Author: "David G. Clark" / Topic: medicine - Searchworks@Jio Institute Digital Library Search Results

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1. Randomized Controlled Trial of a Cognitive Intervention to Improve Memory in Heart Failure

Author: David G. Clark, Heather Burney, Marita G. Titler, Susan J. Pressler, Susan G. Dorsey, Irmina Gradus-Pizlo, Bruno Giordani, Sujuan Gao, Kelly L. Wierenga, Kittie Reid Lake, Miyeon Jung, and Dean G. Smith
Subjects: Comparative Effectiveness Research, medicine.medical_specialty, Activities of daily living, Clinical Trials and Supportive Activities, Clinical Sciences, Nursing, Cardiorespiratory Medicine and Haematology, Cardiovascular, computerized cognitive training, Article, law.invention, Quality of life (healthcare), Cognition, Randomized controlled trial, cognitive dysfunction, Clinical Research, law, Behavioral and Social Science, Activities of Daily Living, Medicine, Humans, nurse-enhancement intervention, Heart Failure, Cognitive Intervention, Recall, business.industry, Working memory, Prevention, Brain-Derived Neurotrophic Factor, Rehabilitation, Cognitive training, Cardiovascular System & Hematology, Physical therapy, Quality of Life, Cardiology and Cardiovascular Medicine, business
Abstract: Background The objective of this 3-arm randomized controlled trial was to evaluate efficacy of computerized cognitive training (CCT) to improve primary outcomes of delayed recall memory and serum brain-derived neurotrophic factor (BDNF) levels and secondary outcomes of working memory, instrumental activities of daily living (IADL), and health-related quality of life (HRQL) among patients with heart failure (HF). Methods and Results Patients (N = 256) were randomly assigned to 8 weeks of CCT using BrainHQ, computerized crossword puzzles active control intervention, and usual care. All patients received weekly nurse enhancement interventions. Data were collected at enrollment and baseline visits and at 10 weeks and 4 and 8 months. In mixed effects models, there were no statistically significant group or group by time differences in outcomes. There were statistically significant differences over time in all outcomes in all groups. Patients improved over time on measures of delayed recall memory, working memory, IADL, and HRQL and had decreased serum BDNF. Conclusions CCT did not improve outcomes compared with the active control intervention and usual care. Nurse enhancement interventions may have led to improved outcomes over time. Future studies are needed to test nurse enhancement interventions in combination with other cognitive interventions to improve memory in HF. LaySummary In 256 patients with heart failure, 8 weeks of computerized cognitive training, computerized crossword puzzles, or usual care were studied for effects on (1st) recall memory and serum brain-derived neurotrophic factor (BDNF) and (2nd) working memory, instrumental activities of daily living (IADL), and health-related quality of life (HRQL). Measurements were at baseline, 10 weeks, 4- and 8-months. Nurse enhancement interventions (e.g., support, assessment) were provided. Recall memory, working memory, IADL, and HRQL improved over time. There were no statistically significant differences among treatment groups over time. BDNF unexpectedly decreased. Nurse enhancement interventions may explain improved outcomes. Future studies are needed.
Published: 2021

2. Effects of Melatonin and AVG on Plant Growth of Three Pilea Species in Darkness

Author: Chi Dinh Nguyen, Diying Xiang, Heqiang Huo, David G. Clark, and Jayson Opgenorth
Subjects: Melatonin, Chlorophyll content, Plant growth, Darkness, Botany, medicine, Plant Science, Horticulture, Biology, Pilea, biology.organism_classification, medicine.drug
Published: 2020
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3. Identifying Breeding Priorities for Blueberry Flavor Using Biochemical, Sensory, and Genotype by Environment Analyses.

Author: Jessica L Gilbert, Matthew J Guthart, Salvador A Gezan, Melissa Pisaroglo de Carvalho, Michael L Schwieterman, Thomas A Colquhoun, Linda M Bartoshuk, Charles A Sims, David G Clark, and James W Olmstead
Subjects: Medicine, Science
Abstract: Breeding for a subjective goal such as flavor is challenging, as many blueberry cultivars are grown worldwide, and identifying breeding targets relating to blueberry flavor biochemistry that have a high degree of genetic control and low environmental variability are priorities. A variety of biochemical compounds and physical characters induce the sensory responses of taste, olfaction, and somatosensation, all of which interact to create what is perceived flavor. The goal of this study was to identify the flavor compounds with a larger genetic versus environmental component regulating their expression over an array of cultivars, locations, and years. Over the course of three years, consumer panelists rated overall liking, texture, sweetness, sourness, and flavor intensity of 19 southern highbush blueberry (Vaccinium corymbosum hybrids) genotypes in 30 sensory panels. Significant positive correlations to overall liking of blueberry fruit (P
Published: 2015
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4. Strawberry flavor: diverse chemical compositions, a seasonal influence, and effects on sensory perception.

Author: Michael L Schwieterman, Thomas A Colquhoun, Elizabeth A Jaworski, Linda M Bartoshuk, Jessica L Gilbert, Denise M Tieman, Asli Z Odabasi, Howard R Moskowitz, Kevin M Folta, Harry J Klee, Charles A Sims, Vance M Whitaker, and David G Clark
Subjects: Medicine, Science
Abstract: Fresh strawberries (Fragaria x ananassa) are valued for their characteristic red color, juicy texture, distinct aroma, and sweet fruity flavor. In this study, genetic and environmentally induced variation is exploited to capture biochemically diverse strawberry fruit for metabolite profiling and consumer rating. Analyses identify fruit attributes influencing hedonics and sensory perception of strawberry fruit using a psychophysics approach. Sweetness intensity, flavor intensity, and texture liking are dependent on sugar concentrations, specific volatile compounds, and fruit firmness, respectively. Overall liking is most greatly influenced by sweetness and strawberry flavor intensity, which are undermined by environmental pressures that reduce sucrose and total volatile content. The volatile profiles among commercial strawberry varieties are complex and distinct, but a list of perceptually impactful compounds from the larger mixture is better defined. Particular esters, terpenes, and furans have the most significant fits to strawberry flavor intensity. In total, thirty-one volatile compounds are found to be significantly correlated to strawberry flavor intensity, only one of them negatively. Further analysis identifies individual volatile compounds that have an enhancing effect on perceived sweetness intensity of fruit independent of sugar content. These findings allow for consumer influence in the breeding of more desirable fruits and vegetables. Also, this approach garners insights into fruit metabolomics, flavor chemistry, and a paradigm for enhancing liking of natural or processed products.
Published: 2014
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5. Duration of verbal fluency inter‐word intervals and risk of cognitive impairment

Author: Matthew Ayers, Sujuan Gao, Justin Bushnell, Fred Unverzagt, Viriginia G. Wadley, and David G. Clark
Subjects: medicine.medical_specialty, Epidemiology, Health Policy, Early disease, Audiology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Duration (music), medicine, Verbal fluency test, Neurology (clinical), Geriatrics and Gerontology, Psychology, Cognitive impairment, Word (computer architecture)
Published: 2020
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6. Secondary tauopathy in a genetic synucleinopathy, mitochondrial protein–associated neurodegeneration (MPAN)

Author: Randall L. Woltjer, Naly Setthavongsack, Penelope Hogarth, Susan J. Hayflick, Alison Freed, David G. Clark, Marlous van der Weijden, Dolly Zhen, Kristen Shirley, Daphne Garcia, Victoria Krajbich, Suh Young Jeong, Vy Nguyen, Allison Gregory, and Katrina Wakeman
Subjects: Alpha-synuclein, Epidemiology, Health Policy, Neurodegeneration, Neuropathology, Biology, medicine.disease, Cell biology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Developmental Neuroscience, chemistry, medicine, Neurology (clinical), Tauopathy, Geriatrics and Gerontology, Mitochondrial protein
Published: 2020
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7. Parts-Prospecting for a High-Efficiency Thiamin Thiazole Biosynthesis Pathway

Author: Guillaume A.W. Beaudoin, Thomas A. Colquhoun, Jiayi Sun, Jesse F. Gregory, Keun H. Cho, Maria Ralat, Andrew D. Hanson, Cindy L. Sigler, Jaya Joshi, Jenelle A. Patterson, Zhanao Deng, and David G. Clark
Subjects: 0106 biological sciences, Physiology, Methanococcus, Research Articles - Focus Issue, Plant Science, medicine.disease_cause, 01 natural sciences, chemistry.chemical_compound, Bacterial Proteins, Escherichia coli, Genetics, medicine, Araceae, Thiamine, Thiazole, chemistry.chemical_classification, Bacteria, food and beverages, Plants, Directed evolution, Plant cell, Biosynthetic Pathways, Complementation, Thiazoles, Enzyme, Metabolic Engineering, Biochemistry, chemistry, Alternative complement pathway, Function (biology), 010606 plant biology & botany
Abstract: Plants synthesize the thiazole precursor of thiamin (cThz-P) via THIAMIN4 (THI4), a suicide enzyme that mediates one reaction cycle and must then be degraded and resynthesized. It has been estimated that this THI4 turnover consumes 2% to 12% of the maintenance energy budget and that installing an energy-efficient alternative pathway could substantially increase crop yield potential. Available data point to two natural alternatives to the suicidal THI4 pathway: (i) nonsuicidal prokaryotic THI4s that lack the active-site Cys residue on which suicide activity depends, and (ii) an uncharacterized thiazole synthesis pathway in flowers of the tropical arum lily Caladium bicolor that enables production and emission of large amounts of the cThz-P analog 4-methyl-5-vinylthiazole (MVT). We used functional complementation of an Escherichia coli ΔthiG strain to identify a nonsuicidal bacterial THI4 (from Thermovibrio ammonificans) that can function in conditions like those in plant cells. We explored whether C. bicolor synthesizes MVT de novo via a novel route, via a suicidal or a nonsuicidal THI4, or by catabolizing thiamin. Analysis of developmental changes in MVT emission, extractable MVT, thiamin level, and THI4 expression indicated that C. bicolor flowers make MVT de novo via a massively expressed THI4 and that thiamin is not involved. Functional complementation tests indicated that C. bicolor THI4, which has the active-site Cys needed to operate suicidally, may be capable of suicidal and – in hypoxic conditions – nonsuicidal operation. T. ammonificans and C. bicolor THI4s are thus candidate parts for rational redesign or directed evolution of efficient, nonsuicidal THI4s for use in crop improvement.
Published: 2018
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8. Differential Impact of Index Stroke on Dementia Risk in African-Americans Compared to Whites

Author: E.J. Amella, Catrina Sims-Robinson, Robert J. Adams, Andrea D. Boan, A. Benitez, Daniel T. Lackland, Bruce Ovbiagele, and David G. Clark
Subjects: Male, medicine.medical_specialty, Time Factors, Index (economics), Databases, Factual, South Carolina, 030204 cardiovascular system & hematology, Risk Assessment, White People, Article, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Risk Factors, Internal medicine, Prevalence, medicine, Humans, Dementia, Dementia diagnosis, Cognitive impairment, Stroke, Aged, Proportional Hazards Models, Differential impact, Aged, 80 and over, Proportional hazards model, business.industry, Incidence, Rehabilitation, Age Factors, Health Status Disparities, Middle Aged, Prognosis, medicine.disease, Black or African American, Female, Surgery, Neurology (clinical), Diagnosis code, Cognition Disorders, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract: OBJECTIVE: To compare whites and African-Americans in terms of dementia risk following index stroke. METHODS: The data consisted of billing and International Classification of Diseases, Ninth Revision diagnosis codes from the South Carolina Revenue and Fiscal Affairs office on all hospital discharges within the state between 2000 and 2012. The sample consisted of 68,758 individuals with a diagnosis of ischemic stroke prior to 2010 (49,262 white [71.65%] and 19,496 African-Americans [28.35%]). We identified individuals in the dataset who were subsequently diagnosed with any of 5 categories of dementia and evaluated time to dementia diagnosis in Cox Proportional Hazards models. We plotted cumulative hazard curves to illustrate the effect of race on dementia risk after controlling for age, sex, and occurrence of intervening stroke. RESULTS: Age at index stroke was significantly different between the 2 groups, with African-Americans being younger on average (70.0 [SD 12.5] in whites versus 64.5 [SD 14.1] in African-Americans, P
Published: 2018
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9. Patient and Caregiver Assessment of the Benefits From the Clinical Use of Amyloid PET Imaging

