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1. Association of common genetic variants with brain microbleeds: A Genome-wide Association Study

Author: Knol, Maria J, Lu, Dongwei, Traylor, Matthew, Adams, Hieab HH, Romero, José Rafael J, Smith, Albert V, Fornage, Myriam, Hofer, Edith, Liu, Junfeng, Hostettler, Isabel C, Luciano, Michelle, Trompet, Stella, Giese, Anne-Katrin, Hilal, Saima, van den Akker, Erik B, Vojinovic, Dina, Li, Shuo, Sigurdsson, Sigurdur, van der Lee, Sven J, Jack, Clifford R, Wilson, Duncan, Yilmaz, Pinar, Satizabal, Claudia L, Liewald, David CM, van der Grond, Jeroen, Chen, Christopher, Saba, Yasaman, van der Lugt, Aad, Bastin, Mark E, Windham, B Gwen, Cheng, Ching Yu, Pirpamer, Lukas, Kantarci, Kejal, Himali, Jayandra J, Yang, Qiong, Morris, Zoe, Beiser, Alexa S, Tozer, Daniel J, Vernooij, Meike W, Amin, Najaf, Beekman, Marian, Koh, Jia Yu, Stott, David J, Houlden, Henry, Schmidt, Reinhold, Gottesman, Rebecca F, MacKinnon, Andrew D, DeCarli, Charles, Gudnason, Vilmundur, Deary, Ian J, van Duijn, Cornelia M, Slagboom, P Eline, Wong, Tien Yin, Rost, Natalia S, Jukema, J Wouter, Mosley, Thomas H, Werring, David J, Schmidt, Helena, Wardlaw, Joanna M, Ikram, M Arfan, Seshadri, Sudha, Launer, Lenore J, Markus, Hugh S, and Initiative, for the Alzheimer’s Disease Neuroimaging
Subjects: Stroke, Human Genome, Neurosciences, Brain Disorders, Genetics, Prevention, Aetiology, 2.1 Biological and endogenous factors, Aged, Aged, 80 and over, Alleles, Apolipoprotein E2, Apolipoprotein E4, Apolipoproteins E, Case-Control Studies, Cerebral Hemorrhage, Cerebral Small Vessel Diseases, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk, White Matter, Alzheimer's Disease Neuroimaging Initiative, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract: ObjectiveTo identify common genetic variants associated with the presence of brain microbleeds (BMBs).MethodsWe performed genome-wide association studies in 11 population-based cohort studies and 3 case-control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel. BMBs were rated on susceptibility-weighted or T2*-weighted gradient echo MRI sequences, and further classified as lobar or mixed (including strictly deep and infratentorial, possibly with lobar BMB). In a subset, we assessed the effects of APOE ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMBs.ResultsBMBs were detected in 3,556 of the 25,862 participants, of which 2,179 were strictly lobar and 1,293 mixed. One locus in the APOE region reached genome-wide significance for its association with BMB (lead single nucleotide polymorphism rs769449; odds ratio [OR]any BMB [95% confidence interval (CI)] 1.33 [1.21-1.45]; p = 2.5 × 10-10). APOE ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19-1.50]; p = 1.0 × 10-6) but not with mixed BMB counts (OR [95% CI] 1.04 [0.86-1.25]; p = 0.68). APOE ε2 alleles did not show associations with BMB counts. Variants previously related to deep intracerebral hemorrhage and lacunar stroke, and a risk score of cerebral white matter hyperintensity variants, were associated with BMB.ConclusionsGenetic variants in the APOE region are associated with the presence of BMB, most likely due to the APOE ε4 allele count related to a higher number of strictly lobar BMBs. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.
Published: 2020

2. Cross-sectional Associations of β-Amyloid, Tau, and Cerebrovascular Biomarkers With Neurodegeneration in Probable Dementia With Lewy Bodies

Author: Ferreira, Daniel, Przybelski, Scott A, Lesnick, Timothy G, Schwarz, Christopher G, Diaz-Galvan, Patricia, Graff-Radford, Jonathan, Senjem, Matthew L, Fields, Julie A, Knopman, David S, Jones, David T., Savica, Rodolfo, Ferman, Tanis J., Graff-Radford, Neill, Lowe, Val J., Jack, Clifford R., Petersen, Ronald C, Westman, Eric, Boeve, Brad F, and Kantarci, Kejal
Published: 2022
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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. A phase 3 trial of IV immunoglobulin for Alzheimer disease

