Aβ, florbetapir-PET, and fluorodeoxyglucose (FDG)-PET.ResultsIncreased burden of parietal, occipital, and frontal PVWMH was associated with elevated cerebral amyloid evidenced by high florbetapir-PET signal (p < 0.01) and low CSF-Aβ (p < 0.01). In logistic regression models, including PVWMH, age, sex, APOE status, vascular risk factors, pulse pressure, vascular secondary prevention medications, education, ethnicity, and race, parietal, occipital, and frontal PVWMH burden was independently associated with high florbetapir-PET uptake (p < 0.05). In a similar logistic regression model, parietal and occipital (p < 0.05) but not frontal (p = 0.05) PVWMH were independently associated with CSF-Aβ. Weaker associations were found between parieto-occipital PVWMH and elevated CSF-tau (p < 0.05) and occipital PVWMH and elevated CSF-phospho-tau (p < 0.05). PVWMH were associated with cerebral hypometabolism on FDG-PET independent of CSF-Aβ levels (p < 0.05). Absolute and consistency of agreement intraclass correlation coefficients were, respectively, 0.83 and 0.83 for frontal, 0.78 and 0.8 for parietal, and 0.45 and 0.75 for occipital PVWMH measurements.ConclusionsIncreased PVWMH were associated with elevated cerebral amyloid independent of potential confounders such as age, APOE genotype, and vascular risk factors. The mechanisms underlying the association between PVWMH and cerebral amyloid remain to be clarified.

Published
2016

11. Memory, executive, and multidomain subtle cognitive impairment

Author

Toledo, Jon B, Bjerke, Maria, Chen, Kewei, Rozycki, Martin, Jack, Clifford R, Weiner, Michael W, Arnold, Steven E, Reiman, Eric M, Davatzikos, Christos, Shaw, Leslie M, Trojanowski, John Q, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jagust, William, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Liu, Enchi, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, JQ, Shaw, Les, Lee, Virginia MY, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Leon, Sue, Schneider, Stacy, Marson, Daniel, Griffith, Randall, and Clark, David

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Biomedical Imaging, Aging, Behavioral and Social Science, Clinical Research, Alzheimer's Disease, Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Mental health, Aged, Aged, 80 and over, Alzheimer Disease, Biomarkers, Brain, Cognition Disorders, Cognitive Dysfunction, Disease Progression, Executive Function, Female, Humans, Magnetic Resonance Imaging, Male, Memory Disorders, Multimodal Imaging, Positron-Emission Tomography, Alzheimer's Disease Neuroimaging Initiative, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveWe studied the biomarker signatures and prognoses of 3 different subtle cognitive impairment (SCI) groups (executive, memory, and multidomain) as well as the subjective memory complaints (SMC) group.MethodsWe studied 522 healthy controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cutoffs for executive, memory, and multidomain SCI were defined using participants who remained cognitively normal (CN) for 7 years. CSF Alzheimer disease (AD) biomarkers, composite and region-of-interest (ROI) MRI, and fluorodeoxyglucose-PET measures were compared in these participants.ResultsUsing a stringent cutoff (fifth percentile), 27.6% of the ADNI participants were classified as SCI. Most single ROI or global-based measures were not sensitive to detect differences between groups. Only MRI-SPARE-AD (Spatial Pattern of Abnormalities for Recognition of Early AD), a quantitative MRI pattern-based global index, showed differences between all groups, excluding the executive SCI group. Atrophy patterns differed in memory SCI and SMC. The CN and the SMC groups presented a similar distribution of preclinical dementia stages. Fifty percent of the participants with executive, memory, and multidomain SCI progressed to mild cognitive impairment or dementia at 7, 5, and 2 years, respectively.ConclusionsOur results indicate that (1) the different SCI categories have different clinical prognoses and biomarker signatures, (2) longitudinally followed CN subjects are needed to establish clinical cutoffs, (3) subjects with SMC show a frontal pattern of brain atrophy, and (4) pattern-based analyses outperform commonly used single ROI-based neuroimaging biomarkers and are needed to detect initial stages of cognitive impairment.

Published
2015

12. Brain structure and function as mediators of the effects of amyloid on memory

Author

Mattsson, Niklas, Insel, Philip S, Aisen, Paul S, Jagust, William, Mackin, Scott, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Liu, Enchi, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, JQ, Shaw, Les, Lee, Virginia MY, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Mitsis, Effie, and Romirowsky, Aliza

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Biomedical Imaging, Aging, Alzheimer's Disease, Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, 2.1 Biological and endogenous factors, Aetiology, Neurological, Mental health, Aged, Aged, 80 and over, Amyloid beta-Peptides, Brain, Cohort Studies, Female, Follow-Up Studies, Humans, Male, Memory, Episodic, Middle Aged, Prospective Studies, Radionuclide Imaging, Alzheimer's Disease Neuroimaging Initiative, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveThe objective of this study was to test whether effects of β-amyloid (Aβ) pathology on episodic memory were mediated by metabolism and gray matter volume in the early stages of Alzheimer disease.MethodsThis was a prospective cohort study. We measured baseline Aβ (using florbetapir-PET), brain function (using fluorodeoxyglucose-PET), and brain structure (using MRI). A mediation analysis was performed to test whether statistical effects of Aβ positivity on cross-sectional and longitudinal episodic memory were mediated by hypometabolism or regional gray matter volume in cognitively healthy controls (CN, n = 280) and mild cognitive impairment (MCI, n = 463).ResultsLower memory scores were associated with Aβ positivity (CN, mildly; MCI, strongly), smaller gray matter volumes (CN, few regions, including hippocampus; MCI, widespread), and hypometabolism. Smaller volumes and hypometabolism mediated effects of Aβ in MCI but not in CN. The strongest individual regions mediated up to approximately 25%. A combination of brain structure and function mediated up to approximately 40%. In several regions, gray matter atrophy and hypometabolism predicted episodic memory without being associated (at p < 0.05) with Aβ positivity.ConclusionsChanges in brain structure and function appear to be, in part, downstream events from Aβ pathology, ultimately resulting in episodic memory deficits. However, Aβ pathology is also strongly related to memory deficits through mechanisms that are not quantified by these imaging measurements, and episodic memory decline is partly caused by Alzheimer disease-like brain changes independently of Aβ pathology.

Published
2015

13. Brain amyloidosis ascertainment from cognitive, imaging, and peripheral blood protein measures

Author

Apostolova, Liana G, Hwang, Kristy S, Avila, David, Elashoff, David, Kohannim, Omid, Teng, Edmond, Sokolow, Sophie, Jack, Clifford R, Jagust, William J, Shaw, Leslie, Trojanowski, John Q, Weiner, Michael W, Thompson, Paul M, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jagust, Wiliam, Trojanowki, JQ, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Gamst, Anthony, Sakin, Andrew J, Morris, John, Potter, William Z, Montine, Tom, Donohue, Michael, Walter, Sarah, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Shaw, Lee, Lee, Virginia M-Y, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Harvey, Danielle, Kornak, John, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Dolen, Sara, Quinn, Joseph, Schneider, Lon, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Tang, Cheuk, Marzloff, George, deToledo-Morrell, Leyla, Shah, Raj C, Duara, Ranjan, Varon, Daniel, Robers, Peggy, Albert, Marilyn S, Kozauer, Nicholas, Zerrate, Maria, Rusinek, Henry, de Leon, Mony J, De Santi, Susan M, Doraiswamy, P Murali, Petrella, Jeffrey R, Aiello, Marilyn, Arnold, Steve, and Karlawish, Jason H

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Biomedical Imaging, Aging, Behavioral and Social Science, Clinical Research, Alzheimer's Disease, Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, 4.2 Evaluation of markers and technologies, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Neurological, Aged, Algorithms, Alzheimer Disease, Amyloid beta-Peptides, Amyloidosis, Aniline Compounds, Biomarkers, Brain, Cognition, Cognitive Dysfunction, Cohort Studies, Databases, Factual, Disease Progression, Female, Humans, Male, Neuropsychological Tests, Pattern Recognition, Automated, Peptide Fragments, Positron-Emission Tomography, Sensitivity and Specificity, Thiazoles, Alzheimer's Disease Neuroimaging Initiative, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundThe goal of this study was to identify a clinical biomarker signature of brain amyloidosis in the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) mild cognitive impairment (MCI) cohort.MethodsWe developed a multimodal biomarker classifier for predicting brain amyloidosis using cognitive, imaging, and peripheral blood protein ADNI1 MCI data. We used CSF β-amyloid 1-42 (Aβ42) ≤ 192 pg/mL as proxy measure for Pittsburgh compound B (PiB)-PET standard uptake value ratio ≥ 1.5. We trained our classifier in the subcohort with CSF Aβ42 but no PiB-PET data and tested its performance in the subcohort with PiB-PET but no CSF Aβ42 data. We also examined the utility of our biomarker signature for predicting disease progression from MCI to Alzheimer dementia.ResultsThe CSF training classifier selected Mini-Mental State Examination, Trails B, Auditory Verbal Learning Test delayed recall, education, APOE genotype, interleukin 6 receptor, clusterin, and ApoE protein, and achieved leave-one-out accuracy of 85% (area under the curve [AUC] = 0.8). The PiB testing classifier achieved an AUC of 0.72, and when classifier self-tuning was allowed, AUC = 0.74. The 36-month disease-progression classifier achieved AUC = 0.75 and accuracy = 71%.ConclusionsAutomated classifiers based on cognitive and peripheral blood protein variables can identify the presence of brain amyloidosis with a modest level of accuracy. Such methods could have implications for clinical trial design and enrollment in the near future.Classification of evidenceThis study provides Class II evidence that a classification algorithm based on cognitive, imaging, and peripheral blood protein measures identifies patients with brain amyloid on PiB-PET with moderate accuracy (sensitivity 68%, specificity 78%).

Published
2015

14. Mild cognitive impairment with suspected nonamyloid pathology (SNAP)

Author

Caroli, Anna, Prestia, Annapaola, Galluzzi, Samantha, Ferrari, Clarissa, van der Flier, Wiesje M, Ossenkoppele, Rik, Van Berckel, Bart, Barkhof, Frederik, Teunissen, Charlotte, Wall, Anders E, Carter, Stephen F, Schöll, Michael, Choo, Il Han, Grimmer, Timo, Redolfi, Alberto, Nordberg, Agneta, Scheltens, Philip, Drzezga, Alexander, Frisoni, Giovanni B, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R, Jagust, William, Trojanowki, JQ, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Gamst, Anthony, Saykin, Andrew J, Morris, John, Potter, William Z, Montine, Tom, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Shaw, Les, Lee, Virginia M-Y, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Harvey, Danielle, Kornak, John, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Dolen, Sara, Quinn, Joseph, Schneider, Lon, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, and Mintun, Mark A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Aging, Alzheimer's Disease, Neurosciences, Brain Disorders, Acquired Cognitive Impairment, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, 2.1 Biological and endogenous factors, Aetiology, Neurological, Aged, Aged, 80 and over, Cognitive Dysfunction, Databases, Factual, Disease Progression, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neurodegenerative Diseases, Plaque, Amyloid, Predictive Value of Tests, Alzheimer's Disease Neuroimaging Initiative, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectivesThe aim of this study was to investigate predictors of progressive cognitive deterioration in patients with suspected non-Alzheimer disease pathology (SNAP) and mild cognitive impairment (MCI).MethodsWe measured markers of amyloid pathology (CSF β-amyloid 42) and neurodegeneration (hippocampal volume on MRI and cortical metabolism on [(18)F]-fluorodeoxyglucose-PET) in 201 patients with MCI clinically followed for up to 6 years to detect progressive cognitive deterioration. We categorized patients with MCI as A+/A- and N+/N- based on presence/absence of amyloid pathology and neurodegeneration. SNAPs were A-N+ cases.ResultsThe proportion of progressors was 11% (8/41), 34% (14/41), 56% (19/34), and 71% (60/85) in A-N-, A+N-, SNAP, and A+N+, respectively; the proportion of APOE ε4 carriers was 29%, 70%, 31%, and 71%, respectively, with the SNAP group featuring a significantly different proportion than both A+N- and A+N+ groups (p ≤ 0.005). Hypometabolism in SNAP patients was comparable to A+N+ patients (p = 0.154), while hippocampal atrophy was more severe in SNAP patients (p = 0.002). Compared with A-N-, SNAP and A+N+ patients had significant risk of progressive cognitive deterioration (hazard ratio = 2.7 and 3.8, p = 0.016 and p < 0.001), while A+N- patients did not (hazard ratio = 1.13, p = 0.771). In A+N- and A+N+ groups, none of the biomarkers predicted time to progression. In the SNAP group, lower time to progression was correlated with greater hypometabolism (r = 0.42, p = 0.073).ConclusionsOur findings support the notion that patients with SNAP MCI feature a specific risk progression profile.

Published
2015

15. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial

Author

Boxer, Adam L, Lang, Anthony E, Grossman, Murray, Knopman, David S, Miller, Bruce L, Schneider, Lon S, Doody, Rachelle S, Lees, Andrew, Golbe, Lawrence I, Williams, David R, Corvol, Jean-Cristophe, Ludolph, Albert, Burn, David, Lorenzl, Stefan, Litvan, Irene, Roberson, Erik D, Höglinger, Günter U, Koestler, Mary, Jack, Clifford R, Van Deerlin, Viviana, Randolph, Christopher, Lobach, Iryna V, Heuer, Hilary W, Gozes, Illana, Parker, Lesley, Whitaker, Steve, Hirman, Joe, Stewart, Alistair J, Gold, Michael, Morimoto, Bruce H, and Investigators, for the AL-108-231

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Rare Diseases, Clinical Research, Clinical Trials and Supportive Activities, Brain Disorders, Neurosciences, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Aged, Double-Blind Method, Female, Humans, Male, Oligopeptides, Supranuclear Palsy, Progressive, Treatment Outcome, AL-108-231 Investigators, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundIn preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP.MethodsIn a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720.Findings313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95% CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (-0·20 [-0·20 to -0·17] vs -0·20 [-0·22 to -0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 [12%] of 156 vs 13 [8%] of 156, rhinorrhoea 15 [10%] vs eight [5%], and nasal discomfort 15 [10%] vs one [

Published
2014

16. Vascular burden and Alzheimer disease pathologic progression

Author

Lo, Raymond Y, Jagust, William J, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R, Jagust, William, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Liu, Enchi, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, JQ, Shaw, Les, Lee, Virginia MY, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Mitsis, Effie, Romirowsky, Aliza, deToledo-Morrell, Leyla, Shah, Raj C, Duara, Ranjan, and Varon, Daniel

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Aging, Biomedical Imaging, Dementia, Brain Disorders, Clinical Research, Vascular Cognitive Impairment/Dementia, Alzheimer's Disease, Neurosciences, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Neurological, Cardiovascular, Aged, Alzheimer Disease, Atrophy, Brain, Cognitive Dysfunction, Disease Progression, Female, Genotype, Humans, Leukoencephalopathies, Longitudinal Studies, Magnetic Resonance Imaging, Male, Positron-Emission Tomography, Alzheimer's Disease Neuroimaging Initiative, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveTo investigate the vascular contribution to longitudinal changes in Alzheimer disease (AD) biomarkers.MethodsThe Alzheimer's Disease Neuroimaging Initiative is a clinic based, longitudinal study with CSF, PET, and MRI biomarkers repeatedly measured in participants with normal cognition (NC), mild cognitive impairment (MCI), and mild AD. Participants with severe cerebrovascular risks were excluded. Cardiovascular risk scores and MRI white matter hyperintensities (WMHs) were treated as surrogate markers for vascular burden. Generalized estimating equations were applied, and both vascular burden and its interaction with time (vascular burden × time) or time-varying WMHs were entered into regression models to assess whether biomarker rates of change were modified by vascular burden.ResultsCardiovascular risk profiles were not predictive of progression in CSF β₄₂-amyloid, [¹⁸F]fluorodeoxyglucose (FDG) PET uptake, and MRI hippocampal atrophy. Greater baseline cardiovascular risks or WMHs were generally associated with cognitive impairment, particularly poor executive function. WMHs increased over time with a faster rate in MCI and AD than in NC. Increased time-varying WMH was associated with faster decline in executive function and lower FDG uptake in NC. Otherwise, WMH was not associated with CSF and MRI biomarkers in the 3 groups. These findings remained unchanged after accounting for APOE4.ConclusionIncreased WMHs are associated with aging, decreased glucose metabolism, and decline in executive function but do not affect AD-specific pathologic progression, suggesting that the vascular contribution to dementia is probably additive although not necessarily independent of the amyloid pathway.

Published
2012

17. Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans.

Author

Bakken, Trygve E, Roddey, J Cooper, Djurovic, Srdjan, Akshoomoff, Natacha, Amaral, David G, Bloss, Cinnamon S, Casey, B J, Chang, Linda, Ernst, Thomas M, Gruen, Jeffrey R, Jernigan, Terry L, Kaufmann, Walter E, Kenet, Tal, Kennedy, David N, Kuperman, Joshua M, Murray, Sarah S, Sowell, Elizabeth R, Rimol, Lars M, Mattingsdal, Morten, Melle, Ingrid, Agartz, Ingrid, Andreassen, Ole A, Schork, Nicholas J, Dale, Anders M, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jack, Clifford R, Jr, Jagust, William, Trojanowki, John Q, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Saykin, Andrew J, Morris, John, Liu, Enchi, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, J Q, Shaw, Les, Lee, Virginia M Y, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, and Griffith, Randall

Subjects
Adolescent, Adult, Aged, Brain: pathology, Brain Mapping: methods, Cohort Studies, Diagnostic Imaging: methods, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Genotype, Humans, Male, Middle Aged, Models, Genetic, Phosphoric Diester Hydrolases: genetics, Polymorphism, Single Nucleotide, Saccharomyces cerevisiae: metabolism, Visual Cortex: anatomy & histology, pathology
Abstract

Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.

Published
2012

18. A roadmap for the prevention of dementia: the inaugural Leon Thal Symposium.

Author

Khachaturian, Zaven S, Petersen, Ronald C, Gauthier, Serge, Buckholtz, Neil, Corey-Bloom, Jodey P, Evans, Bill, Fillit, Howard, Foster, Norman, Greenberg, Barry, Grundman, Michael, Sano, Mary, Simpkins, James, Schneider, Lon S, Weiner, Michael W, Galasko, Doug, Hyman, Bradley, Kuller, Lew, Schenk, Dale, Snyder, Stephen, Thomas, Ronald G, Tuszynski, Mark H, Vellas, Bruno, Wurtman, Richard J, Snyder, Peter J, Frank, Richard A, Albert, Marilyn, Doody, Rachelle, Ferris, Steven, Kaye, Jeffrey, Koo, Edward, Morrison-Bogorad, Marcelle, Reisberg, Barry, Salmon, David P, Gilman, Sid, Mohs, Richard, Aisen, Paul S, Breitner, John CS, Cummings, Jeffrey L, Kawas, Claudia, Phelps, Creighton, Poirier, Judes, Sabbagh, Marwan, Touchon, Jacques, Khachaturian, Ara S, and Bain, Lisa J

Subjects
Humans, Dementia, Drug Design, Clinical Trials as Topic, Geriatrics, Neurosciences, Clinical Sciences
Published
2008

19. Estrogen Replacement Therapy for Treatment of Mild to Moderate Alzheimer Disease: A Randomized Controlled Trial

Author

Mulnard, Ruth A, Cotman, Carl W, Kawas, Claudia, van Dyck, Christopher H, Sano, Mary, Doody, Rachelle, Koss, Elizabeth, Pfeiffer, Eric, Jin, Shelia, Gamst, Anthony, Grundman, Michael, Thomas, Ronald, Thal, Leon J, and Study, for the Alzheimer's Disease Cooperative

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Brain Disorders, Acquired Cognitive Impairment, Clinical Research, Dementia, Clinical Trials and Supportive Activities, Prevention, Aging, Neurodegenerative, Alzheimer's Disease, Estrogen, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Neurological, Aged, Alzheimer Disease, Double-Blind Method, Estrogen Replacement Therapy, Estrogens, Conjugated (USP), Female, Humans, Hysterectomy, Linear Models, Mental Status Schedule, Middle Aged, Severity of Illness Index, Treatment Outcome, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

ContextSeveral reports from small clinical trials have suggested that estrogen replacement therapy may be useful for the treatment of Alzheimer disease (AD) in women.ObjectiveTo determine whether estrogen replacement therapy affects global, cognitive, or functional decline in women with mild to moderate AD.DesignThe Alzheimer's Disease Cooperative Study, a randomized, double-blind, placebo-controlled clinical trial conducted between October 1995 and January 1999.SettingThirty-two study sites in the United States.ParticipantsA total of 120 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 28 who had had a hysterectomy.InterventionsParticipants were randomized to estrogen, 0.625 mg/d (n = 42), or 1.25 mg/d (n = 39), or to identically appearing placebo (n = 39). One subject withdrew after randomization but before receiving medication; 97 subjects completed the trial.Main outcome measuresThe primary outcome measure was change on the Clinical Global Impression of Change (CGIC) 7-point scale, analyzed by intent to treat; secondary outcome measures included other global measures as well as measures of mood, specific cognitive domains (memory, attention, and language), motor function, and activities of daily living; compared by the combined estrogen groups vs the placebo group at 2, 6, 12, and 15 months of follow-up.ResultsThe CGIC score for estrogen vs placebo was 5.1 vs 5.0 (P = .43); 80% of participants taking estrogen vs 74% of participants taking placebo worsened (P = .48). Secondary outcome measures also showed no significant differences, with the exception of the Clinical Dementia Rating Scale, which suggested worsening among patients taking estrogen (mean posttreatment change in score for estrogen, 0.5 vs 0.2 for placebo; P = .01).ConclusionsEstrogen replacement therapy for 1 year did not slow disease progression nor did it improve global, cognitive, or functional outcomes in women with mild to moderate AD. The study does not support the role of estrogen for the treatment of this disease. The potential role of estrogen in the prevention of AD, however, requires further research.

Published
2000

20. A Double-Blind, Placebo-Controlled Multicenter Study of Tacrine for Alzheimer's Disease

Author

Davis, Kenneth L, Thal, Leon J, Gamzu, Elkan R, Davis, Charles S, Woolson, Robert F, Gracon, Stephen I, Drachman, David A, Schneider, Lon S, Whitehouse, Peter J, Hoover, Toni M, Morris, John C, Kawas, Claudia H, Knopman, David S, Earl, Nancy L, Kumar, Vinod, and Doody, Rachelle S

Subjects
Aging, Alzheimer's Disease, Clinical Trials and Supportive Activities, Neurodegenerative, Acquired Cognitive Impairment, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Behavioral and Social Science, Dementia, Brain Disorders, Neurosciences, Mental Health, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Neurological, Good Health and Well Being, Activities of Daily Living, Alzheimer Disease, Double-Blind Method, Humans, Middle Aged, Psychological Tests, Tacrine, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundIn Alzheimer's disease, there is a marked decline in the function of cholinergic neurons in the brain. However, studies of treatment with cholinesterase inhibitors have produced conflicting results. We conducted a multicenter trial to evaluate whether the cholinesterase inhibitor tacrine (1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate) could improve cognition in patients with Alzheimer's disease.MethodsOf 632 eligible patients with probable Alzheimer's disease, 215 improved while receiving tacrine during a preliminary crossover phase to determine responsiveness and the best dose. The 215 patients were randomly assigned to receive either placebo or their best dose of tacrine (10 or 20 mg four times a day) in a six-week, double-blind trial. The primary measures of efficacy were the cognitive subscale of the Alzheimer's Disease Assessment Scale and the Clinical Global Impression of Change scale; the secondary measures included the Mini-Mental State Examination and the assessment of the activities of daily living.ResultsAt the end of the six-week trial, the patients receiving tacrine had a mean adjusted cognitive-subscale score of 30.3 (Alzheimer's Disease Assessment Scale) as compared with 32.7 in patients receiving placebo. This represents a smaller decline (by 2.4 points) in cognitive performance in the tacrine group (P < 0.001). There were no differences between the groups in their global-rating scores. The tacrine group had a significantly smaller decline in the activities of daily living. The results of the Mini-Mental State Examination favored tacrine, but the differences were small and not statistically significant (a score of 16.0 with tacrine vs. 15.3 with placebo; P = 0.08). Gastrointestinal symptoms, elevation of aminotransferase levels, and headache were the most frequent side effects; all could be reversed by reducing the dose or discontinuing treatment.ConclusionsIn this short-term study in patients with Alzheimer's disease who were selected for apparent responsiveness to tacrine, treatment with tacrine resulted in a statistically significant reduction in the decline of cognitive function, although this reduction was not large enough to be detected by the study physicians' global assessments of the patients.