Author: Keith N. Fargo, Sujuan Gao, Bradford C. Dickerson, Jared R. Brosch, Susan De Santi, David G. Clark, Gil D. Rabinovici, Mary Guerriero Austrom, Rafid Mustafa, Bradley S. Glazier, Liana G. Apostolova, Maria C. Carrillo, and Martha Tierney
Subjects: Male, medicine.medical_specialty, MEDLINE, Amyloid pet, Article, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Surveys and Questionnaires, Life insurance, Health care, medicine, Humans, Cognitive Dysfunction, 030212 general & internal medicine, Cognitive decline, Psychiatry, Amyloid beta-Peptides, business.industry, Middle Aged, Clinical Practice, Psychiatry and Mental health, Clinical Psychology, Early Diagnosis, Positive response, Caregivers, Positron-Emission Tomography, Family medicine, Female, Geriatrics and Gerontology, business, Gerontology, Disability insurance, 030217 neurology & neurosurgery
Abstract: Introduction Few studies to date have explored patient and caregiver views on the clinical use of amyloid positron emission tomography (PET). Methods A 7-item questionnaire assessing patient and caregiver views (510 total respondents) toward amyloid PET imaging was advertised broadly through alz.org/trialmatch. Results We received 510 unique responses from 48 US states, 2 Canadian provinces, the Dominican Republic, and Greece. Both patients and caregivers indicated that they would want to receive amyloid imaging if offered the opportunity. Over 88% of respondents had a positive response (∼10% with neutral and 2% with negative responses) to whether amyloid PET should be offered routinely and be reimbursed. Such information was felt to be useful for long-term legal, financial, and health care planning. Respondents identifying with early age cognitive decline (younger than 65 y) were more likely to explore options for disability insurance (P=0.03). Responders from the Midwest were more likely to utilize information from amyloid imaging for legal planning (P=0.02), disability insurance (P=0.02), and life insurance (P=0.04) than other US regions. Discussion Patients and caregivers supported the use of amyloid PET imaging in clinical practice and felt that the information would provide significant benefits particularly in terms of future planning.
Published: 2018
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10. Cascaded Multi-view Canonical Correlation (CaMCCo) for Early Diagnosis of Alzheimer’s Disease via Fusion of Clinical, Imaging and Omic Features

Author: Sterling C. Johnson, Paul Malloy, Joy L. Taylor, Alan J. Lerner, Pradeep Garg, Pierre N. Tariot, David G. Clark, Steven G. Potkin, Franklin Watkins, Howard Bergman, Dana M. Pogorelec, Charles D. Smith, Pradeep Varma, Stephen Pasternack, Betty Lind, Saba Wolday, Douglas W. Scharre, Donna Munic, Marwan N. Sabbagh, Adam S. Fleisher, Joanne S. Allard, Cynthia Hunt, Lidia Glodzik, Charles Bernick, Daniel D'Agostino, Owen T. Carmichael, Geoffrey Tremont, Christopher H. van Dyck, Maria Carroll, Po Lu, Leslie Gordineer, Catherine Mc-Adams-Ortiz, Irina Rachisky, Antero Sarrael, Clifford R. Jack, David Bachman, Dick Trost, Scott Herring, Arthur W. Toga, Evan Fletcher, Christina A. Michel, Lon S. Schneider, Francine Parfitt, Kelly M. Makino, Anahita Adeli, Daniel Varon, Christine M. Belden, Nunzio Pomara, Thomas O. Obisesan, Howard Feldman, Howard Chertkow, Sandra W. Jacobson, Haibo Wang, Greg Jicha, Laura A. Flashman, George Bartzokis, Beau M. Ances, Stacy Schneider, Earl A. Zimmerman, Munir Chowdhury, Bruce L. Miller, Javier Villanueva-Meyer, Kristin Fargher, Michael W. Weiner, Dana Nguyen, Ranjan Duara, T. Y. Lee, Lisa C. Silbert, Benita Mudge, Marilyn S. Albert, James J. Lah, Janet S. Cellar, Gad A. Marshall, Michael Lin, Marc Seltzer, Leslie Shaw, Bojana Stefanovic, Daniel C. Marson, Kyle B. Womack, Liberty Teodoro, Connie Brand, Nadira Trncic, Maria Kataki, Russell H. Swerdlow, Paul S. Aisen, Brigid Reynolds, Mony J. de Leon, Sandra E. Black, Rachelle S. Doody, Paula Ogrocki, Andrew J. Saykin, Raymundo Hernando, Leyla deToledo-Morrell, Anna Burke, Sherye A. Sirrel, Henry W. Querfurth, Jeffrey R. Petrella, Norman R. Relkin, Judith L. Heidebrink, Vernice Bates, Mary L. Creech, David C. Perry, Curtis Caldwell, Sara Dolen, Anton P. Porsteinsson, Patricia Lynn Johnson, Erik D. Roberson, Effie M. Mitsis, Kathleen Johnson, John Q. Trojanowki, Raina Carter, James E. Galvin, Karen Blank, John C. Morris, Bryan M. Spann, Keith A. Johnson, Jared R. Tinklenberg, Stephen Salloway, Ronald J. Killiany, Mimi Dang, Smita Kittur, Mary Quiceno, Kaycee M. Sink, Helen Vanderswag, Erin E. Franklin, Robbartha, Kim Martin, Gaby Thai, Allyson C. Rosen, Karen L. Bell, Tracy Kendall, P. M. Doraiswamy, Kathleen Tingus, Angela Oliver, Adrian Preda, Mary L. Hynes, Laurel A. Beckett, William J. Jagust, Jeffrey M. Burns, Ronald C. Petersen, Allan I. Levey, Balebail Ashok Raj, Lawrence S. Honig, Martin R. Farlow, Richard E. Carson, Dana Mathews, David S. Knopman, Robert C. Green, Jerome A. Yesavage, Elizabeth Finger, Ann Marie Hake, David S. Geldmacher, Yaakov Stern, Raj C. Shah, M.-Marsel Mesulam, Ruth A. Mulnard, Jacobo Mintzer, Howard J. Rosen, Peggy Roberts, Joseph F. Quinn, Raymond Scott Turner, Maria T. Greig, Salvador Borges-Neto, Jeffrey Kaye, Randall Griffith, Diana R. Kerwin, Neill R. Graff-Radford, James B. Brewer, John C. Brockington, Ging-Yuek Robin Hsiung, Anant Madabhushi, Andrew E. Budson, Martha G. MacAvoy, Stephen Correia, Terence Z. Wong, Michelle Rainka, Elizabeth Oates, Alexander Norbash, Chiadi U. Onyike, Gloria Chaing, Kris Johnson, Hillel Grossman, Gary R. Conrad, Nancy Johnson, Lisa D. Ravdin, Mauricio Beccera, Reisa A. Sperling, Heather Johnson, Kristine Lipowski, Charles DeCarli, Barton Lane, Joanne L. Lord, Carl H. Sadowsky, Chris Hosein, Marissa Natelson Love, M. Ismail, Liana G. Apostolova, Dzintra Celmins, Brian R. Ott, Brittany Cerbone, Sanjay Asthana, Alice D. Brown, Neil W. Kowall, Peter A. Hardy, Andrew Kertesz, Sara S. Mason, Horacio Capote, Pauline Maillard, Stephanie Kielb, Henry Rusinek, Ellen Woo, Jeff D. Williamson, Susan De Santi, Amanda Smith, John M Olichney, Michele Assaly, Karen S. Anderson, Parianne Fatica, Brandy R. Matthews, Michael Borrie, Susan Rountree, Chuang Kuo Wu, Curtis Tatsuoka, Teresa Villena, Asha Singanamalli, Borna Bonakdarpour, Colleen S. Albers, Cynthia M. Carlsson, Bonnie S. Goldstein, Sonia Pawluczyk, Edward Coleman, Kenneth M. Spicer, Jared R. Brosch, William Brooks, Partha Sinha, Stephanie Reeder, Daniel Silverman, Robert B. Santulli, Godfrey D. Pearlson, Mark A. Mintun, and Sandra Weintraub
Subjects: 0301 basic medicine, Male, Proteomics, Science, Neuroimaging, Disease, Sensitivity and Specificity, Article, 03 medical and health sciences, 0302 clinical medicine, Text mining, Alzheimer Disease, medicine, Humans, Cognitive Dysfunction, Set (psychology), Aged, Aged, 80 and over, Multidisciplinary, Modalities, business.industry, Pattern recognition, Alzheimer’s Disease Neuroimaging Initiative, Genomics, Models, Theoretical, medicine.disease, 030104 developmental biology, Categorization, Case-Control Studies, Medicine, Female, Artificial intelligence, Alzheimer's disease, business, Canonical correlation, 030217 neurology & neurosurgery, Algorithms, Biomarkers
Abstract: The introduction of mild cognitive impairment (MCI) as a diagnostic category adds to the challenges of diagnosing Alzheimer’s Disease (AD). No single marker has been proven to accurately categorize patients into their respective diagnostic groups. Thus, previous studies have attempted to develop fused predictors of AD and MCI. These studies have two main limitations. Most do not simultaneously consider all diagnostic categories and provide suboptimal fused representations using the same set of modalities for prediction of all classes. In this work, we present a combined framework, cascaded multiview canonical correlation (CaMCCo), for fusion and cascaded classification that incorporates all diagnostic categories and optimizes classification by selectively combining a subset of modalities at each level of the cascade. CaMCCo is evaluated on a data cohort comprising 149 patients for whom neurophysiological, neuroimaging, proteomic and genomic data were available. Results suggest that fusion of select modalities for each classification task outperforms (mean AUC = 0.92) fusion of all modalities (mean AUC = 0.54) and individual modalities (mean AUC = 0.90, 0.53, 0.71, 0.73, 0.62, 0.68). In addition, CaMCCo outperforms all other multi-class classification methods for MCI prediction (PPV: 0.80 vs. 0.67, 0.63).
Published: 2017
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11. Sphingosine-1-phosphate receptor-1 (S1P1) is expressed by lymphocytes, dendritic cells, and endothelium and modulated during inflammatory bowel disease

Author: Thangaraj Karuppuchamy, Robert Peach, David G. Clark, Hugh Rosen, Pedro J. Gonzalez-Cabrera, Paul Jedlicka, Giorgos Bamias, Gor Sarkisyan, En-hui Behrens, Jesus Rivera-Nieves, Fiona Scott, Joshua D. Boyer, Lauren Gima, and Marisol Veny
Subjects: 0301 basic medicine, Ozanimod, Endothelium, Lymphocyte, Immunology, Mice, Transgenic, Inflammation, Inflammatory bowel disease, Article, Mice, 03 medical and health sciences, chemistry.chemical_compound, Cell Movement, medicine, Animals, Humans, Immunologic Factors, Immunology and Allergy, Ileitis, Lymphocytes, Colitis, Receptor, Cells, Cultured, Oxadiazoles, Fingolimod Hydrochloride, business.industry, Dextran Sulfate, Dendritic Cells, Inflammatory Bowel Diseases, medicine.disease, Intestines, Mice, Inbred C57BL, Disease Models, Animal, Receptors, Lysosphingolipid, 030104 developmental biology, medicine.anatomical_structure, chemistry, Indans, Cancer research, medicine.symptom, business, Immunologic Memory
Abstract: The sphingosine-1-phosphate receptor-1 (S1P1) agonist ozanimod ameliorates ulcerative colitis, yet its mechanism of action is unknown. Here, we examine the cell subsets that express S1P1 in intestine using S1P1-eGFP mice, the regulation of S1P1 expression in lymphocytes after administration of dextran sulfate sodium (DSS), after colitis induced by transfer of CD4+CD45RBhi cells, and by crossing a mouse with TNF-driven ileitis with S1P1-eGFP mice. We then assayed the expression of enzymes that regulate intestinal S1P levels, and the effect of FTY720 on lymphocyte behavior and S1P1 expression. We found that not only T and B cells express S1P1, but also dendritic (DC) and endothelial cells. Furthermore, chronic but not acute inflammatory signals increased S1P1 expression, while the enzymes that control tissue S1P levels in mice and humans with inflammatory bowel disease (IBD) were uniformly dysregulated, favoring synthesis over degradation. Finally, we observed that FTY720 reduced T-cell velocity and induced S1P1 degradation and retention of Naïve but not effector T cells. Our data demonstrate that chronic inflammation modulates S1P1 expression and tissue S1P levels and suggests that the anti-inflammatory properties of S1PR agonists might not be solely due to their lymphopenic effects, but also due to potential effects on DC migration and vascular barrier function.
Published: 2017
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12. Brain multiplexes reveal morphological connectional biomarkers fingerprinting late brain dementia states