Author: Relkin, Norman R, Thomas, Ronald G, Rissman, Robert A, Brewer, James B, Rafii, Michael S, van Dyck, Christopher H, Jack, Clifford R, Sano, Mary, Knopman, David S, Raman, Rema, Szabo, Paul, Gelmont, David M, Fritsch, Sandor, Aisen, Paul S, Ahern, Geoffrey, Yaari, Roy, Sabbagh, Marwan, Mirza, Nadeem, Bernick, Charles, Bell, Karen, Turner, R Scott, Obisesan, Thomas, Chertkow, Howard, Zabar, Yuval, Knopman, David, Mintzer, Jacobo, Grossman, Hillel, Sadowski, Martin, Wu, Chuang-Kuo, Quinn, Joseph, Borrie, Michael, Petrie, William, Ott, Brian, Keegan, Andrew, Grossberg, George, Bari, Moammed, Cohen, Sharon, Richter, Ralph, Lerner, Alan, Mulnard, Ruth, Potkin, Steven, Rafii, Michael, Brockington, John, Hsiung, Robin, Schultz, Susan, Burns, Jeffrey, Jicha, Gregory, Burke, William, Arnold, Steven, Porsteinsson, Anton, Smith, Amanda, Schneider, Lon, Quiceno, Mary, Zamrini, Edward, Asthana, Sanjay, Burgat, FT, Duara, Ranjan, and van Dyck, Christopher
Subjects: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Aging, Clinical Trials and Supportive Activities, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Neurodegenerative, Clinical Research, Dementia, Acquired Cognitive Impairment, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Neurological, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Apolipoprotein E4, Biomarkers, Brain, Canada, Cognition, Double-Blind Method, Female, Humans, Immunoglobulins, Intravenous, Male, Middle Aged, Nootropic Agents, Peptide Fragments, Treatment Failure, United States, Alzheimer's Disease Cooperative Study, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract: ObjectiveWe tested biweekly infusions of IV immunoglobulin (IVIg) as a possible treatment for mild to moderate Alzheimer disease (AD) dementia.MethodsIn a phase 3, double-blind, placebo-controlled trial, we randomly assigned 390 participants with mild to moderate AD to receive placebo (low-dose albumin) or IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL) administered IV at doses of 0.2 or 0.4 g/kg every 2 weeks for 18 months. The primary cognitive outcome was change from baseline to 18 months on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale; the primary functional outcome was 18-month change on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. Safety and tolerability data, as well as serial MRIs and plasma samples, were collected throughout the study from all enrolled participants.ResultsNo beneficial effects were observed in the dual primary outcome measures for the 2 IVIg doses tested. Significant decreases in plasma Aβ42 (but not Aβ40) levels were observed in IVIg-treated participants. Analysis of safety data showed no difference between IVIg and placebo in terms of the rate of occurrence of amyloid-related imaging abnormalities (brain edema or microhemorrhage). IVIg-treated participants had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo.ConclusionsParticipants with mild to moderate AD showed good tolerability of treatment with low-dose human IVIg for 18 months but did not show beneficial effects on cognition or function relative to participants who received placebo.Clinicaltrialsgov identifierNCT00818662.Classification of evidenceThis study provides Class II evidence that IVIg infusions performed every 2 weeks do not improve cognition or function at 18 months in patients with mild to moderate AD.
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. A/T/N

Author: Jack, Clifford R, Bennett, David A, Blennow, Kaj, Carrillo, Maria C, Feldman, Howard H, Frisoni, Giovanni B, Hampel, Harald, Jagust, William J, Johnson, Keith A, Knopman, David S, Petersen, Ronald C, Scheltens, Philip, Sperling, Reisa A, and Dubois, Bruno
Subjects: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Biomedical Imaging, Neurodegenerative, Alzheimer's Disease, Aging, Dementia, Acquired Cognitive Impairment, Clinical Research, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, 4.2 Evaluation of markers and technologies, Neurological, Alzheimer Disease, Amyloid beta-Peptides, Biomarkers, Brain, Humans, Nerve Degeneration, Neuroimaging, Peptide Fragments, tau Proteins, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract: Biomarkers have become an essential component of Alzheimer disease (AD) research and because of the pervasiveness of AD pathology in the elderly, the same biomarkers are used in cognitive aging research. A number of current issues suggest that an unbiased descriptive classification scheme for these biomarkers would be useful. We propose the "A/T/N" system in which 7 major AD biomarkers are divided into 3 binary categories based on the nature of the pathophysiology that each measures. "A" refers to the value of a β-amyloid biomarker (amyloid PET or CSF Aβ42); "T," the value of a tau biomarker (CSF phospho tau, or tau PET); and "N," biomarkers of neurodegeneration or neuronal injury ([(18)F]-fluorodeoxyglucose-PET, structural MRI, or CSF total tau). Each biomarker category is rated as positive or negative. An individual score might appear as A+/T+/N-, or A+/T-/N-, etc. The A/T/N system includes the new modality tau PET. It is agnostic to the temporal ordering of mechanisms underlying AD pathogenesis. It includes all individuals in any population regardless of the mix of biomarker findings and therefore is suited to population studies of cognitive aging. It does not specify disease labels and thus is not a diagnostic classification system. It is a descriptive system for categorizing multidomain biomarker findings at the individual person level in a format that is easy to understand and use. Given the present lack of consensus among AD specialists on terminology across the clinically normal to dementia spectrum, a biomarker classification scheme will have broadest acceptance if it is independent from any one clinically defined diagnostic scheme.
Published: 2016

7. A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers.

Author: Jack, Clifford R, Bennett, David A, Blennow, Kaj, Carrillo, Maria C, Feldman, Howard H, Frisoni, Giovanni B, Hampel, Harald, Jagust, William J, Johnson, Keith A, Knopman, David S, Petersen, Ronald C, Scheltens, Philip, Sperling, Reisa A, and Dubois, Bruno
Subjects: Brain, Humans, Alzheimer Disease, Nerve Degeneration, Peptide Fragments, tau Proteins, Amyloid beta-Peptides, Neuroimaging, Biomarkers, Neurology & Neurosurgery, Clinical Sciences, Neurosciences, Cognitive Sciences
Abstract: Biomarkers have become an essential component of Alzheimer disease (AD) research and because of the pervasiveness of AD pathology in the elderly, the same biomarkers are used in cognitive aging research. A number of current issues suggest that an unbiased descriptive classification scheme for these biomarkers would be useful. We propose the "A/T/N" system in which 7 major AD biomarkers are divided into 3 binary categories based on the nature of the pathophysiology that each measures. "A" refers to the value of a β-amyloid biomarker (amyloid PET or CSF Aβ42); "T," the value of a tau biomarker (CSF phospho tau, or tau PET); and "N," biomarkers of neurodegeneration or neuronal injury ([(18)F]-fluorodeoxyglucose-PET, structural MRI, or CSF total tau). Each biomarker category is rated as positive or negative. An individual score might appear as A+/T+/N-, or A+/T-/N-, etc. The A/T/N system includes the new modality tau PET. It is agnostic to the temporal ordering of mechanisms underlying AD pathogenesis. It includes all individuals in any population regardless of the mix of biomarker findings and therefore is suited to population studies of cognitive aging. It does not specify disease labels and thus is not a diagnostic classification system. It is a descriptive system for categorizing multidomain biomarker findings at the individual person level in a format that is easy to understand and use. Given the present lack of consensus among AD specialists on terminology across the clinically normal to dementia spectrum, a biomarker classification scheme will have broadest acceptance if it is independent from any one clinically defined diagnostic scheme.
Published: 2016