Published
1992

21. Glucose metabolism patterns: A potential index to characterize brain ageing and predict high conversion risk into cognitive impairment

Author

Jiang, Jiehui, Sheng, Can, Aisen, Paul, Dang, Mimi, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Oliver, Angela, Petersen, Ronald, Marson, Daniel, Griffith, Randall, Clark, David, Geldmacher, David, Brockington, John, Roberson, Erik, Grossman, Hillel, Mitsis, Effie, de Toledo-Morrell, Leyla, Shah, Raj C, Jack, Clifford R, Duara, Ranjan, Varon, Daniel, Greig, Maria T, Roberts, Peggy, Onyike, Chiadi, D'Agostino, Daniel, Kielb, Stephanie, Galvin, James E, Cerbone, Brittany, Michel, Christina A, Jagust, William, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Murali Doraiswamy, P., Petrella, Jeffrey R, Wong, Terence Z, Arnold, Steven E, Karlawish, Jason H, Wolk, David, Trojanowski, John Q, Smith, Charles D, Jicha, Greg, Hardy, Peter, Sinha, Partha, Oates, Elizabeth, Conrad, Gary, Lopez, Oscar L, Oakley, MaryAnn, Simpson, Donna M, Porsteinsson, Anton P, Toga, Arthur W, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Saleem Ismail, M., Brand, Connie, Mulnard, Ruth A, Thai, Gaby, McAdams-Ortiz, Catherine, Womack, Kyle, Mathews, Dana, Beckett, Laurel, Quiceno, Mary, Diaz-Arrastia, Ramon, King, Richard, Weiner, Myron, Martin-Cook, Kristen, DeVous, Michael, I Levey, Allan, Lah, James J, Cellar, Janet S, Burns, Jeffrey M, Green, Robert C, Anderson, Heather S, Swerdlow, Russell H, Apostolova, Liana, Tingus, Kathleen, Woo, Ellen, Silverman, Daniel H S, Lu, Po H, Bartzokis, George, Graff-Radford, Neill R, Parfitt, Francine, Saykin, Andrew J, Kendall, Tracy, Johnson, Heather, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Herring, Scott, Hunt, Cynthia, van Dyck, Christopher H, Carson, Richard E, MacAvoy, Martha G, Morris, John, Chertkow, Howard, Bergman, Howard, Hosein, Chris, Robin Hsiung, Ging-Yuek, Feldman, Howard, Mudge, Benita, Assaly, Michele, Bernick, Charles, Munic, Donna, Kertesz, Andrew, Chen, Guanqun, Shaw, Leslie, Rogers, John, Trost, Dick, Kerwin, Diana, Lipowski, Kristine, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Khachaturian, Zaven, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Marshall, Gad, Frey, Meghan, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan N, Sorensen, Greg, Belden, Christine M, Jacobson, Sandra A, Sirrel, Sherye A, Kowall, Neil, Killiany, Ronald, Budson, Andrew E, Norbash, Alexander, Johnson, Patricia Lynn, Allard, Joanne, Lerner, Alan, Kuller, Lew, Ogrocki, Paula, Hudson, Leon, Fletcher, Evan, Carmichae, Owen, Olichney, John, DeCarli, Charles, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, Raichle, Marcus, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Paul, Steven, Scharre, Douglas W, Kataki, Maria, Adeli, Anahita, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Anderson, Karen, Santulli, Robert B, Davies, Peter, Kitzmiller, Tamar J, Schwartz, Eben S, Sink, Kaycee M, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Fillit, Howard, Malloy, Paul, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Mintzer, Jacobo, Spicer, Kenneth, Bachman, David, Pasternak, Stephen, Rachinsky, Irina, Drost, Dick, Hefti, Franz, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K, Ponto, Laura L Boles, Shim, Hyungsub, Elizabeth Smith, Karen, Relkin, Norman, Chaing, Gloria, Raudin, Lisa, Holtzman, David, Smith, Amanda, Fargher, Kristin, Raj, Balebail Ashok, Neylan, Thomas, Grafman, Jordan, Davis, Melissa, Morrison, Rosemary, Hayes, Jacqueline, Finley, Shannon, Friedl, Karl, Liu, Chunhua, Mesulam, Marek M, Fleischman, Debra, Arfanakis, Konstantinos, James, Olga, Massoglia, Dino, Jay Fruehling, J., Harding, Sandra, Peskind, Elaine R, Petrie, Eric C, Li, Gail, Yesavage, Jerome A, Potter, William, Taylor, Joy L, Furst, Ansgar J, Snyder, Peter, Schwartz, Adam, Montine, Tom, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Jin, Shichen, Jiminez, Gus, Harvey, Danielle, Bernstein, Matthew, Thompson, Paul, Schuff, Norbert, Borowski, Bret, Gunter, Jeff, Senjem, Matt, Vemuri, Prashanthi, Jones, David, Li, Lanlan, Kantarci, Kejal, Ward, Chad, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Landau, Susan, Cairns, Nigel J, Householder, Erin, Jiang, Xueyan, Taylor-Reinwald, Lisa, Lee, Virginia, Korecka, Magdalena, Figurski, Michal, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven G, Shen, Li, Faber, Kelley, Han, Ying, Kim, Sungeun, Nho, Kwangsik, Thal, Leon, Buckholtz, Neil, Albert, Marylyn, Frank, Richard, Hsiao, John, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Initiative, Alzheimer’s Disease Neuroimaging, Carter, Raina, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Beccera, Mauricio, Teodoro, Liberty, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Fleisher, Adam, Weiner, Michael W, Heidebrink, Judith L, Lord, Joanne L, Mason, Sara S, Albers, Colleen S, Knopman, David S, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, and Rountree, Susan

Subjects
Glucose metabolism, Positron emission tomography, Aging, Pattern, Brain, Glucose, Brain ageing, Alzheimer Disease, Fluorodeoxyglucose F18, Positron-Emission Tomography, Humans, Original Article, Cognitive Dysfunction, ddc:610, Geriatrics and Gerontology, Aged
Abstract

Exploring individual hallmarks of brain ageing is important. Here, we propose the age-related glucose metabolism pattern (ARGMP) as a potential index to characterize brain ageing in cognitively normal (CN) elderly people. We collected (18)F-fluorodeoxyglucose ((18)F-FDG) PET brain images from two independent cohorts: the Alzheimer’s Disease Neuroimaging Initiative (ADNI, N = 127) and the Xuanwu Hospital of Capital Medical University, Beijing, China (N = 84). During follow-up (mean 80.60 months), 23 participants in the ADNI cohort converted to cognitive impairment. ARGMPs were identified using the scaled subprofile model/principal component analysis method, and cross-validations were conducted in both independent cohorts. A survival analysis was further conducted to calculate the predictive effect of conversion risk by using ARGMPs. The results showed that ARGMPs were characterized by hypometabolism with increasing age primarily in the bilateral medial superior frontal gyrus, anterior cingulate and paracingulate gyri, caudate nucleus, and left supplementary motor area and hypermetabolism in part of the left inferior cerebellum. The expression network scores of ARGMPs were significantly associated with chronological age (R = 0.808, p

Published
2022

22. Trial of Prasinezumab in Early-Stage Parkinson's Disease

Author

Pagano, Gennaro, Taylor, Kirsten I, Mollenhauer, Brit, López-Manzanares, Lydia, Russell, David S, Boyd, James T, Nicholas, Anthony P, Luquin, María R, Hauser, Robert A, Gasser, Thomas, Poewe, Werner, Ricci, Benedicte, Anzures-Cabrera, Judith, Boulay, Anne, Vogt, Annamarie, Boess, Frank G, Dukart, Juergen, D'Urso, Giulia, Finch, Rebecca, Zanigni, Stefano, Monnet, Annabelle, Pross, Nathalie, Hahn, Andrea, Marchesi, Maddalena, Svoboda, Hanno, Britschgi, Markus, Lipsmeier, Florian, Volkova-Volkmar, Ekaterina, Lindemann, Michael, Dziadek, Sebastian, Holiga, Štefan, Rukina, Daria, Kustermann, Thomas, Kerchner, Geoffrey A, Simuni, Tanya, Fontoura, Paulo, Umbricht, Daniel, Doody, Rachelle, Nikolcheva, Tania, Bonni, Azad, Investigators, PASADENA, Group, Prasinezumab Study, Marek, Kenneth, Postuma, Ronald B, Pavese, Nicola, Stocchi, Fabrizio, and Azulay, Jean-Philippe

Subjects
Dopamine Plasma Membrane Transport Proteins, Parkinson Disease, General Medicine, therapeutic use [Antibodies, Monoclonal, Humanized], Antibodies, Monoclonal, Humanized, drug therapy [Parkinson Disease], Antiparkinson Agents, Treatment Outcome, Double-Blind Method, therapeutic use [Dopamine Plasma Membrane Transport Proteins], alpha-Synuclein, Humans, ddc:610, antagonists & inhibitors [alpha-Synuclein], therapeutic use [Antiparkinson Agents]
Abstract

Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson's disease. The monoclonal antibody prasinezumab, directed at aggregated α-synuclein, is being studied for its effect on Parkinson's disease.In this phase 2 trial, we randomly assigned participants with early-stage Parkinson's disease in a 1:1:1 ratio to receive intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every 4 weeks for 52 weeks. The primary end point was the change from baseline to week 52 in the sum of scores on parts I, II, and III of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 236, with higher scores indicating greater impairment). Secondary end points included the dopamine transporter levels in the putamen of the hemisphere ipsilateral to the clinically more affected side of the body, as measured by 123I-ioflupane single-photon-emission computed tomography (SPECT).A total of 316 participants were enrolled; 105 were assigned to receive placebo, 105 to receive 1500 mg of prasinezumab, and 106 to receive 4500 mg of prasinezumab. The baseline mean MDS-UPDRS scores were 32.0 in the placebo group, 31.5 in the 1500-mg group, and 30.8 in the 4500-mg group, and mean (±SE) changes from baseline to 52 weeks were 9.4±1.2 in the placebo group, 7.4±1.2 in the 1500-mg group (difference vs. placebo, -2.0; 80% confidence interval [CI], -4.2 to 0.2; P = 0.24), and 8.8±1.2 in the 4500-mg group (difference vs. placebo, -0.6; 80% CI, -2.8 to 1.6; P = 0.72). There was no substantial difference between the active-treatment groups and the placebo group in dopamine transporter levels on SPECT. The results for most clinical secondary end points were similar in the active-treatment groups and the placebo group. Serious adverse events occurred in 6.7% of the participants in the 1500-mg group and in 7.5% of those in the 4500-mg group; infusion reactions occurred in 19.0% and 34.0%, respectively.Prasinezumab therapy had no meaningful effect on global or imaging measures of Parkinson's disease progression as compared with placebo and was associated with infusion reactions. (Funded by F. Hoffmann-La Roche and Prothena Biosciences; PASADENA ClinicalTrials.gov number, NCT03100149.).

Published
2022

23. KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease

Author

Neitzel, Julia, Franzmeier, Nicolai, Petersen, Ronald, Clark, David, Geldmacher, David, Brockington, John, Roberson, Erik, Grossman, Hillel, Mitsis, Effie, deToledo-Morrell, Leyla, Shah, Raj C, Duara, Ranjan, Varon, Daniel, Jack, Clifford R, Greig, Maria T, Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, D'Agostino, Daniel, Kielb, Stephanie, Galvin, James E, Pogorelec, Dana M, Cerbone, Brittany, Michel, Christina A, Jagust, William, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P Murali, Petrella, Jeffrey R, Wong, Terence Z, Arnold, Steven E, Karlawish, Jason H, Wolk, David, Trojanowki, John Q, Smith, Charles D, Jicha, Greg, Hardy, Peter, Sinha, Partha, Oates, Elizabeth, Conrad, Gary, Lopez, Oscar L, Oakley, MaryAnn, Simpson, Donna M, Porsteinsson, Anton P, Toga, Arthur W, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Ismail, Muhammad, Brand, Connie, Mulnard, Ruth A, Thai, Gaby, Mc Adams Ortiz, Catherine, Womack, Kyle, Mathews, Dana, Beckett, Laurel, Quiceno, Mary, Arrastia, Ramon Diaz, King, Richard, Weiner, Myron, Cook, Kristen Martin, DeVous, Michael, Levey, Allan I, Lah, James J, Cellar, Janet S, Burns, Jeffrey M, Green, Robert C, Anderson, Heather S, Swerdlow, Russell H, Apostolova, Liana, Tingus, Kathleen, Woo, Ellen, Silverman, Daniel H S, Lu, Po H, Bartzokis, George, Radford, Neill R Graff, ParfittH, Francine, Saykin, Andrew J, Kendall, Tracy, Johnson, Heather, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Herring, Scott, Hunt, Cynthia, van Dyck, Christopher H, Carson, Richard E, MacAvoy, Martha G, Morris, John, Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Ging Yuek Robin, Feldman, Howard, Mudge, Benita, Past, Michele Assaly, Shaw, Leslie, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek Marsel, Lipowski, Kristine, Wu, Chuang Kuo, Johnson, Nancy, Rubinski, Anna, Liu, Enchi, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Marshall, Gad, Frey, Meghan, Montine, Tom, Yesavage, Jerome, Taylor, Joy L, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan N, Belden, Christine M, Jacobson, Sandra A, Sirrel, Sherye A, Kowall, Neil, Thomas, Ronald G, Killiany, Ronald, Budson, Andrew E, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Allard, Joanne, Lerner, Alan, Ogrocki, Paula, Hudson, Leon, Donohue, Michael, Fletcher, Evan, Carmichael, Owen, Olichney, John, DeCarli, Charles, Kittur, Smita, Borrie, Michael, Lee, T. Y., Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Walter, Sarah, Carlsson, Cynthia M, Potkin, Steven G, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W, Gessert, Devon, Kataki, Maria, Adeli, Anahita, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Anderson, Karen, Santulli, Robert B, Kitzmiller, Tamar J, Sather, Tamie, Schwartz, Eben S, SinkS, Kaycee M, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Jiminez, Gus, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Mintzer, Jacobo, Spicer, Kenneth, Bachman, David, Finger, Elizabether, Pasternak, Stephen, Rachinsky, Irina, Drost, Dick, Harvey, Danielle, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K, Ponto, Laura L Boles, Shim, Hyungsub, Smith, Karen Elizabeth, Relkin, Norman, Chaing, Gloria, Raudin, Lisa, Bernstein, Matthew, Smith, Amanda, Fargher, Kristin, Raj, Balebail Ashok, Dichgans, Martin, Fox, Nick, Thompson, Paul, Schuff, Norbert, DeCArli, Charles, Borowski, Bret, Gunter, Jeff, Senjem, Matt, Vemuri, Prashanthi, Jones, David, Kantarci, Kejal, Brendel, Matthias, Ward, Chad, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Landau, Susan, Cairns, Nigel J, Householder, Erin, Reinwald, Lisa Taylor, Initiative, Alzheimer’s Disease Neuroimaging, Lee, Virginia, Korecka, Magdalena, Figurski, Michal, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kelley, Faber, Kim, Sungeun, Malik, Rainer, Nho, Kwangsik, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Carter, Raina, Dolen, Sara, Ewers, Michael, Schneider, Lon S, Pawluczyk, Sonia, Beccera, Mauricio, Teodoro, Liberty, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Fleisher, Adam, Heidebrink, Judith L, Lord, Joanne L, Weiner, Michael, Mason, Sara S, Albers, Colleen S, Knopman, David S, Johnson, Kris, Doody, Rachelle S, Meyer, Javier Villanueva, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Stern, Yaakov, Aisen, Paul, Honig, Lawrence S, Bell, Karen L, Ances, Beau, Morris, John C, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, OliverNG, Angela, Griffith, Randall, Radiology & Nuclear Medicine, and Epidemiology

Subjects
Male, Heterozygote, metabolism [Amyloid beta-Peptides], Molecular imaging, Gene Expression, genetics [Alzheimer Disease], klotho protein, tau Proteins, Polymorphism, Single Nucleotide, Article, metabolism [Apolipoproteins E], Apolipoproteins E, genetics [Memory Disorders], Alzheimer Disease, mental disorders, Humans, metabolism [Glucuronidase], diagnostic imaging [Brain], Klotho Proteins, Aged, Glucuronidase, Memory Disorders, Amyloid beta-Peptides, genetics [Glucuronidase], methods [Positron-Emission Tomography], metabolism [Memory Disorders], Brain, Alzheimer's disease, Middle Aged, metabolism [tau Proteins], Haplotypes, metabolism [Brain], Positron-Emission Tomography, genetics [Apolipoproteins E], Dementia, Female, ddc:500, metabolism [Alzheimer Disease], Protein Binding
Abstract

Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer’s disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VShet and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VShet showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This association of KL-VShet on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VShet was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VShet carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VShet against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia., The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.

Published
2021

24. Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration

Author

Franzmeier, Nicolai, Suárez-Calvet, M., Kleinberger, Gernot, Doraiswamy, P Murali, Petrella, Jeffrey R, Arnold, Steven E, Karlawish, Jason H, Wolk, David, Smith, Charles D, Jicha, Greg, Hardy, Peter, Lopez, Oscar L, Oakley, Mary Ann, Haass, Christian, Simpson, Donna M, Ismail, M Saleem, Brand, Connie, Mulnard, Ruth A, Thai, Gaby, Mc-Adams-Ortiz, Catherine, Diaz-Arrastia, Ramon, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I, Ewers, Michael, Lah, James J, Cellar, Janet S, Burns, Jeffrey M, Anderson, Heather S, Swerdlow, Russell H, Bartzokis, George, Silverman, Daniel H S, Lu, Po H, Apostolova, Liana, Graff-Radford, Neill R, Initiative, Alzheimer’s Disease Neuroimaging, Parfitt, Francine, Johnson, Heather, Farlow, Martin, Herring, Scott, Hake, Ann M, van Dyck, Christopher H, Carson, Richard E, MacAvoy, Martha G, Chertkow, Howard, Bergman, Howard, Weiner, Michael, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Ging-Yuek Robin, Feldman, Howard, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Aisen, Paul, Bernick, Charles, Munic, Donna, Wu, Chuang-Kuo, Johnson, Nancy, Mesulam, Marsel, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Novak, Gerald, Reynolds, Brigid, Sperling, Reisa A, Frey, Meghan, Johnson, Keith A, Rosen, Allyson, Tinklenberg, Jared, Ashford, Wes, Sabbagh, Marwan, Belden, Christine, Jacobson, Sandra, Green, Robert C, Killiany, Ronald, Norbash, Alexander, Nair, Anil, Obisesan, Thomas O, Wolday, Saba, Bwayo, Salome K, Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Montine, Tom, Carmichael, Owen, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Potkin, Steven G, Preda, Adrian, Petersen, Ronald, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Hendin, Barry A, Scharre, Douglas W, Kataki, Maria, Frontzkowski, Lukas, Gamst, Anthony, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Hosp, Hartford, Pearlson, Godfrey D, Blank, Karen, Anderson, Karen, Santulli, Robert B, Schwartz, Eben S, Williamson, Jeff D, Thomas, Ronald G, Sink, Kaycee M, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Donohue, Michael, Mintzer, Jacobo, Longmire, Crystal Flynn, Spicer, Kenneth, Walter, Sarah, Gessert, Devon, Sather, Tamie, Beckett, Laurel, Harvey, Danielle, Kornak, John, Jack, Clifford R, Moore, Annah, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Jagust, William, Bandy, Dan, Hohman, Timothy J, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Morris, John, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, J. Q., Shaw, Les, Morenas-Rodriguez, Estrella, Lee, Virginia M Y, Korecka, Magdalena, Toga, Arthur W, Crawford, Karen, Neu, Scott, Saykin, Andrew J, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Nuscher, Brigitte, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Dolen, Sara, Quinn, Joseph, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Shaw, Leslie, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Trojanowski, John Q, Morris, John C, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Mitsis, Effie, Romirowsky, Aliza, deToledo-Morrell, Leyla, Dichgans, Martin, Shah, Raj C, Duara, Ranjan, Varon, Daniel, Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, Kielb, Stephanie, Rusinek, Henry, de Leon, Mony J, and Glodzik, Lidia

Subjects
Male, Aging, pathology [Cognitive Dysfunction], Apolipoprotein E4, Cognitive decline, genetics [Alzheimer Disease], Neurodegenerative, lcsh:Geriatrics, Alzheimer's Disease, lcsh:RC346-429, pathology [Alzheimer Disease], Immunologic, Receptors, 80 and over, 2.1 Biological and endogenous factors, sTREM2, Microglial activation, Aetiology, Receptors, Immunologic, genetics [Apolipoprotein E4], Aged, 80 and over, Membrane Glycoproteins, pathology [Nerve Degeneration], cerebrospinal fluid [Alzheimer Disease], cerebrospinal fluid [Cognitive Dysfunction], Neurological, Female, cerebrospinal fluid [Membrane Glycoproteins], Alzheimer’s disease, Research Article, Clinical Sciences, ApoE4, Clinical Research, Alzheimer Disease, ddc:570, Acquired Cognitive Impairment, Genetics, Humans, Cognitive Dysfunction, Genetic Predisposition to Disease, Neurodegeneration, lcsh:Neurology. Diseases of the nervous system, Aged, Neurology & Neurosurgery, Neurosciences, genetics [Cognitive Dysfunction], Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Alzheimer’s Disease Neuroimaging Initiative, Brain Disorders, lcsh:RC952-954.6, Nerve Degeneration, Dementia
Abstract

Background The Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration. Methods We included 708 subjects ranging from cognitively normal (CN, n = 221) to mild cognitive impairment (MCI, n = 414) and AD dementia (n = 73) from the Alzheimer’s disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years). Results Across the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive (p = 0.001, Cohen’s f 2 = 0.137) and memory decline (p = 0.006, Cohen’s f 2 = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen’s f 2 = 0.089), independent of CSF markers of primary AD pathology (i.e. Aβ1–42, p-tau181). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group. Conclusion Our results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.

Published
2020

25. Neuropathologic features associated with basal forebrain atrophy in Alzheimer disease

Author

Teipel, Stefan J, Fritz, H-Christian, Toga, Arthur W., Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, Kielb, Stephanie, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P. Murali, Petrella, Jeffrey R., Beckett, Laurel, Coleman, R. Edward, Arnold, Steven E., Karlawish, Jason H., Wolk, David, Smith, Charles D., Jicha, Greg, Hardy, Peter, Lopez, Oscar L., Oakley, MaryAnn, Simpson, Donna M., Green, Robert C., Porsteinsson, Anton P., Goldstein, Bonnie S., Martin, Kim, Makino, Kelly M., Ismail, M. Saleem, Brand, Connie, Mulnard, Ruth A., Thai, Gaby, Mc-Adams-Ortiz, Catherine, Womack, Kyle, Saykin, Andrew J., Mathews, Dana, Quiceno, Mary, Diaz-Arrastia, Ramon, King, Richard, Weiner, Myron, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I., Lah, James J., Cellar, Janet S., Morris, John, Burns, Jeffrey M., Anderson, Heather S., Swerdlow, Russell H., Apostolova, Liana, Lu, Po H., Bartzokis, George, Silverman, Daniel H. S., Graff-Radford, Neill R, Parfitt, Francine, Johnson, Heather, Liu, Enchi, Farlow, Martin R., Hake, Ann Marie, Matthews, Brandy R., Herring, Scott, van Dyck, Christopher H., Carson, Richard E., MacAvoy, Martha G., Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Ging-Yuek Robin, Feldman, Howard, Mudge, Benita, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Montine, Tom, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek-Marsel, Lipowski, Kristina, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Petersen, Ronald, Scott Turner, Raymond, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A., Johnson, Keith A., Marshall, Gad, Frey, Meghan, Yesavage, Jerome, Taylor, Joy L., Lane, Barton, Aisen, Paul, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan, Belden, Christine, Jacobson, Sandra, Kowall, Neil, Killiany, Ronald, Budson, Andrew E., Norbash, Alexander, Johnson, Patricia Lynn, Grothe, Michel, Gamst, Anthony, Obisesan, Thomas O., Wolday, Saba, Bwayo, Salome K., Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Carmichael, Owen, Olichney, John, DeCarli, Charles, Thomas, Ronald G., Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M., Potkin, Steven G., Preda, Adrian, Nguyen, Dana, Donohue, Michael, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W., Kataki, Maria, Zimmerman, Earl A., Celmins, Dzintra, Walter, Sarah, Brown, Alice D., Pearlson, Godfrey D., Blank, Karen, Anderson, Karen, Santulli, Robert B., Schwartz, Eben S., Sink, Kaycee M., Williamson, Jeff D., Garg, Pradeep, Gessert, Devon, Watkins, Franklin, Ott, Brian R., Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J., Miller, Bruce L., Mintzer, Jacobo, Sather, Tamie, Longmire, Crystal Flynn, Spicer, Kenneth, Finger, Elizabether, Rachinsky, Irina, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K., Boles Ponto, Laura L., Shim, Hyungsub, Smith, Karen Elizabeth, Relkin, Norman, Chaing, Gloria, Raudin, Lisa, Smith, Amanda, Fargher, Kristin, Raj, Balebail Ashok, Harvey, Danielle, Initiative, Alzheimer's Disease Neuroimaging, Kornak, John, Jack, Clifford R., Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, Weiner, Michael, Jagust, William, Bandy, Dan, Koeppe, Robert A., Foster, Norm, Reiman, Eric M., Chen, Kewei, Mathis, Chet, Cairns, Nigel J., Taylor-Reinwald, Lisa, Trojanowki, J. Q., Shaw, Les, Lee, Virginia M Y, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Foroud, Tatiana M., Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J., Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S., Pawluczyk, Sonia, Spann, Bryan M., Brewer, James, Vanderswag, Helen, Heidebrink, Judith L., Lord, Joanne L., Johnson, Kris, Doody, Rachelle S., Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S., Bell, Karen L., Morris, John C., Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A., Schneider, Stacy, Trojanowki, John Q., Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Mitsis, Effie, Romirowsky, Aliza, deToledo-Morrell, Leyla, Shah, Raj C., Duara, Ranjan, Varon, Daniel, Instituto de Salud Carlos III, European Commission, and Ministerio de Ciencia, Innovación y Universidades (España)

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Multivariate analysis, diagnostic imaging [Basal Forebrain], Basal Forebrain, pathology [Basal Forebrain], Logistic regression, Article, 03 medical and health sciences, pathology [Alzheimer Disease], 0302 clinical medicine, Atrophy, Alzheimer Disease, Internal medicine, Ischaemic stroke, Medicine, Humans, ddc:610, Stroke, Cost implications, Aged, Aged, 80 and over, pathology [Atrophy], business.industry, medicine.disease, Magnetic Resonance Imaging, 030104 developmental biology, Charlson comorbidity index, Female, Neurology (clinical), Alzheimer's disease, business, diagnostic imaging [Alzheimer Disease], 030217 neurology & neurosurgery
Abstract

Alzheimer's Disease Neuroimaging Initiative., [Objective] To study the neuropathologic correlates of cholinergic basal forebrain (BF) atrophy as determined using antemortem MRI in the Alzheimer disease (AD) spectrum., [Methods] We determined associations between BF volume from antemortem MRI brain scans and postmortem assessment of neuropathologic features, including neuritic plaques, neurofibrillary tangles (NFTs), Lewy body (LB) pathology, and TDP-43, in 64 cases of the Alzheimer's Disease Neuroimaging Initiative cohort. For comparison, we assessed neuropathologic features associated with hippocampal and parahippocampal gyrus atrophy. In addition to region of interest–based analysis, we determined the association of neuropathologic features with whole brain gray matter volume using regionally unbiased voxel-based volumetry., [Results] BF atrophy was associated with Thal amyloid phases (95% confidence interval [CI] −0.49 to −0.01, p = 0.049) and presence of LB pathology (95% CI −0.54 to −0.06, p = 0.015), as well as with the degree of LB pathology within the nucleus basalis Meynert (95% CI −0.54 to −0.07, p = 0.025). These effects were no longer significant after false discovery rate (FDR) correction. Hippocampal atrophy was significantly associated with the presence of TDP-43 pathology (95% CI −0.61 to −0.17, p = 0.003; surviving FDR correction), in addition to dentate gyrus NFT load (95% CI −0.49 to −0.01, p = 0.044; uncorrected). Voxel-based analysis confirmed spatially restricted effects of Thal phases and presence of LB pathology on BF volume., [Conclusions] These findings indicate that neuropathologic correlates of regional atrophy differ substantially between different brain regions that are typically involved in AD-related neurodegeneration, including different susceptibilities to common comorbid pathologies., M.J.G. is supported by the “Miguel Servet” program [CP19/00031] of the Spanish Instituto de Salud Carlos III (ISCIII-FEDER).