Author: Jerome A. Yesavage, Thomas O. Obisesan, Ann Marie Hake, Yaakov Stern, Betty Lind, Daniel D'Agostino, Daniel Varon, Christine M. Belden, Evan Fletcher, Jef Williamson, Howard Feldman, Pauline Maillard, Stephanie Kielb, Dana Mathews, Henry Rusinek, Sonia Pawluczyk, Donna Munic, Michele Assaly, Ines Mahjoub, Barton Lane, Andrew J. Saykin, Raymundo Hernando, Randall Grifth, Paul S. Aisen, Brittany Cerbone, Saba Wolday, Douglas W. Scharre, Karen S. Anderson, Sara S. Mason, Marwan N. Sabbagh, Geofrey Tremont, Stacy Schneider, Marilyn S. Albert, Tracy Kendall, P. M. Doraiswamy, Antero Sarrael, Kenneth M. Spicer, George Bartzokis, Parianne Fatica, Christopher H. van Dyck, Maria Carroll, Benita Mudge, Beau M. Ances, Brandy R. Matthews, Allyson C. Rosen, Chiadi U. Onyike, Gloria Chaing, Helen Vanderswag, Javier Villanueva-Meyer, Stephanie Reeder, Erin E. Franklin, Sandra Weintraub, Liberty Teodoro, Connie Brand, Arthur W. Toga, Mony J. de Leon, Sandra E. Black, Robert C. Green, Russell H. Swerdlow, Leyla deToledo-Morrell, Bryan M. Spann, Judith L. Heidebrink, Leslie Shaw, Ruth A. Mulnard, Rob Bartha, Sterling C. Johnson, Kristin Fargher, Susan De Santi, Curtis Caldwell, Rachelle S. Doody, Erik D. Roberson, Norman R. Relkin, Kathleen Johnson, Raj C. Shah, Kris Johnson, Diana Kerwin, M.-Marsel Mesulam, Howard J. Rosen, Peggy Roberts, Michael Borrie, Martin R. Farlow, Steven G. Potkin, Reisa A. Sperling, John Q. Trojanowki, Amanda Smith, James J. Lah, Mary L. Creech, Janet S. Cellar, Michael Lin, Terence Z. Wong, Howard Bergman, Dana M. Pogorelec, Gaby Thai, Jacobo Mintzer, Raina Carter, Heather Johnson, Francine Parftt, Karen Blank, Daniel C. Marson, Nancy Johnson, Susan Rountree, Michelle Rainka, Elizabeth Oates, Stephen Correia, John C. Morris, Alan J. Lerner, Pradeep Garg, Mauricio Beccera, Mary L. Hynes, Chuang Kuo Wu, Curtis Tatsuoka, Brian R. Ott, Joy L. Taylor, Mohamed Ali Mahjoub, Adrian Preda, Islem Rekik, Ronald C. Petersen, Kathleen Tingus, Vernice Bates, Irina Rachisky, Neill Graf-Radford, Alexander Norbash, Teresa Villena, Paul Malloy, Cliford Jack, Pierre N. Tariot, Anton P. Porsteinsson, Jefrey Burns, Owen Carmichael, Maria T. Greig, Marc Seltzer, Pradeep Varma, Jefrey Petrella, James E. Galvin, Joseph F. Quinn, Franklin Watkins, John M Olichney, Joanne L. Lord, Raymond Scott Turner, Adam S. Fleisher, Salvador Borges-Neto, James B. Brewer, Carl H. Sadowsky, Andrew E. Budson, Martha G. MacAvoy, Joanne S. Allard, L. Schneider, Stephen Salloway, Kim Martin, Mary Quiceno, Kaycee M. Sink, Sanjay Asthana, Laurel A. Beckett, Alice D. Brown, David S. Knopman, Neil W. Kowall, Efe Mitsis, Elizabeth Finger, David C. Perry, Bojana Stefanovic, David S. Geldmacher, Andrew Kertesz, Cynthia M. Carlsson, Charles Bernick, Earl A. Zimmerman, Bonnie S. Goldstein, Dzintra Celmins, Paula Ogrocki, Daniel H.S. Silverman, David G. Clark, Charles D. Smith, Nunzio Pomara, Stephen Pasternack, Howard Chertkow, Christina A. Michel, Sandra W. Jacobson, Po Lu, Peter A. Hardy, Greg Jicha, David Bachman, Laura A. Flashman, Munir Chowdhury, Bruce L. Miller, Ging Yuek Robin Hsiung, Horacio Capote, Gad A. Marshall, Brigid Reynolds, Jefrey Kaye, Patricia Lynn Johnson, Ronald J. Killiany, Mimi Dang, Smita Kittur, Lawrence S. Honig, Ranjan Duara, T. Y. Lee, Keith A. Johnson, Karen L. Bell, Allan I. Levey, Scott Herring, Michael W. Weiner, Ellen Woo, Dana Nguyen, Robert B. Santulli, Godfrey D. Pearlson, Mark A. Mintun, Sara Dolen, Jared R. Tinklenberg, Edward Coleman, Jared R. Brosch, John C. Brockington, William Brooks, Partha Sinha, M. Ismail, Balebail Ashok Raj, Lisa D. Ravdin, Kristine Lipowski, Charles DeCarli, Borna Bonakdarpour, Colleen S. Albers, Chris Hosein, Marissa Natelson Love, Kyle B. Womack, Maria Kataki, Nadira Trncic, Anna Burke, Sherye A. Sirrel, Henry W. Querfurth, Liana G. Apostolova, Angela Oliver, William J. Jagust, Richard E. Carson, Cynthia Hunt, Lidia Glodzik, Hillel Grossman, Gary R. Conrad, Leslie Gordineer, Catherine Mc-Adams-Ortiz, Dick Trost, Kelly M. Makino, Anahita Adeli, and Lisa C. Silbert
Subjects: Right entorhinal cortex, Models, Neurological, lcsh:Medicine, Biology, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, medicine, Humans, Middle frontal gyrus, Dementia, Patient treatment, lcsh:Science, Cognitive impairment, Multidisciplinary, Extramural, lcsh:R, Brain, Diagnostic marker, Alzheimer’s Disease Neuroimaging Initiative, medicine.disease, Magnetic Resonance Imaging, Brain region, lcsh:Q, Cognition Disorders, Neuroscience, Biomarkers, 030217 neurology & neurosurgery
Abstract: Accurate diagnosis of mild cognitive impairment (MCI) before conversion to Alzheimer’s disease (AD) is invaluable for patient treatment. Many works showed that MCI and AD affect functional and structural connections between brain regions as well as the shape of cortical regions. However, ‘shape connections’ between brain regions are rarely investigated -e.g., how morphological attributes such as cortical thickness and sulcal depth of a specific brain region change in relation to morphological attributes in other regions. To fill this gap, we unprecedentedly design morphological brain multiplexes for late MCI/AD classification. Specifically, we use structural T1-w MRI to define morphological brain networks, each quantifying similarity in morphology between different cortical regions for a specific cortical attribute. Then, we define a brain multiplex where each intra-layer represents the morphological connectivity network of a specific cortical attribute, and each inter-layer encodes the similarity between two consecutive intra-layers. A significant performance gain is achieved when using the multiplex architecture in comparison to other conventional network analysis architectures. We also leverage this architecture to discover morphological connectional biomarkers fingerprinting the difference between late MCI and AD stages, which included the right entorhinal cortex and right caudal middle frontal gyrus.
Published: 2018
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13. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author: John Hardy, Nick C. Fox, Lena Lilius, Christine Van Broeckhoven, Mindy J. Katz, Carlos Cruchaga, Joshua W. Miller, Carol Brayne, Letizia Concari, Christopher Shaw, Minerva M. Carrasquillo, Richard Mayeux, Anne Boland, Charles DeCarli, Helena C. Chui, Laura B. Cantwell, Yoland Aladro Benito, Chuang Kuo Wu, Elaine R. Peskind, Andrew McDavid, M. Ilyas Kamboh, Amanda Smith, Pascual Sánchez-Juan, Jean-François Deleuze, Jayanadra J. Himali, Thomas H. Mosley, Thomas J. Montine, Chuanhai Cao, Andreas J. Forstner, Thomas G. Beach, Robert Barber, Miquel Aguilar, Liming Qu, Jerome I. Rotter, Matthew J. Huentelman, Christiane Reitz, Christopher J. O'Donnell, Steven G. Younkin, Bradley T. Hyman, Bruce L. Miller, Rachelle S. Doody, Eric B. Larson, Ronald L. Hamilton, Todd E. Golde, Steven E. Arnold, Melissa E. Garcia, Rachel Raybould, Lena Kilander, Mark A. Sager, Kevin Morgan, Kathryn L. Lunetta, William Perry, Joseph D. Buxbaum, Craig S. Atwood, Thomas D. Bird, Michael Conlon O'Donovan, Robert Olaso, Juan Fortea, Susanne Moebus, Lisa L. Barnes, Rachel Marshall, Huntington Potter, Mercè Boada, Shahzad Ahmad, Paolo Caffarra, Daniel C. Marson, Jonathan L. Haines, Perrie M. Adams, John M Olichney, Lars Lannfelt, Stefanie Heilmann-Heimbach, Markus M. Nöthen, Shubhabrata Mukherjee, John Malamon, Xue Wang, Christopher S. Carlson, Karen Ritchie, Roger N. Rosenberg, Paul K. Crane, Alexa S. Beiser, Céline Bellenguez, Robert C. Green, Maria Urbano, Petra Proitsi, John Powell, Elisa Majounie, Ammar Al-Chalabi, Hakon Hakonarson, Yogen Patel, Martin Scherer, Julie Williams, Richard B. Lipton, Vincent Dermecourt, Adam L. Boxer, Gerard D. Schellenberg, David G. Clark, Anita L. DeStefano, Joel H. Kramer, Victoria Alvarez, Nandini Badarinarayan, Oscar L. Lopez, Chris Corcoran, Ubaldo Bonuccelli, Donald R. Royall, James Bowen, Monica Diez Fairen, Tricia A. Thornton-Wells, Nilufer Ertekin-Taner, Florence Pasquier, Martin Ingelsson, Yi Zhao, John R. Gilbert, Valentina Escott-Price, Amanda B. Kuzma, Fabienne Garzia, Reinhard Heun, Otto Valladares, Andrew J. Saykin, Sara Ortega-Cubero, Liana G. Apostolova, Henry L. Paulson, John K Kauwe, Imelda Barber, Carolina Ceballos Diaz, Douglas Galasko, M. Arfan Ikram, Lluís Tárraga, Carlo Caltagirone, Joan S. Reisch, Wolfgang Maier, Bruno Vellas, Rebecca Sims, Angela Hodges, Matthew P. Frosch, Isabel Henández, Annakaisa Haapasalo, Thor Aspelund, Håkan Thonberg, Aimee Pierce, Roger L. Albin, Wayne W. Poon, Rebecca Sussams, Amy Braddel, Ranjan Duara, Albert V. Smith, Kirk C. Wilhelmsen, Gianfranco Spalletta, Simon Lovestone, Peter Passmore, Ana Frank-García, Cynthia M. Carlsson, Jade Chapman, Nathan D. Price, Philip L. De Jager, John M. Ringman, Seung Hoan Choi, Nicola Denning, Michael John Owen, Clinton T. Baldwin, Amalia C. Bruni, Denis A. Evans, Rudolph E. Tanzi, Dominique Campion, Laura Fratiglioni, Alberto Lleó, Per Hoffmann, Carole Dufouil, Charlotte Forsell, Alun Meggy, Charlene Thomas, Robert S. Stern, James B. Leverenz, Tatiana Foroud, William W. Seeley, James J. Lah, Brian A. Lawlor, Kenneth B. Fallon, Matthias Riemenschneider, Ryan M. Huebinger, Regina M. Carney, Clinton B. Wright, Didier Hannequin, Deborah Blacker, Anne Kinhult-Ståhlbom, Ekaterina Rogaeva, Andrew P. Lieberman, Bernardino Ghetti, Linda J. Van Eldik, Bernadette McGuinness, Thomas Fairchild, Margaret A. Pericak-Vance, Ashok Raj, Reinhold Schmidt, Ronald C. Petersen, Harald Hampel, María J. Bullido, Steven L. Carroll, Maria Candida Deniz Naranjo, Kathleen A. Welsh-Bohmer, Myriam Fornage, Joseph F. Quinn, Caroline Graff, Claudia L. Satizabal, Patrice L. Whitehead, David Wallon, Christopher Medway, Lindsay A. Farrer, Vilmundur Gudnason, Peter St George-Hyslop, Pau Pastor, Frank Jessen, Erin L. Abner, Johanna Jakobsdottir, Hieab H.H. Adams, Roberta Cecchetti, Walter A. Kukull, Thomas S. Wingo, Michelle K. Lupton, Valur Emilsson, Susan M. McCurry, Simon Mead, Hilkka Soininen, Sandra Weintraub, Amy Gerrish, Lindy E. Harrell, Lina Keller, Jean-Charles Lambert, Denise Harold, Stephen Todd, Wei Gu, Maura Gallo, Najaf Amin, Lenore J. Launer, Eleonora Sacchinelli, Mikko Hiltunen, Cécile Dulary, Eliecer Coto, Xueqiu Jian, Nathalie Fievet, Patrizia Mecocci, Sarah Taylor, Eric Boerwinkle, Maria Serpente, Ronald G. Munger, Ina Giegling, Carlo Masullo, Aoibhinn Lynch, Eliezer Masliah, Anne M. Koivisto, Chang En Yu, Qiong Yang, Benedetta Nacmias, Wayne C. McCormick, Kristelle Brown, Alessio Squassina, Deborah C. Mash, Brian W. Kunkle, Makrina Daniilidou, Alison Goate, David Carrell, Kara L. Hamilton-Nelson, Sandra Barral, Vincent Chouraki, Kristel Sleegers, Frank J. Wolters, Joseph E. Parisi, Iwona Kłoszewska, Ronald C. Kim, Sonia Moreno-Grau, Marina Arcaro, Carmen Muñoz Fernadez, Vernon S. Pankratz, Duane Beekly, Sabrina Pichler, Gislain Septier, Delphine Bacq, Amanda J. Myers, Adam C. Naj, Frank Martiniuk, Sudha Seshadri, Badri N. Vardarajan, Joshua A. Sonnen, M.-Marsel Mesulam, Howard J. Rosen, James T. Becker, Chiara Fenoglio, Ge Li, Alberto Pilotto, Mary Sano, Olivier Hanon, Honghuang Lin, Jean Paul G. Vonsattel, W. T. Longstreth, Daniela Galimberti, David C. Rubinsztein, RoseMarie Brundin, Vilmantas Giedraitis, Christine M. Hulette, Peter Holmans, Martin Dichgans, Maria Vronskaya, Céline Derbois, Michelangelo Mancuso, Constantine G. Lyketsos, Christophe Tzourio, Jacques Epelbaum, Raffaele Maletta, Mariet Allen, Hong-Dong Li, James R. Burke, Rik Vandenberghe, David G. Mann, Bruce M. Psaty, Lawrence S. Honig, Beth A. Dombroski, Erik D. Roberson, Cornelia M. van Duijn, Benjamin Grenier-Boley, Seppo Helisalmi, Jean-François Dartigues, Russell H. Swerdlow, Paola Bossù, Ashley R. Winslow, Elio Scarpini, Lesley Jones, Sebastien Engelborghs, John Q. Trojanowski, Jeffrey Kaye, Jenny Lord, Chiara Cupidi, Janet A. Johnston, Dan Rujescu, Feroze Golamaully, Anne Braae, Rafael Blesa, L. Adrienne Cupples, Dennis W. Dickson, Gail P. Jarvik, David W. Fardo, David H. Cribbs, Michael Gill, Jose Bras, Allan I. Levey, Jennifer Williamson, Rhodri Thomas, John C. Morris, Lei Yu, Debby W. Tsuang, Annette M. Hartmann, John H. Growdon, John Collinge, Claudine Berr, Fernando Rivadeneira, Oliver Peters, Albert Hofman, Frank M. LaFerla, Vivianna M. Van Deerlin, James Uphill, David A. Bennett, Onofre Combarros, Gudny Eiriksdottir, Jeremy D. Burgess, Melanie L. Dunstan, Elizabeth Crocco, Keeley J. Brookes, Robert R. Graham, Lon S. Schneider, Eden R. Martin, Matt Hill, Neill R. Graff-Radford, Joseph T. Hughes, Vincenzo Solfrizzi, Taniesha Morgan, Antonio Ciaramella, Bruno Dubois, Juan C. Troncoso, Paolo Bosco, Jordi Clarimón, Daniel H. Geschwind, Virginia Boccardi, Barry Reisberg, Timothy W. Behrens, Annette L. Fitzpatrick, Salvatore Spina, Alexis Brice, Eileen H. Bigio, Marla Gearing, Jeffrey M. Burns, Carol A. Miller, Marilyn S. Albert, Sven J. van der Lee, Sandro Sorbi, C. Dirk Keene, Daniel Levy, Antonio Daniele, Eric M. Reiman, Paramita Chakrabarty, Oscar Sotolongo-Grau, Helena Schmidt, Francesco Panza, Murray A. Raskind, Rita Guerreiro, Gyungah Jun, Anna Karydas, Markus Leber, Harry V. Vinters, Cory C. Funk, Charles C. White, Jill R. Murrell, Sid E. O'Bryant, Nigel J. Cairns, Josée Dupuis, Ann C. McKee, Julie A. Schneider, Megan L. Grove, Malcolm B. Dick, Bradley F. Boeve, Jennifer A. Brody, Sanjay Asthana, Agustín Ruiz, Stefan Herms, Yuning Chen, David Craig, Neil W. Kowall, Maria Donata Orfei, JoAnn T. Tschanz, Florentino Sanchez Garcia, Manuel Mayhaus, Alfredo Ramirez, James Turton, André G. Uitterlinden, Davide Seripa, Lee-Way Jin, Kelley Faber, Maria C. Norton, Shuo Li, Steven H. Ferris, Steffi G. Riedel-Heller, Joshua C. Bis, Li-San Wang, Johannes Kornhuber, Peter Paul De Deyn, Martin R. Farlow, Randall L. Woltjer, Gary W. Beecham, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Icelandic Heart Association [Kopavogur, Iceland] (IHA), John P. Hussman Institute for Human Genomics [Miami, FL, USA], University of Miami [Coral Gables], Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Medicine, University of Washington [Seattle], Dr. John T. Macdonald Foundation [Miami, FL, USA] (Department of Human Genetics), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Department of Genomics [Bonn, Germany] (Institute of Human Genetics), University of Bonn-Institute of Human Genetics [Bonn, Germany], Department of Molecular Genetics, Institut Català de Neurociències Aplicades [Barcelona, Spain], Well Advanced Solutions, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], The University of Texas Health Science Center at Houston (UTHealth), Columbia University [New York], University of Eastern Finland, Life & Brain Center - Department of Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), John P. Hussman Institute for Human Genomics, Neurobiologie de la Croissance et de la Senescence, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Emmy Noether Project (SFB 833), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Boston University [Boston] (BU), Department of Genomics, Institute for Systems Biology [Seattle, WA, USA], Universitätsklinikum Bonn (UKB), Centre of Excellence for Robotic Vision [Canberra], Australian Research Council [Canberra] (ARC), Neuroscience and Mental Health Research Institute [Cardiff, UK] (School of Medicine), Boston University School of Medicine (BUSM), Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, University of Pennsylvania [Philadelphia], Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Department of Epidemiology and Biostatistics, ERASMUS, Hospital Universitario Doctor Negrín [Las Palmas de Gran Canaria, Spain], Department of Neurodegenerative Diseases, University of Mississippi Medical Center (UMMC), Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Penn Neurodegeneration Genomics Center), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioinformatics, GlaxoSmithKline, Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], University of Nottingham, UK (UON), University of Texas Health Science Center, Department of Neurobiology, Caring Sciences and Society (NVS), University of Bari Aldo Moro (UNIBA), Ageing Group, Centre for Public Health, Queen's University [Belfast] (QUB), Mayo Clinic [Jacksonville], Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Università degli Studi di Perugia (UNIPG), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), CHU Rouen, Normandie Université (NU), Universidad Autonoma de Madrid (UAM), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University of Florida [Gainesville] (UF), University of Parma = Università degli studi di Parma [Parme, Italie], Center for Cognitive Disorders AUSL [Parma, Italy], School of Public Health [Boston], Uppsala University, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Xi'an Jiaotong University (Xjtu), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Institute of Gerontology and Geriatrics, Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Geriatric Medicine and Metabolic Diseases, Departments of Nuclear Medicine, University Medical Centre Hamburg-Eppendorf [Hamburg, Germany], University of Texas Southwestern Medical Center [Dallas], University of Cologne, Laboratoire d'Etudes et de Recherche en Informatique d'Angers (LERIA), Université d'Angers (UA), Johns Hopkins University (JHU), Universität Leipzig [Leipzig], University of Iceland [Reykjavik], Metacohorts Consortium, Harvard School of Public Health, Catholic University of Rome, Medical University Graz, Baylor College of Medicine (BCM), Baylor University, University of North Texas Health Science Center [Fort Worth], Santa Lucia Foundation (IRCCS), Nextel S.A. [Bilbao], Massachusetts General Hospital [Boston], Department of Pathology and Laboratory Medicine and Indiana Alzheimer disease Center, Indiana University School of Medicine, Indiana University System-Indiana University System, Joint Institute for the Study of the Atmosphere and Ocean (JISAO), Beijing University of Technology, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Saul B. Korey Department of Neurology, Albert Einstein College of Medicine [New York]-Yeshiva University, Utah State University (USU), Fundació per la Recerca Biomèdica i Social Mútua Terrassa [Barcelona, Spain], Hospital Universitario Mutua de Terrassa, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Medical University of Łódź (MUL), University of Leicester, MRC Prion Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Milan, Fondazione Istituto di Ricerca e Cura Carattere Scientifico [Rome], Università degli Studi di Roma Tor Vergata [Roma], Saarland University Hospital, Universitat Autònoma de Barcelona (UAB), Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Universidade do Porto, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Experimental and Clinical Pharmacology, St. James Hospital and Trinity College [Dublin, Ireland], School of Medicine [Dublin], Trinity College Dublin, University of Sheffield [Sheffield], Lancaster University, University of Michigan [Ann Arbor], University of Michigan System, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, University of Wisconsin-Madison, Rush Alzheimer Disease Center [Chicago, IL, États-Unis], Rush University Medical Center [Chicago], Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), School of Engineering [Cardiff], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Northwestern University Feinberg School of Medicine, Mayo Clinic [Rochester], Swedish Medical Center [Seattle, WA, USA], University of California [San Francisco] (UCSF), University of California, Duke University [Durham], University of Kansas Medical Center [Lawrence], Laboratory of Molecular Neuropsychiatry, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Washington University in Saint Louis (WUSTL), University of South Florida [Tampa] (USF), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Medical University of South Carolina [Charleston] (MUSC), University of Southern California (USC), Los Alamos National Laboratory (LANL), Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Neurology Department, University of California, Davis (UCDavis-Neuro), University of California [Davis] (UC Davis), University of California [Irvine] (UCI), Mount Sinai Medical Center, Indiana State University, University of Alabama at Birmingham [ Birmingham] (UAB), University of Kentucky, New York University [New York] (NYU), NYU System (NYU), Department of Medical and Molecular Genetics, Department of Epidemiology and biostatistics, VU University Medical Center [Amsterdam], Emory University [Atlanta, GA], Department of Neurology, University of California-University of California-David Geffen School of Medicine [Los Angeles], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Department of Medical Genetics, HMNC Brain Health, Alzheimer Disease Research Laboratory, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Laboratoire d'Informatique, Systèmes, Traitement de l'Information et de la Connaissance (LISTIC), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Department of Psychiatry, School of Medicine-Johns Hopkins University and Johns Hopkins Bayview Medical Center, Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Department of neurosciences, University of California [San Diego] (UC San Diego), Department of Physics and Astronomy [Fort Worth], Texas Christian University (TCU), Department of Computer Science [University of California, Davis], Indiana University System, Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), Department of Laboratory Medicine and Pathology, Mayo Clinic, Institute for Memory Impairments and Neurological Disorders [Irvine], University of Colorado Anschutz [Aurora], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Keck School of Medicine [Los Angeles], Indiana University [South Bend], Massachusetts General Hospital, Novartis Institutes for Biomedical Research [Cambridge, MA, USA], Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, UCLA Medical Center-David Geffen School of Medicine [Los Angeles], University of California-University of California-University of California [Los Angeles] (UCLA), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Institut de Génomique d'Evry (IG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Antwerp (UA), Institute Born-Bunge, Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], University of Kuopio, Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Laboratoire d'Analyse Génomique, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Inserm-U1167, Dpt Gériatrie [CHU Broca], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Epidemiology, University of Washington, School of Medicine [Los Angeles], Albert Einstein College of Medicine [New York], IdiPAZ - Instituto de Investigación La Paz [Madrid, Spain], Instituto de Física Teórica UAM/CSIC (IFT), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Department of Internal Medicine, University of Central Asturias [Oviedo, Spain], Human Genome Sequencing Center, Baylor College of Medicine, Baylor University-Baylor University, Department of Epidemiology, Erasmus Medical Centre, Translational Genomics Research Institute [Phoenix, AZ, USA], University of Arizona, Banner Alzheimer's Institute [Phoenix, AZ, États-Unis], University of Texas Health Science Center at San Antonio [San Antonio], Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department. of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico, Centre for Research in Neurodegenerative Diseases, VA Puget Sound Health Care System/GRECC [Seattle, WA, USA], University of Pisa - Università di Pisa, Pfizer Worldwide Research and Development [Cambridge, MA, USA], Università cattolica del Sacro Cuore [Piacenza e Cremona] (Unicatt), Texas Tech University Health Sciences Center, Texas Tech University [Lubbock] (TTU), Saarland University [Saarbrücken], University of Bonn, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Cambridge Institute for Medical Research (CIMR), Department of Molecular Neurosciences, Institute of Neurology, UCL, Institute of Psychiatry, Institute of psychiatry, University of British Columbia (UBC), the Clinical Neuroscience Research Group, University of Manchester [Manchester]-Greater Manchester Neurosciences Centre, Aristotle University of Thessaloniki, Memory and Dementia Centre, 3rd Department of Neurology, G. Pa, University of Barcelona, University of Southampton, Department of Psychiatry [Oxford] (POWIC), University of Oxford [Oxford]-The Warneford Hospital, School of Psychology [Cardiff University], Department of Medical Sciences, UCL, Institute of Neurology [London], Washington University School of Medicine, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), School of Medecine, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], School of Life Sciences, Department of Neuroscience, Mayo Clinic Jacksonville, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Clínica Universidad de Navarra [Pamplona], Neurodegenerative Brain Diseases Group, VIB, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University-Medical Research Council, Brigham Young University (BYU), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, The Gertrude H Sergivesky Center, Columbia University College of Physicians and Surgeons, Genetic Epidemiology Unit, Section of Clinical and Molecular Neurogenetics, Universität zu Lübeck [Lübeck], University of Pennsylvania - Department of Pathology & Laboratory Medecine, Framingham Heart Study [Framingham, MA, USA], ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), European Project: 29845,LSH-ACC-MENTOR, University of Pennsylvania-University of Pennsylvania, Universität Bonn = University of Bonn-Institute of Human Genetics [Bonn, Germany], Universität Leipzig-Universität Leipzig, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Università degli Studi di Perugia = University of Perugia (UNIPG), Universidad Autónoma de Madrid (UAM), Università degli studi di Parma = University of Parma (UNIPR), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Universität Leipzig, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Yeshiva University- Albert Einstein College of Medicine [New York], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Università degli Studi di Milano = University of Milan (UNIMI), Saarland University Hospital (UKS), Università degli Studi di Firenze = University of Florence (UniFI), Universidade do Porto = University of Porto, University of California (UC)-University of California (UC), University of California [San Francisco] (UC San Francisco), University of California (UC), University of Kansas Medical Center [Kansas City, KS, USA], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of California [Irvine] (UC Irvine), University of Kentucky (UK), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Department of Computer Science [Univ California Davis] (CS - UC Davis), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA], Universität Bonn = University of Bonn, University of Oxford-The Warneford Hospital, Medical Research Council-Cardiff University, Universität zu Lübeck = University of Lübeck [Lübeck], Epidemiology, Neurology, Gastroenterology & Hepatology, Internal Medicine, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Eberhard Karls Universität Tübingen, IRCCS 'Casa Sollievo della Sofferenza', Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (Ciberned), University of Florida [Gainesville], University of Parma, Troubles cognitifs dégénératifs et vasculaires (U1171), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-INSERM, Yeshiva University- Albert Einstein College of Medicine, Institut d’Électronique, de Microélectronique et de Nanotechnologie (IEMN) - UMR 8520 (IEMN), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université Polytechnique Hauts-de-France (UPHF)-Ecole Centrale de Lille-Université Polytechnique Hauts-de-France (UPHF)-Institut supérieur de l'électronique et du numérique (ISEN), Autonomous University of Barcelona (UAB), Università degli Studi di Firenze [Firenze], Universidade do Porto [Porto], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Washington University in St Louis, University of South Florida (USF), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, McGill University, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique, Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Albert Einstein College of Medicine, Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Università Cattolica del S. Cuore - Catholic University of the Sacred Hearth, University of Florence (UNIFI), CIBER de Enfermedades Neurodegenerativas (CIBERNED), Universität zu Lübeck [Lübeck] - University of Lübeck [Lübeck], [ANR-10-IAIHU-06],« Investissements d'avenir » ,Agence nationale de la recherche (ANR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Department of Psychiatry, van der Lee, Sven J [0000-0003-1606-8643], Naj, Adam C [0000-0002-9621-2942], Badarinarayan, Nandini [0000-0002-6944-748X], Chouraki, Vincent [0000-0002-4698-1794], Graham, Robert R [0000-0001-7151-4277], Hoffmann, Per [0000-0002-6573-983X], Smith, Albert V [0000-0003-1942-5845], Satizabal, Claudia L [0000-0002-1115-4430], Brody, Jennifer A [0000-0001-8509-148X], Wolters, Frank J [0000-0003-2226-4050], Lupton, Michelle K [0000-0002-7274-7299], Lin, Honghuang [0000-0003-3043-3942], Adams, Hieab H [0000-0003-3687-2508], Giedraitis, Vilmantas [0000-0003-3423-2021], Pasquier, Florence [0000-0001-9880-9788], Chen, Yuning [0000-0002-7358-7055], Bossù, Paola [0000-0002-1432-0078], Ghetti, Bernardino [0000-0002-1842-8019], Yang, Qiong [0000-0002-3658-1375], Aspelund, Thor [0000-0002-7998-5433], Bullido, María J [0000-0002-6477-1117], Rivadeneira, Fernando [0000-0001-9435-9441], Rubinsztein, David C [0000-0001-5002-5263], Al-Chalabi, Ammar [0000-0002-4924-7712], Tsolaki, Magda [0000-0002-2072-8010], De Jager, Philip L [0000-0002-8057-2505], Dickson, Dennis W [0000-0001-7189-7917], Van Broeckhoven, Christine [0000-0003-0183-7665], Ikram, M Arfan [0000-0003-0372-8585], Amouyel, Philippe [0000-0001-9088-234X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Berr, Claudine, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, and Mentoring of LifeSciHealth-Multipliers in the Accession Candidate Countries - LSH-ACC-MENTOR - 29845 - OLD
Subjects: 0301 basic medicine, Linkage disequilibrium, [SDV]Life Sciences [q-bio], Medizin, Sequence Homology, Genome-wide association study, genetics [Alzheimer Disease], metabolism [Microglia], Linkage Disequilibrium, 0302 clinical medicine, genetics [Protein Interaction Maps], genetics [Membrane Glycoproteins], Gene Frequency, Immunologic, genetics [Adaptor Proteins, Signal Transducing], Receptors, genetics [Exome], Odds Ratio, Innate, genetics [Receptors, Immunologic], Exome, Protein Interaction Maps, genetics [Genetic Predisposition to Disease], Receptors, Immunologic, ABI3 protein, human, Genetics, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amino Acid Sequence, Case-Control Studies, Gene Expression Profiling, Genetic Predisposition to Disease, Genotype, Humans, Immunity, Innate, Membrane Glycoproteins, Microglia, Phospholipase C gamma, Sequence Homology, Amino Acid, Polymorphism, Single Nucleotide, Adaptor Proteins, Single Nucleotide, 3. Good health, [SDV] Life Sciences [q-bio], Amino Acid, Settore MED/26 - NEUROLOGIA, genetics [Phospholipase C gamma], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, Common disease-common variant, Biology, Article, 03 medical and health sciences, ddc:570, medicine, Journal Article, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Polymorphism, Allele frequency, TREM2 protein, human, TREM2, Case-control study, Signal Transducing, Immunity, medicine.disease, R1, Minor allele frequency, genetics [Immunity, Innate], 030104 developmental biology, Human medicine, 030217 neurology & neurosurgery
Abstract: International audience; We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
Published: 2017
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14. [P4–327]: PATIENT AND CAREGIVER ASSESSMENT OF THE BENEFITS FROM THE CLINICAL USE OF AMYLOID‐PET IMAGING