8. 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

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. Eligibility for Anti-Amyloid Treatment in a Population-Based Study of Cognitive Aging

Author: Pittock, Rioghna R., primary, Aakre, Jeremiah A., additional, Castillo, Anna M., additional, Ramanan, Vijay K., additional, Kremers, Walter K., additional, Jack, Clifford R., additional, Vemuri, Prashanthi, additional, Lowe, Val J., additional, Knopman, David S., additional, Petersen, Ronald C., additional, Graff-Radford, Jonathan, additional, and Vassilaki, Maria, additional
Published: 2023
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12. 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

13. 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

14. 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

15. 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

16. White Matter Degeneration Pathways Associated With Tau Deposition in Alzheimer Disease

Author: Jianqiao Tian, Sheelakumari Raghavan, Robert I. Reid, Scott A. Przybelski, Timothy G. Lesnick, Robel K. Gebre, Jonathan Graff-Radford, Christopher G. Schwarz, Val J. Lowe, Kejal Kantarci, David S. Knopman, Ronald C. Petersen, Clifford R. Jack, and Prashanthi Vemuri
Subjects: Neurology (clinical)
Published: 2023

17. Cerebral Amyloid Angiopathy Pathology and Its Association With Amyloid-β PET Signal

Author: McCarter, Stuart J., Lesnick, Timothy G., Lowe, Val, Mielke, Michelle M., Constantopoulos, Eleni, Rabinstein, Alejandro A., Przybelski, Scott A., Botha, Hugo, Jones, David T., Ramanan, Vijay K., Jack, Clifford R., Petersen, Ronald C., Knopman, David, Boeve, Bradley F., Murray, Melissa E., Dickson, Dennis W., Vemuri, Prashanthi, Kantarci, Kejal, Reichard, R. Ross, and Graff-Radford, Jonathan
Published: 2021
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18. Association of Olfaction and Microstructural Integrity of Brain Tissue in Community-Dwelling Adults

Author: Shrestha, Srishti, primary, Zhu, Xiaoqian, additional, Sullivan, Kevin J., additional, Blackshear, Chad, additional, Deal, Jennifer A., additional, Sharrett, A. Richey, additional, Kamath, Vidyulata, additional, Schneider, Andrea L.C., additional, Jack, Clifford R., additional, Huang, Juebin, additional, Palta, Priya, additional, Reid, Robert I., additional, Knopman, David S., additional, Gottesman, Rebecca F., additional, Chen, Honglei, additional, Windham, B. Gwen, additional, Griswold, Michael E., additional, and Mosley, Thomas H., additional
Published: 2023
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19. Midlife Systemic Inflammatory Markers Are Associated With Late-Life Brain Volume

Author: Walker, Keenan A., primary, Hoogeveen, Ron C., additional, Folsom, Aaron R., additional, Ballantyne, Christie M., additional, Knopman, David S., additional, Windham, B. Gwen, additional, Jack, Clifford R., additional, and Gottesman, Rebecca F., additional
Published: 2023
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20. Association of Plasma Biomarkers of Alzheimer Disease With Cognition and Medical Comorbidities in a Biracial Cohort

Author: Ramanan, Vijay K., primary, Graff-Radford, Jonathan, additional, Syrjanen, Jeremy, additional, Shir, Dror, additional, Algeciras-Schimnich, Alicia, additional, Lucas, John, additional, Martens, Yuka A., additional, Carrasquillo, Minerva M., additional, Day, Gregory S., additional, Ertekin-Taner, Nilüfer, additional, Lachner, Christian, additional, Willis, Floyd B., additional, Knopman, David S., additional, Jack, Clifford R., additional, Petersen, Ronald C., additional, Vemuri, Prashanthi, additional, Graff-Radford, Neill, additional, and Mielke, Michelle M., additional
Published: 2023
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21. Mild Cognitive Impairment at Risk for Lewy Body Dementia

Author: Chen, Qin, Lowe, Val J., Boeve, Bradley F., Przybelski, Scott A., Miyagawa, Toji, Senjem, Matthew L., Jack, Clifford R., Jr, Lesnick, Timothy G., Kremers, Walter K., Fields, Julie A., Min, Hoon-Ki, Schwarz, Christopher G., Gunter, Jeffrey L., Graff-Radford, Jonathan, Savica, Rodolfo, Knopman, David S., Jones, David, Ferman, Tanis J., Graff-Radford, Neill R., Petersen, Ronald C., and Kantarci, Kejal
Published: 2021
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22. A prospective analysis of leisure-time physical activity in mid-life and beyond and brain damage on MRI in older adults

Author: Palta, Priya, Sharrett, A. Richey, Gabriel, Kelley Pettee, Gottesman, Rebecca F., Folsom, Aaron R., Power, Melinda C., Evenson, Kelly R., Jack, Clifford R., Jr, Knopman, David S., Mosley, Thomas H., and Heiss, Gerardo
Published: 2021
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23. MRI and pathology of REM sleep behavior disorder in dementia with Lewy bodies