Published
2020

26. The genetic architecture of the human cerebral cortex

Author

Grasby, Katrina L, Jahanshad, Neda, Shatokhina, Natalia, Mirza-Schreiber, Nazanin, Moreira, Jose C V, Mühleisen, Thomas W, Müller-Myhsok, Bertram, Najt, Pablo, Nakahara, Soichiro, Nho, Kwangsik, Olde Loohuis, Loes M, Orfanos, Dimitri Papadopoulos, Pearson, John F, Zsembik, Leo C P, Pitcher, Toni L, Pütz, Benno, Quidé, Yann, Ragothaman, Anjanibhargavi, Rashid, Faisal M, Reay, William R, Redlich, Ronny, Reinbold, Céline S, Repple, Jonathan, Richard, Geneviève, Thomopoulos, Sophia I, Riedel, Brandalyn C, Risacher, Shannon L, Rocha, Cristiane S, Mota, Nina Roth, Salminen, Lauren, Saremi, Arvin, Saykin, Andrew J, Schlag, Fenja, Schmaal, Lianne, Schofield, Peter R, Zhu, Alyssa H, Secolin, Rodrigo, Shapland, Chin Yang, Shen, Li, Shin, Jean, Shumskaya, Elena, Sønderby, Ida E, Sprooten, Emma, Tansey, Katherine E, Teumer, Alexander, Thalamuthu, Anbupalam, Strike, Lachlan T, Tordesillas-Gutiérrez, Diana, Turner, Jessica A, Uhlmann, Anne, Vallerga, Costanza Ludovica, van der Meer, Dennis, van Donkelaar, Marjolein M J, van Eijk, Liza, van Erp, Theo G M, van Haren, Neeltje E M, van Rooij, Daan, Agartz, Ingrid, van Tol, Marie-José, Veldink, Jan H, Verhoef, Ellen, Walton, Esther, Wang, Mingyuan, Wang, Yunpeng, Wardlaw, Joanna M, Wen, Wei, Westlye, Lars T, Whelan, Christopher D, Alhusaini, Saud, Witt, Stephanie H, Wittfeld, Katharina, Wolf, Christiane, Wolfers, Thomas, Wu, Jing Qin, Yasuda, Clarissa L, Zaremba, Dario, Zhang, Zuo, Zwiers, Marcel P, Artiges, Eric, Almeida, Marcio A A, Assareh, Amelia A, Ayesa-Arriola, Rosa, Belger, Aysenil, Brandt, Christine L, Brown, Gregory G, Cichon, Sven, Curran, Joanne E, Davies, Gareth E, Degenhardt, Franziska, Dennis, Michelle F, Alnæs, Dag, Dietsche, Bruno, Djurovic, Srdjan, Doherty, Colin P, Espiritu, Ryan, Garijo, Daniel, Gil, Yolanda, Gowland, Penny A, Green, Robert C, Häusler, Alexander N, Heindel, Walter, Amlien, Inge K, Ho, Beng-Choon, Hoffmann, Wolfgang U, Holsboer, Florian, Homuth, Georg, Hosten, Norbert, Jack, Clifford R, Jang, MiHyun, Jansen, Andreas, Kimbrel, Nathan A, Kolskår, Knut, Painter, Jodie N, Andersson, Micael, Koops, Sanne, Krug, Axel, Lim, Kelvin O, Luykx, Jurjen J, Mathalon, Daniel H, Mather, Karen A, Mattay, Venkata S, Matthews, Sarah, Mayoral Van Son, Jaqueline, McEwen, Sarah C, Ard, Tyler, Melle, Ingrid, Morris, Derek W, Mueller, Bryon A, Nauck, Matthias, Nordvik, Jan E, Nöthen, Markus M, O'Leary, Daniel S, Opel, Nils, Martinot, Marie-Laure Paillère, Pike, G Bruce, Armstrong, Nicola J, Preda, Adrian, Quinlan, Erin B, Rasser, Paul E, Ratnakar, Varun, Reppermund, Simone, Steen, Vidar M, Tooney, Paul A, Torres, Fábio R, Veltman, Dick J, Voyvodic, James T, Ashley-Koch, Allison, Whelan, Robert, White, Tonya, Yamamori, Hidenaga, Adams, Hieab H H, Bis, Joshua C, Debette, Stephanie, Decarli, Charles, Fornage, Myriam, Gudnason, Vilmundur, Hofer, Edith, Atkins, Joshua R, Ikram, M Arfan, Launer, Lenore, Longstreth, W. T., Lopez, Oscar L, Mazoyer, Bernard, Mosley, Thomas H, Roshchupkin, Gennady V, Satizabal, Claudia L, Schmidt, Reinhold, Seshadri, Sudha, Bernard, Manon, Yang, Qiong, Initiative, Alzheimer’s Disease Neuroimaging, Consortium, CHARGE, Consortium, EPIGEN, Consortium, IMAGEN, Consortium, SYS, Initiative, Parkinson’s Progression Markers, Alvim, Marina K M, Ames, David, Anderson, Tim J, Brouwer, Rachel M, Andreassen, Ole A, Arias-Vasquez, Alejandro, Bastin, Mark E, Baune, Bernhard T, Beckham, Jean C, Blangero, John, Boomsma, Dorret I, Brodaty, Henry, Brunner, Han G, Buckner, Randy L, Buimer, Elizabeth E L, Buitelaar, Jan K, Bustillo, Juan R, Cahn, Wiepke, Cairns, Murray J, Calhoun, Vince, Carr, Vaughan J, Caseras, Xavier, Caspers, Svenja, Cavalleri, Gianpiero L, Cendes, Fernando, Bülow, Robin, Corvin, Aiden, Crespo-Facorro, Benedicto, Dalrymple-Alford, John C, Dannlowski, Udo, de Geus, Eco J C, Deary, Ian J, Delanty, Norman, Depondt, Chantal, Desrivières, Sylvane, Donohoe, Gary, Bürger, Christian, Espeseth, Thomas, Fernández, Guillén, Fisher, Simon E, Flor, Herta, Forstner, Andreas J, Francks, Clyde, Franke, Barbara, Glahn, David C, Gollub, Randy L, Grabe, Hans J, Colodro-Conde, Lucía, Cannon, Dara M, Gruber, Oliver, Håberg, Asta K, Hariri, Ahmad R, Hartman, Catharina A, Hashimoto, Ryota, Heinz, Andreas, Henskens, Frans A, Hillegers, Manon H J, Hoekstra, Pieter J, Holmes, Avram J, Chakravarty, Mallar, Hong, L Elliot, Hopkins, William D, Hulshoff Pol, Hilleke E, Jernigan, Terry L, Jönsson, Erik G, Kahn, René S, Kennedy, Martin A, Kircher, Tilo T J, Kochunov, Peter, Kwok, John B J, Chen, Qiang, Le Hellard, Stephanie, Loughland, Carmel M, Martin, Nicholas G, Martinot, Jean-Luc, McDonald, Colm, McMahon, Katie L, Meyer-Lindenberg, Andreas, Michie, Patricia T, Morey, Rajendra A, Mowry, Bryan, Cheung, Joshua W, Nyberg, Lars, Oosterlaan, Jaap, Ophoff, Roel A, Pantelis, Christos, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W J H, Polderman, Tinca J C, Posthuma, Danielle, Rietschel, Marcella, Couvy-Duchesne, Baptiste, Roffman, Joshua L, Rowland, Laura M, Sachdev, Perminder S, Sämann, Philipp G, Schall, Ulrich, Schumann, Gunter, Scott, Rodney J, Sim, Kang, Sisodiya, Sanjay M, Smoller, Jordan W, Dale, Anders M, Sommer, Iris E, St Pourcain, Beate, Stein, Dan J, Toga, Arthur W, Trollor, Julian N, Van der Wee, Nic J A, van 't Ent, Dennis, Völzke, Henry, Walter, Henrik, Weber, Bernd, Dalvie, Shareefa, Weinberger, Daniel R, Wright, Margaret J, Zhou, Juan, Stein, Jason L, Thompson, Paul M, Medland, Sarah E, Consortium, Enhancing NeuroImaging Genetics through Meta-Analysis, Witte, A Veronica, Darin, Abigail, Fleisher, Adam, de Araujo, Tânia K, Pierce, Aimee, Mintz, Akiva, Lerner, Alan, Reith, Alastair D, Hofman, Albert, Espay, Alberto, Ihlenfeld, Albrecht, Ing, Alex, Iranzo, Alex, Beiser, Alexa S, de Zubicaray, Greig I, Norbash, Alexander, Barbot, Alexis, Rudolph, Alice, Portillo, Alicia, Chalker, Alison, Levey, Allan I, Rosen, Allyson, Smith, Amanda, Catafau, Ana, de Zwarte, Sonja M C, Ulysse, Anaztasia, Uitterlinden, André G, Becker, Andreas, Budson, Andrew E, Kertesz, Andrew, Siderowf, Andrew, Bralten, Janita, den Braber, Anouk, Singleton, Andrew, James, Angela, Oliver, Angela, Mishra, Aniket, Hake, Ann Marie, Burke, Anna, Sarrael, Antero, Porsteinsson, Anton P, Stringaris, Argyris, McCoy, Arita, Doan, Nhat Trung, Villringer, Arno, Lenahan, Art, Toga, Arthur, Bokde, Arun, Rawlins, Ashlee, Lamb, Ashley, Lee, Athena, Raj, Balebail Ashok, Tran, Baochan, Dohm, Katharina, Ruggeri, Barbara, Saba, Barbara, Lane, Barton, Yanez, Beatriz, Ances, Beau, Dunlop, Becky, Mudge, Benita, Ravina, Bernard, Ittermann, Bernd, Ehrlich, Stefan, van Noort, Betteke, Lind, Betty, Shah, Bina, Stefanovic, Bojana, Goldstein, Bonnie S, Bonakdarpour, Borna, Matthews, Brandy R, Borowski, Bret, Ott, Brian R, Reynolds, Brigid, Engelbrecht, Hannah-Ruth, Mollenhauer, Brit, Miller, Bruce L, Psaty, Bruce M, Spann, Bryan M, Sadowsky, Carl, Linder, Carly, Franz, Carol E, Tanner, Caroline, Kopil, Catherine, Thomas, Cathi-Ann, Erk, Susanne, Ward, Chad, Bernick, Charles, Smith, Charles D, DeCarli, Charles, Caspell, Chelsea, Deeley, Cheryl, Riordan, Cheryl, Mathis, Chet, Onyike, Chiadi, Heyn, Chris Chinthaka, Fan, Chun Chieh, Hosein, Chris, Leach, Christi, Bÿchel, Christian, Gigliotti, Christina, Hunter, Christine, Belden, Christine M, Tzourio, Christophe, Coffey, Christopher, van Dyck, Christopher H, Clark, Christopher M, Fedko, Iryna O, Wu, Chuang-Kuo, Albers, Colleen S, Chu, Congying, Brand, Connie, Isensee, Corinna, van Duijn, Cornelia M, Bishop, Courtney, Bodge, Courtney, Foley, Sonya F, Tatsuoka, Curtis, Casaceli, Cynthia, Carlsson, Cynthia M, Mathews, Dana, D'Agostino, Daniel, Silverman, Daniel H S, Marson, Daniel, Berg, Daniela, Harvey, Danielle, Jennings, Danna, Ford, Judith M, Wolk, David A, Goldstein, David B, Bachman, David, Brooks, David, Clark, David, Geldmacher, David, Hart, David, Holtzman, David, Jones, David, Hibar, Derrek P, Fukunaga, Masaki, Knopman, David, Hewitt, David L, Perry, David, Russell, David, Standaert, David, Winkfield, David, Green, Davis Robert C, Fontaine, Deborah, Miller, Delwyn D, Gessert, Devon, Garrett, Melanie E, Kerwin, Diana, Willeke, Diana, Drost, Dick, Papadopoulos, Dimitri, Rowe, Dominic, Simpson, Donna M, Muni, Donna, Galasko, Douglas, Scharre, Douglas W, Fillmer, Ariane, Ge, Tian, Bartha, Rob, Celmins, Dzintra, Zimmerman, Earl A, Teng, Edmond, Tolosa, Eduardo, Coleman, Edward, Zamrini, Edward, Mitsis, Effie, Finger, Elizabeth, Giddaluru, Sudheer, Oates, Elizabeth, Sosa, Elizabeth, Woo, Ellen, Rogalski, Emily, Lethbridge, Emma, Dooley, Eoin, Foster, Eric, Reiman, Eric M, Quinlan, Erin Burke, Goldman, Aaron L, Franklin, Erin, Heinzen, Erin L, Fletcher, Evan, Sprenger, Fabienne, Crivello, Fabrice, Biondo, Francesca, Parfitt, Francine, Hefti, Franz, Beyer, Frauke, Nees, Frauke, Green, Melissa J, Leonard, Gabriel, Robert, Gabriel, Thai, Gaby, Marshall, Gad A, Barker, Gareth, Conrad, Gary, Tremont, Geoffrey, Bartzokis, George, Groenewold, Nynke A, Hsiung, Ging-Yuek Robin, Malferrari, Giulia, Chiang, Gloria, Pearlson, Godfrey D, Liang, Grace, Jicha, Greg, Sorensen, Greg, Todd, Gretchen, Jimenez, Gustavo, Grotegerd, Dominik, Zare, Habil, Grabe, Hans Jörgen, Vanderswag, Helen, Schmidt, Helena, Venkov, Heli, Lemaitre, Hervé, Gurholt, Tiril P, Grossman, Hillel, Shill, Holly, Soares, Holly, Lin, Honghuang, Capote, Horacio, Bergman, Howard, Chertkow, Howard, Feldman, Howard, Fillit, Howard, Rosen, Howard J, Gutman, Boris A, Koleva, Hristina, Fernandez, Hubert, Garavan, Hugh, Shim, Hyungsub, Grachev, Igor D, Richard, Irene, Filippi, Irina, Rachinsky, Irina, Wurster, Isabel, Lind, Penelope A, Hansell, Narelle K, Mintzer, Jacobo, Ziolkowski, Jaimie, Brewer, James, Lah, James J, Leverenz, James, Becker, James T, Tetrud, James, Singleton-Garvin, Jamika, Egebjerg, Jan, Cellar, Janet S, Harris, Mathew A, Pentilla, Jani, Brosch, Jared R, Tinklenberg, Jared, Karlawish, Jason H, Meyer, Javier Villanueva, Himali, Jayandra J, Poline, Jean-Baptiste, Gunter, Jeff, Kaye, Jeffrey A, Harrison, Marc B, Dalley, Jeffrey, Burns, Jeffrey M, Petrella, Jeffrey R, Mule, Jennifer, Salazar, Jennifer, Rotter, Jerome I, Yesavage, Jerome, Cedarbaum, Jesse, Jiang, Jiyang, Haswell, Courtney C, Allard, Joanne, Lord, Joanne L, Hetelle, Joel, Kwok, John B, Brockington, John, Morris, John C, Hsiao, John, Morris, John, Olichney, John, Trojanowki, John Q, Hauser, Michael, Rogers, John, Seibyl, John, Yankey, Jon, Dubow, Jordan S, Jankovic, Joseph, Quinn, Joseph, Kass, Joseph S, Taylor, Joy L, Heidebrink, Judith L, Herms, Stefan, Trollor, Julian, Fröhner, Juliane, Anderson, Karen, Blank, Karen, Crawford, Karen, Smith, Karen Ekstam, Bell, Karen L, Williams, Karen, Kieburtz, Karl, Heslenfeld, Dirk J, Gauss, Katharina, Gloer, Katherine, Johnson, Kathleen, Tingus, Kathleen, DeMarco, Kathryn, Sink, Kaycee M, Hawkins, Keith A, Johnson, Keith A, Kantarci, Kejal, Ho, New Fei, Faber, Kelley, Harless, Kelly, Makino, Kelly M, Marek, Kenneth, Spicer, Kenneth, Shianna, Kevin, Chen, Kewei, Nam, Ki Won, Martin, Kim, Poki-Walker, Kim, Hoehn, David, Seppi, Klaus, Johnson, Kris, Fargher, Kristin, Lipowski, Kristine, Espay, Kristy, Womack, Kyle, Chahine, Lama, Flashman, Laura A, Daedelow, Laura, Hoffmann, Per, Leary, Laura, Beckett, Laurel, Honig, Lawrence S, Thal, Leon, Shaw, Leslie M, Kuller, Lew, Apostolova, Liana, Teodoro, Liberty, Rees, Linda, Pizzagalli, Fabrizio, Holleran, Laurena, Lewis, Lindsay, Hergesheimer, Lindsey, Silbert, Lisa C, Ravdin, Lisa, Taylor-Reinwald, Lisa, Uribe, Liz, Schneider, Lon S, Daiello, Lori A, Richer, Louis, Poustka, Luise, Hoogman, Martine, Pirpamer, Lukas, Mesulam, M Marcel, Ismail, M Saleem, Ranola, Madelaine, Korecka, Magdalena, Raichle, Marc, Seltzer, Marc, van der Brug, Marcel, Hottenga, Jouke-Jan, Mesulam, Marek-Marsel, Carrillo, Maria, Carroll, Maria, Knol, Maria J, Kataki, Maria, Greig-Custo, Maria T, Paillere, Marie-Laure, Albert, Marilyn, Love, Marissa Natelson, Ikeda, Masashi, Mintun, Mark A, Frasier, Mark, Logue, Mark, Minton, Mark, Loeffler, Markus, Scholz, Markus, Baca, Marne, Farlow, Martin R, Sadowski, Martin, Janowitz, Deborah, Creech, Mary L, Hynes, Mary L, Quiceno, Mary, Oakley, MaryAnn, Harris, Mat, Senjem, Matt, Bernstein, Matthew, Panizzon, Matthew S, Stern, Matthew, Becerra, Mauricio, Jansen, Iris E, Witbracht, Megan, Vernooij, Meike W, Brandabur, Melanie, Keltz, Melanie, Lamar, Melissa, Yang, Mia, Ahlijanian, Michael, Borrie, Michael, Neale, Michael C, Donohue, Michael, Jia, Tianye, Lyons, Michael J, Lin, Michael, Rapp, Michael, Smolka, Michael, Weiner, Michael W, Weiner, Michael, Figurski, Michal, Perron, Michel, Assaly, Michele, Luciano, Michelle, Jockwitz, Christiane, Rainka, Michelle, Dang, Mimi, Sheikh, Mohammed O, Ghanbari, Mohsen, Gaikwad, Mrunalini, Chowdhury, Munir, Trncic, Nadira, Amin, Najaf, Johnson, Nancy, Kanai, Ryota, Kowalksi, Nancy, Monahan, Nancy, Gillespie, Nathan A, Pacini, Nathaniel, Buckholtz, Neil, Kowall, Neil, Graff-Radford, Neill R, Fox, Nick, Pavese, Nicola, Karama, Sherif, Cairns, Nigel J, Schuff, Norbert, Foster, Norm, Relkin, Norman, Oyonumo, Ntekim E, Pomara, Nunzio, James, Olga, Ogunlana, Olu, Ching, Christopher R K, Kasperaviciute, Dalia, Carmichael, Owen, Doraiswamy, P Murali, Casalin, Paola, Barone, Paolo, Fatica, Parianne, Conrod, Patricia, Johnson, Patricia Lynn, Samuels, Patricia, Aisen, Paul, Malloy, Paul, Kaufmann, Tobias, Thompson, Paul, Ogrocki, Paula, Bezivin-Frere, Pauline, Maillard, Pauline, Fontoura, Paulo, Taylor, Peggy, Hogarth, Penelope, Gowland, Penny, Davies, Peter, Kelly, Sinead, Hardy, Peter, Snyder, Peter J, Snyder, Peter, Amouyel, Philippe, Muglia, Pierandrea, Tariot, Pierre, Lu, Po H, Varma, Pradeep, Vemuri, Prashanthi, Kikuchi, Masataka, Doody, Rachelle S, Carter, Raina, Shah, Raj C, Griffith, Randall, Yeh, Randy, Duara, Ranjan, Tarawneh, Rawan, James, Raymond, Turner, Raymond Scott, Klein, Marieke, Hernando, Raymundo, Silverstein, Rebecca, Sperling, Reisa A, Wilson, Renee, Carson, Richard E, Frank, Richard, El Khouli, Riham, Koeppe, Robert A, Santulli, Robert B, Knapp, Michael, Hauser, Robert, Umek, Robert, Radtke, Rodney, Killiany, Ronald, Petersen, Ronald, Rodriguez, Rosemarie, Miranda, Ruben, Knodt, Annchen R, Bruehl, Ruediger, Xia, Rui, Swerdlow, Russell H, Ottmann, Ruth, Millenet, Sabina, Borges-Neto, Salvador, Frank, Samuel, Black, Sandra, Weintraub, Sandra, Obradov, Sanja, Krämer, Bernd, Asthana, Sanjay, Vaishnavi, Sanjeev, Dolen, Sara, Mason, Sara S, Hohmann, Sarah, Kremen, Sarah, Miller, Sarah, Walter, Sarah, Herring, Scott, Neu, Scott, Lam, Max, Aydin, Semiha, Ahmad, Shahzad, Harlan, Sherry, Sirrel, Sherye A, Lasch, Shirley, Hu, Shu-Ching, Li, Shuo, Kittur, Smita, Chowdhury, Sohini, Lancaster, Thomas M, Pawluczyk, Sonia, Maingault, Sophie, Schneider, Stacy, Seiler, Stephan, Guthrie, Stephanie, Kielb, Stephanie, Reeder, Stephanie, Correia, Stephen, Pasternak, Stephen, McMahon, Mary Agnes B, Lee, Phil H, Salloway, Stephen, Johnson, Sterling, Williams, Steve, Chao, Steven, Arnold, Steven E, Paul, Steven, Potkin, Steven, Factor, Stewart, Isaacson, Stuart, Lett, Tristram A, Kim, Sungeun, Ainscough, Susan, Schultz, Susan K, Landau, Susan, Mendick, Susan, Rountree, Susan, Ostrowizki, Suzanne, Veillette, Suzanne, van der Lee, Sven J, Desrivieres, Sylvane, Lewis, Lindsay B, Lee, T-Y, Simuni, Tanya, Foroud, Tatiana, Foroud, Tatiana M, Wong, Terence Z, Villena, Teresa, Comery, Thomas, Obisesan, Thomas O, Lopes-Cendes, Iscia, Banaschewski, Tobias, Sherer, Todd, Montine, Tom, Paus, Tomáš, Robbins, Trevor, Bromberg, Uli, Völker, Uwe, Pavlik, Valory, Arnedo, Vanessa, Kiyasova, Vera, Bates, Vernice, Logovinsky, Veronika, Sossi, Vesna, Shibley, Victoria, Frouin, Vincent, Lee, Virginia, Poewe, Werner, Jagust, William, Brooks, William M, Macciardi, Fabio, Pavlosky, William, Potter, William, Kremen, William S, Longstreth, William T, Niessen, Wiro J, Jian, Xueqiu, Stern, Yaakov, Saba, Yasaman, Cabrera, Yuliana, Grimmer, Yvonne, Marquand, Andre F, Khachaturian, Zaven, Mari, Zoltan, Mathias, Samuel R, Melzer, Tracy R, Milaneschi, Yuri, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Movement Disorder (MD), Alzheimer’s Disease Neuroimaging Initiative, CHARGE Consortium, EPIGEN Consortium, IMAGEN Consortium, SYS Consortium, Parkinson’s Progression Markers Initiative, Stochastics, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Science and Society, Cognitive Psychology, IBBA, APH - Personalized Medicine, Complex Trait Genetics, APH - Methodology, Clinical Neuropsychology, Sociology and Social Gerontology, Amsterdam Neuroscience - Complex Trait Genetics, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Neurology, Psychiatry, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Human genetics, APH - Digital Health, Psychology, Precision Medicine Institute of Psychiatry, Child and Adolescent Psychiatry / Psychology, Radiology & Nuclear Medicine, Clinical Genetics, Epidemiology, Medical Informatics, Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neurodegeneratives Diseases Institute (IMN-UMR CNRS 5293), Centre National de la Recherche Scientifique (CNRS), General Paediatrics, ARD - Amsterdam Reproduction and Development, Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Brain mapping, 0302 clinical medicine, Cognition, Cortex (anatomy), ComputingMilieux_MISCELLANEOUS, Cerebral Cortex, 0303 health sciences, Brain Mapping, Multidisciplinary, COMMON VARIANTS, Parkinson Disease, Organ Size, Central sulcus, Magnetic Resonance Imaging, medicine.anatomical_structure, Cerebral cortex, Neuroinformatics, EXPRESSION, endocrine system, central sulcus, SURFACE-AREA, Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, medicine, Attention deficit hyperactivity disorder, Humans, General, Gene, METAANALYSIS, 030304 developmental biology, Progenitor, CORTICAL SULCI, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetic variants, Genetic Variation, Attention Deficit Disorder with Hyperactivity, Genetic Loci, Genome-Wide Association Study, functional annotation, medicine.disease, Genetic architecture, 030104 developmental biology, Evolutionary biology, OBSERVER-INDEPENDENT CHARACTERIZATION, Multiple comparisons problem, ddc:320, genome-wide association, Neuroscience, 030217 neurology & neurosurgery
Abstract

Enhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group., The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Published
2020

27. Severity dependent distribution of impairments in PSP and CBS: Interactive Visualizations

Author

Brittain, Claire, McCarthy, Andrew, investigators, PROPSPERA, Tolosa, E., Buongiorno, M. T., Bargalló, N., Burguera, J. A., Martinez, I., Ruiz-Mart'ınez, J., Narrativel, I., Vivancos, F., Ybot, I., Aguilar, M., 4RNTI-1authors, Quilez, P., Boada, M., Lafuente, A., Hernandez, I., López-Lozano, J. J., Mata, M., Kupsch, A., Lipp, A., Ebersbach, G., Schmidt, T., PSP, Tau Restoration on, Hahn, K., Höllerhage, M., Oertel, W. H., Respondek, G., Stamelou, M., Reichmann, H., Wolz, M., Schneider, C., Klingelhöfer, L., Berg, D., Williams, David, Maetzler, W., Srulijes, K. K., Ludolph, A., Kassubek, J., Steiger, M., Tyler, K., Burn, D. J., Morris, L., Lees, A., Ling, H., Lafontaine, Anne Louise, Hauser, R., McClain, T., Truong, D., Jenkins, S., Litvan, I., Houghton, D., Ferrara, J., Bordelon, Y., Gratiano, A., Golbe, L., Marras, Connie, Mark, M., Uitti, R., Ven Gerpen, J., Jog, Mandar, Panisset, Michael, Lang, Anthony, Parker, Lesley, Irizarry, Michael C, Stewart, Alistair J, Corvol, Jean-Christophe, Azulay, Jean-Philippe, Couratier, Philippe, Mollenhauer, Brit, Lorenzl, Stefan, Ludolph, Albert, Benecke, Reiner, Lipp, Axel, Reichmann, Heinz, McDermott, Dana, Woitalla, Dirk, Chan, Dennis, Zermansky, Adam, Burn, David, Lees, Andrew, Gozes, Illana, Boxer, Adam, Miller, Bruce L, Lobach, Iryna V, Roberson, Erik, Biglan, Kevin, Honig, Lawrence, Zamrini, Edward, Pahwa, Rajesh, Bordelon, Yvette, Driver-Dunkley, Erika, Lessig, Stephanie, Lew, Mark, Womack, Kyle, Boeve, Brad, Ferrara, Joseph, Höglinger, Günter U, Hillis, Argyle, Kaufer, Daniel, Kumar, Rajeev, Xie, Tao, Gunzler, Steven, Zesiewicz, Theresa, Dayalu, Praveen, Golbe, Lawrence, Grossman, Murray, Jankovic, Joseph, McGinnis, Scott, Santiago, Anthony, Tuite, Paul, Isaacson, Stuart, Leegwater-Kim, Julie, Litvan, Irene, Knopman, David S, Schneider, Lon S, Doody, Rachelle S, Del Ser, Teodoro, Golbe, Lawrence I, Roberson, Erik D, Koestler, Mary, Jack, Clifford R, Van Deerlin, Viviana, Randolph, Christopher, Whitaker, Steve, Hirman, Joe, Gold, Michael, Morimoto, Bruce H, Boxer, Adam L, Nuebling G, Georg, Hensler, Mira, Paul, Sabine, Zwergal, Andreas, Heuer, Hilary W, Tartaglia, Maria C, McGinnis, Scott M, Dickerson, Bradford C, Kornak, John, Group, AL-108-231 Study, Schuff, Norbert, Rabinovici, Gil D, Rosen, Howard J, Gómez, J. C., Tijero, B., Berganzo, K., Garc'ıa de Yebenes, J., Lopez Sendón, J. L., and Garcia, G.