Author: Maria C. Carrillo, Gil D. Rabinovici, Martha Tierney, David G. Clark, Bradley S. Glazier, Sujuan Gao, Jared R. Brosch, Liana G. Apostolova, Susan De Santi, Mary Guerriero Austrom, Rafid Mustafa, Bradford C. Dickerson, and Keith N. Fargo
Subjects: medicine.medical_specialty, medicine.diagnostic_test, Epidemiology, business.industry, Health Policy, Amyloid pet, Clinical Practice, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Positive response, Developmental Neuroscience, Positron emission tomography, Family medicine, Life insurance, Health care, medicine, Neurology (clinical), Geriatrics and Gerontology, Cognitive decline, business, Disability insurance
Abstract: Introduction Few studies to date have explored patient and caregiver views on the clinical use of amyloid positron emission tomography (PET). Methods A 7-item questionnaire assessing patient and caregiver views (510 total respondents) toward amyloid PET imaging was advertised broadly through alz.org/trialmatch. Results We received 510 unique responses from 48 US states, 2 Canadian provinces, the Dominican Republic, and Greece. Both patients and caregivers indicated that they would want to receive amyloid imaging if offered the opportunity. Over 88% of respondents had a positive response (∼10% with neutral and 2% with negative responses) to whether amyloid PET should be offered routinely and be reimbursed. Such information was felt to be useful for long-term legal, financial, and health care planning. Respondents identifying with early age cognitive decline (younger than 65 y) were more likely to explore options for disability insurance (P=0.03). Responders from the Midwest were more likely to utilize information from amyloid imaging for legal planning (P=0.02), disability insurance (P=0.02), and life insurance (P=0.04) than other US regions. Discussion Patients and caregivers supported the use of amyloid PET imaging in clinical practice and felt that the information would provide significant benefits particularly in terms of future planning.
Published: 2017
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15. Ploidy Levels and Pollen Stainability of Lantana camara Cultivars and Breeding Lines