Author: Murray, Melissa E, Ferman, Tanis J, Boeve, Bradley F, Przybelski, Scott A, Lesnick, Timothy G, Liesinger, Amanda M, Senjem, Matthew L, Gunter, Jeffrey L, Preboske, Gregory M, Lowe, Val J, Vemuri, Prashanthi, Dugger, Brittany N, Knopman, David S, Smith, Glenn E, Parisi, Joseph E, Silber, Michael H, Graff-Radford, Neill R, Petersen, Ronald C, Jack, Clifford R, Dickson, Dennis W, and Kantarci, Kejal
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Dementia, Lewy Body Dementia, Acquired Cognitive Impairment, Neurodegenerative, Neurosciences, Sleep Research, Brain Disorders, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Amyloid beta-Peptides, Autopsy, Brain, Cohort Studies, Female, Humans, Image Processing, Computer-Assisted, Lewy Body Disease, Likelihood Functions, Magnetic Resonance Imaging, Male, REM Sleep Behavior Disorder, Retrospective Studies, Severity of Illness Index, alpha-Synuclein, tau Proteins, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract: ObjectiveTo determine structural MRI and digital microscopic characteristics of REM sleep behavior disorder in individuals with low-, intermediate-, and high-likelihood dementia with Lewy bodies (DLB) at autopsy.MethodsPatients with autopsy-confirmed low-, intermediate-, and high-likelihood DLB, according to the probability statement recommended by the third report of the DLB Consortium, and antemortem MRI, were identified (n = 75). The clinical history was assessed for presence (n = 35) and absence (n = 40) of probable REM sleep behavior disorder (pRBD), and patients' antemortem MRIs were compared using voxel-based morphometry. Pathologic burdens of phospho-tau, β-amyloid, and α-synuclein were measured in regions associated with early neuropathologic involvement, the hippocampus and amygdala.ResultspRBD was present in 21 patients (60%) with high-likelihood, 12 patients (34%) with intermediate-likelihood, and 2 patients (6%) with low-likelihood DLB. Patients with pRBD were younger, more likely to be male (p ≤ 0.001), and had a more frequent neuropathologic diagnosis of diffuse (neocortical) Lewy body disease. In the hippocampus and amygdala, phospho-tau and β-amyloid burden were lower in patients with pRBD compared with those without pRBD (p < 0.01). α-Synuclein burden did not differ in the hippocampus, but trended in the amygdala. Patients without pRBD had greater atrophy of temporoparietal cortices, hippocampus, and amygdala (p < 0.001) than those with pRBD; atrophy of the hippocampus (p = 0.005) and amygdala (p = 0.02) were associated with greater phospho-tau burdens in these regions.ConclusionPresence of pRBD is associated with a higher likelihood of DLB and less severe Alzheimer-related pathology in the medial temporal lobes, whereas absence of pRBD is characterized by Alzheimer-like atrophy patterns on MRI and increased phospho-tau burden.
Published: 2013

24. Witnessed apneas are associated with elevated tau-PET levels in cognitively unimpaired elderly

Author: Carvalho, Diego Z., St. Louis, Erik K., Schwarz, Christopher G., Lowe, Val J., Boeve, Bradley F., Przybelski, Scott A., Reddy, Ashritha, Mielke, Michelle M., Knopman, David S., Petersen, Ronald C., Jack, Clifford R., Jr, and Vemuri, Prashanthi
Published: 2020
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25. Imaging markers for Alzheimer disease

Author: Frisoni, Giovanni B, Bocchetta, Martina, Chételat, Gael, Rabinovici, Gil D, de Leon, Mony J, Kaye, Jeffrey, Reiman, Eric M, Scheltens, Philip, Barkhof, Frederik, Black, Sandra E, Brooks, David J, Carrillo, Maria C, Fox, Nick C, Herholz, Karl, Nordberg, Agneta, Jack, Clifford R, Jagust, William J, Johnson, Keith A, Rowe, Christopher C, Sperling, Reisa A, Thies, William, Wahlund, Lars-Olof, Weiner, Michael W, Pasqualetti, Patrizio, and DeCarli, Charles
Subjects: Acquired Cognitive Impairment, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, Dementia, Aging, Alzheimer's Disease, Biomedical Imaging, Brain Disorders, Neurodegenerative, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, 4.2 Evaluation of markers and technologies, Alzheimer Disease, Biomarkers, Fluorodeoxyglucose F18, Humans, Magnetic Resonance Imaging, Radiography, Tomography, Emission-Computed, Single-Photon, ISTAART's NeuroImaging Professional Interest Area, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract: Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, ¹⁸F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured ("metric": visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR-), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR- between 0.25 and 0.08, whereas prognostic LR+ and LR- were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR- from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR-. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR-. Within markers, the largest proportion of diagnostic LR+ and LR- variability was within ¹⁸F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.
Published: 2013

26. 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

27. Predicting missing biomarker data in a longitudinal study of Alzheimer disease

Author: Lo, Raymond Y., Jagust, William J., Aisen, Paul, Jack, Clifford R., Toga, Arthur W., Beckett, Laurel, Gamst, Anthony, Soares, Holly, C. Green, Robert, 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, Chen, Kewei, Morris, John, Lee, Virginia M.-Y., Korecka, Magdalena, Crawford, Karen, Neu, Scott, Harvey, Danielle, Kornak, John, Saykin, Andrew J., Foroud, Tatiana M., Potkin, Steven, Shen, Li, Buckholtz, Neil, Kaye, Jeffrey, Dolen, Sara, Quinn, Joseph, Schneider, Lon, Pawluczyk, Sonia, Spann, Bryan M., Brewer, James, Vanderswag, Helen, Heidebrink, Judith L., Lord, Joanne L., Petersen, Ronald, 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, Marson, Daniel, Griffith, Randall, Clark, David, Grossman, Hillel, Tang, Cheuk, Marzloff, George, Toledo-Morrell, Leylade, Shah, Raj C., Duara, Ranjan, Varon, Daniel, 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, 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, Brand, Connie, Richard, Jennifer, 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., Burns, Jeffrey M., Anderson, Heather S., and Laubinger, Mary M.
Abstract: Objective:To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD).Methods:The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI.Results:CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ42. Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD.Conclusion:The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.
Published: 2012