Subjects
0301 basic medicine, Male, Activities of daily living, physiopathology [Supranuclear Palsy, Progressive], Disease, Severity of Illness Index, diagnosis [Supranuclear Palsy, Progressive], Predictive models, 0302 clinical medicine, diagnosis [Basal Ganglia Diseases], Aged, 80 and over, Neurodegenerative Diseases, Syndrome, Middle Aged, Corticobasal syndrome, Prognosis, Neurology, Disease Progression, Female, Tauopathy, Supranuclear Palsy, Progressive, Natural history study, PSP rating scale, medicine.medical_specialty, physiopathology [Basal Ganglia Diseases], diagnosis [Neurodegenerative Diseases], Models, Neurological, Article, Progressive supranuclear palsy, 03 medical and health sciences, Physical medicine and rehabilitation, Basal Ganglia Diseases, Rating scale, medicine, Humans, ddc:610, Aged, Interactive visualizations, business.industry, physiopathology [Neurodegenerative Diseases], Data Visualization, medicine.disease, Gait, eye diseases, Clinical trial, 030104 developmental biology, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract

Background: Progressive supranuclear palsy (PSP)-Richardson's Syndrome and Corticobasal Syndrome (CBS) are the two classic clinical syndromes associated with underlying four repeat (4R) tau pathology. The PSP Rating Scale is a commonly used assessment in PSP clinical trials; there is an increasing interest in designing combined 4R tauopathy clinical trials involving both CBS and PSP. Objectives: To determine contributions of each domain of the PSP Rating Scale to overall severity and characterize the probable sequence of clinical progression of PSP as compared to CBS. Methods: Multicenter clinical trial and natural history study data were analyzed from 545 patients with PSP and 49 with CBS. Proportional odds models were applied to model normalized cross-sectional PSP Rating Scale, estimating the probability that a patient would experience impairment in each domain using the PSP Rating Scale total score as the index of overall disease severity. Results: The earliest symptom domain to demonstrate impairment in PSP patients was most likely to be Ocular Motor, followed jointly by Gait/Midline and Daily Activities, then Limb Motor and Mentation, and finally Bulbar. For CBS, Limb Motor manifested first and ocular showed less probability of impairment throughout the disease spectrum. An online tool to visualize predicted disease progression was developed to predict relative disability on each subscale per overall disease severity. Conclusion: The PSP Rating Scale captures disease severity in both PSP and CBS. Modelling how domains change in relation to one other at varying disease severities may facilitate detection of therapeutic effects in future clinical trials.

Published
2018

28. In vivo staging of regional amyloid deposition

Author

Grothe, Michel J, Barthel, Henryk, Aisen, Paul, Romirowsky, Aliza, deToledo-Morrell, Leyla, Shah, Raj C, Duara, Ranjan, Varon, Daniel, Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, Kielb, Stephanie, Rusinek, Henry, Petersen, Ronald, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P Murali, Petrella, Jeffrey R, Coleman, R Edward, Arnold, Steven E, Karlawish, Jason H, Wolk, David, Smith, Charles D, Jack, Clifford R, Jicha, Greg, Hardy, Peter, Lopez, Oscar L, Oakley, MaryAnn, Simpson, Donna M, Porsteinsson, Anton P, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Ismail, M Saleem, Jagust, William, Brand, Connie, Mulnard, Ruth A, Thai, Gaby, Mc-Adams-Ortiz, Catherine, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Diaz-Arrastia, Ramon, King, Richard, Weiner, Myron, Trojanowki, John Q, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I, Lah, James J, Cellar, Janet S, Burns, Jeffrey M, Anderson, Heather S, Swerdlow, Russell H, Apostolova, Liana, Lu, Po H, Toga, Arthur W, Bartzokis, George, Silverman, Daniel H S, Parfitt, Francine, Johnson, Heather, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Herring, Scott, van Dyck, Christopher H, Carson, Richard E, Beckett, Laurel, MacAvoy, Martha G, Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Robin Hsiung, Ging-Yuek, Feldman, Howard, Mudge, Benita, Green, Robert C, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek-Marsel, Lipowski, Kristina, Wu, Chuang-Kuo, Saykin, Andrew J, Johnson, Nancy, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Marshall, Gad, Morris, John, Frey, Meghan, Yesavage, Jerome, Taylor, Joy L, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan, Belden, Christine, Jacobson, Sandra, Kowall, Neil, Sepulcre, Jorge, Liu, Enchi, Killiany, Ronald, Budson, Andrew E, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Bwayo, Salome K, Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Carmichael, Owen, Olichney, John, DeCarli, Charles, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Montine, Tom, Carlsson, Cynthia M, Potkin, Steven G, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W, Kataki, Maria, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Anderson, Karen, Santulli, Robert B, Schwartz, Eben S, Sink, Kaycee M, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Gamst, Anthony, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Mintzer, Jacobo, Longmire, Crystal Flynn, Spicer, Kenneth, Finger, Elizabether, Rachinsky, Irina, Thomas, Ronald G, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K, Boles Ponto, Laura L, Shim, Hyungsub, Smith, Karen Elizabeth, Relkin, Norman, Chaing, Gloria, Donohue, Michael, Raudin, Lisa, Smith, Amanda, Fargher, Kristin, Raj, Balebail Ashok, Walter, Sarah, Gessert, Devon, Dyrba, Martin, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Sabri, Osama, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Teipel, Stefan J, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, J. Q., Shaw, Les, Lee, Virginia M Y, Korecka, Magdalena, Initiative, Alzheimer's Disease Neuroimaging, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Weiner, Michael, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, and Mitsis, Effie

Subjects
0301 basic medicine, Male, Pathology, Aging, diagnostic imaging [Cognitive Dysfunction], cerebrospinal fluid [Amyloid beta-Peptides], metabolism [Cognitive Dysfunction], 0302 clinical medicine, diagnostic imaging [Cerebral Cortex], metabolism [Neostriatum], Aged, 80 and over, Cerebral Cortex, Neocortex, Aniline Compounds, methods [Positron-Emission Tomography], amyloid beta-protein (1-42), medicine.anatomical_structure, diagnostic imaging [Neostriatum], Cerebral cortex, Cohort, Disease Progression, florbetapir, Ethylene Glycols, Female, Alzheimer's disease, metabolism [Alzheimer Disease], metabolism [Biomarkers], medicine.medical_specialty, Amyloid, metabolism [Amyloid beta-Peptides], Article, Temporal lobe, 03 medical and health sciences, Neuroimaging, Alzheimer Disease, mental disorders, medicine, Dementia, Humans, Cognitive Dysfunction, ddc:610, metabolism [Aging], cerebrospinal fluid [Peptide Fragments], Aged, Amyloid beta-Peptides, business.industry, metabolism [Cerebral Cortex], medicine.disease, Peptide Fragments, Neostriatum, 030104 developmental biology, Cross-Sectional Studies, Positron-Emission Tomography, Neurology (clinical), business, diagnostic imaging [Alzheimer Disease], 030217 neurology & neurosurgery, Biomarkers
Abstract

Objectives:To estimate a regional progression pattern of amyloid deposition from cross-sectional amyloid-sensitive PET data and evaluate its potential for in vivo staging of an individual's amyloid pathology.Methods:Multiregional analysis of florbetapir (18F-AV45)–PET data was used to determine individual amyloid distribution profiles in a sample of 667 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, including cognitively normal older individuals (CN) as well as patients with mild cognitive impairment and Alzheimer disease (AD) dementia. The frequency of regional amyloid positivity across CN individuals was used to construct a 4-stage model of progressing amyloid pathology, and individual distribution profiles were used to evaluate the consistency of this hierarchical stage model across the full cohort.Results:According to a 4-stage model, amyloid deposition begins in temporobasal and frontomedial areas, and successively affects the remaining associative neocortex, primary sensory-motor areas and the medial temporal lobe, and finally the striatum. Amyloid deposition in these brain regions showed a highly consistent hierarchical nesting across participants, where only 2% exhibited distribution profiles that deviated from the staging scheme. The earliest in vivo amyloid stages were mostly missed by conventional dichotomous classification approaches based on global florbetapir-PET signal, but were associated with significantly reduced CSF Aβ42 levels. Advanced in vivo amyloid stages were most frequent in patients with AD and correlated with cognitive impairment in individuals without dementia.Conclusions:The highly consistent regional hierarchy of PET-evidenced amyloid deposition across participants resembles neuropathologic observations and suggests a predictable regional sequence that may be used to stage an individual's progress of amyloid pathology in vivo.

Published
2017

29. Multimodal characterization of older APOE2 carriers reveals selective reduction of amyloid load

Author

Grothe, Michel J, Villeneuve, Sylvia, Petersen, Ronald, Leyla deToledo-Morrell, PhD, Shah, Raj C, Duara, Ranjan, Varon, Daniel, Roberts Cna, Peggy, Albert, Marilyn, Onyike, Chiadi, Kielb, Stephanie, Rusinek, Henry, de Leon, Mony J, Jack, Clifford R, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P Murali, Petrella, Jeffrey R, Coleman, R Edward, Arnold, Steven E, Karlawish, Jason H, Wolk, David, Smith, Charles D, Jicha, Greg, Jagust, William, Hardy, Peter, Lopez, Oscar L, Oakley, MaryAnn, Simpson, Donna M, Porsteinsson, Anton P, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Ismail, M Saleem, Brand, Connie, Trojanowki, John Q, Mulnard, Ruth A, Thai, Gaby, Mc-Adams-Ortiz, Catherine, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Diaz-Arrastia, Ramon, King, Richard, Weiner, Myron, Martin-Cook, Kristen, Toga, Arthur W, DeVous, Michael, Levey, Allan I, Lah, James J, Cellar, Janet S, Burns, Jeffrey M, Anderson, Heather S, Swerdlow, Russell H, Apostolova, Liana, Lu, Po H, Bartzokis, George, Beckett, Laurel, Silverman, Daniel H S, Graff-Radford Mbbch, Neill R, Parfitt, Francine, Johnson, Heather, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Herring, Scott, van Dyck, Christopher H, Carson, Richard E, Green, Robert C, MacAvoy, Martha G, Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Robin Hsiung, Ging-Yuek, Feldman, Howard, Mudge, Benita, Saykin, Andrew J, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek-Marsel, Lipowski, Kristina, Wu, Chuang-Kuo, Morris, John, Johnson, Nancy, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Marshall, Gad, Liu, Enchi, Frey, Meghan, Yesavage, Jerome, Taylor, Joy L, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan, Belden, Christine, Jacobson, Sandra, Kowall, Neil, Dyrba, Martin, Killiany, Ronald, Budson, Andrew E, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Bwayo, Salome K, Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Montine, Tom, Fletcher, Evan, Carmichael, Owen, Olichney, John, DeCarli, Charles, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Dr Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Potkin, Steven G, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Aisen, Paul, Scharre, Douglas W, Kataki, Maria, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Anderson, Karen, Santulli, Robert B, Gamst, Anthony, Schwartz, Eben S, Sink, Kaycee M, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Thomas, Ronald G, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Mintzer, Jacobo, Longmire, Crystal Flynn, Spicer, Kenneth, Finger, Elizabether, Rachinsky, Irina, Donohue, Michael, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K, Boles Ponto, Laura L, Shim, Hyungsub, Smith, Karen Elizabeth, Relkin, Norman, Chaing, Gloria, Walter, Sarah, Raudin, Lisa, Smith, Amanda, Fargher, Kristin, Raj, Balebail Ashok, Gessert, Devon, Sather, Tamie, Bartrés-Faz, David, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Wirth, Miranka, Thompson, Paul, Schuff, Norbert, Alexander, Gene, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Initiative, Alzheimer's Disease Neuroimaging, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, J. Q., Shaw, Les, Lee, Virginia M Y, Korecka, Magdalena, Crawford, Karen, Weiner, Michael, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Mitsis, Effie, and Romirowsky, Aliza

Subjects
0301 basic medicine, Oncology, Male, Aging, Apolipoprotein E2, diagnostic imaging [Cognitive Dysfunction], Apolipoprotein E3, metabolism [Gray Matter], Disease, Multimodal Imaging, metabolism [Cognitive Dysfunction], pathology [Aging], 0302 clinical medicine, Genotype, Medicine, Gray Matter, medicine.diagnostic_test, Brain, Organ Size, Magnetic Resonance Imaging, metabolism [Glucose], cerebrospinal fluid [Biomarkers], Positron emission tomography, genetics [Aging], genetics [Apolipoprotein E3], Female, Alzheimer's disease, medicine.medical_specialty, Amyloid, Heterozygote, Neuroimaging, Article, 03 medical and health sciences, Fluorodeoxyglucose F18, Internal medicine, genetics [Apolipoprotein E2], Dementia, Humans, Cognitive Dysfunction, ddc:610, metabolism [Aging], Allele, diagnostic imaging [Brain], metabolism [Amyloid], Aged, business.industry, diagnostic imaging [Gray Matter], Magnetic resonance imaging, medicine.disease, 030104 developmental biology, Glucose, metabolism [Brain], Positron-Emission Tomography, Neurology (clinical), Radiopharmaceuticals, business, 030217 neurology & neurosurgery, Biomarkers
Abstract

Objective:To comprehensively assess neurobiological effects of the protective APOE2 allele in the aged brain using a cross-sectional multimodal neuroimaging approach.Methods:Multimodal neuroimaging data were obtained from a total of 572 older individuals without dementia (cognitively normal and mild cognitive impairment) enrolled in the Alzheimer's Disease Neuroimaging Initiative and included assessments of regional amyloid load with AV45-PET, glucose metabolism with fluorodeoxyglucose-PET, and gray matter volume with structural MRI. Imaging indexes of APOE2 carriers were contrasted to risk-neutral APOE3 homozygotes, and analyses were controlled for age, sex, education, and clinical diagnosis. Additional models examined genotype-specific effects of age on the imaging markers.Results:In region-of-interest–based analyses, APOE2 carriers had significantly less precuneal amyloid pathology and did not show the typical age-related increase in amyloid load, although the age × genotype interaction was only trend-level significant. In contrast, parietal metabolism and hippocampal volume did not differ between APOE2 and APOE3 genotypes, and both groups showed comparable negative effects of age on these markers. The amyloid specificity of APOE2-related brain changes was corroborated in 2 complementary analyses: spatially unbiased voxel-wise analyses showing widespread reductions in amyloid deposition but no differences in gray matter volume or metabolism and an analysis of CSF-based biomarkers showing a significant effect on amyloid but not on tau pathology.Conclusions:Regarding the range of Alzheimer disease biomarkers considered in the present study, the APOE2 allele appears to have a relatively selective effect on reduced accumulation of amyloid pathology in the aged brain.

Published
2016

30. A Hidden Markov Model approach to analyze longitudinal ternary outcomes when some observed states are possibly misclassified

Author

Benoit, Julia S., Chan, Wenyaw, Luo, Sheng, Yeh, Hung-Wen, and Doody, Rachelle

Subjects
Early Diagnosis, Models, Statistical, Time Factors, Treatment Outcome, Data Interpretation, Statistical, Humans, Longitudinal Studies, Article, Algorithms, Markov Chains, Data Accuracy
Abstract

Understanding the dynamic disease process is vital in early detection, diagnosis, and measuring progression. Continuous-time Markov chain (CTMC) methods have been used to estimate state-change intensities but challenges arise when stages are potentially misclassified. We present an analytical likelihood approach where the hidden state is modeled as a three-state CTMC model allowing for some observed states to be possibly misclassified. Covariate effects of the hidden process and misclassification probabilities of the hidden state are estimated without information from a 'gold standard' as comparison. Parameter estimates are obtained using a modified expectation-maximization (EM) algorithm, and identifiability of CTMC estimation is addressed. Simulation studies and an application studying Alzheimer's disease caregiver stress-levels are presented. The method was highly sensitive to detecting true misclassification and did not falsely identify error in the absence of misclassification. In conclusion, we have developed a robust longitudinal method for analyzing categorical outcome data when classification of disease severity stage is uncertain and the purpose is to study the process' transition behavior without a gold standard.

Published
2016

31. Does posterior cingulate hypometabolism result from disconnection or local pathology across preclinical and clinical stages of Alzheimer's disease?

Author

Teipel, Stefan, Grothe, Michel J, Trojanowki, John Q, Quinn, Joseph, Silbert, Lisa, Lind, Betty, Carter, Raina, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Becerra, Mauricio, Teodoro, Liberty, Spann, Bryan M, Toga, Arthur W, Brewer, James, Vanderswag, Helen, Fleisher, Adam, Heidebrink, Judith L, Lord, Joanne L, Petersen, Ronald, Mason, Sara S, Albers, Colleen S, Knopman, David, Johnson, Kris, Beckett, Laurel, Doody, Rachelle S, Villanueva-Meyer, Javier, Pavlik, Valory, Shibley, Victoria, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Green, Robert C, Ances, Beau, Morris, John C, Carroll, Maria, Creech, Mary L, Franklin, Erin, Mintun, Mark A, Schneider, Stacy, Oliver, Angela, Marson, Daniel, Geldmacher, David, Saykin, Andrew J, Love, Marissa Natelson, Griffith, Randall, Clark, David, Brockington, John, Roberson, Erik, Grossman, Hillel, Mitsis, Effie, Shah, Raj C, deToledo-Morrell, Leyla, Duara, Ranjan, Morris, John, Greig-Custo, Maria T, Barker, Warren, Albert, Marilyn, Onyike, Chiadi, D'Agostino, Daniel, Kielb, Stephanie, Sadowski, Martin, Sheikh, Mohammed O, Ulysse, Anaztasia, Gaikwad, Mrunalini, Shaw, Leslie M, Doraiswamy, P Murali, Petrella, Jeffrey R, Borges-Neto, Salvador, Wong, Terence Z, Coleman, Edward, Arnold, Steven E, Karlawish, Jason H, Wolk, David A, Clark, Christopher M, Smith, Charles D, Khachaturian, Zaven, Jicha, Greg, Hardy, Peter, Sinha, Partha, Oates, Elizabeth, Conrad, Gary, Lopez, Oscar L, Oakley, MaryAnn, Simpson, Donna M, Porsteinsson, Anton P, Goldstein, Bonnie S, Sorensen, Greg, Martin, Kim, Makino, Kelly M, Ismail, M Saleem, Brand, Connie, Potkin, Steven G, Preda, Adrian, Nguyen, Dana, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Carrillo, Maria, Levey, Allan I, Lah, James J, Cellar, Janet S, Burns, Jeffrey M, Swerdlow, Russell H, Brooks, William M, Apostolova, Liana, Tingus, Kathleen, Woo, Ellen, Silverman, Daniel H S, Initiative, Alzheimer´s Disease Neuroimaging, Kuller, Lew, Lu, Po H, Bartzokis, George, Graff-Radford, Neill R, Parfitt, Francine, Poki-Walker, Kim, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Brosch, Jared R, Herring, Scott, Raichle, Marc, van Dyck, Christopher H, Carson, Richard E, MacAvoy, Martha G, Varma, Pradeep, Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Paul, Steven, Hsiung, Ging-Yuek Robin, Feldman, Howard, Mudge, Benita, Assaly, Michele, Finger, Elizabeth, Pasternack, Stephen, Rachisky, Irina, Trost, Dick, Kertesz, Andrew, Bernick, Charles, Davies, Peter, Munic, Donna, Mesulam, Marek-Marsel, Rogalski, Emily, Lipowski, Kristine, Weintraub, Sandra, Bonakdarpour, Borna, Kerwin, Diana, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Fillit, Howard, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Marshall, Gad, Yesavage, Jerome, Taylor, Joy L, Lane, Barton, Hefti, Franz, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan N, Belden, Christine M, Jacobson, Sandra A, Sirrel, Sherye A, Kowall, Neil, Killiany, Ronald, Budson, Andrew E, Norbash, Alexander, Holtzman, David, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Allard, Joanne, Lerner, Alan, Ogrocki, Paula, Tatsuoka, Curtis, Fatica, Parianne, Fletcher, Evan, Maillard, Pauline, Mesulam, M Marcel, Olichney, John, DeCarli, Charles, Carmichael, Owen, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Potter, William, Tariot, Pierre, Burke, Anna, Milliken, Ann Marie, Trncic, Nadira, Reeder, Stephanie, Bates, Vernice, Snyder, Peter, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W, Kataki, Maria, Kelley, Brendan, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Weiner, Michael W, Schwartz, Adam, Anderson, Karen, Flashman, Laura A, Seltzer, Marc, Hynes, Mary L, Santulli, Robert B, Sink, Kaycee M, Gordineer, Leslie, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Tremont, Geoffrey, Daiello, Lori A, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Perry, David, Mintzer, Jacobo, Montine, Tom, Spicer, Kenneth, Bachman, David, Pasternak, Stephen, Rachinsky, Irina, Rogers, John, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K, Smith, Karen Ekstam, Koleva, Hristina, Nam, Ki Won, Shim, Hyungsub, Relkin, Norman, Chiang, Gloria, Lin, Michael, Ravdin, Lisa, Aisen, Paul, Smith, Amanda, Raj, Balebail Ashok, Fargher, Kristin, Weiner, Michael, Harvey, Danielle, Thomas, Ronald G, Jack, Clifford R, Jagust, William, Neylan, Thomas, Grafman, Jordan, Donohue, Michael, Gessert, Devon, Sather, Tamie, Davis, Melissa, Morrison, Rosemary, Walter, Sarah, Jiminez, Gus, Hayes, Jacqueline, Finley, Shannon, Bernstein, Matthew, Borowski, Bret, Gunter, Jeff, Senjem, Matt, Kantarci, Kejal, Ward, Chad, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Landau, Susan, Cairns, Nigel J, Householder, Erin, Lee, Virginia, Korecka, Magdalena, Figurski, Michal, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Faber, Kelley, Kim, Sungeun, Nho, Kwangsik, Friedl, Karl, Balasubramanian, Archana B, Fleischman, Debra, Arfanakis, Konstantinos, Mason, Jennifer, Varon, Daniel, Greig, Maria T, James, Olga, Goldstein, Bonnie, Martin, Kimberly S, Sim, Iris, Massoglia, Dino, Brawman-Mintzer, Olga, Martinez, Walter, Rosen, Howard, Behan, Kelly, Johnson, Sterling C, Fruehling, J Jay, Harding, Sandra, Peskind, Elaine R, Petrie, Eric C, Li, Gail, Yesavage, Jerome A, Furst, Ansgar J, Chao, Steven, Fox, Nick, Thompson, Paul, Schuff, Norbert, DeCArli, Charles, Vemuri, Prashanthi, Jones, David, Mathis, Chet, Taylor-Reinwald, Lisa, Thal, Lean, Thal, Leon, Buckholtz, Neil, Snyder, Peter J, Frank, Richard, Hsiao, John, and Kaye, Jeffrey

Subjects
Male, Pathology, Aging, physiopathology [Cognitive Dysfunction], diagnostic imaging [Cognitive Dysfunction], Hippocampus, 030218 nuclear medicine & medical imaging, metabolism [Cognitive Dysfunction], 0302 clinical medicine, Cognition, pathology [Gray Matter], Cortex (anatomy), Image Processing, Computer-Assisted, Gray Matter, diagnostic imaging [Hippocampus], General Medicine, Middle Aged, Magnetic Resonance Imaging, medicine.anatomical_structure, Female, metabolism [Alzheimer Disease], medicine.medical_specialty, Amyloid, Grey matter, Gyrus Cinguli, physiopathology [Alzheimer Disease], Article, 03 medical and health sciences, Atrophy, Neuroimaging, Alzheimer Disease, Fluorodeoxyglucose F18, mental disorders, metabolism [Gyrus Cinguli], medicine, Dementia, Humans, Cognitive Dysfunction, Radiology, Nuclear Medicine and imaging, ddc:610, chemistry [Fluorodeoxyglucose F18], physiopathology [Gyrus Cinguli], Aged, business.industry, diagnostic imaging [Gray Matter], medicine.disease, pathology [Hippocampus], Posterior cingulate, Positron-Emission Tomography, bacteria, business, diagnostic imaging [Alzheimer Disease], 030217 neurology & neurosurgery
Abstract

Posterior cingulate cortex (PCC) hypometabolism as measured by FDG PET is an indicator of Alzheimer’s disease (AD) in prodromal stages, such as in mild cognitive impairment (MCI), and has been found to be closely associated with hippocampus atrophy in AD dementia. We studied the effects of local and remote atrophy and of local amyloid load on the PCC metabolic signal in patients with different preclinical and clinical stages of AD. We determined the volume of the hippocampus and PCC grey matter based on volumetric MRI scans, PCC amyloid load based on AV45 PET, and PCC metabolism based on FDG PET in 667 subjects participating in the Alzheimer’s Disease Neuroimaging Initiative spanning the range from cognitively normal ageing through prodromal AD to AD dementia. In cognitively normal individuals and those with early MCI, PCC hypometabolism was exclusively associated with hippocampus atrophy, whereas in subjects with late MCI it was associated with both local and remote effects of atrophy as well as local amyloid load. In subjects with AD dementia, PCC hypometabolism was exclusively related to local atrophy. Our findings suggest that the effects of remote pathology on PCC hypometabolism decrease and the effects of local pathology increase from preclinical to clinical stages of AD, consistent with a progressive disconnection of the PCC from downstream cortical and subcortical brain regions.