Author: Carol D. Robacker, David G. Clark, David M. Czarnecki, Zhanao Deng, and Amanda J. Hershberger
Subjects: Chromosome number, biology, Pollen, Botany, Lantana camara, medicine, Cultivar, Horticulture, Ploidy, medicine.disease_cause, biology.organism_classification, Medicinal plants, Invasive species
Abstract: Lantana camara L., a popular nursery and landscape plant, is categorized as an invasive species in Florida, because it produces viable pollen and cross-pollinates with the native species Lantana depressa Small. The invasive potential of L. camara is a challenging issue for the nursery and landscape industry, so sterile non-invasive cultivars are needed to replace fertile invasive ones. This study aimed to determine the ploidy level and male fertility of both commercial L. camara cultivars and breeding lines to identify male-sterile cultivars and assess the effectiveness of sterile triploid production in L. camara. A polyploid series was identified among 32 L. camara cultivars and breeding lines. Male fertility, based on pollen stainability, varied widely among the cultivars/breeding lines. Ploidy level was the most important factor determining L. camara pollen stainability/male sterility. On average, diploids exhibited the highest pollen stainability (64.6%) followed by tetraploids (45.1%), pentaploids (34.6%), and hexaploids (18.0%). Triploids showed the lowest pollen stainability (9.3%), suggesting that generating triploids would be an effective genetic approach to producing sterile L. camara and reducing its pollen-mediated invasiveness. Pollen stainability of triploid cultivars, Balandpawn (LandmarkTM Pink Dawn PP15,516), Lemon Drop, Miss Huff, New Gold, New Red Lantana, Red Butler, Red Spread Lantana, Samson Lantana, and Sunset Lantana was consistently below 10%. A number of triploid cultivars had pollen stainability approaching 20% to 30%, indicating a necessity for careful examination and screening of newly produced triploids to ensure high sterility in selected triploids. Pollen stainability variation was observed within ploidy levels, implying the existence of other genetic and environmental factors that influence the pollen stainability/male fertility of L. camara. Results from this study suggest that there is excellent potential to develop genetically sterile cultivars in L. camara for the U.S. nursery and landscape industry.
Published: 2014
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16. Lower Hippocampal Volume Predicts Decrements in Lane Control Among Drivers With Amnestic Mild Cognitive Impairment