28. β-Amyloid Load on PET Along the Continuum of Dementia With Lewy Bodies

Author: Diaz-Galvan, Patricia, primary, Przybelski, Scott A, additional, Lesnick, Timothy G, additional, Schwarz, Christopher G, additional, Senjem, Matthew L, additional, Gunter, Jeffrey L, additional, Jack, Clifford R., additional, Paul Min, Hoon-Ki, additional, Jain, Manoj, additional, Miyagawa, Toji, additional, Forsberg, Leah K, additional, Fields, Julie A, additional, Savica, Rodolfo, additional, Graff-Radford, Jonathan, additional, Jones, David T., additional, Botha, Hugo, additional, St Louis, Erik K., additional, Knopman, David S, additional, Ramanan, Vijay K, additional, Ross, Owen, additional, Graff-Radford, Neill, additional, Day, Gregory S, additional, Dickson, Dennis W., additional, Ferman, Tanis J., additional, Petersen, Ronald C, additional, Lowe, Val J., additional, Boeve, Brad F, additional, and Kantarci, Kejal, additional
Published: 2023
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29. Association of Polysomnographic Sleep Parameters With Neuroimaging Biomarkers of Cerebrovascular Disease in Older Adults With Sleep Apnea

Author: Carvalho, Diego Z., primary, McCarter, Stuart J., additional, St Louis, Erik K., additional, Przybelski, Scott A, additional, Johnson Sparrman, Kohl L., additional, Somers, Virend K., additional, Boeve, Brad F, additional, Petersen, Ronald C, additional, Jack, Clifford R., additional, Graff-Radford, Jonathan, additional, and Vemuri, Prashanthi, additional
Published: 2023
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30. Longitudinal anatomic, functional, and molecular characterization of Pick disease phenotypes

Author: Whitwell, Jennifer L., Tosakulwong, Nirubol, Schwarz, Christopher C., Senjem, Matthew L., Spychalla, Anthony J., Duffy, Joseph R., Graff-Radford, Jon, Machulda, Mary M., Boeve, Bradley F., Knopman, David S., Petersen, Ronald C., Lowe, Val J., Jack, Clifford R., Jr, Dickson, Dennis W., Parisi, Joseph E., and Josephs, Keith A.
Published: 2020
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31. β-Amyloid and tau biomarkers and clinical phenotype in dementia with Lewy bodies

Author: Ferreira, Daniel, Przybelski, Scott A., Lesnick, Timothy G., Lemstra, Afina W., Londos, Elisabet, Blanc, Frederic, Nedelska, Zuzana, Schwarz, Christopher G., Graff-Radford, Jonathan, Senjem, Matthew L., Fields, Julie A., Knopman, David S., Savica, Rodolfo, Ferman, Tanis J., Graff-Radford, Neill R., Lowe, Val J., Jack, Clifford R., Jr, Petersen, Ronald C., Mollenhauer, Brit, Garcia-Ptacek, Sara, Abdelnour, Carla, Hort, Jakub, Bonanni, Laura, Oppedal, Ketil, Kramberger, Milica G., Boeve, Bradley F., Aarsland, Dag, Westman, Eric, and Kantarci, Kejal
Published: 2020
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32. Type 2 diabetes mellitus, brain atrophy, and cognitive decline

Author: Moran, Chris, Beare, Richard, Wang, Wei, Callisaya, Michele, Srikanth, Velandai, Weiner, Michael, Aisen, Paul, 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, Green, Robert C., Montine, Tom, Petersen, Ronald, Aisen, Paul, Gamst, Anthony, Thomas, Ronald G., Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Beckett, Laurel, Harvey, Danielle, Gamst, Anthony, Donohue, Michael, Kornak, John, Jack, Clifford R., Jr., Dale, Anders, Bernstein, Matthew, Felmlee, Joel, Fox, Nick, Thompson, Paul, Schuff, Norbert, Alexander, Gene, DeCarli, Charles, Jagust, William, Bandy, Dan, 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, 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, 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., Petersen, Ronald, 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, Varon, Daniel, 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., 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., Porsteinsson, Anton P., Goldstein, Bonnie S., Martin, Kim, Makino, Kelly M., Ismail, M. Saleem, Brand, Connie, Mulnard, Ruth A., Thai, Gaby, McAdams-Ortiz, Catherine, Womack, Kyle, 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., 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, 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, Robin Hsiung, Ging-Yuek, Feldman, Howard, Mudge, Benita, 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, Reynolds, Brigid, Sperling, Reisa A., Johnson, Keith A., Marshall, Gad, Frey, Meghan, Yesavage, Jerome, Taylor, Joy L., Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan, Belden, Christine, Jacobson, Sandra, 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, 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, Scharre, Douglas W., Kataki, Maria, Zimmerman, Earl A., Celmins, Dzintra, Brown, Alice D., Pearlson, Godfrey D., Blank, Karen, Anderson, Karen, 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, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J., Miller, Bruce L., Mintzer, Jacobo, Longmire, Crystal Flynn, Spicer, Kenneth, Finger, Elizabether, Rachinsky, Irina, Rogers, John, Kertesz, Andrew, 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, and Raj, Balebail Ashok
Published: 2019
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33. CSF biomarkers in Olmsted County: Evidence of 2 subclasses and associations with demographics

Author: Van Harten, Argonde C., Wiste, Heather J., Weigand, Stephen D., Mielke, Michelle M., Kremers, Walter K., Eichenlaub, Udo, Batrla-Utermann, Richard, Dyer, Roy B., Algeciras-Schimnich, Alicia, Knopman, David S., Jack, Clifford R., Jr, and Petersen, Ronald C.
Published: 2020
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34. Utility of FDG-PET in diagnosis of Alzheimer-related TDP-43 proteinopathy

Author: Buciuc, Marina, Botha, Hugo, Murray, Melissa E., Schwarz, Christopher G., Senjem, Matthew L., Jones, David T., Knopman, David S., Boeve, Bradley F., Petersen, Ronald C., Jack, Clifford R., Jr, Petrucelli, Leonard, Parisi, Joseph E., Dickson, Dennis W., Lowe, Val, Whitwell, Jennifer L., and Josephs, Keith A.
Published: 2020
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35. Better stress coping associated with lower tau in amyloid-positive cognitively unimpaired older adults