Published
2016

32. Body mass index is associated with biological CSF markers of core brain pathology of Alzheimer's disease

Author

Ewers, Michael, Schmitz, Susanne, Vellas, Bruno, Morris, John C, Ances, Beau, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Dubois, Bruno, Mitsis, Effie, Romirowsky, Aliza, deToledo-Morrell, Leyla, Shah, Raj C, Duara, Ranjan, Varon, Daniel, Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, Kielb, Stephanie, Blennow, Kaj, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, Doraiswamy, P Murali, Petrella, Jeffrey R, Coleman, R Edward, Arnold, Steven E, Karlawish, Jason H, Wolk, David, Smith, Charles D, Buerger, Katharina, Jicha, Greg, Hardy, Peter, Lopez, Oscar L, Oakley, MaryAnn, Simpson, Donna M, Porsteinsson, Anton P, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Ismail, M Saleem, Teipel, Stefan J, Brand, Connie, Mulnard, Ruth A, Thai, Gaby, Mc-Adams-Ortiz, Catherine, Diaz-Arrastia, Ramon, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I, Lah, James J, Cellar, Janet S, Weiner, Michael, Burns, Jeffrey M, Anderson, Heather S, Swerdlow, Russell H, Apostolova, Liana, Lu, Po H, Bartzokis, George, Silverman, Daniel H S, Graff-Radford, Neill R, Parfitt, Francine, Johnson, Heather, Hampel, Harald, Farlow, Martin, Herring, Scott, Hake, Ann M, van Dyck, Christopher H, Carson, Richard E, MacAvoy, Martha G, Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Initiative, Alzheimer's Disease Neuroimaging, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Ging-Yuek Robin, Feldman, Howard, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek-Marsel, Lipowski, Kristina, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Aisen, Paul, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Marshall, Gad, Frey, Meghan, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan, Belden, Christine, Jacobson, Sandra, Hansson, Oskar, Kowall, Neil, Killiany, Ronald, Budson, Andrew E, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Bwayo, Salome K, Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Carmichael, Owen, Olichney, John, DeCarli, Charles, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, Johnson, Sterling, Petersen, Ronald, Asthana, Sanjay, Carlsson, Cynthia M, Potkin, Steven G, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Jack, Clifford R, Rainka, Michelle, Hendin, Barry A, Scharre, Douglas W, Kataki, Maria, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Anderson, Karen, Jagust, William, Saykin, Andrew J, Santulli, Robert B, Schwartz, Eben S, Sink, Kaycee M, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Tremont, Geoffrey, Trojanowki, John Q, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Mintzer, Jacobo, Longmire, Crystal Flynn, Spicer, Kenneth, Toga, Arthur W, Beckett, Laurel, Green, Robert C, Walsh, Cathal, Morris, John, Liu, Enchi, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Fitzpatrick, Annette, Gessert, Devon, Sather, Tamie, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Bennett, David, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Minthon, Lennart, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, J. Q., Shaw, Les, Lee, Virginia M Y, Korecka, Magdalena, Trojanowski, John Q, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Shaw, Leslie M, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Faluyi, Yetunde O, Heidebrink, Judith L, Lord, Joanne L, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, and Bell, Karen L

Subjects
Male, Apolipoprotein E, Aging, Pathology, Neurology, epidemiology [Alzheimer Disease], Statistics as Topic, cerebrospinal fluid [Amyloid beta-Peptides], Comorbidity, Body Mass Index, Cerebrospinal fluid, pathology [Brain], Prevalence, Aged, 80 and over, biology, General Neuroscience, Brain, Middle Aged, Prognosis, amyloid beta-protein (1-42), cerebrospinal fluid [Cognition Disorders], cerebrospinal fluid [Alzheimer Disease], cerebrospinal fluid [Biomarkers], Biomarker (medicine), Female, epidemiology [United States], Alzheimer's disease, Psychology, Alzheimer's Disease Neuroimaging Initiative, epidemiology [Cognition Disorders], medicine.medical_specialty, Tau protein, tau Proteins, Alzheimer Disease, medicine, Humans, ddc:610, cerebrospinal fluid [Peptide Fragments], Aged, Amyloid beta-Peptides, medicine.disease, United States, Peptide Fragments, cerebrospinal fluid [tau Proteins], metabolism [Brain], biology.protein, pathology [Cognition Disorders], Neurology (clinical), Geriatrics and Gerontology, Cognition Disorders, Body mass index, Biomarkers, Developmental Biology
Abstract

Weight changes are common in aging and Alzheimer's disease (AD) and postmortem findings suggest a relation between lower body mass index (BMI) and increased AD brain pathology. In the current multicenter study, we tested whether lower BMI is associated with higher core AD brain pathology as assessed by cerebrospinal fluid (CSF)-based biological markers of AD in 751 living subjects: 308 patients with AD, 296 subjects with amnestic mild cognitive impairment (MCI), and 147 elderly healthy controls (HC). Based upon a priori cutoff values on CSF concentration of total tau and beta-amyloid (Aβ(1-42)), subjects were binarized into a group with abnormal CSF biomarker signature (CSF+) and those without (CSF-). Results showed that BMI was significantly lower in the CSF+ when compared with the CSF- group (F = 27.7, df = 746, p0.001). There was no interaction between CSF signature and diagnosis or apolipoprotein E (ApoE) genotype. In conclusion, lower BMI is indicative of AD pathology as assessed with CSF-based biomarkers in demented and nondemented elderly subjects.

Published
2012

33. Identification of common variants associated with human hippocampal and intracranial volumes

Author

Stein, Jason L, Medland, Sarah E, Bernard, Manon, Nauck, Matthias, Nöthen, Markus M., Olvera, Rene L, Pandolfo, Massimo, Pike, G Bruce, Puls, Ralf, Reinvang, Ivar, Rentería, Miguel E, Rietschel, Marcella, Roffman, Joshua L, Brown, Andrew A, Royle, Natalie A, Rujescu, Dan, Savitz, Jonathan, Schnack, Hugo G, Schnell, Knut, Seiferth, Nina, Smith, Colin, Steen, Vidar M, Valdés Hernández, Maria C, Van den Heuvel, Martijn, Cannon, Dara M, van der Wee, Nic J, Van Haren, Neeltje E M, Veltman, Joris A, Völzke, Henry, Walker, Robert, Westlye, Lars T, Whelan, Christopher D, Agartz, Ingrid, Boomsma, Dorret I, Cavalleri, Gianpiero L, Chakravarty, M Mallar, Dale, Anders M, Djurovic, Srdjan, Drevets, Wayne C, Hagoort, Peter, Hall, Jeremy, Heinz, Andreas, Jack, Clifford R, Foroud, Tatiana M, Le Hellard, Stephanie, Macciardi, Fabio, Christoforou, Andrea, Montgomery, Grant W, Poline, Jean Baptiste, Porteous, David J, Sisodiya, Sanjay M, Starr, John M, Sussmann, Jessika, Toga, Arthur W, Veltman, Dick J, Walter, Henrik, Weiner, Michael W, Domin, Martin, Initiative, Alzheimer's Disease Neuroimaging, Consortium, EPIGEN, Consortium, IMAGEN, Group, Saguenay Youth Study, Bis, Joshua C, Ikram, M Arfan, Smith, Albert V, Gudnason, Vilmundur, Tzourio, Christophe, Vernooij, Meike W, Grimm, Oliver, Launer, Lenore J, DeCarli, Charles, Seshadri, Sudha, Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology, Andreassen, Ole A, Apostolova, Liana G, Bastin, Mark E, Blangero, John, Brunner, Han G, Buckner, Randy L, Hollinshead, Marisa, Cichon, Sven, Coppola, Giovanni, de Zubicaray, Greig I, Deary, Ian J, Donohoe, Gary, de Geus, Eco J C, Espeseth, Thomas, Fernández, Guillén, Glahn, David C, Grabe, Hans J, Holmes, Avram J, Hardy, John, Hulshoff Pol, Hilleke E, Jenkinson, Mark, Kahn, René S, McDonald, Colm, McIntosh, Andrew M, McMahon, Francis J, McMahon, Katie L, Meyer-Lindenberg, Andreas, Morris, Derek W, Homuth, Georg, Müller-Myhsok, Bertram, Nichols, Thomas E, Ophoff, Roel A, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W, Potkin, Steven G, Sämann, Philipp G, Saykin, Andrew J, Schumann, Gunter, Vasquez, Alejandro Arias, Hottenga, Jouke-Jan, Smoller, Jordan W, Wardlaw, Joanna M, Weale, Michael E, Martin, Nicholas G, Franke, Barbara, Wright, Margaret J, Thompson, Paul M, Consortium, Enhancing Neuro Imaging Genetics through Meta-Analysis, Weiner, Michael, Aisen, Paul, Langan, Camilla, Petersen, Ronald, Jagust, William, Trojanowki, John Q, Beckett, Laurel, Green, Robert C, Morris, John, Liu, Enchi, Lopez, Lorna M, Montine, Tom, Gamst, Anthony, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Hansell, Narelle K, Harvey, Danielle, Kornak, John, Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Hwang, Kristy S, Thompson, Paul, Schuff, Norbert, Alexander, Gene, Bandy, Dan, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Kim, Sungeun, Cairns, Nigel J, Taylor-Reinwald, Lisa, Trojanowki, J. Q., Shaw, Les, Lee, Virginia M Y, Korecka, Magdalena, Crawford, Karen, Neu, Scott, Laje, Gonzalo, Potkin, Steven, Shen, Li, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lee, Phil H, Lind, Betty, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Liu, Xinmin, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Ances, Beau, Carroll, Maria, Loth, Eva, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Mitsis, Effie, Romirowsky, Aliza, deToledo-Morrell, Leyla, Hibar, Derrek P, Lourdusamy, Anbarasu, Shah, Raj C, Duara, Ranjan, Varon, Daniel, Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, Kielb, Stephanie, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, Mattingsdal, Morten, De Santi, Susan, Doraiswamy, P Murali, Petrella, Jeffrey R, Coleman, R Edward, Arnold, Steven E, Karlawish, Jason H, Wolk, David, Smith, Charles D, Jicha, Greg, Hardy, Peter, Mohnke, Sebastian, Lopez, Oscar L, Oakley, MaryAnn, Simpson, Donna M, Porsteinsson, Anton P, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Ismail, M Saleem, Mulnard, Ruth A, Thai, Gaby, Maniega, Susana Muñoz, Mc-Adams-Ortiz, Catherine, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Diaz-Arrastia, Ramon, King, Richard, Weiner, Myron, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I, Nho, Kwangsik, Lah, James J, Cellar, Janet S, Burns, Jeffrey M, Anderson, Heather S, Swerdlow, Russell H, Apostolova, Liana, Lu, Po H, Bartzokis, George, Silverman, Daniel H S, Graff-Radford, Neill R, Nugent, Allison C, Parfitt, Francine, Johnson, Heather, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Herring, Scott, van Dyck, Christopher H, Carson, Richard E, MacAvoy, Martha G, Chertkow, Howard, O'Brien, Carol, Bergman, Howard, Hosei, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Ging-Yuek Robin, Feldman, Howard, Mudge, Benita, Assaly, Michele, Kertesz, Andrew, Papmeyer, Martina, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek-Marsel, Lipowski, Kristina, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Pütz, Benno, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Marshall, Gad, Frey, Meghan, Yesavage, Jerome, Ramasamy, Adaikalavan, Taylor, Joy L, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan, Belden, Christine, Jacobson, Sandra, Kowall, Neil, Killiany, Ronald, Budson, Andrew E, Senstad, Rudy E, Rasmussen, Jerod, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Bwayo, Salome K, Lerner, Alan, Hudson, Leon, Ogrocki, Paula, Fletcher, Evan, Carmichael, Owen, Rijpkema, Mark, Olichney, John, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Risacher, Shannon L, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W, Kataki, Maria, Roddey, J Cooper, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Anderson, Karen, Santulli, Robert B, Schwartz, Eben S, Sink, Kaycee M, Rose, Emma J, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J, Ryten, Mina, Miller, Bruce L, Mintzer, Jacobo, Longmire, Crystal Flynn, Spicer, Kenneth, Finger, Elizabeth, Rachinsky, Irina, Drost, Dick, Cavalleri, Gianpiero, Alhusaini, Saud, Delanty, Norman, Whelan, Christopher, Sisodiya, Sanjay, Kasperaviciute, Dalia, Matarin, Mar, Depondt, Chantal, Goldstein, David B, Heinzen, Erin L, Shianna, Kevin, Sprooten, Emma, Radtke, Rodney, Ottmann, Ruth, Sergievsky, G. H., Schumann, G., Conrod, P., Reed, L., Barker, G., Williams, S., Loth, E., Struve, M., Strengman, Eric, Lourdusamy, A., Cattrell, A., Nymberg, C., Topper, L., Smith, L., Havatzias, S., Stueber, K., Mallik, C., Stacey, D., Wong, C Peng, Teumer, Alexander, Werts, H., Andrew, C., Desrivieres, S., Heinz, A., Gallinat, J., Häke, I., Ivanov, N., Klär, A., Reuter, J., Winkler, Anderson M, Trabzuni, Daniah, Palafox, C., Hohmann, C., Schilling, C., Lüdemann, K., Romanowski, A., Ströhle, A., Wolff, E., Rapp, M., Ittermann, B., Brühl, R., Turner, Jessica, Ihlenfeld, A., Walaszek, B., Schubert, F., Garavan, H., Connolly, C., Jones, J., Lalor, E., McCabe, E., Ní Shiothcháin, A., Whelan, R., van Eijk, Kristel, Spanagel, R., Leonardi-Essmann, F., Sommer, W., Flor, H., Vollstaedt-Klein, S., Nees, F., Banaschewski, T., Poustka, L., Steiner, S., Mann, K., van Erp, Theo G M, Buehler, M., Rietschel, M., Stolzenburg, E., Schmal, C., Schirmbeck, F., Paus, T., Gowland, P., Heym, N., Lawrence, C., Newman, C., van Tol, Marie-Jose, Pausova, Z., Smolka, M., Huebner, T., Ripke, S., Mennigen, E., Muller, K., Ziesch, V., Büchel, C., Bromberg, U., Fadai, T., Wittfeld, Katharina, Lueken, L., Yacubian, J., Finsterbusch, J., Martinot, J. L., Artiges, E., Bordas, N., de Bournonville, S., Bricaud, Z., Gollier Briand, F., Lemaitre, H., Wolf, Christiane, Massicotte, J., Miranda, R., Paillère Martinot, M. L., Penttilä, J., Poline, J. B., Barbot, A., Schwartz, Y., Lalanne, C., Frouin, V., Thyreau, B., Woudstra, Saskia, Dalley, J., Mar, A., Robbins, T., Subramaniam, N., Theobald, D., Richmond, N., de Rover, M., Molander, A., Jordan, E., Robinson, E., Aleman, Andre, Hipolata, L., Moreno, M., Arroyo, M., Stephens, D., Ripley, T., Crombag, H., Pena, Y., Lathrop, M., Zelenika, D., Heath, S., Lanzerath, D., Heinrichs, B., Spranger, T., Fuchs, B., Speiser, C., Resch, F., Haffner, J., Parzer, P., Brunner, R., Klaassen, A., Toro, Roberto, Almasy, Laura, Klaassen, I., Constant, P., Mignon, X., Thomsen, T., Zysset, S., Vestboe, A., Ireland, J., Rogers, J., Binder, Elisabeth B, Chakravarty, Mallar, Smith, Albert Vernon, van der Lijn, Fedde, Crivello, Fabrice, Fornage, Myriam, Shulman, Joshua M, Brohawn, David G, Schmidt, Helena, Srikanth, Velandai, Schuur, Maaike, Yu, Lei, Choi, Seung-Hoan, Sigurdsson, Sigurdur, Verhaaren, Benjamin F J, DeStefano, Anita L, Lambert, Jean-Charles, Cantor, Rita M, Struchalin, Maksim, Stankovich, Jim, Ibrahim-Verbaas, Carla A, Fleischman, Debra, Zijdenbos, Alex, den Heijer, Tom, Mazoyer, Bernard, Coker, Laura H, Enzinger, Christian, Danoy, Patrick, Carless, Melanie A, Amin, Najaf, Arfanakis, Konstantinos, van Buchem, Mark A, de Bruijn, Renée F A G, Beiser, Alexa, Dufouil, Carole, Huang, Juebin, Cavalieri, Margherita, Thomson, Russell, Niessen, Wiro J, Corvin, Aiden, Chibnik, Lori B, Gislason, Gauti K, Hofman, Albert, Pikula, Aleksandra, Amouyel, Philippe, Freeman, Kevin B, Phan, Thanh G, Oostra, Ben A, Nalls, Michael A, Uitterlinden, Andre G, Czisch, Michael, Au, Rhoda, Elbaz, Alexis, Beare, Richard J, van Swieten, John C, Lopez, Oscar, Harris, Tamara B, Chouraki, Vincent, Breteler, Monique M B, De Jager, Philip L, Becker, James T, Curran, Joanne E, Knopman, David, Fazekas, Franz, Wolf, Philip A, van der Lugt, Aad, Longstreth, W. T., Brown, Mathew A, Bennett, David A, van Duijn, Cornelia M, Davies, Gail, Mosley, Thomas H, Schmidt, Reinhold, de Almeida, Marcio A A, Appel, Katja, Duggirala, Ravi, Dyer, Thomas D, Erk, Susanne, Fagerness, Jesen, Fox, Peter T, Freimer, Nelson B, Gill, Michael, Göring, Harald H H, Bartecek, Richard, Hagler, Donald J, Hoehn, David, Holsboer, Florian, Hoogman, Martine, Hosten, Norbert, Jahanshad, Neda, Johnson, Matthew P, Kent, Jack W, Kochunov, Peter, Bergmann, Ørjan, Lancaster, Jack L, Lawrie, Stephen M, Liewald, David C, Mandl, René, Mattheisen, Manuel, Meisenzahl, Eva, Melle, Ingrid, Moses, Eric K, Mühleisen, Thomas W, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Queensland Institute of Medical Research, Radboud University Medical Center [Nijmegen], Yale University School of Medicine, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Universität Greifswald - University of Greifswald, Universität Heidelberg [Heidelberg], University Medical Center [Utrecht], University of Oslo (UiO), University of Toronto, National University of Ireland [Galway] (NUI Galway), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], University of Bergen (UiB), Harvard University [Cambridge], VU University Amsterdam, University of Edinburgh, Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], National Institutes of Health [Bethesda] (NIH), Department of Forensic and Neurodevelopmental Sciences, King‘s College London, Institute of Psychiatry, Psychology & Neuroscience, King's College London, Georgia State University, University System of Georgia (USG), Department of Psychiatry and Human Behavior [Irvine], University of California [Irvine] (UCI), Leiden University Medical Center (LUMC), Dundee Technopole, CXR Biosciences Ltd, University of Groningen [Groningen], Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), Department of Genetics, Southwest Foundation for Biomedical Research, Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, The University of Texas Health Science Center at Houston (UTHealth), Center for Neurobehavioral Genetics, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Department of Computer Science, Durham University, Laboratoire des symbioses tropicales et méditerranéennes (UMR LSTM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of California, Institute of Neurology [London], University College of London [London] (UCL), University of California [San Francisco] (UCSF), Department of Medicine, University of Washington [Seattle], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre Émile Durkheim (CED), Sciences Po Bordeaux - Institut d'études politiques de Bordeaux (IEP Bordeaux)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Salermo, Università degli Studi di Salerno (UNISA), School of Psychology, University of Queensland, University of Queensland [Brisbane], Hartford Hospital, Lancaster University, Centre for Advanced Imaging, McConnell Brain Imaging Centre (MNI), McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Stanley Center for Psychiatric Research, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Faculteit Medische Wetenschappen/UMCG, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Biological Psychology, Neuroscience Campus Amsterdam - Brain Imaging, EMGO+ - Mental Health, EPIGEN Consortium, IMAGENConsortium, Saguenay Youth Study Group, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium, Psychiatry, NCA - Brain Imaging, EMGO - Mental health, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Virology, Epidemiology, Clinical Chemistry, Erasmus MC other, Radiology & Nuclear Medicine, University of California (UC)-University of California (UC), Yale School of Medicine [New Haven, Connecticut] (YSM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg] = Heidelberg University, Harvard University, Vrije Universiteit Amsterdam [Amsterdam] (VU), University of California [Irvine] (UC Irvine), Universiteit Leiden, University of California (UC), University of California [San Francisco] (UC San Francisco), Università degli Studi di Salerno = University of Salerno (UNISA), University of Iceland [Reykjavik], McGill University, University of Bergen (UIB), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Bijvoet Center of Biomolecular Research, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, UMR5116, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), and McGill University-McGill University

Subjects
Netherlands Twin Register (NTR), Pathology, 110 012 Social cognition of verbal communication, [SDV]Life Sciences [q-bio], Hippocampus, Genome-wide association study, DCN PAC - Perception action and control, Hippocampal formation, physiopathology [Brain], Bioinformatics, 0302 clinical medicine, 130 000 Cognitive Neurology & Memory, TEMPORAL-LOBE EPILEPSY, 110 014 Public activities, Renal disorder [IGMD 9], 0303 health sciences, medicine.diagnostic_test, Translational research Immune Regulation [ONCOL 3], Brain, Human brain, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], ALZHEIMERS-DISEASE, medicine.anatomical_structure, Brain size, genetics [Chromosomes, Human, Pair 12], genetics [Polymorphism, Single Nucleotide], Biomarker (medicine), NA+/H+ EXCHANGER, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Genetic Markers, medicine.medical_specialty, 110 000 Neurocognition of Language, DCN MP - Plasticity and memory, A neurocomputational model for the Processing of Linguistic Utterances based on the Unification-Space architecture [110 007 PLUS], BRAIN VOLUME, UNIFIED APPROACH, 110 013 Binding and the MUC-model, Neuroimaging, Biology, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], 03 medical and health sciences, AUTOMATED SEGMENTATION, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, ddc:570, FUNCTIONAL IMPLICATIONS, Genetics, medicine, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, Chromosomes, Human, Pair 12, Magnetic resonance imaging, Genetic Loci, physiopathology [Hippocampus], 110 009 The human brain and Chinese prosody, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], HUMAN HEIGHT, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 108202.pdf (Publisher’s version ) (Closed access) Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 x 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 x 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 x 10(-7)). 01 mei 2012