Author: Cynthia Owsley, Jan A. den Hollander, Virginia G. Wadley, Lindy E. Harrell, Daniel C. Marson, John C. Brockington, Ozioma C. Okonkwo, Luke E. Stoeckel, Karlene Ball, Jennifer Elgin, David G. Clark, H. Randall Griffith, and Christopher C. Stewart
Subjects: Gerontology, medicine.medical_specialty, medicine.diagnostic_test, Case-control study, Poison control, Magnetic resonance imaging, Odds ratio, medicine.disease, Psychiatry and Mental health, Atrophy, Internal medicine, medicine, Cardiology, Dementia, Biomarker (medicine), Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, Psychology
Abstract: Objectives: There are few methods to discern driving risks in patients with early dementia and mild cognitive impairment (MCI). We aimed to determine whether structural magnetic resonance imaging (MRI) of the hippocampus—a biomarker of probable Alzheimer pathology and a measure of disease severity in those affected—is linked to objective ratings of on-road driving performance in older adults with and without amnestic MCI. Methods: In all, 49 consensus-diagnosed participants from an Alzheimer’s Disease Research Center (15 diagnosed with amnestic MCI and 34 demographically similar controls) underwent structural MRI and on-road driving assessments. Results: Mild atrophy of the left hippocampus was associated with less-than-optimal ratings in lane control but not with other discrete driving skills. Decrements in left hippocampal volume conferred higher risk for less-than-optimal lane control ratings in the patients with MCI (B = −1.63, standard error [SE] = .74, Wald = 4.85, P = .028), but not in controls (B = 0.13, SE = .415, Wald = 0.10, P = .752). The odds ratio and 95% confidence interval for below-optimal lane control in the MCI group was 4.41 (1.18-16.36), which was attenuated to 3.46 (0.88-13.60) after accounting for the contribution of left hippocampal volume. Conclusion: These findings suggest that there may be a link between hippocampal atrophy and difficulties with lane control in persons with amnestic MCI. Further study appears warranted to better discern patterns of brain atrophy in MCI and Alzheimer disease and whether these could be early markers of clinically meaningful driving risk.
Published: 2013
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17. Longitudinal measurement and hierarchical classification framework for the prediction of Alzheimer's disease

Author: Mary L. Hynes, Liberty Teodoro, John C. Brockington, Connie Brand, Paul Malloy, Russell H. Swerdlow, Ronald C. Petersen, Judith L. Heidebrink, Pierre N. Tariot, Curtis Caldwell, Clifford R. Jack, David G. Clark, Neill R. Graff-Radford, Charles D. Smith, Geoffrey Tremont, Ranjan Duara, Stephen Pasternack, T. Y. Lee, Owen Carmichael, Nadira Trncic, Irina Rachisky, Daniel D'Agostino, James J. Lah, Steven G. Potkin, Howard Bergman, Dana M. Pogorelec, Lon S. Schneider, Anna Burke, Sherye A. Sirrel, Henry W. Querfurth, Michael Lin, David Bachman, Edward Coleman, Michele Assaly, Allyson C. Rosen, Jeffrey M. Burns, Balebail Ashok Raj, Jared R. Brosch, Joanne L. Lord, William Brooks, Brigid Reynolds, Karen S. Anderson, Sandra Jacobson, Nunzio Pomara, Patricia Lynn Johnson, George Bartzokis, Parianne Fatica, Benita Mudge, Dana Nguyen, Carl H. Sadowsky, Michael Borrie, Qianjin Feng, Chiadi U. Onyike, Partha Sinha, Gloria Chaing, Howard Chertkow, Leyla deToledo-Morrell, Bojana Stefanovic, Richard E. Carson, Wufan Chen, Ronald J. Killiany, Mimi Dang, Thomas O. Obisesan, Christopher H. van Dyck, Maria Carroll, Gaby Thai, Arthur W. Toga, Chuang Kuo Wu, Erik D. Roberson, Effie M. Mitsis, Smita Kittur, Keith A. Johnson, Dana Mathews, Sara Dolen, Raj C. Shah, M.-Marsel Mesulam, Howard J. Rosen, Karen L. Bell, Ging-Yuek Robin Hsiung, Teresa Villena, Kris Johnson, Saba Wolday, Douglas W. Scharre, Kyle B. Womack, Maria Kataki, Barton Lane, Angela Oliver, Greg Jicha, Reisa A. Sperling, Wei Yang, David S. Geldmacher, Lawrence S. Honig, Sanjay Asthana, Janet S. Cellar, William J. Jagust, Dzintra Celmins, Susan Rountree, Christina A. Michel, Allan I. Levey, Tracy Kendall, Lisa D. Ravdin, Jared R. Tinklenberg, Brittany Cerbone, Alice D. Brown, Marilyn S. Albert, Andrew J. Saykin, Raymundo Hernando, Sandra Weintraub, John Q. Trojanowki, Raina Carter, Betty Lind, Kristin Fargher, Sterling C. Johnson, P. Murali Doraiswamy, Jeffrey R. Petrella, Neil W. Kowall, Sara S. Mason, Heather Johnson, Mary L. Creech, Stacy Schneider, Donna Munic, Liana G. Apostolova, Peter A. Hardy, Munir Chowdhury, Bruce L. Miller, Ruth A. Mulnard, Curtis Tatsuoka, Po H. Lu, Daniel C. Marson, Pauline Maillard, John C. Morris, Marwan N. Sabbagh, Jeffrey Kaye, Hillel Grossman, Gary R. Conrad, Karen Blank, Meiyan Huang, Stephanie Kielb, Andrew Kertesz, Jerome A. Yesavage, Leslie Shaw, Martin R. Farlow, Maria T. Greig, Jacobo Mintzer, Susan De Santi, David S. Knopman, Marc Seltzer, Scott Herring, Joy L. Taylor, Vernice Bates, Rob Bartha, Cynthia Hunt, Henry Rusinek, Randall Griffith, Cynthia M. Carlsson, Charles Bernick, Bonnie S. Goldstein, Rachelle S. Doody, Leslie Gordineer, Catherine Mc-Adams-Ortiz, Kim Martin, Howard Feldman, David C. Perry, Horacio Capote, Lidia Glodzik, Stephen Correia, James B. Brewer, Elizabeth Finger, Jeff D. Williamson, Franklin Watkins, Borna Bonakdarpour, Colleen S. Albers, M. Saleem Ismail, Alan J. Lerner, Daniel Varon, Christine M. Belden, Sonia Pawluczyk, Paul S. Aisen, Pradeep Garg, Kelly M. Makino, Laurel A. Beckett, Peggy Roberts, Nancy Johnson, Anahita Adeli, Terence Z. Wong, Michelle Rainka, Elizabeth Oates, Amanda Smith, Kenneth M. Spicer, Laura A. Flashman, Kristine Lipowski, Charles DeCarli, Stephanie Reeder, Mauricio Beccera, Dick Trost, Alexander Norbash, Lisa C. Silbert, Michael W. Weiner, Gad A. Marshall, Ann Marie Hake, Pradeep Varma, Francine Parfitt, Chris Hosein, Adam S. Fleisher, Marissa Natelson Love, Joanne S. Allard, Earl A. Zimmerman, Kathleen Tingus, Brian R. Ott, Joseph F. Quinn, Anton P. Porsteinsson, Paula Ogrocki, Raymond Scott Turner, Salvador Borges-Neto, James E. Galvin, Yaakov Stern, Andrew E. Budson, Martha G. MacAvoy, Daniel H.S. Silverman, Robert B. Santulli, Adrian Preda, Godfrey D. Pearlson, Mark A. Mintun, Stephen Salloway, Mary Quiceno, Kaycee M. Sink, John M Olichney, Antero Sarrael, Beau M. Ances, Javier Villanueva-Meyer, Mony J. de Leon, Sandra E. Black, Bryan M. Spann, Diana R. Kerwin, Ellen Woo, Helen Vanderswag, Erin E. Franklin, Robert C. Green, and Norman R. Relkin
Subjects: Male, Computer science, Neuroimaging, Disease, computer.software_genre, Sensitivity and Specificity, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Predictive Value of Tests, mental disorders, medicine, Dementia, Humans, Cognitive Dysfunction, Longitudinal Studies, Cognitive impairment, Aged, Aged, 80 and over, Multidisciplinary, medicine.diagnostic_test, business.industry, Brain, Pattern recognition, Magnetic resonance imaging, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Early Diagnosis, Disease Progression, Female, Data mining, Artificial intelligence, business, computer, 030217 neurology & neurosurgery, Alzheimer's Disease Neuroimaging Initiative, Follow-Up Studies
Abstract: Accurate prediction of Alzheimer’s disease (AD) is important for the early diagnosis and treatment of this condition. Mild cognitive impairment (MCI) is an early stage of AD. Therefore, patients with MCI who are at high risk of fully developing AD should be identified to accurately predict AD. However, the relationship between brain images and AD is difficult to construct because of the complex characteristics of neuroimaging data. To address this problem, we present a longitudinal measurement of MCI brain images and a hierarchical classification method for AD prediction. Longitudinal images obtained from individuals with MCI were investigated to acquire important information on the longitudinal changes, which can be used to classify MCI subjects as either MCI conversion (MCIc) or MCI non-conversion (MCInc) individuals. Moreover, a hierarchical framework was introduced to the classifier to manage high feature dimensionality issues and incorporate spatial information for improving the prediction accuracy. The proposed method was evaluated using 131 patients with MCI (70 MCIc and 61 MCInc) based on MRI scans taken at different time points. Results showed that the proposed method achieved 79.4% accuracy for the classification of MCIc versus MCInc, thereby demonstrating very promising performance for AD prediction.
Published: 2017