Author: Arenaza-Urquijo, Eider M., Przybelski, Scott A., Machulda, Mary M., Knopman, David S., Lowe, Val J., Mielke, Michelle M., Reddy, Ashritha L., Geda, Yonas E., Jack, Clifford R., Jr, Petersen, Ronald C., and Vemuri, Prashanthi
Published: 2020
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36. Linear vs volume measures of ventricle size: Relation to present and future gait and cognition

Author: Crook, Julia E., Gunter, Jeffrey L., Ball, Colleen T., Jones, David T., Graff-Radford, Jonathan, Knopman, David S., Boeve, Bradley F., Petersen, Ronald C., Jack, Clifford R., and Graff-Radford, Neill R.
Published: 2020
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37. β-Amyloid PET and neuropathology in dementia with Lewy bodies

Author: Kantarci, Kejal, Lowe, Val J., Chen, Qin, Przybelski, Scott A., Lesnick, Timothy G., Schwarz, Christopher G., Senjem, Matthew L., Gunter, Jeffrey L., Jack, Clifford R., Jr, Graff-Radford, Jonathan, Jones, David T., Knopman, David S., Graff-Radford, Neill, Ferman, Tanis J., Parisi, Joseph E., Dickson, Dennis W., Petersen, Ronald C., Boeve, Bradley F., and Murray, Melissa E.
Published: 2020
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38. Cerebral microbleed incidence, relationship to amyloid burden: The Mayo Clinic Study of Aging

Author: Graff-Radford, Jonathan, Lesnick, Timothy, Rabinstein, Alejandro A., Gunter, Jeff, Aakre, Jeremiah, Przybelski, Scott A., Spychalla, Anthony J., Huston, John, III, Brown, Robert D., Jr, Mielke, Michelle M., Lowe, Val J., Knopman, David S., Petersen, Ronald C., Jack, Clifford R., Jr, Vemuri, Prashanthi, Kremers, Walter, and Kantarci, Kejal
Published: 2020
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39. β-Amyloid Load on PET Along the Continuum of Dementia With Lewy Bodies

Author: Patricia Diaz-Galvan, Scott A Przybelski, Timothy G Lesnick, Christopher G Schwarz, Matthew L Senjem, Jeffrey L Gunter, Clifford R. Jack, Hoon-Ki Paul Min, Manoj Jain, Toji Miyagawa, Leah K Forsberg, Julie A Fields, Rodolfo Savica, Jonathan Graff-Radford, David T. Jones, Hugo Botha, Erik K. St Louis, David S Knopman, Vijay K Ramanan, Owen Ross, Neill Graff-Radford, Gregory S Day, Dennis W. Dickson, Tanis J. Ferman, Ronald C Petersen, Val J. Lowe, Brad F Boeve, and Kejal Kantarci
Subjects: Neurology (clinical)
Abstract: Background:Amyloid-β plaques can co-occur with Lewy-related pathology in patients with dementia with Lewy bodies (DLB), but amyloid-β load at prodromal stages of DLB still needs to be elucidated. We investigated amyloid-β load on PET throughout the DLB continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD) to a stage of mild cognitive impairment with Lewy bodies (MCI-LB), and finally DLB.Methods:We performed a cross-sectional study in patients with a diagnosis of iRBD, MCI-LB, or DLB from the Mayo Clinic Alzheimer’s Disease Research Center. Amyloid-β levels were measured by Pittsburgh compound B (PiB) PET and global cortical standard uptake value ratio (SUVr) was calculated. Global cortical PiB SUVr values from each clinical group were compared to each other and to cognitively unimpaired individuals (CU; n=100) balanced on age and sex using ANCOVA. We used multiple linear regression testing for interaction to study the influences of sex andAPOEε4 status on PiB SUVr along the DLB continuum.Results:Of the 162 patients, 16 had iRBD, 64 had MCI-LB, and 82 had DLB. Compared to CU, global cortical PiB SUVr was higher in DLB (p <0.001) and MCI-LB (p=0.012). The DLB group included the highest proportion of amyloid-β positive patients (60%), followed by MCI-LB (41%), iRBD (25%), and finally CU (19%). Global cortical PiB SUVr was higher inAPOEε4 carriers compared toAPOEε4 non-carriers in MCI-LB (pp=0.049). Women had higher PiB SUVr with older age compared to men across the DLB continuum (βeta estimate=0.014,p=0.02).Conclusion:In this cross-sectional study, levels of amyloid-β load was higher further along the DLB continuum. Whereas amyloid-β levels were comparable to cognitively unimpaired individuals in iRBD, a significant elevation in amyloid-β levels was observed in the pre-dementia stage of MCI-LB and in DLB. Specifically,APOEε4 carriers had higher amyloid-β levels thanAPOEε4 non-carriers and women tended to have higher amyloid-β levels than men as they got older. These findings have important implications in targeting patients within the DLB continuum for clinical trials of disease-modifying therapies.
Published: 2023

40. Association of Polysomnographic Sleep Parameters With Neuroimaging Biomarkers of Cerebrovascular Disease in Older Adults With Sleep Apnea