Published
2012

34. Common genetic variants influence human subcortical brain structures

Author

Hibar, Derrek P, Stein, Jason L, Aribisala, Benjamin S, de Zubicaray, Greig I, Dillman, Allissa, Duggirala, Ravi, Dyer, Thomas D, Erk, Susanne, Fedko, Iryna O, Ferrucci, Luigi, Foroud, Tatiana M, Fox, Peter T, Fukunaga, Masaki, Armstrong, Nicola J, Gibbs, J Raphael, Göring, Harald H H, Green, Robert C, Guelfi, Sebastian, Hansell, Narelle K, Hartman, Catharina A, Hegenscheid, Katrin, Heinz, Andreas, Hernandez, Dena G, Heslenfeld, Dirk J, Bernard, Manon, Hoekstra, Pieter J, Holsboer, Florian, Homuth, Georg, Hottenga, Jouke-Jan, Ikeda, Masashi, Jack, Clifford R, Jenkinson, Mark, Johnson, Robert, Kanai, Ryota, Keil, Maria, Bohlken, Marc M, Kent, Jack W, Kochunov, Peter, Kwok, John B, Lawrie, Stephen M, Liu, Xinmin, Longo, Dan L, McMahon, Katie L, Meisenzahl, Eva, Melle, Ingrid, Mohnke, Sebastian, Boks, Marco P, Montgomery, Grant W, Mostert, Jeanette C, Mühleisen, Thomas W, Nalls, Michael A, Nichols, Thomas E, Nilsson, Lars G, Nöthen, Markus M, Ohi, Kazutaka, Olvera, Rene L, Perez-Iglesias, Rocio, Bralten, Janita, Pike, G Bruce, Potkin, Steven G, Reinvang, Ivar, Reppermund, Simone, Rietschel, Marcella, Romanczuk-Seiferth, Nina, Rosen, Glenn D, Rujescu, Dan, Schnell, Knut, Schofield, Peter R, Brown, Andrew A, Smith, Colin, Steen, Vidar M, Sussmann, Jessika E, Thalamuthu, Anbupalam, Toga, Arthur W, Traynor, Bryan J, Troncoso, Juan, Turner, Jessica A, Valdés Hernández, Maria C, van 't Ent, Dennis, Chakravarty, M Mallar, van der Brug, Marcel, van der Wee, Nic J A, van Tol, Marie-Jose, Veltman, Dick J, Wassink, Thomas H, Westman, Eric, Zielke, Ronald H, Zonderman, Alan B, Ashbrook, David G, Hager, Reinmar, Chen, Qiang, Lu, Lu, McMahon, Francis J, Morris, Derek W, Williams, Robert W, Brunner, Han G, Buckner, Randy L, Buitelaar, Jan K, Cahn, Wiepke, Calhoun, Vince D, Cavalleri, Gianpiero L, Ching, Christopher R K, Crespo-Facorro, Benedicto, Dale, Anders M, Davies, Gareth E, Delanty, Norman, Depondt, Chantal, Djurovic, Srdjan, Drevets, Wayne C, Espeseth, Thomas, Gollub, Randy L, Ho, Beng-Choon, Renteria, Miguel E, Cuellar-Partida, Gabriel, Hoffmann, Wolfgang, Hosten, Norbert, Kahn, René S, Le Hellard, Stephanie, Meyer-Lindenberg, Andreas, Müller-Myhsok, Bertram, Nauck, Matthias, Nyberg, Lars, Pandolfo, Massimo, Penninx, Brenda W J H, den Braber, Anouk, Roffman, Joshua L, Sisodiya, Sanjay M, Smoller, Jordan W, van Bokhoven, Hans, van Haren, Neeltje E M, Völzke, Henry, Walter, Henrik, Weiner, Michael W, Wen, Wei, White, Tonya, Giddaluru, Sudheer, Agartz, Ingrid, Andreassen, Ole A, Blangero, John, Boomsma, Dorret I, Brouwer, Rachel M, Cannon, Dara M, Cookson, Mark R, de Geus, Eco J C, Deary, Ian J, Donohoe, Gary, Goldman, Aaron L, Fernández, Guillén, Fisher, Simon E, Francks, Clyde, Glahn, David C, Grabe, Hans J, Gruber, Oliver, Hardy, John, Hashimoto, Ryota, Hulshoff Pol, Hilleke E, Jönsson, Erik G, Grimm, Oliver, Kloszewska, Iwona, Lovestone, Simon, Mattay, Venkata S, Mecocci, Patrizia, McDonald, Colm, McIntosh, Andrew M, Ophoff, Roel A, Paus, Tomas, Pausova, Zdenka, Ryten, Mina, Guadalupe, Tulio, Sachdev, Perminder S, Saykin, Andrew J, Simmons, Andy, Singleton, Andrew, Soininen, Hilkka, Wardlaw, Joanna M, Weale, Michael E, Weinberger, Daniel R, Adams, Hieab H H, Launer, Lenore J, Hass, Johanna, Seiler, Stephan, Schmidt, Reinhold, Chauhan, Ganesh, Satizabal, Claudia L, Becker, James T, Yanek, Lisa, van der Lee, Sven J, Ebling, Maritza, Fischl, Bruce, Longstreth, W. T., Woldehawariat, Girma, Greve, Douglas, Schmidt, Helena, Nyquist, Paul, Vinke, Louis N, van Duijn, Cornelia M, Xue, Luting, Mazoyer, Bernard, Bis, Joshua C, Gudnason, Vilmundur, Seshadri, Sudha, Holmes, Avram J, Ikram, M Arfan, Initiative, Alzheimer’s Disease Neuroimaging, Consortium, CHARGE, EPIGEN, IMAGEN, SYS, Martin, Nicholas G, Wright, Margaret J, Schumann, Gunter, Franke, Barbara, Hoogman, Martine, Thompson, Paul M, Medland, Sarah E, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jagust, William, Trojanowki, John Q, Beckett, Laurel, Arias-Vasquez, Alejandro, Janowitz, Deborah, Morris, John, Shaw, Leslie M, Khachaturian, Zaven, Sorensen, Greg, Carrillo, Maria, Kuller, Lew, Raichle, Marc, Paul, Steven, Jia, Tianye, Davies, Peter, Fillit, Howard, Hefti, Franz, Holtzman, Davie, Mesulman, M Marcel, Potter, William, Snyder, Peter, Schwartz, Adam, Montine, Tom, Kim, Sungeun, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Jiminez, Gus, Harvey, Danielle, Klein, Marieke, Bernstein, Matthew, Fox, Nick, Thompson, Paul, Schuff, Norbert, DeCarli, Charles, Borowski, Bret, Gunter, Jeff, Senjem, Matt, Kraemer, Bernd, Vemuri, Prashanthi, Jones, David, Kantarci, Kejal, Ward, Chad, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Lee, Phil H, Landau, Susan, Cairns, Nigel J, Householder, Erin, Taylor-Reinwald, Lisa, Trojanowki, J. Q., Shaw, Les, Lee, Virginia M Y, Korecka, Magdalena, Figurski, Michal, Olde Loohuis, Loes M, Crawford, Karen, Neu, Scott, Potkin, Steven, Shen, Li, Faber, Kelley, Nho, Kwangsik, Luciano, Michelle, Thal, Leon, Frank, Richard, Snyder, Peter J, Buckholtz, Neil, Macare, Christine, Albert, Marilyn, Hsiao, John, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Carter, Raina, Dolen, Sara, Gutman, Boris A, Schneider, Lon S, Mather, Karen A, Pawluczyk, Sonia, Beccera, Mauricio, Teodoro, Liberty, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Fleisher, Adam, Heidebrink, Judith L, Lord, Joanne L, Desrivières, Sylvane, Mattheisen, Manuel, Mason, Sara S, Albers, Colleen S, Knopman, David, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Stern, Yaakov, Milaneschi, Yuri, Honig, Lawrence S, Bell, Karen L, Ances, Beau, Morris, John C, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Oliver, Angela, Marson, Daniel, Griffith, Randall, Clark, David, Geldmacher, David, Brockington, John, Roberson, Erik, Grossman, Hillel, Mitsis, Effie, deToledo-Morrell, Leyla, Shah, Raj C, Papmeyer, Martina, Duara, Ranjan, Varon, Daniel, Greig, Maria T, Roberts, Peggy, Onyike, Chiadi, D'Agostino, Daniel, Kielb, Stephanie, Galvin, James E, Pogorelec, Dana M, Ramasamy, Adaikalavan, Cerbone, Brittany, Michel, Christina A, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P Murali, Petrella, Jeffrey R, Wong, Terence Z, Arnold, Steven E, Risacher, Shannon L, Karlawish, Jason H, Wolk, David, Smith, Charles D, Jicha, Greg, Hardy, Peter, Sinha, Partha, Oates, Elizabeth, Conrad, Gary, Lopez, Oscar L, Oakley, MaryAnn, Roiz-Santiañez, Roberto, Simpson, Donna M, Porsteinsson, Anton P, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Ismail, M Saleem, Brand, Connie, Mulnard, Ruth A, Thai, Gaby, Mc-Adams-Ortiz, Catherine, Rose, Emma J, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Diaz-Arrastia, Ramon, King, Richard, Weiner, Myron, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I, Lah, James J, Salami, Alireza, Cellar, Janet S, Burns, Jeffrey M, Anderson, Heather S, Swerdlow, Russell H, Apostolova, Liana, Tingus, Kathleen, Woo, Ellen, Silverman, Daniel H S, Lu, Po H, Bartzokis, George, Sämann, Philipp G, Graff-Radford, Neill R, Parfitt, Francine, Kendall, Tracy, Johnson, Heather, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Herring, Scott, Hunt, Cynthia, van Dyck, Christopher H, Jahanshad, Neda, Schmaal, Lianne, Carson, Richard E, MacAvoy, Martha G, Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Yuek Robin, Feldman, Howard, Schork, Andrew J, Mudge, Benita, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek-Marsel, Lipowski, Kristine, Shin, Jean, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Strike, Lachlan T, Marshall, Gad, Frey, Meghan, Yesavage, Jerome, Taylor, Joy L, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan N, Belden, Christine M, Jacobson, Sandra A, Teumer, Alexander, Sirrel, Sherye A, Kowall, Neil, Killiany, Ronald, Budson, Andrew E, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Allard, Joanne, Lerner, Alan, van Donkelaar, Marjolein M J, Ogrocki, Paula, Hudson, Leon, Fletcher, Evan, Carmichael, Owen, Olichney, John, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, van Eijk, Kristel R, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Reeder, Stephanie, Bates, Vernice, Walters, Raymond K, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W, Kataki, Maria, Adeli, Anahita, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Westlye, Lars T, Anderson, Karen, Santulli, Robert B, Kitzmiller, Tamar J, Schwartz, Eben S, Sink, Kaycee M, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Whelan, Christopher D, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Mintzer, Jacobo, Spicer, Kenneth, Bachman, David, Finger, Elizabether, Toro, Roberto, Winkler, Anderson M, Pasternak, Stephen, Rachinsky, Irina, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K, Ponto, Laura L Boles, Zwiers, Marcel P, Shim, Hyungsub, Smith, Karen Elizabeth, Relkin, Norman, Chaing, Gloria, Raudin, Lisa, Smith, Amanda, Fargher, Kristin, Raj, Balebail Ashok, Amin, Najaf, Becker, Diane, Alhusaini, Saud, Beiser, Alexa, Debette, Stéphanie, DeStefano, Anita, Hofer, Edith, Hofman, Albert, Niessen, Wiro J, Smith, Albert, Tzourio, Christophe, Vaidya, Dhananjay, Athanasiu, Lavinia, Vernooij, Meike W, Goldstein, David B, Heinzen, Erin L, Shianna, Kevin, Radtke, Rodney, Ottmann, Ruth, Albrecht, Lisa, Andrew, Chris, Arroyo, Mercedes, Artiges, Eric, Ehrlich, Stefan, Aydin, Semiha, Bach, Christine, Banaschewski, Tobias, Barbot, Alexis, Barker, Gareth, Boddaert, Nathalie, Bokde, Arun, Bricaud, Zuleima, Bromberg, Uli, Bruehl, Ruediger, Hakobjan, Marina M H, Büchel, Christian, Cachia, Arnaud, Cattrell, Anna, Conrod, Patricia, Constant, Patrick, Crombag, Hans, Czech, Katharina, Dalley, Jeffrey, Decideur, Benjamin, Desrivieres, Sylvane, Hartberg, Cecilie B, Fadai, Tahmine, Flor, Herta, Frouin, Vincent, Fuchs, Birgit, Gallinat, Jürgen, Garavan, Hugh, Briand, Fanny Gollier, Gowland, Penny, Head, Kay, Heinrichs, Bert, Haukvik, Unn K, Heym, Nadja, Hübner, Thomas, Ihlenfeld, Albrecht, Ireland, James, Ittermann, Bernd, Ivanov, Nikolay, Jones, Jennifer, Klaassen, Arno, Heister, Angelien J G A M, Lalanne, Christophe, Lathrop, Mark, Lanzerath, Dirk, Lemaitre, Hervé, Lüdemann, Katharina, Mallik, Catherine, Mangin, Jean-François, Mann, Karl, Mar, Adam, Hoehn, David, Martinot, Jean-Luc, Massicotte, Jessica, Mennigen, Eva, Mesquita de Carvahlo, Fabiana, Mignon, Xavier, Miranda, Ruben, Müller, Kathrin, Nees, Frauke, Nymberg, Charlotte, Paillere, Marie-Laure, Wittfeld, Katharina, Kasperaviciute, Dalia, Pena-Oliver, Yolanda, Poline, Jean-Baptiste, Poustka, Luise, Rapp, Michael, Reed, Laurence, Robert, Gabriel, Reuter, Jan, Liewald, David C M, Ripke, Stephan, Ripley, Tamzin, Robbins, Trevor, Rodehacke, Sarah, Romanowski, Alexander, Ruggeri, Barbara, Schilling, Christina, Schmäl, Christine, Schmidt, Dirk, Lopez, Lorna M, Schneider, Sophia, Schroeder, Markus, Schubert, Florian, Schwartz, Yannick, Smolka, Michael, Sommer, Wolfgang, Spanagel, Rainer, Speiser, Claudia, Spranger, Tade, Stedman, Alicia, Makkinje, Remco R R, Steiner, Sabina, Stephens, Dai, Strache, Nicole, Ströhle, Andreas, Struve, Maren, Subramaniam, Naresh, Theobald, David, Topper, Lauren, Vollstaedt-Klein, Sabine, Walaszek, Bernadeta, Matarin, Mar, Weiß, Katharina, Werts, Helen, Whelan, Robert, Williams, Steve, Yacubian, Juliana, Ziesch, Veronika, Zilbovicius, Monica, Wong, C Peng, Lubbe, Steven, Naber, Marlies A M, Martinez-Medina, Lourdes, Kepa, Agnes, Fernandes, Alinda, Tahmasebi, Amir, Abrahamowicz, Michal, Gaudet, Daniel, Leonard, Gabriel, Perron, Michel, Richer, Louis, Seguin, Jean, McKay, D Reese, Veillette, Suzanne, Needham, Margaret, Nugent, Allison C, Pütz, Benno, Abramovic, Lucija, Royle, Natalie A, Sprooten, Emma, Trabzuni, Daniah, van der Marel, Saskia S L, van Hulzen, Kimm J E, Walton, Esther, Wolf, Christiane, Almasy, Laura, Ames, David, Andersson, Micael, Arepalli, Sampath, Assareh, Amelia A, Bastin, Mark E, Brodaty, Henry, Bulayeva, Kazima B, Carless, Melanie A, Cichon, Sven, Corvin, Aiden, Curran, Joanne E, Czisch, Michael, MUMC+: DA Klinische Genetica (5), RS: GROW - Developmental Biology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Université de Montréal. Faculté de médecine. Département de psychiatrie et d'addictologie, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), QIMR Berghofer Medical Research Institute, Department of Psychiatry, Donders Centre for Neuroscience, Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen], Department of Human Genetics, Radboud University Medical Center [Nijmegen], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, PRES Sorbonne Paris Cité, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Greifswald University Hospital, University Medical Center [Utrecht], European Commission, University of Edinburgh, Lagos State University (LASU), Heriot-Watt University [Edinburgh] (HWU), Unité d'expérimentation sur les Ruminants de Theix, Institut National de la Recherche Agronomique (INRA), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], University of Oslo (UiO), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], School of Technical Physics, Xidian University, Dept. of Mechanical Engineering, McMaster University [Hamilton, Ontario], Biological Psychology, Neuroscience Campus Amsterdam & EMGO Institute for Health and Care Research, VU University & VU Medical Center, Amsterdam 1081 BT, The Netherlands, Haukeland University Hospital, University of Bergen (UiB), Physicochimie des Processus de Combustion et de l’Atmosphère - UMR 8522 (PC2A), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Universität Heidelberg [Heidelberg] = Heidelberg University, Language and Genetics Department [Nijmegen], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, International Max Planck Research School for Language Sciences (IMPRS ), Georgia Institute of Technology [Atlanta], National Institutes of Health [Bethesda] (NIH), Yale University [New Haven], Massachusetts General Hospital [Boston], Mental Health Sciences Unit, University College of London [London] (UCL), Beijing Normal University (BNU), Indiana University School of Medicine, Indiana University System, Indiana Alzheimer Disease Center, Indiana University System-Indiana University System, Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen 37075, Germany, Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, University of California (UC), Medstar Research Institute, Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia, Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Institute of Human Genetics, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], VU University Medical Center [Amsterdam], Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Umeå Centre for Functional Brain Imaging (UFBI), Umeå University, Umeå 901 87, Sweden, Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), Department of Cognitive Sciences [Univ California San Diego] (CogSci - UC San Diego), The Hospital for sick children [Toronto] (SickKids), Queensland Institute of Medical Research, School of Psychology, University of Queensland, Brisbane 4072, Australia, University of Queensland [Brisbane], Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia, Department of Genomics of Common Disease, Imperial College London, Department of Psychology [Oslo], Faculty of Social Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Deutsche Bundesbank, Department of Neurology and Neurosurgery [Montreal], McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), MetaGenoPolis, Department of Psychiatric Research and Development, Diakonhjemmet Hospital, Oslo 0319, Norway, UCL Institute of Neurology and Epilepsy Society, Department of Medicine, Clinical And Experimental Epilepsy, Dpt of Psychiatry [New Haven], Yale School of Medicine [New Haven, Connecticut] (YSM), Hartford Hospital, Neuropsychiatric Genetics Research Group and Department of Psychiatry, Trinity College Institute of Psychiatry, Trinity College Dublin, Dublin 2, Ireland, Institute of Food & Health, University College Dublin, University College Dublin [Dublin] (UCD), Statistical Genetics Group, State Key Laboratory of Lead Compound Research, WuXi AppTec, Co., Ltd, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL, Institute of Neurology [London], Department of Genetics, King Faisal Specialist Hospital and Research Centre (KFSH & RC), Centre épigénétique et destin cellulaire (EDC), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Dundee Technopole, CXR Biosciences Ltd, Ninewells Hospital and Medical School, Biomedical Research Centre, University of Dundee, Southwest Foundation for Biomedical Research, Department of Psychiatry and National Ageing Research Institute, University of Melbourne, Department of Clinical Genetics, Department of Medical Parasitology and Mycology, School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-Tehran University of Medical Siences, Centre for Healthy Brain Ageing, University of New South Wales [Sydney] (UNSW), Dementia Collaborative Research Centre, N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Texas Biomedical Research Institute [San Antonio, TX], Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Division of Medical Genetics, University of Basel (Unibas), Trinity College Dublin-St. James's Hospital, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Department of Materials Science & Metallurgy, University of Cambridge [UK] (CAM), Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], School of Psychology, University of Queensland, Laboratory of Neurogenetics, The University of Texas Health Science Center at Houston (UTHealth), Department of Genomics, Department of Medical and Molecular Genetics, South Texas Veterans Health Care System, San Antonio, Texas 78229, USA, Biofunctional Imaging, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan, Public Health Genomics Unit, Department of Biomolecular Engineering, Rheinische Friedrich-Wilhelms-Universität Bonn, Estación Experimental de Pastos y Forrajes 'Indio Hatuey', University Medical Center Groningen [Groningen] (UMCG), Neuronal Plasticity / Mouse Behaviour, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Department of Psychiatry, Fujita Health University School of Medicine, Toyoake 470-1192, Japan, Department of Radiology, Mayo Clinic, Department of Clinical Neurology [Oxford], University of Oxford-FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital], University of Maryland School of Medicine, University of Maryland System, University of Sussex, Institute of Cognitive Neuroscience, United Kingdom Met Office [Exeter], University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System-University of Maryland School of Medicine, Department of Civil and Structural Engineering, The Hong Kong Polytechnic University [Hong Kong] (POLYU)-The Hong Kong Polytechnic University [Hong Kong] (POLYU), Columbia University Irving Medical Center (CUIMC), Lymphocyte Cell Biology Unit, Laboratory of Genetics, Centre for Advanced Imaging, Psychiatry and Psychotherapy, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetic Epidemiology Unit, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Statistics [Warwick], University of Warwick [Coventry], Osaka University [Osaka], Institute of Psychiatry, King’s College London, London SE5 8AF, UK, University of Calgary, Psychiatry and Human Behavior, University of California, Irvine, California 92617, USA, University of California [Irvine] (UC Irvine), Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], University Hospital Mannheim | Universitätsmedizin Mannheim-University Hospital Mannheim | Universitätsmedizin Mannheim, Space and Naval Warfare Systems Center, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Department of Psychiatry, Division of Medical Psychology, Genetics of Mental Illness and Brain Function, Neuroscience Research Australia, Développement et amélioration des plantes (UMR DAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia, Laboratory of Neuro Imaging [Los Angeles] (LONI), Departamento de Física Aplicada, Universidade de Vigo, Georgia State University, University System of Georgia (USG), Genentech, Inc. [San Francisco], Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Universiteit Leiden, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Department of Neurobiology, Care Sciences and Society, Karolinska Institutet [Stockholm], University of Manchester [Manchester], The University of Tennessee Health Science Center [Memphis] (UTHSC), iangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong 226001, China, Centre for Ultrahigh Bandwidth Devices for Optical Systems (CUDOS), Macquarie University, Cognitive Neuroscience Laboratory (CNL), Harvard University, Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud University [Nijmegen]-Radboud University [Nijmegen], Icahn School of Medicine at Mount Sinai [New York] (MSSM), The Mind Research Network, Department of Electrical and Computer Engineering [Albuquerque] (ECE Department), The University of New Mexico [Albuquerque], Division of Molecular and Cellular Therapeutics, Scottish Association for Marine Science (SAMS), Structural Biology Laboratory, Department of Chemistry, University of York, Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Department of Neurology, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Deparment of Medical Genetics, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Psychiatry, University of Iowa, University of Iowa [Iowa City], Institute for Community Medicine, Department Epidemiology of Health Care and Community Health, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig-Universität Leipzig, Institute of Clinical Chemistry and Laboratory Medicine, Department of Health Science, Division of Health and Rehabilitation, Luleå University of Technology (LUT), Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Psychiatric and Neurodevelopmental Genetics Unit, 849 Department of Human Genetics, Institute for Community Medicine, Institute for Energy Systems and Thermodynamics, Renyi Institute, Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, NSW, Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam 3000 CB, The Netherlands, Department of Radiology, Erasmus University Medical Centre, Rotterdam 3015 CN, The Netherlands, Vrije Universiteit Amsterdam [Amsterdam] (VU), Cell Biology and Gene Expression Section, National Institute of Health, Bethesda, Dept of Psychology, Laboratoire de Recherche Magellan, Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Institut d'Administration des Entreprises (IAE) - Lyon, Institut de Socio-économie des Entreprises et des ORganisations (ISEOR), Institut de socio-économie des entreprises et des organisations, Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Laboratoire d'Informatique de Grenoble (LIG), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Centre for Allergy Research, Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital [Stockholm], Medical University of Łódź (MUL), Psychiatry Institute, Department of Health and Human Services, Institute of Gerontology and Geriatrics, Università degli Studi di Perugia = University of Perugia (UNIPG), Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), Australian Centre for Research into Injury in Sport and its Prevention, Monash University [Clayton], University Medical Center [Utrecht]-Brain Center Rudolf Magnus, School of Psychology [Nottingham], University of Nottingham, UK (UON), McConnell Brain Imaging Centre (MNI), SickKids - The Hospital for sick children, European Centre for Medium-Range Weather Forecasts (ECMWF), University of Eastern Finland, Centre for Population Health Sciences, Lieber Institute for Brain Development [Baltimore] (LIBD), Johns Hopkins University (JHU), Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz 8010, Austria, Austrian Institute of Technology [Vienna] (AIT), INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, INSERM, Neuroepidemiology U708, Bordeaux, France, Karlsruhe Institute of Technology (KIT), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Harvard Medical School [Boston] (HMS), Computer Science and Artificial Intelligence Laboratory [Cambridge] (CSAIL), Massachusetts Institute of Technology (MIT), University of Washington [Seattle], Department of Physics [Stockholm], Stockholm University, Center for Medical Systems Biology, Netherlands Genomics Initiative, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Boston University [Boston] (BU), Groupe d'Imagerie Neurofonctionnelle (GIN - UMR 5296), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Faculty of Medicine, University of Iceland [Reykjavik], Icelandic Heart Association, Kopavogur, Iceland., Boston University School of Medicine (BUSM), Laboratoire d'Ingénierie des Matériaux de Bretagne (LIMATB), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of California-University of California, Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Gènes, Synapses et Cognition, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), UE 1354 Unité d'expérimentation sur les Ruminants de Theix, Institut National de la Recherche Agronomique (INRA)-Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de la Recherche Agronomique (INRA)-Unité d'expérimentation sur les Ruminants de Theix (UE RT), Radboud university [Nijmegen], McGill University, University of Bergen (UIB), Universität Heidelberg [Heidelberg], Beijing Normal University, University of California, University of Bonn, Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Neurosciences [San Diego], Department of Cognitive Sciences [San Diego], The Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, Canada, McGill University-McGill University, US 1367 MetaGénoPolis, Institut National de la Recherche Agronomique (INRA)-Département Microbiologie et Chaîne Alimentaire (MICA), Institut National de la Recherche Agronomique (INRA)-MetaGénoPolis (MGP), Yale University School of Medicine, King Faisal Specialist Hospital and Research Centre, Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Texas Biomedical Research Institute [San Antonio, Texas], Bijvoet Center of Biomolecular Research, Academic Unit for Psychiatry of Old Age, University of Melbourne, Melbourne 3101, Australia, Department of Genomics, Life & Brain Center, University of Bonn, Bonn D-53127, Germany, University of Oxford [Oxford]-FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital], School of Psychology, University of Sussex, Brighton BN1 9QH, UK, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Department of Neurology [University of Calgary], Department of Clinical Neuroscience [University of Calgary], University of California [Irvine] (UCI), Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Universidate de Vigo, Harvard University [Cambridge], Radboud university [Nijmegen]-Radboud university [Nijmegen], Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Centre de Recherche Magellan, Institut d'Administration des Entreprises (IAE) - Lyon-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon, Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Università degli Studi di Perugia (UNIPG), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Bretagne Sud (UBS)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), The Alzheimer’s Disease Neuroimaging Initiative, The CHARGE Consortium, EPIGEN, IMAGEN, SYS, Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen], Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital]-University of Oxford [Oxford], Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), University of Oxford [Oxford]- John Radcliffe Hospital [Oxford University Hospital]-FMRIB Centre, Neurology, Psychiatry, Anatomy and neurosciences, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Biological Psychology, Cognitive Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, EMGO+ - Mental Health, Child and Adolescent Psychiatry / Psychology, Epidemiology, Radiology & Nuclear Medicine, Laboratory of Neuro Imaging, David Geffen School of Medicine, University of California, Los Angeles, California, USA, Donders Centre for Neuroscience, Radboud University Nijmegen Medical Centre, MRC- SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK, Génétique humaine et Fonctions cognitives - Human Genetics and Cognitive Functions, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Greifswald 17487, Germany, Department of Psychiatry, University Medicine Greifswald, Greifswald 17489, Germany, Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands, Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4 2XU, UK, Department of Computer Science, Lagos State University, Lagos, Nigeria, Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK, Heriot-Watt University [Edinburgh] ( HWU ), Institut National de la Recherche Agronomique ( INRA ) -Physiologie Animale et Systèmes d'Elevage ( PHASE ) -Unité d'expérimentation sur les Ruminants de Theix ( UE RT ), Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands, Department of Cognitive Neuroscience, Radboud university medical center, Nijmegen 6500 HB, The Netherlands, NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo N-0316, Norway, NORMENT - KG Jebsen Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0424, Norway, Montreal Neurological Institute [Montréal], NORMENT - KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 5021, Norway, Physicochimie des Processus de Combustion et de l’Atmosphère - UMR 8522 ( PC2A ), Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The Netherlands, International Max Planck Research School for Language Sciences, Nijmegen 6525 XD, The Netherlands, Human Genetics Branch and Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health Intramural Research Program, Bethesda, Maryland 20892, USA, Department of Psychology, Yale University, New Haven, Connecticut 06511, USA, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02115, USA, University College of London [London] ( UCL ), Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Center for Neurobehavioral Genetics, University of California, Los Angeles, California 90095, USA, Université de Bonn, Department of Psychiatry, Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam 1081 HL, The Netherlands, Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh EH10 5HF, UK, Imperial College London-School of public health-MRC-HPA Centre for Environment and Health, Cibersam (Centro Investigación Biomédica en Red Salud Mental), Madrid 28029, Spain, Institut Parisien de Chimie Moléculaire ( IPCM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Aging Research Center [Karolinska Institutet] ( ARC ), Max Planck Institute of Psychiatry, Munich 80804, Germany, Multimodal Imaging Laboratory, Department of Neurosciences, University of California, San Diego, California 92093, USA, Department of Cognitive Sciences, University of California, San Diego, California 92161, USA, Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia, Department of Psychology, University of Oslo, Oslo 0373, Norway, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal H3A 2B4, Canada, Molecular and Cellular Therapeutics, The Royal College of Surgeons, Dublin 2, Ireland, Institut National de la Recherche Agronomique ( INRA ) -MetaGénoPolis ( MGP ) -Microbiologie et Chaîne Alimentaire ( MICA ), UCL Institute of Neurology, London, United Kingdom and Epilepsy Society, London WC1N 3BG, UK, Department of Medicine, Imperial College London, London W12 0NN, UK, Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK, Yale School of Medicine, Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut 06106, USA, University College Dublin [Dublin] ( UCD ), Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK, Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia, Centre épigénétique et destin cellulaire ( EDC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), School of public health-Tehran University of Medical Siences, University of New South Wales [Sydney] ( UNSW ), Texas Biomedical Research Institute, San Antonio, Texas 78245, USA, Institute of Neuroscience and Medicine ( INM-1 ), University of Basel ( Unibas ), Cambridge University, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA, University of Texas Health Science Center, San Antonio, Texas 78229, USA, Clinical Research Branch, National Institute on Aging, Baltimore, Maryland 20892, USA, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald 17475, Germany, University Medical Center Groningen, University of Groningen, University of Greifswald, Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA, NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland Medical School, Baltimore, Maryland 21201, USA, nstitute of Cognitive Neuroscience, University College London, London WC1N 3AR, UK, Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland, Baltimore, Maryland 21201, USA, Department of Pathology and Cell Biology, Columbia University Medical Center, New York 10032, USA, Lymphocyte Cell Biology Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA, University of Oslo ( UiO ) -Institute of Clinical Medicine-Oslo University Hospital, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo ( UiO ) -European Network of Bipolar Research Expert Centers (ENBREC) Group, Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, CCM, Berlin 10117, Germany, Erasmus MC, Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH), Bethesda, Maryland, USA, Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Central Institute of Mental Health, UMR 1098 Développement et Amélioration des Plantes, Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -MontpellierSupAgro ( MontpellierSupAgro ) -Génétique et amélioration des plantes ( G.A.P. ) -Développement et Amélioration des Plantes ( DAP ), Laboratory of Neuro Imaging [Los Angeles] ( LONI ), University of California at Los Angeles [Los Angeles] ( UCLA ), Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK, Genentech, South San Francisco, California 94080, USA, Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands, LUMC, Carver College of Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm SE-141 83, Sweden, Behavioral Epidemiology Section, National Institute on Aging Intramural Research Program, Baltimore, Maryland 20892, USA, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK, Center for Integrative and Translational Genomics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA, Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA, Centre Interlangues - Texte, Image, Langage ( TIL ), Université de Bourgogne ( UB ), Centre for Ultrahigh Bandwidth Devices for Optical Systems ( CUDOS ), Icahn School of Medicine at Mount Sinai [New York], The Mind Research Network & LBERI, Albuquerque, New Mexico 87106, USA, Department of ECE, University of New Mexico, Albuquerque, New Mexico 87131, USA, Scottish Association for Marine Science ( SAMS ), Department of Neurology, Hopital Erasme, Universite Libre de Bruxelles, Brussels 1070, Belgium, National Institutes of Health ( NIH ) -National Institute of Mental Health (NIMH), Harvard Medical School [Boston] ( HMS ) -Massachusetts General Hospital [Boston], Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242, USA, Luleå University of Technology ( LUT ), Broad Institute of MIT and Harvard, Massachusetts General Hospital, Vrije Universiteit Amsterdam [Amsterdam] ( VU ), Université Jean Moulin - Lyon III-Institut d'Administration des Entreprises (IAE) - Lyon, Institut de Socio-économie des Entreprises et des ORganisations ( ISEOR ), University Medicine Greifswald,-HELIOS Hospital Stralsund, Laboratoire d'Informatique de Grenoble ( LIG ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National Polytechnique de Grenoble ( INPG ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan, Karolinska University Hospital (Solna), Medical University of Łódź ( MUL ), National Institutes of Health ( NIH ), University of Perugia, Commonwealth Scientific and Industrial Research Organisation, University Medical Center Utrecht-Brain Center Rudolf Magnus, University of Nottingham, UK ( UON ), McConnell Brain Imaging Centre ( MNI ), The Hospital for sick children [Toronto] ( SickKids ), Department of Medical and Molecular Genetics, King’s College London, London SE1 9RT, UK, European Centre for Medium-Range Weather Forecasts ( ECMWF ), Lieber Institute for Brain Development, Baltimore, Maryland 21205, USA, Departments of Psychiatry, Neurology, Neuroscience and the Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, Austrian Institute of Technology [Vienna] ( AIT ), Karlsruhe Institute of Technology ( KIT ), General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA, Department of Radiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA, Computer Science and Artificial Intelligence Laboratory [Cambridge] ( CSAIL ), Massachusetts Institute of Technology ( MIT ), Department of Epidemiology, University of Washington, Seattle, Washington, USA, Department of Neurology, University of Washington, Seattle, Washington, USA, Department of Physics, Stockholm University ( Department of Physics, Stockholm University ), Université de Lille, Sciences Humaines et Sociales, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA, Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands, Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA, Groupe d'Imagerie Neurofonctionnelle ( GIN - UMR 5296 ), Service NEUROSPIN ( NEUROSPIN ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université de Bordeaux ( UB ), Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA, Faculty of Medicine, University of Iceland, Reykjavik, Iceland, Department of Neurology, Boston University School of Medicine, Framingham Heart Study, Boston, MA, Department of Neurology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands, Laboratoire d'Ingénierie des Matériaux de Bretagne ( LIMATB ), Université de Bretagne Sud ( UBS ) -Institut Brestois du Numérique et des Mathématiques ( IBNM ), Université de Brest ( UBO ) -Université de Brest ( UBO ) -Université de Brest ( UBO ), King's College, Department of Psychiatry, Radboud university medical center, Nijmegen 6500 HB, The Netherlands, and Broad Institute of © 2012 Nature America, Inc. All rights reserved. Nature Ge N etics aDV a NCE ONLINE PUBLIC a TION 7 l e t t e r s Harvard and MIT, Cambridge, Massachusetts, US