18. MRI volume of the medial frontal cortex predicts financial capacity in patients with mild Alzheimer’s disease

Author: Katherine Belue, Roy C. Martin, John C. Brockington, H. Randall Griffith, Kristen L. Triebel, David G. Clark, Luke E. Stoeckel, Daniel C. Marson, Lindy E. Harrell, Ozioma C. Okonkwo, Jan A. den Hollander, Jacquelynn N. Copeland, and Christopher C. Stewart
Subjects: Male, Financing, Personal, Cognitive Neuroscience, Decision Making, Statistics as Topic, Precuneus, Sensitivity and Specificity, behavioral disciplines and activities, Article, Angular gyrus, Behavioral Neuroscience, Cellular and Molecular Neuroscience, Atrophy, Cognitive Reserve, Alzheimer Disease, medicine, Humans, Cognitive Dysfunction, Radiology, Nuclear Medicine and imaging, Aged, Cognitive reserve, Finance, medicine.diagnostic_test, business.industry, Neuropsychology, Reproducibility of Results, Magnetic resonance imaging, Organ Size, medicine.disease, Magnetic Resonance Imaging, Frontal Lobe, Psychiatry and Mental health, medicine.anatomical_structure, Neurology, Frontal lobe, Female, Neurology (clinical), Alzheimer's disease, Psychology, business
Abstract: Persons with mild Alzheimer's disease (AD) have significant deficits in financial abilities. This study examined the relationship between brain structure volumes, cognition, and financial capacity in patients with mild AD. Sixteen mild AD patients and 16 older adult comparisons completed the Financial Capacity Instrument (FCI), a psychometric measure of financial abilities, and also underwent magnetic resonance imaging (MRI) to obtain volumes of the bilateral hippocampi, angular gyri, precunei, and medial and dorsolateral frontal cortices. Mild AD patients performed significantly below comparisons on the FCI and had significantly smaller hippocampi. Among mild AD patients, FCI performance was moderately correlated with frontal (medial and dorsolateral frontal cortex) and posterior (angular gyri and precunei) cortical volumes. Stepwise regression demonstrated that medial frontal cortex volume predicted FCI score. The relationship between medial frontal cortex volume and overall FCI score was partially mediated by two measures of simple attention (DRS Attention, DRS Construction). The findings suggest that medial frontal cortex atrophy and associated declines in simple attention play an increasingly important role in declining financial skills in patients with mild AD.
Published: 2013
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19. Clinical, Imaging, Pathological, and Biochemical Characterization of a Novel Presenilin 1 Mutation (N135Y) Causing Alzheimer's Disease

Author: David G. Clark, Kyle A. Den Beste, Randall J. Bateman, Tammie L.S. Benzinger, J. Nicholas Cochran, Erik D. Roberson, John C. Morris, David S. Geldmacher, Marissa Natelson Love, and Brian A. Gordon
Subjects: 0301 basic medicine, Proband, Adult, Aging, Pathology, medicine.medical_specialty, Spastic gait, Neuroimaging, Neuropsychological Tests, Presenilin, Article, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Alzheimer Disease, medicine, PSEN1, Presenilin-1, Missense mutation, Humans, Genetic Testing, Genetic Association Studies, Amyloid beta-Peptides, General Neuroscience, Brain, Electroencephalography, Middle Aged, medicine.disease, Magnetic Resonance Imaging, 030104 developmental biology, Positron-Emission Tomography, Mutation (genetic algorithm), Mutation, Female, Neurology (clinical), Geriatrics and Gerontology, Psychology, 030217 neurology & neurosurgery, Developmental Biology, Executive dysfunction
Abstract: We present two cases of early-onset Alzheimer's disease due to a novel N135Y mutation in PSEN1. The proband presented with memory and other cognitive symptoms at age 32. Detailed clinical characterization revealed initial deficits in memory with associated dysarthria, progressing to involve executive dysfunction, spastic gait, and episodic confusion with polyspike discharges on long-term electroencephalography. Amyloid- and FDG-PET scans showed typical results of Alzheimer's disease. By history, the proband's father had developed cognitive symptoms at age 42 and died at age 48. Neuropathological evaluation confirmed Alzheimer's disease, with moderate to severe amyloid angiopathy. Skeletal muscle showed type 2 fiber– predominant atrophy with pale central clearing. Genetic testing of the proband revealed an N135Y missense mutation in PSEN1. This mutation was predicted to be pathogenic by in silico analysis. Biochemical analysis confirmed that the mutation caused an increased Aβ42/Aβ40 ratio, consistent with other PSEN1 mutations and with a loss of presenilin function.
Published: 2016

20. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Author: Marla Gearing, David G. Clark, Steven L. Carroll, Marianne Johnstone, Darwin L. Conwell, Gregory A. Cote, Sandra Weintraub, Matthew P. Frosch, Stuart Sherman, Badri N. Vardarajan, Joshua A. Sonnen, Lindy E. Harrell, Peter B. Cotton, Lisa L. Barnes, Lawrence S. Honig, Carol A. Miller, Adam Slivka, Michelle A. Anderson, Nadine M. Melhem, David A. Bennett, Joel H. Kramer, Jill P. Smith, Michele D. Lewis, Mary Ganguli, Jean Paul Vonsatte, Thomas J. Montine, Lee-Way Jin, Kenneth B. Fallon, Marilyn S. Albert, Eliezer Masliah, John H. Growdon, Barry Reisberg, Chuanhai Cao, Patricia L. Kramer, Douglas J. Hartman, Allan I. Levey, Jennifer Williamson, Vivianna M. Van Deerlin, Wayne W. Poon, Alison Goate, Vijay P. Singh, Bernie Devlin, Christiane Reitz, Ann C. McKee, Amanda Smith, Neill R. Graff-Radford, Walter A. Kukul, John Baillie, Andres Gelrud, Ranjan Duara, Thomas D. Bird, Clinton B. Wright, Deborah Blacker, Chiao-Feng Lin, Ge Li, Ronald C. Kim, Deborah C. Mash, Debby W. Tsuang, John P. Neoptolemos, Timothy B. Gardner, Kathryn L. Lunetta, Steven G. Younkin, Kara L. Hamilton-Nelson, Ronald L. Hamilton, F. Yesim Demirci, Eric M. Reiman, Charles DeCarli, John M Olichney, Richard Mayeux, Gregory A. Jicha, Michael R. O'Connell, Matt Tector, Eileen H. Bigio, Jonathan D. Glass, M. Ilyas Kamboh, Randall E. Brand, Christopher Lawrence, Steven E. Arnold, Jessica LaRusch, Elaine R. Peskind, David H. Cribbs, M.-Marsel Mesulam, Constantine G. Lyketsos, Michelle L. Kienholz, Frank M. LaFerla, Duane Beekly, Kelley Faber, Salvatore Spina, Gyungah Jun, Thiruvengadam Muniraj, Erik D. Roberson, Anna Karydas, Steven H. Ferris, Bruce L. Miller, Randall L. Woltjer, Li-San Wang, Lon S. Schneider, John C. Morris, John Q. Trojanowski, Jeffrey Kaye, Joseph E. Parisi, Nilufer Ertekin-Taner, Harry V. Vinters, Lidiya Orlichenko, Robert Barber, Chris E. Forsmark, Mary Sano, Bimaljit S. Sandhu, Peter A. Banks, Martin R. Farlow, Bradley T. Hyman, Joseph F. Quinn, Gary W. Beecham, James A. DiSario, Hakon Hakonarson, Daniel C. Marson, Adam C. Naj, Frank Martiniuk, Oscar L. Lopez, Mary E. Money, Julia Mayerle, William Greenhalf, Kathryn Roeder, Adam L. Boxer, Christine M. Hulette, Gerard D. Schellenberg, Georgios I. Papachristou, Douglas Galasko, James R. Burke, Donna B. Stolz, Murray A. Raskind, Peter Simon, Linda J. Van Eldik, Robert A. Hawes, Chang En Yu, Tatiana Foroud, Jonathan L. Haines, Stephen R. Wisniewski, William W. Seeley, Dhiraj Yadav, James J. Lah, C. Mel Wilcox, Sid Gilman, Liana G. Apostolova, Howard J. Rosen, Clinton T. Baldwin, Robert S. Stern, Narcis O. Zarnescu, Dennis W. Dickson, Margaret A. Pericak-Vance, Ashok Raj, Stephen T. Amann, Joseph D. Buxbaum, Ronald C. Petersen, Robert C. Green, David C. Whitcomb, Rudolph E. Tanzi, Lindsay A. Farrer, Helena C. Chui, Laura B. Cantwell, Wendy J. Mack, Samer Alkaade, Nigel J. Cairns, Thomas G. Beach, Frank Ulrich Weiss, Alyssa M. Krasinskas, Elizabeth Head, Nalini M. Guda, Julie A. Schneider, Malcolm B. Dick, Roger N. Rosenberg, Jill R. Murrel, Otto Valladares, Andrew J. Saykin, Huntington Potter, John R. Gilbert, Neil W. Kowall, Joseph Romagnuolo, Markus M. Lerch, Aimee Pierce, Roger L. Albin, John M. Ringman, James B. Leverenz, Carlos Cruchaga, Joshua W. Miller, Lei Yu, M. Michael Barmada, Lambertus Klei, Andrew P. Lieberman, Bernardino Ghetti, Robert Sutton, Kathleen A. Welsh-Bohmer, Juan C. Troncoso, Edward H. Koo, Elizabeth Crocco, Eden R. Martin, Daniel H. Geschwind, and Regina M. Carney
Subjects: Male, Pancreatic disease, Pancreatitis, Alcoholic, Genome-wide association study, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Sex Factors, Gene Frequency, Genotype, Genetics, medicine, PRSS2, Humans, Genetic Predisposition to Disease, Trypsin, Allele, Allele frequency, Homozygote, Genetic Variation, medicine.disease, 3. Good health, Hemizygote, 030220 oncology & carcinogenesis, Immunology, Claudins, Mutation, Trypsinogen, Pancreatitis, 030211 gastroenterology & hepatology, Female, Genome-Wide Association Study
Abstract: Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).
Published: 2012

21. Alzheimer disease pathology in cognitively healthy elderly: A genome-wide study

Author: Patricia L. Kramer, Randall L. Woltjer, Kathleen A. Welsh-Bohmer, David G. Clark, William R. Markesbery, Haiyan Xu, R. Scott Turner, Jeffrey Kaye, Walter A. Kukull, John C. Morris, Deniz Erten-Lyons, Juan C. Troncoso, David A. Bennett, Ronald C. Petersen, Douglas Galasko, Jurg Ott, and Shawn K. Westaway
Subjects: Male, Aging, Pathology, medicine.medical_specialty, Cell Adhesion Molecules, Neuronal, Health Status, Nerve Tissue Proteins, tau Proteins, Genome-wide association study, Context (language use), Neuropathology, Polymorphism, Single Nucleotide, Article, Cohort Studies, Cognition, Alzheimer Disease, Genotype, medicine, Humans, Dementia, Longitudinal Studies, Reelin, Phosphorylation, Allele, Aged, Aged, 80 and over, Extracellular Matrix Proteins, biology, General Neuroscience, Serine Endopeptidases, Neurofibrillary Tangles, medicine.disease, Reelin Protein, biology.protein, Female, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, Psychology, Neuroscience, Genome-Wide Association Study, Signal Transduction, Developmental Biology
Abstract: Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 344 non-demented subjects with autopsy (201 subjects with low and 143 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided genome-wide significant evidence that variants in the RELNgene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through β-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia.
Published: 2011
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22. Residual vectors for Alzheimer disease diagnosis and prognostication