Author: Diego Z. Carvalho, Stuart J. McCarter, Erik K. St Louis, Scott A Przybelski, Kohl L. Johnson Sparrman, Virend K. Somers, Brad F Boeve, Ronald C Petersen, Clifford R. Jack, Jonathan Graff-Radford, and Prashanthi Vemuri
Subjects: Neurology (clinical)
Abstract: Background and Objectives:Our objective was to determine whether polysomnographic (PSG) sleep parameters are associated with neuroimaging biomarkers of cerebrovascular disease (CVD) related to white matter integrity in older adults with obstructive sleep apnea (OSA).Methods:From the population-based Mayo Clinic Study of Aging, we identified participants without dementia who underwent at least one brain MRI and PSG. We quantified two CVD biomarkers: white matter hyperintensities (WMH) from FLAIR-MRI and fractional anisotropy of the genu of the corpus callosum (genu FA) from diffusion MRI. For this cross-sectional analysis, we fit linear models to assess associations between PSG parameters (N1%, N3% [slow-wave sleep], mean oxyhemoglobin saturation, and log of apnea-hypopnea index [AHI]) and CVD biomarkers (log of WMH and log of genu FA), respectively, while adjusting for age (at MRI), sex, APOε4 status, composite cardiovascular and metabolic conditions (CMC) score, REM stage percentage, sleep duration, and interval between MRI and PSG.Results:We included 140 participants with FLAIR-MRI (of which 103 had additional diffusion MRI). The mean ± s.d. age was 72.7 ± 9.6 years old at MRI with nearly 60% being men. The absolute median (IQR) interval between MRI and PSG was 1.74 (0.9 – 3.2) years. 90.7% were cognitively unimpaired during both assessments. For every 10-point decrease in N3%, there was a 0.058 (95% CI 0.006 to 0.111, p=0.030) increase in the log of WMH and 0.006 decrease (95% CI -0.012 to -0.0002, p=0.042) in the log of genu FA. After matching for age, sex, and N3%, participants with severe OSA had higher WMH (median [IQR] 0.007 [0.005 to 0.015] vs. 0.006 [0.003 to 0.009], p=0.042) and lower genu FA (median [IQR] 0.57 [0.55 to 0.63] vs. 0.63 [0.58 to 0.65], p=0.007), when compared with those with mild/moderate OSA.Discussion:We found that reduced slow-wave sleep and severe OSA were associated with higher burden of white matter abnormalities in predominantly cognitively unimpaired older adults, which may contribute to greater risk of cognitive impairment, dementia, and stroke. Our study supports the association between sleep depth/fragmentation and intermittent hypoxia and CVD biomarkers. Longitudinal studies are required to assess causation.
Published: 2023

41. Cerebrospinal fluid dynamics disorders: Relationship to Alzheimer biomarkers and cognition

Author: Graff-Radford, Jonathan, Gunter, Jeffrey L., Jones, David T., Przybelski, Scott A., Schwarz, Christopher G., Huston, John, III, Lowe, Val, Elder, Benjamin D., Machulda, Mary M., Gunter, Nathaniel B., Petersen, Ronald C., Kantarci, Kejal, Vemuri, Prashanthi, Mielke, Michelle M., Knopman, David S., Graff-Radford, Neill R., and Jack, Clifford R., Jr
Published: 2019
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42. A brief history of “Alzheimer disease”: Multiple meanings separated by a common name

Author: Knopman, David S., Petersen, Ronald C., and Jack, Clifford R., Jr
Published: 2019
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43. Association between white matter hyperintensities, cortical volumes, and late-onset epilepsy

Author: Johnson, Emily L., Krauss, Gregory L., Lee, Alexandra K., Schneider, Andrea L.C., Kucharska-Newton, Anna M., Huang, Juebin, Jack, Clifford R., Jr, and Gottesman, Rebecca F.
Published: 2019
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44. The influence of β-amyloid on [18F]AV-1451 in semantic variant of primary progressive aphasia

Author: Whitwell, Jennifer L., Martin, Peter R., Duffy, Joseph R., Clark, Heather M., Machulda, Mary M., Schwarz, Christopher G., Weigand, Stephen D., Sintini, Irene, Senjem, Matthew L., Ertekin-Taner, Nilufer, Botha, Hugo, Utianski, Rene L., Graff-Radford, Jonathan, Jones, David T., Boeve, Bradley F., Knopman, David S., Petersen, Ronald C., Jack, Clifford R., Jr, Lowe, Val J., and Josephs, Keith A.
Published: 2019
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45. Cerebral microbleeds: Prevalence and relationship to amyloid burden

Author: Graff-Radford, Jonathan, Botha, Hugo, Rabinstein, Alejandro A., Gunter, Jeffrey L., Przybelski, Scott A., Lesnick, Timothy, Huston, John, III, Flemming, Kelly D., Preboske, Gregory M., Senjem, Matthew L., Brown, Robert D., Jr, Mielke, Michelle M., Roberts, Rosebud O., Lowe, Val J., Knopman, David S., Petersen, Ronald C., Kremers, Walter, Vemuri, Prashanthi, Jack, Clifford R., Jr, and Kantarci, Kejal
Published: 2018
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46. White Matter Degeneration Pathways Associated With Tau Deposition in Alzheimer Disease

Author: Tian, Jianqiao, primary, Raghavan Pillai, Sheela Kumari, additional, Reid, Robert I., additional, Przybelski, Scott A, additional, Lesnick, Timothy G, additional, Gebre, Robel K., additional, Graff-Radford, Jonathan, additional, Schwarz, Christopher G, additional, Lowe, Val J., additional, Kantarci, Kejal, additional, Knopman, David S, additional, Petersen, Ronald C, additional, Jack, Clifford R., additional, and Vemuri, Prashanthi, additional
Published: 2023
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47. Cross-sectional associations of tau-PET signal with cognition in cognitively unimpaired adults

Author: Lowe, Val J., Bruinsma, Tyler J., Wiste, Heather J., Min, Hoon-Ki, Weigand, Stephen D., Fang, Ping, Senjem, Matthew L., Therneau, Terry M., Boeve, Bradley F., Josephs, Keith A., Pandey, Mukesh K., Murray, Melissa E., Kantarci, Kejal, Jones, David T., Vemuri, Prashanthi, Graff-Radford, Jonathan, Schwarz, Christopher G., Machulda, Mary M., Mielke, Michelle M., Roberts, Rosebud O., Knopman, David S., Petersen, Ronald C., and Jack, Clifford R., Jr
Published: 2019
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48. Sex Differences in the Association Between Midlife Cardiovascular Conditions or Risk Factors With Midlife Cognitive Decline