Subjects
CHROMATIN, Male, Netherlands Twin Register (NTR), Aging, Identification, nervous-system, human geography, SEGMENTATION, Caudate nucleus, Apoptosis, Expression, Genome-wide association study, Striatum, Hippocampal formation, Hippocampus, BASAL GANGLIA, 130 000 Cognitive Neurology & Memory, Basal ganglia, genetics [Gene Expression Regulation, Developmental], Hippocampal, Child, anatomy & histology [Skull], Aged, 80 and over, Genetics, Sex Characteristics, KINECTIN, Genome-wide association, Multidisciplinary, Putamen, Brain, Gene Expression Regulation, Developmental, blood, brain, disease incidence, genetic variation, neurology, Organ Size, Human brain, Middle Aged, organization, Magnetic Resonance Imaging, genetics [Genetic Variation], Chromatin, Dynamics, genetics [Membrane Proteins], medicine.anatomical_structure, genetics [Aging], Anatomy & histology, [ SCCO.NEUR ] Cognitive science/Neuroscience, Female, ddc:500, anatomy & histology [Caudate Nucleus], Neuroinformatics, EXPRESSION, Adult, Adolescent, Evolution, anatomy & histology [Hippocampus], ORGANIZATION, genetics [Genetic Loci], Biology, Article, Young Adult, SDG 3 - Good Health and Well-being, Journal Article, medicine, Humans, GENOME-WIDE ASSOCIATION, General, genetics [Apoptosis], Kinectin, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], HIPPOCAMPAL, IDENTIFICATION, genetics [Organ Size], [SCCO.NEUR]Cognitive science/Neuroscience, Skull, segmentation, Genetic Variation, Membrane Proteins, NERVOUS-SYSTEM, anatomy & histology [Putamen], Genetic Loci, KTN1 protein, human, Caudate Nucleus, anatomy & histology [Brain], Neuroscience, Genome-Wide Association Study
Abstract

Contains fulltext : 144426.pdf (Publisher’s version ) (Closed access) Contains fulltext : 144426pre.pdf (Author’s version preprint ) (Open Access) The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 x 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. 6 p.

Published
2015

35. Alzheimer's disease cerebrospinal fluid biomarker in cognitively normal subjects

Author

Toledo, Jon B, Zetterberg, Henrik, Osorio, Ricardo S, Taylor-Reinwald, Lisa, Shaw, Leslie M, Trojanowki, John Q, Lee, Virginia, Korecka, Magdalena, Figurski, Michal, Toga, Arthur W, Crawford, Karen, Neu, Scott, Saykin, Andrew J, Vanderstichele, Hugo, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Faber, Kelley, Kim, Sungeun, Nho, Kwangsik, Weiner, Michael W, Thal, Lean, Khachaturian, Zaven, Thal, Leon, Vandijck, Manu, Buckholtz, Neil, Snyder, Peter J, Potter, William, Paul, Steven, Albert, Marylyn, Frank, Richard, Hsiao, John, Kaye, Jeffrey, Hampel, Harald, Quinn, Joseph, Silbert, Lisa, Lind, Betty, Carter, Raina, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Beccera, Mauricio, Teodoro, Liberty, Spann, Bryan M, Teipel, Stefan, Brewer, James, Vanderswag, Helen, Fleisher, Adam, Heidebrink, Judith L, Lord, Joanne L, Petersen, Ronald, Mason, Sara S, Albers, Colleen S, Knopman, David, Johnson, Kris, Moghekar, Abhay, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Ances, Beau, Morris, John C, Albert, Marilyn, Carroll, Maria, Creech, Mary L, Franklin, Erin, Mintun, Mark A, Schneider, Stacy, Oliver, Angela, Marson, Daniel, Griffith, Randall, Clark, David, Geldmacher, David, Hu, William T, Brockington, John, Roberson, Erik, Love, Marissa Natelson, Grossman, Hillel, Mitsis, Effie, Shah, Raj C, deToledo-Morrell, Leyla, Duara, Ranjan, Varon, Daniel, Greig, Maria T, Monge Argilés, Jose A, Roberts, Peggy, Onyike, Chiadi, D' Agostino, Daniel, Kielb, Stephanie, Galvin, James E, Cerbone, Brittany, Michel, Christina A, Pogorelec, Dana M, Rusinek, Henry, Gorostidi, Ana, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P Murali, Petrella, Jeffrey R, Borges-Neto, Salvador, Wong, Terence Z, Coleman, Edward, Arnold, Steven E, Karlawish, Jason H, van Harten, Argonde C, Teunissen, Charlotte E, Wolk, David, Clark, Christopher M, Smith, Charles D, Jicha, Greg, Hardy, Peter, Sinha, Partha, Oates, Elizabeth, Conrad, Gary, Lopez, Oscar L, Oakley, MaryAnn, De Deyn, Peter P, Simpson, Donna M, Porsteinsson, Anton P, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Ismail, M Saleem, Brand, Connie, Mulnard, Ruth A, Thai, Gaby, Mc-Adams-Ortiz, Catherine, Hyman, Bradley T, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Levey, Allan I, Lah, James J, Cellar, Janet S, Burns, Jeffrey M, Swerdlow, Russell H, Brooks, William M, Apostolova, Liana, Molinuevo, Jose L, Tingus, Kathleen, Woo, Ellen, Silverman, Daniel H S, Lu, Po H, Bartzokis, George, Graff-Radford, Neill R, Parfitt, Francine, Kendall, Tracy, Johnson, Heather, Farlow, Martin R, Frisoni, Giovanni B, Hake, Ann Marie, Matthews, Brandy R, Brosch, Jared R, Herring, Scott, Hunt, Cynthia, van Dyck, Christopher H, Carson, Richard E, MacAvoy, Martha G, Varma, Pradeep, Chertkow, Howard, Linazasoro, Gurutz, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Ging-Yuek Robin, Feldman, Howard, Mudge, Benita, Assaly, Michele, Finger, Elizabeth, Pasternack, Stephen, Rachisky, Irina, Trost, Dick, Kertesz, Andrew, Bernick, Charles, Munic, Donna, Mesulam, Marek-Marsel, Lipowski, Kristine, Weintraub, MaSandra, Bonakdarpour, Borna, van der Flier, Wiesje M, Kerwin, Diana, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Scheltens, Philip, Marshall, Gad, Yesavage, Jerome, Taylor, Joy L, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan N, Belden, Christine M, Jacobson, Sandra A, Sirrel, Sherye A, Blennow, Kaj, Kowall, Neil, Killiany, Ronald, Budson, Andrew E, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Allard, Joanne, Lerner, Alan, Ogrocki, Paula, Tatsuoka, Curtis, Fatica, Parianne, Fletcher, Evan, Maillard, Pauline, Olichney, John, DeCarli, Charles, Carmichael, Owen, Kittur, Smita, Borrie, Michael, Lee, T-Y, Trojanowski, John Q, Bartha, Rob, Asthana, Sanjay, Carlsson, Cynthia M, Potkin, Steven G, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Burke, Anna, Trncic, Nadira, Initiative, Alzheimer’s Disease Neuroimaging, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W, Kataki, Maria, Adeli, Anahita, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Anderson, Karen, Flashman, Laura A, Seltzer, Marc, Hynes, Mary L, Santulli, Robert B, Sink, Kaycee M, Gordineer, Leslie, Williamson, Jeff D, Aisen, Paul, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Weiner, Michael, Perry, David, Mintzer, Jacobo, Spicer, Kenneth, Bachman, David, Finger, Elizabether, Pasternak, Stephen, Rachinsky, Irina, Rogers, John, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K, Ponto, Laura L Boles, Shim, Hyungsub, Smith, Karen Ekstam, Relkin, Norman, Chaing, Gloria, Lin, Michael, Ravdin, Lisa, Smith, Amanda, Raj, Balebail Ashok, Fargher, Kristin, Green, Robert C, Jack, Clifford R, Harvey, Danielle, Jagust, William, Neylan, Thomas, Grafman, Jordan, Montine, Tom, Thomas, Ronald G, Donohue, Michael, Gessert, Devon, Sather, Tamie, Davis, Melissa, Morrison, Rosemary, Martinez-Lage, Pablo, Jiminez, Gus, Hayes, Jacqueline, Finley, Shannon, Bernstein, Matthew, Borowski, Bret, Gunter, Jeff, Senjem, Matt, Kantarci, Kejal, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Landau, Susan, Cairns, Nigel J, Beckett, Laurel, Householder, Erin, Fleischman, Debra, Arfanakis, Konstantinos, Morris, John, James, Olga, Goldstein, Bonnie, Martin, Kimberly S, McAdams-Ortiz, Catherine, Massoglia, Dino, Brawman-Mintzer, Olga, Martinez, Walter, Rosen, Howard, Behan, Kelly, Sorensen, Greg, Johnson, Sterling C, Fruehling, J Jay, Harding, Sandra, Peskind, Elaine R, Petrie, Eric C, Li, Gail, Yesavage, Jerome A, Furst, Ansgar J, Carrillo, Maria, Chao, Steven, Bocchio-Chiavetto, Luisella, Kuller, Lew, Raichle, Marc, Davies, Peter, Fillit, Howard, Hefti, Franz, Holtzman, Davie, Mesulam, M Marcel, Snyder, Peter, Rami, Lorena, Schwartz, Adam, Walter, Sarah, Hansson, Oskar, Balasubramanian, Archana B, Mason, Jennifer, Sim, Iris, Fox, Nick, Sperling, Reisa, Thompson, Paul, Schuff, Norbert, DeCArli, Charles, Vemuri, Prashanthi, Jones, David, Ward, Chad, Engelborghs, Sebastiaan, Mathis, Chet, Neurology, Clinical chemistry, NCA - neurodegeneration, and Clinical sciences

Subjects
Apolipoprotein E, Male, Pathology, Neurology, genetics [Alzheimer Disease], cerebrospinal fluid [Amyloid beta-Peptides], Neuropsychological Tests, Gastroenterology, Severity of Illness Index, etiology [Neurodegenerative Diseases], Alzheimer Disease/cerebrospinal fluid, Cohort Studies, ddc:616.89, Cognition, Cerebrospinal fluid, Genotype, Cognition/physiology, Aged, 80 and over, Medicine(all), physiology [Cognition], Age Factors, Neurodegenerative Diseases, Middle Aged, amyloid beta-protein (1-42), cerebrospinal fluid [Alzheimer Disease], Biomarker (medicine), Cohort studies, Female, Alzheimer's disease, Peptide Fragments/cerebrospinal fluid, Psychology, Adult, medicine.medical_specialty, tau Proteins, Neurodegenerative Diseases/etiology, physiopathology [Alzheimer Disease], Apolipoproteins E, Alzheimer Disease, Internal medicine, mental disorders, medicine, Dementia, Humans, ddc:610, cerebrospinal fluid [Peptide Fragments], Pathological, Aged, Analysis of Variance, Amyloid beta-Peptides, tau Proteins/cerebrospinal fluid, Original Articles, medicine.disease, Peptide Fragments, Amyloid beta-Peptides/cerebrospinal fluid, cerebrospinal fluid [tau Proteins], genetics [Apolipoproteins E], Neurology (clinical), Human medicine, aged, 80 and over, Apolipoproteins E/genetics
Abstract

In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimers disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 4084 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimers disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.

Published
2015

36. Comparison of Visual and Quantitative Florbetapir F 18 Positron Emission Tomography Analysis in Predicting Mild Cognitive Impairment Outcomes

Author

Schreiber, Stefanie, Landau, Susan M, Gamst, Anthony, Cellar, Janet S, Burns, Jeffrey M, Anderson, Heather S, Laubinger, Mary M, Bartzokis, George, Silverman, Daniel H S, Lu, Po H, Graff-Radford, Neill R, Parfitt, Francine, Johnson, Heather, Soares, Holly, Farlow, Martin, Herring, Scott, Hake, Ann M, van Dyck, Christopher H, MacAvoy, Martha G, Benincasa, Amanda L, Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Green, Robert C, Graham, Simon, Caldwell, Curtis, Hsiung, Ging-Yuek Robin, Feldman, Howard, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Montine, Tom, Wu, Chuang-Kuo, Johnson, Nancy, Mesulam, Marsel, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Scott, Johnson, Kathleen B, Behan, Kelly E, Sperling, Reisa A, Thomas, Ronald G, Rentz, Dorene M, Johnson, Keith A, Rosen, Allyson, Tinklenberg, Jared, Ashford, Wes, Sabbagh, Marwan, Connor, Donald, Jacobson, Sandra, Killiany, Ronald, Norbash, Alexander, Donohue, Michael, Nair, Anil, Obisesan, Thomas O, Jayam-Trouth, Annapurni, Wang, Paul, Lerner, Alan, Hudson, Leon, Ogrocki, Paula, DeCarli, Charles, Fletcher, Evan, Carmichael, Owen, Walter, Sarah, Kittur, Smita, Mirje, Seema, Borrie, Michael, Lee, T-Y, Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Potkin, Steven G, Preda, Adrian, Dale, Anders, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Hendin, Barry A, Scharre, Douglas W, Kataki, Maria, Bernstein, Matthew, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Gandy, Sam, Marenberg, Marjorie E, Rovner, Barry W, Pearlson, Godfrey, Blank, Karen, Anderson, Karen, Saykin, Andrew J, Felmlee, Joel, Santulli, Robert B, Englert, Jessica, Williamson, Jeff D, Sink, Kaycee M, Watkins, Franklin, Ott, Brian R, Cohen, Ronald, Salloway, Stephen, Malloy, Paul, Fero, Allison, Fox, Nick, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Mintzer, Jacobo, Thompson, Paul, Schuff, Norbert, Alexander, Gene, Bandy, Dan, Chen, Kewei, Morris, John, Lee, Virginia M-Y, Korecka, Magdalena, Schreiber, Frank, Crawford, Karen, Neu, Scott, Harvey, Danielle, Kornak, John, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Buckholtz, Neil, Kaye, Jeffrey, Jagust, William J, Dolen, Sara, Quinn, Joseph, Schneider, Lon, Pawluczyk, Sonia, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Petersen, Ronald, Initiative, Alzheimer's Disease Neuroimaging, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Morris, John C, Mintun, Mark A, Schneider, Stacy, Aisen, Paul, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Tang, Cheuk, Marzloff, George, deToledo-Morrell, Leyla, Shah, Raj C, Duara, Ranjan, Varon, Daniel, Jack, Clifford R, Roberts, Peggy, Albert, Marilyn S, Pedroso, Julia, Toroney, Jaimie, Rusinek, Henry, de Leon, Mony J, De Santi, Susan M, Doraiswamy, P Murali, Petrella, Jeffrey R, Aiello, Marilyn, Toga, Arthur W, Clark, Christopher M, Pham, Cassie, Nunez, Jessica, Smith, Charles D, Given, Curtis A, Hardy, Peter, Lopez, Oscar L, Oakley, MaryAnn, Simpson, Donna M, Ismail, M Saleem, Beckett, Laurel, Brand, Connie, BA, Jennifer Richard, Mulnard, Ruth A, Thai, Gaby, Mc-Adams-Ortiz, Catherine, Diaz-Arrastia, Ramon, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I, and Lah, James J

Subjects
Male, medicine.medical_specialty, diagnostic imaging [Cognitive Dysfunction], metabolism [Amyloid beta-Peptides], Context (language use), Standardized uptake value, Neuroimaging, Alzheimer Disease, Fluorodeoxyglucose F18, Predictive Value of Tests, medicine, Humans, Cognitive Dysfunction, therapy [Cognitive Dysfunction], ddc:610, Longitudinal Studies, Psychiatry, Aged, Aged, 80 and over, Amyloid beta-Peptides, medicine.diagnostic_test, therapy [Alzheimer Disease], business.industry, methods [Positron-Emission Tomography], diagnosis [Alzheimer Disease], complications [Alzheimer Disease], Middle Aged, medicine.disease, Inter-rater reliability, Treatment Outcome, Positron emission tomography, Positron-Emission Tomography, Predictive value of tests, Biomarker (medicine), Female, Neurology (clinical), Alzheimer's disease, Psychology, Nuclear medicine, business, analysis [Biomarkers], complications [Cognitive Dysfunction], Biomarkers
Abstract

Importance The applicability of β-amyloid peptide (Aβ) positron emission tomography (PET) as a biomarker in clinical settings to aid in selection of individuals at preclinical and prodromal Alzheimer disease (AD) will depend on the practicality of PET image analysis. In this context, visual-based Aβ PET assessment seems to be the most feasible approach. Objectives To determine the agreement between visual and quantitative Aβ PET analysis and to assess the ability of both techniques to predict conversion from mild cognitive impairment (MCI) to AD. Design, Setting, and Participants A longitudinal study was conducted among the Alzheimer’s Disease Neuroimaging Initiative (ADNI) sites in the United States and Canada during a 1.6-year mean follow-up period. The study was performed from September 21, 2010, to August 11, 2014; data analysis was conducted from September 21, 2014, to May 26, 2015. Participants included 401 individuals with MCI receiving care at a specialty clinic (219 [54.6%] men; mean [SD] age, 71.6 [7.5] years; 16.2 [2.7] years of education). All participants were studied with florbetapir F 18 [ 18 F] PET. The standardized uptake value ratio (SUVR) positivity threshold was 1.11, and one reader rated all images, with a subset of 125 scans rated by a second reader. Main Outcomes and Measures Sensitivity and specificity of positive and negative [ 18 F] florbetapir PET categorization, which was estimated with cerebrospinal fluid Aβ1-42 as the reference standard. Risk for conversion to AD was assessed using Cox proportional hazards regression models. Results The frequency of Aβ positivity was 48.9% (196 patients; visual analysis), 55.1% (221 patients; SUVR), and 64.8% (166 patients; cerebrospinal fluid), yielding substantial agreement between visual and SUVR data (κ = 0.74) and between all methods (Fleiss κ = 0.71). For approximately 10% of the 401 participants in whom visual and SUVR data disagreed, interrater reliability was moderate (κ = 0.44), but it was very high if visual and quantitative results agreed (κ = 0.92). Visual analysis had a lower sensitivity (79% vs 85%) but higher specificity (96% vs 90%), respectively, compared with SUVR. The conversion rate was 15.2% within a mean of 1.6 years, and a positive [ 18 F] florbetapir baseline scan was associated with a 6.91-fold (SUVR) or 11.38-fold (visual) greater hazard for AD conversion, which changed only modestly after covariate adjustment for apolipoprotein e4, concurrent fludeoxyglucose F 18 PET scan, and baseline cognitive status. Conclusions and Relevance Visual and SUVR Aβ PET analysis may be equivalently used to determine Aβ status for individuals with MCI participating in clinical trials, and both approaches add significant value for clinical course prognostication.

Published
2015

37. Applying automated MR-based diagnostic methods to the memory clinic: A prospective study

Author

Klöppel, Stefan, Peter, Jessica, Schroeter, Matthias L, Nho, Kwangsik, Weiner, Michael W, Thal, Lean, Khachaturian, Zaven, Thal, Leon, Buckholtz, Neil, Snyder, Peter J, Potter, William, Paul, Steven, Perneczky, Robert, Albert, Marylyn, Frank, Richard, Hsiao, John, Kaye, Jeffrey, Quinn, Joseph, Silbert, Lisa, Lind, Betty, Carter, Raina, Dolen, Sara, Häussermann, Peter, Schneider, Lon S, Pawluczyk, Sonia, Beccera, Mauricio, Teodoro, Liberty, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Fleisher, Adam, Heidebrink, Judith L, Lord, Joanne L, Vach, Werner, Petersen, Ronald, Mason, Sara S, Albers, Colleen S, Knopman, David, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Urbach, Horst, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Ances, Beau, Morris, John C, Carroll, Maria, Creech, Mary L, Franklin, Erin, Mintun, Mark A, Schneider, Stacy, Teipel, Stefan, Oliver, Angela, Marson, Daniel, Griffith, Randall, Clark, David, Geldmacher, David, Brockington, John, Roberson, Erik, Love, Marissa Natelson, Grossman, Hillel, Mitsis, Effie, Hüll, Michael, Shah, Raj C, deToledo-Morrell, Leyla, Duara, Ranjan, Varon, Daniel, Greig, Maria T, Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, D'Agostino, Daniel, Kielb, Stephanie, Abdulkadir, Ahmed, Galvin, James E, Cerbone, Brittany, Michel, Christina A, Pogorelec, Dana M, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P Murali, Petrella, Jeffrey R, Initiative, Alzheimer’s Disease Neuroimaging, Wong, Terence Z, Coleman, Edward, Arnold, Steven E, Karlawish, Jason H, Wolk, David, Clark, Christopher M, Smith, Charles D, Jicha, Greg, Hardy, Peter, Sinha, Partha, Oates, Elizabeth, Conrad, Gary, Lopez, Oscar L, Oakley, MaryAnn, Simpson, Donna M, Porsteinsson, Anton P, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Ismail, M Saleem, Ludl, Anna, Aisen, Paul, Brand, Connie, Mulnard, Ruth A, Thai, Gaby, Mc-Adams-Ortiz, Catherine, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Levey, Allan I, Lah, James J, Cellar, Janet S, Weiner, Michael, Burns, Jeffrey M, Swerdlow, Russell H, Brooks, William M, Apostolova, Liana, Tingus, Kathleen, Woo, Ellen, Silverman, Daniel H S, Lu, Po H, Bartzokis, George, Graff-Radford, Neill R, Parfitt, Francine, Kendall, Tracy, Johnson, Heather, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Brosch, Jared R, Herring, Scott, Hunt, Cynthia, van Dyck, Christopher H, Carson, Richard E, MacAvoy, Martha G, Varma, Pradeep, Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Ging-Yuek Robin, Jack, Clifford R, Feldman, Howard, Mudge, Benita, Assaly, Michele, Finger, Elizabeth, Pasternack, Stephen, Rachisky, Irina, Trost, Dick, Kertesz, Andrew, Bernick, Charles, Munic, Donna, Jagust, William, Mesulam, Marek-Marsel, Lipowski, Kristine, Weintraub, Sandra, Bonakdarpour, Borna, Kerwin, Diana, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Villena, Teresa, Turner, Raymond Scott, Trojanowki, John Q, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Marshall, Gad, Yesavage, Jerome, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan N, Toga, Arthur W, Belden, Christine M, Jacobson, Sandra A, Sirrel, Sherye A, Kowall, Neil, Killiany, Ronald, Budson, Andrew E, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Beckett, Laurel, Allard, Joanne, Lerner, Alan, Ogrocki, Paula, Tatsuoka, Curtis, Fatica, Parianne, Fletcher, Evan, Maillard, Pauline, Olichney, John, DeCarli, Charles, Carmichael, Owen, Green, Robert C, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Potkin, Steven G, Preda, Adrian, Nguyen, Dana, Pilatus, Anne, Saykin, Andrew J, Tariot, Pierre, Burke, Anna, Trncic, Nadira, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W, Kataki, Maria, Morris, John, Adeli, Anahita, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Neuropsychiatry, Olin, Pearlson, Godfrey D, Blank, Karen, Anderson, Karen, Flashman, Laura A, Seltzer, Marc, Shaw, Leslie M, Hynes, Mary L, Santulli, Robert B, Sink, Kaycee M, Gordineer, Leslie, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Perry, David, Mintzer, Jacobo, Spicer, Kenneth, Bachman, David, Finger, Elizabether, Sorensen, Greg, Pasternak, Stephen, Rachinsky, Irina, Rogers, John, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K, Ponto, Laura L Boles, Carrillo, Maria, Shim, Hyungsub, Smith, Karen Ekstam, Relkin, Norman, Chaing, Gloria, Lin, Michael, Ravdin, Lisa, Smith, Amanda, Raj, Balebail Ashok, Fargher, Kristin, Kuller, Lew, Harvey, Danielle, Raichle, Marc, Neylan, Thomas, Grafman, Jordan, Montine, Tom, Thomas, Ronald G, Donohue, Michael, Gessert, Devon, Sather, Tamie, Davis, Melissa, Morrison, Rosemary, Jiminez, Gus, Hayes, Jacqueline, Finley, Shannon, Davies, Peter, Bernstein, Matthew, Borowski, Bret, Gunter, Jeff, Senjem, Matt, Kantarci, Kejal, Koeppe, Robert A, Foster, Norm, Maier, Sabrina, Fillit, Howard, Reiman, Eric M, Chen, Kewei, Landau, Susan, Cairns, Nigel J, Householder, Erin, Lee, Virginia, Korecka, Magdalena, Hefti, Franz, Figurski, Michal, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Faber, Kelley, Kim, Sungeun, Holtzman, Davie, Friedl, Karl, Mesulam, M Marcel, Fleischman, Debra, Arfanakis, Konstantinos, James, Olga, Goldstein, Bonnie, Martin, Kimberly S, McAdams-Ortiz, Catherine, Massoglia, Dino, Brawman-Mintzer, Olga, Snyder, Peter, Martinez, Walter, Rosen, Howard, Behan, Kelly, Schwartz, Adam, Johnson, Sterling C, Fruehling, J Jay, Harding, Sandra, Peskind, Elaine R, Petrie, Eric C, Li, Gail, Yesavage, Jerome A, Taylor, Joy L, Furst, Ansgar J, Chao, Steven, Mader, Irina, Walter, Sarah, Balasubramanian, Archana B, Mason, Jennifer, Sim, Iris, Heimbach, Bernhard, Fox, Nick, Thompson, Paul, Schuff, Norbert, DeCArli, Charles, Frings, Lars, Vemuri, Prashanthi, Jones, David, Ward, Chad, Egger, Karl, Mathis, Chet, Taylor-Reinwald, Lisa, and Dukart, Juergen

Subjects
Male, Aging, Support Vector Machine, 030218 nuclear medicine & medical imaging, pathology [Alzheimer Disease], pathology [Aging], diagnosis [Frontotemporal Dementia], methods [Magnetic Resonance Imaging], 0302 clinical medicine, pathology [Brain], pathology [White Matter], Prospective Studies, Medical diagnosis, Prospective cohort study, General Neuroscience, diagnosis [Alzheimer Disease], Brain, General Medicine, Middle Aged, Magnetic Resonance Imaging, White Matter, Psychiatry and Mental health, Clinical Psychology, machine learning, Frontotemporal Dementia, Disease Progression, Female, Alzheimer's disease, Psychology, diagnosis [Lewy Body Disease], methods [Imaging, Three-Dimensional], Research Article, Frontotemporal dementia, Lewy Body Disease, medicine.medical_specialty, Diagnosis, Differential, Dementia diagnostics, 03 medical and health sciences, Imaging, Three-Dimensional, Physical medicine and rehabilitation, Alzheimer Disease, mental disorders, medicine, Humans, Dementia, ddc:610, Psychiatry, Aged, Lewy body, Memory clinic, pathology [Lewy Body Disease], medicine.disease, Hyperintensity, pathology [Frontotemporal Dementia], Linear Models, prognosis, Geriatrics and Gerontology, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Several studies have demonstrated that fully automated pattern recognition methods applied to structural magnetic resonance imaging (MRI) aid in the diagnosis of dementia, but these conclusions are based on highly preselected samples that significantly differ from that seen in a dementia clinic. At a single dementia clinic, we evaluated the ability of a linear support vector machine trained with completely unrelated data to differentiate between Alzheimer’s disease (AD), frontotemporal dementia (FTD), Lewy body dementia, and healthy aging based on 3D-T1 weighted MRI data sets. Furthermore, we predicted progression to AD in subjects with mild cognitive impairment (MCI) at baseline and automatically quantified white matter hyperintensities from FLAIR-images. Separating additionally recruited healthy elderly from those with dementia was accurate with an area under the curve (AUC) of 0.97 (according to Fig. 4). Multi-class separation of patients with either AD or FTD from other included groups was good on the training set (AUC > 0.9) but substantially less accurate (AUC = 0.76 for AD, AUC = 0.78 for FTD) on 134 cases from the local clinic. Longitudinal data from 28 cases with MCI at baseline and appropriate follow-up data were available. The computer tool discriminated progressive from stable MCI with AUC = 0.73, compared to AUC = 0.80 for the training set. A relatively low accuracy by clinicians (AUC = 0.81) illustrates the difficulties of predicting conversion in this heterogeneous cohort. This first application of a MRI-based pattern recognition method to a routine sample demonstrates feasibility, but also illustrates that automated multi-class differential diagnoses have to be the focus of future methodological developments and application studies

Published
2015

38. Basal forebrain atrophy and cortical amyloid deposition in nondemented elderly subjects

Author

Grothe, Michel J, Ewers, Michael, Bernick, Charles, Black, Sandra, Borrie, Michael, Brewer, James, Burns, Jeffrey, Capote, Horatio, Chertkow, Howard, deToledo-Morrell, Leyla, Doody, Rachelle, Doraiswamy, P Murali, Krause, Bernd, Duara, Ranjan, Farlow, Martin, Finger, Elizabeth, Fleisher, Adam, Galvin, James, Graff-Radford, Neill, Grossman, Hillel, Heidebrink, Judith, Hsiung, Robin, Johnson, Sterling, Heinsen, Helmut, Kaye, Jeffrey, Kerwin, Diana, Kowall, Neil, Lerner, Alan, Levey, Allan, Lopez, Oscar, Marshall, Gad, Marson, Daniel, Mintzer, Jacobo, Mulnard, Ruth, Teipel, Stefan J, Obisesan, Thomas, Olichney, John, Ott, Brian, Petersen, Ronald, Pomara, Nunzio, Porsteinsson, Anton, Potkin, Steven, Relkin, Norman, Reynolds, Brigid, Rosen, Howard, Initiative, Alzheimer's Disease Neuroimaging, Sabbagh, Marwan, Sadowsky, Carl, Salloway, Stephen, Santulli, Robert, Scharre, Douglas, Schneider, Lon, Schultz, Susan, Sink, Kaycee, Smith, Charles, Smith, Amanda, Albert, Marilyn, Stern, Yaakov, van Dyck, Chrstopher, Womack, Kyle, Yesavage, Jerome, Zimmerman, Earl, Ances, Beau, Apostolova, Liana, and Arnold, Steven

Subjects
Male, Apolipoprotein E, Aging, Pathology, diagnostic imaging [Basal Forebrain], pathology [Cognitive Dysfunction], Epidemiology, diagnostic imaging [Cognitive Dysfunction], metabolism [Hippocampus], Hippocampus, metabolism [Cognitive Dysfunction], pathology [Aging], 0302 clinical medicine, diagnostic imaging [Cerebral Cortex], Image Processing, Computer-Assisted, Medicine, Cerebral Cortex, diagnostic imaging [Hippocampus], 0303 health sciences, Basal forebrain, Health Policy, Neurodegeneration, Organ Size, Magnetic Resonance Imaging, Psychiatry and Mental health, metabolism [Basal Forebrain], Female, Amyloid, medicine.medical_specialty, Basal Forebrain, pathology [Basal Forebrain], Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Atrophy, Developmental Neuroscience, Neuroimaging, mental disorders, Humans, Cognitive Dysfunction, ddc:610, metabolism [Aging], Cholinergic neuron, Aged, metabolism [Amyloid], 030304 developmental biology, business.industry, metabolism [Cerebral Cortex], medicine.disease, pathology [Hippocampus], Positron-Emission Tomography, Cholinergic, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery
Abstract

Background Both neurodegeneration of the cholinergic basal forebrain (BF) and deposition of β-amyloid are early events in the course of Alzheimer's disease (AD). Associations between increased amyloid pathology and cholinergic atrophy have been described in autopsy studies. Methods We used structural MRI and AV45-PET amyloid imaging data of 225 cognitively normal or mildly impaired elderly subjects from the Alzheimer's Disease Neuroimaging Initiative to assess in vivo associations between BF atrophy and cortical amyloid deposition. Associations were examined using region-of-interest (ROI) and voxel-based approaches with reference to cytoarchitectonic mappings of the cholinergic BF nuclei. Results ROI- and voxel-based approaches yielded complementary evidence for an association between BF volume and cortical amyloid deposition in presymptomatic and predementia stages of AD, irrespective of age, gender, and APOE genotype. Conclusions The observed correlations between BF atrophy and cortical amyloid load likely reflect associations between cholinergic degeneration and amyloid pathology as reported in neuropathologic examination studies.

Published
2014

39. Exploring Self-neglect in Older Adults: Preliminary Findings of the Self-Neglect Severity Scale and Next Steps

Author

Kelly, P. Adam, Dyer, Carmel B., Pavlik, Valory, Doody, Rachelle, and Jogerst, Gerald

Subjects
Humans, Elder Abuse, Geriatric Assessment, Severity of Illness Index, Article, Aged
Abstract

Despite the public health implications of self-neglect, no tool exists for characterizing this condition. Self-neglecters often have no caregivers or surrogates to interview regarding the neglect and are often too cognitively impaired to provide valid self-reports. In response to this need, researchers from the Consortium for Research in Elder Self-neglect of Texas (CREST) collaborated with other experts in the field of elder self-neglect to design the Self-neglect Severity Scale (SSS). The SSS assesses three domains of self-neglect (hygiene, functioning, and environment) and relies on observational ratings assigned by trained observers. After pilot testing and revision, the SSS was field tested in the homes of subjects who had been reported to and substantiated by Texas Adult Protective Services (APS) as self-neglecting and compared with results of subjects recruited from a local geriatric clinic who were reported to APS but had no history of self-neglect. The first field test demonstrated that the SSS could distinguish elderly self-neglecters from community dwellers who do not self-neglect. The SSS exhibited adequate scale reliability (Cronbach alpha) and correlation with case status. Interrater reliability also appeared adequate, although sensitivity and specificity fell below the conventional acceptable range. Future methods are proposed for refining the SSS to improve its use as the benchmark for identifying elder self-neglect.

Published
2008

40. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author

Sims, Rebecca, Van Der Lee, Sven J, Naj, Adam C, Bellenguez, Céline, Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W, Boland, Anne, Raybould, Rachel, Bis, Joshua C, Martin, Eden R, Grenier-Boley, Benjamin, Heilmann-Heimbach, Stefanie, Chouraki, Vincent, Kuzma, Amanda B, Sleegers, Kristel, Vronskaya, Maria, Ruiz, Agustin, Graham, Robert R, Olaso, Robert, Hoffmann, Per, Grove, Megan L, Vardarajan, Badri N, Hiltunen, Mikko, Nöthen, Markus M, White, Charles C, Hamilton-Nelson, Kara L, Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W, Dulary, Cécile, Herms, Stefan, Smith, Albert V, Funk, Cory C, Derbois, Céline, Forstner, Andreas J, Ahmad, Shahzad, Li, Hongdong, Bacq, Delphine, Harold, Denise, Satizabal, Claudia L, Valladares, Otto, Squassina, Alessio, Thomas, Rhodri, Brody, Jennifer A, Qu, Liming, Sánchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J, Zhao, Yi, Garcia, Florentino Sanchez, Denning, Nicola, Fornage, Myriam, Malamon, John, Naranjo, Maria Candida Deniz, Majounie, Elisa, Mosley, Thomas H, Dombroski, Beth, Wallon, David, Lupton, Michelle K, Dupuis, Josée, Whitehead, Patrice, Fratiglioni, Laura, Medway, Christopher, Jian, Xueqiu, Mukherjee, Shubhabrata, Keller, Lina, Brown, Kristelle, Lin, Honghuang, Cantwell, Laura B, Panza, Francesco, McGuinness, Bernadette, Moreno-Grau, Sonia, Burgess, Jeremy D, Solfrizzi, Vincenzo, Proitsi, Petra, Adams, Hieab H, Allen, Mariet, Seripa, Davide, Pastor, Pau, Cupples, L Adrienne, Price, Nathan D, Hannequin, Didier, Frank-García, Ana, Levy, Daniel, Chakrabarty, Paramita, Caffarra, Paolo, Giegling, Ina, Beiser, Alexa S, Giedraitis, Vilmantas, Hampel, Harald, Garcia, Melissa E, Wang, Xue, Lannfelt, Lars, Mecocci, Patrizia, Eiriksdottir, Gudny, Crane, Paul K, Pasquier, Florence, Boccardi, Virginia, Henández, Isabel, Barber, Robert C, Scherer, Martin, Tarraga, Lluis, Adams, Perrie M, Leber, Markus, Chen, Yuning, Albert, Marilyn S, Riedel-Heller, Steffi, Emilsson, Valur, Beekly, Duane, Braae, Anne, Schmidt, Reinhold, Blacker, Deborah, Masullo, Carlo, Schmidt, Helena, Doody, Rachelle S, Spalletta, Gianfranco, Longstreth, WT, Fairchild, Thomas J, Bossù, Paola, Lopez, Oscar L, Frosch, Matthew P, Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M, Jessen, Frank, Li, Shuo, Kamboh, M Ilyas, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J, Corcoran, Chris, Dunstan, Melanie, Braddel, Amy, Thomas, Charlene, Meggy, Alun, Marshall, Rachel, Gerrish, Amy, Chapman, Jade, Aguilar, Miquel, Taylor, Sarah, Hill, Matt, Fairén, Mònica Díez, Hodges, Angela, Vellas, Bruno, Soininen, Hilkka, Kloszewska, Iwona, Daniilidou, Makrina, Uphill, James, Patel, Yogen, Hughes, Joseph T, Lord, Jenny, Turton, James, Hartmann, Annette M, Cecchetti, Roberta, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Caltagirone, Carlo, Orfei, Maria Donata, Ciaramella, Antonio, Pichler, Sabrina, Mayhaus, Manuel, Gu, Wei, Lleó, Alberto, Fortea, Juan, Blesa, Rafael, Barber, Imelda S, Brookes, Keeley, Cupidi, Chiara, Maletta, Raffaele Giovanni, Carrell, David, Sorbi, Sandro, Moebus, Susanne, Urbano, Maria, Pilotto, Alberto, Kornhuber, Johannes, Bosco, Paolo, Todd, Stephen, Craig, David, Johnston, Janet, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Fox, Nick C, Hardy, John, ARUK Consortium, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barnes, Lisa L, Barral, Sandra, Beach, Thomas G, Becker, James T, Bigio, Eileen H, Bird, Thomas D, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Burns, Jeffrey M, Buxbaum, Joseph D, Cairns, Nigel J, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carrasquillo, Minerva M, Carroll, Steven L, Diaz, Carolina Ceballos, Chui, Helena C, Clark, David G, Cribbs, David H, Crocco, Elizabeth A, DeCarli, Charles, Dick, Malcolm, Duara, Ranjan, Evans, Denis A, Faber, Kelley M, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Gilbert, John R, Graff-Radford, Neill R, Green, Robert C, Growdon, John H, Hamilton, Ronald L, Harrell, Lindy E, Honig, Lawrence S, Huentelman, Matthew J, Hulette, Christine M, Hyman, Bradley T, Jarvik, Gail P, Abner, Erin, Jin, Lee-Way, Jun, Gyungah, Karydas, Anna, Kaye, Jeffrey A, Kim, Ronald, Kowall, Neil W, Kramer, Joel H, LaFerla, Frank M, Lah, James J, Leverenz, James B, Levey, Allan I, Li, Ge, Lieberman, Andrew P, Lunetta, Kathryn L, Lyketsos, Constantine G, Marson, Daniel C, Martiniuk, Frank, Mash, Deborah C, Masliah, Eliezer, McCormick, Wayne C, McCurry, Susan M, McDavid, Andrew N, McKee, Ann C, Mesulam, Marsel, Miller, Bruce L, Miller, Carol A, Miller, Joshua W, Morris, John C, Murrell, Jill R, Myers, Amanda J, O'Bryant, Sid, Olichney, John M, Pankratz, Vernon S, Parisi, Joseph E, Paulson, Henry L, Perry, William, Peskind, Elaine, Pierce, Aimee, Poon, Wayne W, Potter, Huntington, Quinn, Joseph F, Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reitz, Christiane, Ringman, John M, Roberson, Erik D, Rogaeva, Ekaterina, Rosen, Howard J, Rosenberg, Roger N, Sager, Mark A, Saykin, Andrew J, Schneider, Julie A, Schneider, Lon S, Seeley, William W, Smith, Amanda G, Sonnen, Joshua A, Spina, Salvatore, Stern, Robert A, Swerdlow, Russell H, Tanzi, Rudolph E, Thornton-Wells, Tricia A, Trojanowski, John Q, Troncoso, Juan C, Van Deerlin, Vivianna M, Van Eldik, Linda J, Vinters, Harry V, Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A, Wilhelmsen, Kirk C, Williamson, Jennifer, Wingo, Thomas S, Woltjer, Randall L, Wright, Clinton B, Yu, Chang-En, Yu, Lei, Garzia, Fabienne, Golamaully, Feroze, Septier, Gislain, Engelborghs, Sebastien, Vandenberghe, Rik, De Deyn, Peter P, Fernadez, Carmen Muñoz, Benito, Yoland Aladro, Thonberg, Hakan, Forsell, Charlotte, Lilius, Lena, Kinhult-Stählbom, Anne, Kilander, Lena, Brundin, RoseMarie, Concari, Letizia, Helisalmi, Seppo, Koivisto, Anne Maria, Haapasalo, Annakaisa, Dermecourt, Vincent, Fievet, Nathalie, Hanon, Olivier, Dufouil, Carole, Brice, Alexis, Ritchie, Karen, Dubois, Bruno, Himali, Jayanadra J, Keene, C Dirk, Tschanz, JoAnn, Fitzpatrick, Annette L, Kukull, Walter A, Norton, Maria, Aspelund, Thor, Larson, Eric B, Munger, Ron, Rotter, Jerome I, Lipton, Richard B, Bullido, María J, Hofman, Albert, Montine, Thomas J, Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C, Alvarez, Victoria, Rivadeneira, Fernando, Reiman, Eric M, Gallo, Maura, O'Donnell, Christopher J, Reisch, Joan S, Bruni, Amalia Cecilia, Royall, Donald R, Dichgans, Martin, Sano, Mary, Galimberti, Daniela, St George-Hyslop, Peter, Scarpini, Elio, Tsuang, Debby W, Mancuso, Michelangelo, Bonuccelli, Ubaldo, Winslow, Ashley R, Daniele, Antonio, Wu, Chuang-Kuo, GERAD/PERADES, CHARGE, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol, Rubinsztein, David C, Bras, Jose, Guerreiro, Rita, Al-Chalabi, Ammar, Shaw, Christopher E, Collinge, John, Mann, David, Tsolaki, Magda, Clarimón, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C, Owen, Michael J, Behrens, Timothy W, Mead, Simon, Goate, Alison M, Uitterlinden, Andre G, Holmes, Clive, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A, Powell, John, Golde, Todd E, Graff, Caroline, De Jager, Philip L, Morgan, Kevin, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M, Passmore, Peter, Younkin, Steven G, Berr, Claudine, Gudnason, Vilmundur, Rujescu, Dan, Dickson, Dennis W, Dartigues, Jean-François, DeStefano, Anita L, Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A, Van Broeckhoven, Christine, Ikram, M Arfan, Jones, Lesley, Haines, Jonathan L, Tzourio, Christophe, Launer, Lenore J, Escott-Price, Valentina, Mayeux, Richard, Deleuze, Jean-François, Amin, Najaf, Holmans, Peter A, Pericak-Vance, Margaret A, Amouyel, Philippe, Van Duijn, Cornelia M, Ramirez, Alfredo, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha, Williams, Julie, and Schellenberg, Gerard D

Subjects
Membrane Glycoproteins, Genotype, Sequence Homology, Amino Acid, Phospholipase C gamma, Gene Expression Profiling, Polymorphism, Single Nucleotide, Immunity, Innate, Linkage Disequilibrium, 3. Good health, Gene Frequency, Alzheimer Disease, Case-Control Studies, Odds Ratio, Humans, Exome, Genetic Predisposition to Disease, Amino Acid Sequence, Microglia, Protein Interaction Maps, Receptors, Immunologic, Adaptor Proteins, Signal Transducing
Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

41. Amyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer's disease

Author

Pichet Binette, Alexa, Franzmeier, Nicolai, Mattsson-Carlgren, Niklas, Smith, Ruben, Stomrud, Erik, Ossenkoppele, Rik, Hansson, Oskar, Spotorno, Nicola, Ewers, Michael, Brendel, Matthias, Biel, Davina, Initiative, Alzheimer’s Disease Neuroimaging, Strandberg, Olof, Janelidze, Shorena, Palmqvist, Sebastian, Morris, John C, Carroll, Maria, Leon, Sue, Householder, Erin, Mintun, Mark A, Schneider, Stacy, OliverNG, Angela, Griffith, Randall, Clark, David, Geldmacher, David, Brockington, John, Roberson, Erik, Grossman, Hillel, Mitsis, Effie, deToledo-Morrell, Leyla, Shah, Raj C, Duara, Ranjan, Varon, Daniel, Greig, Maria T, Roberts, Peggy, Albert, Marilyn, Onyike, Chiadi, D'Agostino, Daniel, Kielb, Stephanie, Galvin, James E, Pogorelec, Dana M, Cerbone, Brittany, Michel, Christina A, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P Murali, Petrella, Jeffrey R, Wong, Terence Z, Arnold, Steven E, Karlawish, Jason H, Wolk, David, Smith, Charles D, Jicha, Greg, Hardy, Peter, Sinha, Partha, Oates, Elizabeth, Conrad, Gary, Lopez, Oscar L, Oakley, MaryAnn, Simpson, Donna M, Porsteinsson, Anton P, Goldstein, Bonnie S, Martin, Kim, Weiner, Michael, Makino, Kelly M, Ismail, M Saleem, Brand, Connie, Mulnard, Ruth A, Thai, Gaby, Mc Adams Ortiz, Catherine, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Arrastia, Ramon Diaz, Aisen, Paul, King, Richard, Weiner, Myron, Cook, Kristen Martin, DeVous, Michael, Levey, Allan I, Lah, James J, Cellar, Janet S, Burns, Jeffrey M, Anderson, Heather S, Swerdlow, Russell H, Petersen, Ronald, Apostolova, Liana, Tingus, Kathleen, Woo, Ellen, Silverman, Daniel H S, Lu, Po H, Bartzokis, George, Graff Radford, Neill R, ParfittH, Francine, Kendall, Tracy, Johnson, Heather, Jack, Clifford R, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Herring, Scott, Hunt, Cynthia, van Dyck, Christopher H, Carson, Richard E, MacAvoy, Martha G, Chertkow, Howard, Bergman, Howard, Jagust, William, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Ging Yuek Robin, Feldman, Howard, Mudge, Benita, Past, Michele Assaly, Kertesz, Andrew, Rogers, John, Trojanowki, John Q, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek Marsel, Lipowski, Kristine, Wu, Chuang Kuo, Johnson, Nancy, Sadowsky, Carl, Martinez, Walter, Toga, Arthur W, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Marshall, Gad, Frey, Meghan, Yesavage, Jerome, Taylor, Joy L, Beckett, Laurel, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan N, Belden, Christine M, Jacobson, Sandra A, Sirrel, Sherye A, Kowall, Neil, Killiany, Ronald, Budson, Andrew E, Green, Robert C, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Allard, Joanne, Lerner, Alan, Ogrocki, Paula, Hudson, Leon, Fletcher, Evan, Carmichael, Owen, Saykin, Andrew J, Olichney, John, DeCarli, Charles, Kittur, Smita, Borrie, Michael, Lee, T. Y., Bartha, Rob, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Potkin, Steven G, Morris, John, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Fleisher, Adam, Reeder, Stephanie, Bates, Vernice, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W, Kataki, Maria, Shaw, Leslie M, Adeli, Anahita, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Anderson, Karen, Santulli, Robert B, Kitzmiller, Tamar J, Schwartz, Eben S, Liu, Enchi, SinkS, Kaycee M, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Montine, Tom, Rosen, Howard J, Miller, Bruce L, Mintzer, Jacobo, Spicer, Kenneth, Bachman, David, Finger, Elizabether, Pasternak, Stephen, Rachinsky, Irina, Thomas, Ronald G, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K, Ponto, Laura L Boles, Shim, Hyungsub, Smith, Karen Elizabeth, Relkin, Norman, Chaing, Gloria, Donohue, Michael, Raudin, Lisa, Smith, Amanda, Fargher, Kristin, Raj, Balebail Ashok, Walter, Sarah, Gessert, Devon, Sather, Tamie, Jiminez, Gus, Harvey, Danielle, Bernstein, Matthew, Fox, Nick, Thompson, Paul, Schuff, Norbert, DeCArli, Charles, Borowski, Bret, Gunter, Jeff, Senjem, Matt, Vemuri, Prashanthi, Jones, David, Kantarci, Kejal, Ward, Chad, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Landau, Susan, Cairns, Nigel J, Reinwald, Lisa Taylor, Lee, Virginia, Korecka, Magdalena, Figurski, Michal, Crawford, Karen, Neu, Scott, Foroud, Tatiana M, Potkin, Steven, Shen, Li, Kelley, Faber, Kim, Sungeun, Nho, Kwangsik, Kachaturian, Zaven, Frank, Richard, Snyder, Peter J, Molchan, Susan, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Carter, Raina, Dolen, Sara, Schneider, Lon S, Pawluczyk, Sonia, Beccera, Mauricio, Teodoro, Liberty, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Heidebrink, Judith L, Lord, Joanne L, Mason, Sara S, Albers, Colleen S, Knopman, David, Johnson, Kris, Doody, Rachelle S, Meyer, Javier Villanueva, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Stern, Yaakov, Honig, Lawrence S, Bell, Karen L, Ances, Beau, Neurology, and Amsterdam Neuroscience - Neurodegeneration

Subjects
Multidisciplinary, Amyloid beta-Peptides, methods [Positron-Emission Tomography], General Physics and Astronomy, tau Proteins, Neuroimaging, General Chemistry, Amyloidosis, General Biochemistry, Genetics and Molecular Biology, Cross-Sectional Studies, Alzheimer Disease, Positron-Emission Tomography, Humans, Cognitive Dysfunction, ddc:500, Biomarkers
Abstract

For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, we need to better understand the pathophysiological cascade of Aβ- and tau-related processes. Therefore, we set out to investigate how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimer’s disease (AD) continuum. Using human cross-sectional and longitudinal neuroimaging and cognitive assessment data, we show that in early stages of AD, increased concentration of soluble CSF p-tau is strongly associated with accumulation of insoluble tau aggregates across the brain, and CSF p-tau levels mediate the effect of Aβ on tau aggregation. Further, higher soluble p-tau concentrations are mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations is associated with cognitive decline, which is mediated by faster increase of tau aggregates. In contrast, in AD dementia, when Aβ fibrils and soluble p-tau levels have plateaued, cognitive decline is related to the accumulation rate of insoluble tau aggregates. Our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD, before widespread insoluble tau aggregates.

Published
2022

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