Author: Nan Huo, Prashanthi Vemuri, Jonathan Graff-Radford, Jeremy Syrjanen, Mary Machulda, David S. Knopman, Clifford R. Jack, Ronald Petersen, and Michelle M. Mielke
Subjects: Male, Sex Characteristics, Cognition, Risk Factors, Humans, Cognitive Dysfunction, Female, Neurology (clinical), Neuropsychological Tests, Research Article
Abstract: Background and ObjectivesThe prevalence of midlife cardiovascular conditions and risk factors is higher in men than women. Associations between midlife cardiovascular conditions or risk factors and midlife cognitive decline have been reported, but few studies have assessed sex differences in these associations.MethodsWe included 1,857 participants enrolled in the population-based Mayo Clinic Study of Aging who were 50 to 69 years of age at baseline. Participants were evaluated every 15 months by a coordinator, including neurologic evaluation and neuropsychological testing. The neuropsychological testing used 9 tests to calculate global cognitive and domain-specific (memory, language, executive function, and visuospatial skills) z scores. Nurse abstractors reviewed participant medical records to determine the presence of cardiovascular conditions (coronary heart disease, arrhythmias, congestive heart failure) and risk factors (hypertension, diabetes, dyslipidemia, obesity, ever smoking). Linear mixed-effect models evaluated the association between baseline cardiovascular conditions or risk factors and global and domain-specific cognitive decline. Multivariable models adjusted for demographics, APOE genotype, depression, and other medical conditions. Interactions between sex and each cardiovascular condition or risk factor were examined, and results were stratified by sex.ResultsOverall, 1,465 (78.9%) participants had at least 1 cardiovascular condition or risk factor; the proportion of men was higher than women (767 [83.4%] vs 698 [74.5%], p < 0.0001). Cross-sectionally, coronary heart disease and ever smoking were associated with a lower visuospatial z score in multivariable models. Longitudinally, several cardiovascular conditions and risk factors were associated with declines in global and domain-specific z scores but not visuospatial z scores. Most cardiovascular conditions were more strongly associated with cognition among women: coronary heart disease and other cardiovascular conditions were associated with global cognitive decline only in women (all p < 0.05). In addition, diabetes, dyslipidemia, and coronary heart disease were associated with language z score decline only in women (all p < 0.05). However, congestive heart failure was associated with language z score decline only in men (all p < 0.05).DiscussionMidlife cardiovascular conditions and risk factors are associated with midlife cognitive decline. Moreover, specific cardiovascular conditions and risk factors have stronger associations with cognitive decline in midlife for women than men despite the higher prevalence of those conditions in men.
Published: 2022

49. Cerebral Amyloid Angiopathy Pathology and Its Association With Amyloid-β PET Signal

Author: Michelle M. Mielke, Eleni Constantopoulos, Val J. Lowe, Alejandro A. Rabinstein, David T.W. Jones, Dennis W. Dickson, Stuart J. McCarter, Scott A. Przybelski, Ronald C. Petersen, Hugo Botha, Clifford R. Jack, Jonathan Graff-Radford, Timothy G. Lesnick, Prashanthi Vemuri, Melissa E. Murray, R. Ross Reichard, Bradley F. Boeve, Kejal Kantarci, Vijay K. Ramanan, and David S. Knopman
Subjects: Male, Pathology, medicine.medical_specialty, Amyloid, Amyloid β, Amyloid pet, Plaque, Amyloid, Standardized uptake value, Autopsy, chemistry.chemical_compound, Alzheimer Disease, mental disorders, medicine, Humans, Aged, Amyloid beta-Peptides, Aniline Compounds, business.industry, medicine.disease, Cerebral Amyloid Angiopathy, chemistry, Positron-Emission Tomography, Female, Neurology (clinical), Cerebral amyloid angiopathy, Alzheimer's disease, Pittsburgh compound B, business, Research Article
Abstract: Background and ObjectivesTo determine the contribution of cerebral amyloid angiopathy (CAA) to Pittsburgh compound B (PiB)–PET tracer retention.MethodsParticipants from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's Disease Research Center with antemortem PiB-PET imaging for β-amyloid (Aβ) who later underwent autopsy were included in this study. Pathologic regional leptomeningeal, parenchymal, capillary CAA, and Aβ plaque burden were calculated from one hemisphere. Regional lobar amyloid standardized uptake value ratio (SUVR) on PET was calculated from the same hemisphere sampled at autopsy. Single- and multiple-predictor linear regression models were used to evaluate the relative contributions of pathologically determined regional CAA and Aβ plaques to antemortem PiB-PET SUVR.ResultsForty-one participants (30 male, 11 female) with a mean (SD) age at death of 75.7 (10.6) years were included. Twenty-seven (66%) had high PiB signal with a mean (SD) of 2.3 (1.2) years from time of PET scan to death; 24 (59%) had a pathologic diagnosis of Alzheimer disease. On multivariate analysis, CAA was not associated with PiB-PET SUVR, while plaques remained associated with PiB-PET SUVR in all regions (all p < 0.05). In patients without frequent amyloid plaques, CAA was not associated with PiB-PET in any region.DiscussionWe did not find evidence that pathologically confirmed regional CAA burden contributes significantly to proximal antemortem regional PiB-PET signal, suggesting that amyloid PET imaging for measurement of cortical amyloid burden is unconfounded by CAA on a lobar level. Whether CAA burden contributes to PiB-PET signal in patients with severe CAA phenotypes, such as lobar hemorrhage, requires further investigation.
Published: 2021

50. Tau-negative amnestic dementia masquerading as Alzheimer disease dementia

Author: Botha, Hugo, Mantyh, William G., Graff-Radford, Jonathan, Machulda, Mary M., Przybelski, Scott A., Wiste, Heather J., Senjem, Matthew L., Parisi, Joseph E., Petersen, Ronald C., Murray, Melissa E., Boeve, Bradley F., Lowe, Val J., Knopman, David S., Jack, Clifford R., Jr, and Jones, David T.
Published: 2018
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