Author: David G. Clark
Subjects: Bioinformatics, computer.software_genre, Logistic regression, Residual, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Neuroimaging, Similarity (network science), Voxel, Methods, ADNI, Medicine, business.industry, Cosine similarity, Mild cognitive impairment, Pattern recognition, PET scan, medicine.disease, Biomarker (medicine), Data mining, Artificial intelligence, Alzheimer disease, Alzheimer's disease, business, computer, 030217 neurology & neurosurgery
Abstract: Alzheimer disease (AD) is an increasingly prevalent neurodegenerative condition and a looming socioeconomic threat. A biomarker for the disease could make the process of diagnosis easier and more accurate, and accelerate drug discovery. The current work describes a method for scoring brain images that is inspired by fundamental principles from information retrieval (IR), a branch of computer science that includes the development of Internet search engines. For this research, a dataset of 254 baseline 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) scans was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). For a given contrast, a subset of scans (nine of every 10) was used to compute a residual vector that typified the difference, at each voxel, between the two groups being contrasted. Scans that were not used for computing the residual vector (the remaining one of 10 scans) were then compared to the residual vector using a cosine similarity metric. This process was repeated sequentially, each time generating cosine similarity scores on 10% of the FDG-PET scans for each contrast. Statistical analysis revealed that the scores were significant predictors of functional decline as measured by the Functional Activities Questionnaire (FAQ). When logistic regression models that incorporated these scores were evaluated with leave-one-out cross-validation, cognitively normal controls were discerned from AD with sensitivity and specificity of 94.4% and 84.8%, respectively. Patients who converted from mild cognitive impairment (MCI) to AD were discerned from MCI nonconverters with sensitivity and specificity of 89.7% and 62.9%, respectively, when FAQ scores were brought into the model. Residual vectors are easy to compute and provide a simple method for scoring the similarity between an FDG-PET scan and sets of examples from a given diagnostic group. The method is readily generalizable to any imaging modality. Further interdisciplinary work between IR and clinical neuroscience is warranted.
Published: 2011
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23. Novel histopathologic findings in molecularly-confirmed pantothenate kinase-associated neurodegeneration

Author: Marjorie R. Grafe, Susan J. Hayflick, David G. Clark, Randall L. Woltjer, Mark Hiken, P. Hogarth, Michael C. Kruer, Alessandro Malandrini, and Allison Gregory
Subjects: Alpha-synuclein, neuropathology, Pathology, medicine.medical_specialty, Hallervorden-Spatz, Neurodegeneration with brain iron accumulation, alpha-synuclein, Neurodegeneration, pantothenate kinase-associated neurodegeneration (PKAN), Neuropathology, Biology, PANK2, medicine.disease, tau, Pantothenate kinase-associated neurodegeneration, chemistry.chemical_compound, Globus pallidus, chemistry, Basal ganglia, medicine, Neurology (clinical), Neuroscience
Abstract: Pantothenate kinase-associated neurodegeneration is a form of neurodegeneration with brain iron accumulation, characterized by a progressive movement disorder and prominent iron deposition in the globus pallidus. Formerly referred to as Hallervorden–Spatz syndrome, the disorder was renamed pantothenate kinase-associated neurodegeneration after discovery of the causative gene, PANK2. Although the pathological features of clinically characterized Hallervorden–Spatz syndrome have been described, the literature is confounded by the historical use of this term for nearly all conditions with prominent basal ganglia iron accumulation and by the fact that this term encompasses a genetically heterogeneous group of disorders, now referred to as ‘neurodegeneration with brain iron accumulation’. As a result, interpreting reports that precede molecular characterization of specific forms of neurodegeneration with brain iron accumulation is problematic. In the present studies, we describe neuropathological findings in six cases of molecularly confirmed pantothenate kinase-associated neurodegeneration. We identify prominent ubiquinated deposits in pantothenate kinase-associated neurodegeneration. We also characterize two distinct origins of spheroid bodies and delineate histological features of iron deposition. In so doing, we characterize fundamental features of the disease and redefine its nosological relationship to other neurodegenerative disorders.
Published: 2011
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24. Brain Metabolic Correlates of Decision Making in Amnestic Mild Cognitive Impairment

Author: H. Randall Griffith, David G. Clark, Jacqueline Copeland, John C. Brockington, Katherine Belue, Daniel C. Marson, Jan A. den Hollander, Lindy E. Harrell, and Ozioma C. Okonkwo
Subjects: Male, Cingulate cortex, medicine.medical_specialty, Magnetic Resonance Spectroscopy, Decision Making, Health Behavior, Amnesia, Experimental and Cognitive Psychology, Neurological disorder, Neuropsychological Tests, Audiology, Creatine, Article, Choline, Central nervous system disease, chemistry.chemical_compound, mental disorders, medicine, Humans, Memory disorder, Psychiatry, Aged, Aspartic Acid, Cognitive disorder, Brain, Middle Aged, medicine.disease, Psychiatry and Mental health, Neuropsychology and Physiological Psychology, chemistry, Posterior cingulate, Female, Geriatrics and Gerontology, medicine.symptom, Cognition Disorders, Psychology, Inositol
Abstract: Persons with amnestic mild cognitive impairment (MCI) have subtle impairments in medical decision-making capacity (MDC). We examined the relationship between proton magnetic resonance spectroscopy (MRS) and MDC in MCI. Twenty-nine MCI patients and 42 controls underwent MRS to obtain ratios of N-acetylaspartate (NAA)/Creatine (Cr), Choline (Cho)/Cr, and myo-Inositol (mI)/Cr of the posterior cingulate. They also completed the Capacity to Consent to Treatment Instrument (CCTI), a vignette-based instrument measuring decisional standards of expressing choice, appreciating consequences of choice, providing rational reasons for choice, and understanding treatment choices. Patients showed abnormal MRS ratios of mI/Cr and Cho/Cr compared to controls, and impairments on the CCTI understanding and reasoning Standards. Performance on the Reasoning Standard of the CCTI was correlated with NAA/Cr (r = 0.46, p < 0.05). The relationship of NAA/Cr with decision-making suggests a role for posterior cortical neuronal functioning in performance of complex IADLs in MCI.
Published: 2010
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25. Magnetic Resonance Imaging Volume of the Angular Gyri Predicts Financial Skill Deficits in People with Amnestic Mild Cognitive Impairment

Author: Roy C. Martin, John C. Brockington, Daniel C. Marson, H. Randall Griffith, Jan A. den Hollander, Katherine Belue, Christopher C. Stewart, Lindy E. Harrell, Jacquelynn N. Copeland, Ozioma C. Okonkwo, Luke E. Stoeckel, and David G. Clark
Subjects: Finance, medicine.diagnostic_test, business.industry, Cognitive disorder, Precuneus, Amnesia, Magnetic resonance imaging, Neurological disorder, medicine.disease, Angular gyrus, medicine.anatomical_structure, Atrophy, mental disorders, medicine, Memory disorder, Geriatrics and Gerontology, medicine.symptom, business, human activities
Abstract: OBJECTIVES Persons with amnestic mild cognitive impairment (MCI) have demonstrated subtle impairments in IADLs including financial abilities, although the underlying brain changes related to these IADL impairments is poorly understood. The purpose of this investigation was to better understand how brain atrophy in MCI as measured by MRI volumetrics could impact IADLs such as financial abilities.
Published: 2010
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26. Neurocognitive predictors of financial capacity across the dementia spectrum: Normal aging, mild cognitive impairment, and Alzheimer’s disease

Author: John C. Brockington, David G. Clark, Sara Krzywanski, Katherine Belue, H. Randall Griffith, Edward Zamrini, Jacquelynn N. Copeland, Richard E. Powers, Daniel C. Marson, Megan G. Sherod, and Lindy E. Harrell
Subjects: Male, Aging, Activities of daily living, Financial Management, Models, Psychological, Neuropsychological Tests, behavioral disciplines and activities, Article, Mental Processes, Alzheimer Disease, Memory, Predictive Value of Tests, medicine, Humans, Dementia, Attention, Geriatric Assessment, Aged, Language, Finance, Analysis of Variance, medicine.diagnostic_test, Recall, business.industry, General Neuroscience, Cognition, Neuropsychological test, Middle Aged, medicine.disease, Psychiatry and Mental health, Clinical Psychology, Visual Perception, Female, Neurology (clinical), Alzheimer's disease, Verbal memory, Cognition Disorders, business, Psychology, Neurocognitive, Mathematics
Abstract: Financial capacity is a complex instrumental activity of daily living critical to independent functioning of older adults and sensitive to impairment in patients with amnestic mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, little is known about the neurocognitive basis of financial impairment in dementia. We developed cognitive models of financial capacity in cognitively healthy older adults (n = 85) and patients with MCI (n = 113) and mild AD (n = 43). All participants were administered the Financial Capacity Instrument (FCI) and a neuropsychological test battery. Univariate correlation and multiple regression procedures were used to develop cognitive models of overall FCI performance across groups. The control model (R2 = .38) comprised (in order of entry) written arithmetic skills, delayed story recall, and simple visuomotor sequencing. The MCI model (R2 = .69) comprised written arithmetic skills, visuomotor sequencing and set alternation, and race. The AD model (R2 = .65) comprised written arithmetic skills, simple visuomotor sequencing, and immediate story recall. Written arithmetic skills (WRAT-3 Arithmetic) was the primary predictor across models, accounting for 27% (control model), 46% (AD model), and 55% (MCI model) of variance. Executive function and verbal memory were secondary model predictors. The results offer insight into the cognitive basis of financial capacity across the dementia spectrum of cognitive aging, MCI, and AD. (JINS, 2009, 15, 258–267.)
Published: 2009
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27. A computational semantics approach to aphasic sentence comprehension

Author: David G. Clark
Subjects: Linguistics and Language, Computer science, computer.software_genre, Semantics, Language and Linguistics, Semantic role labeling, Agrammatism, Developmental and Educational Psychology, medicine, Parsing, business.industry, Parse tree, LPN and LVN, Syntax, Linguistics, TheoryofComputation_MATHEMATICALLOGICANDFORMALLANGUAGES, Neurology, Otorhinolaryngology, Computational semantics, Neurology (clinical), Artificial intelligence, medicine.symptom, business, computer, Natural language processing, Sentence
Abstract: Background: Patients with brain damage often exhibit difficulty understanding sentences, with certain grammatical constructions posing more of a problem than others. Differences between sentences that are “hard” or “easy” to process have been characterised in terms of modern syntactic theory, leading to a number of insightful proposals regarding the nature of sentence comprehension problems in aphasia. However, little attention has been devoted to the semantic aspects of aphasic sentence comprehension. Aims: The primary aim of this research is to validate the use of a computational semantic approach for modelling aphasic sentence comprehension. Methods & Procedures: The model presented here is an extension of natural language processing software designed by Blackburn and Bos (2006). The original program parses a natural language expression by means of a simple definite clause grammar, assigning a semantic representation to each node in the parse tree. The final result of a successful parse is a sentence f...
Published: 2008
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28. Medical decision-making capacity in mild cognitive impairment: A 3-year longitudinal study

Author: J. N. Copeland, Daniel C. Marson, Lindy E. Harrell, John C. Brockington, Rema Raman, Ozioma C. Okonkwo, Edward Zamrini, K. Belue, Stephanie T. Lanza, H. R. Griffith, and David G. Clark
Subjects: Male, medicine.medical_specialty, Longitudinal study, Time Factors, Decision Making, Amnesia, Neuropsychological Tests, Physical medicine and rehabilitation, Alzheimer Disease, Informed consent, mental disorders, medicine, Humans, Longitudinal Studies, Cognitive impairment, Psychiatry, Aged, Psychiatric Status Rating Scales, Informed Consent, Consent to treatment, Cognitive disorder, Articles, Middle Aged, Medical decision making, medicine.disease, Disease Progression, Female, Neurology (clinical), Alzheimer's disease, medicine.symptom, Cognition Disorders, Psychology
Abstract: Objective: To investigate longitudinal change in the medical decision-making capacity (MDC) of patients with amnestic mild cognitive impairment (MCI) under different consent standards. Methods: Eighty-eight healthy older controls and 116 patients with MCI were administered the Capacity to Consent to Treatment Instrument at baseline and at 1 to 3 (mean = 1.7) annual follow-up visits thereafter. Covariate-adjusted random coefficient regressions were used to examine differences in MDC trajectories across MCI and control participants, as well as to investigate the impact of conversion to Alzheimer disease on MCI patients’ MDC trajectories. Results: At baseline, MCI patients performed significantly below controls only on the three clinically relevant standards of appreciation, reasoning, and understanding. Compared with controls, MCI patients experienced significant declines over time on understanding but not on any other consent standard. Conversion affected both the elevation (a decrease in performance) and slope (acceleration in subsequent rate of decline) of MCI patients’ MDC trajectories on understanding. A trend emerged for conversion to be associated with a performance decrease on reasoning in the MCI group. Conclusions: Medical decision-making capacity (MDC) decline in mild cognitive impairment (MCI) is a relatively slow but detectable process. Over a 3-year period, patients with amnestic MCI show progressive decline in the ability to understand consent information. This decline accelerates after conversion to Alzheimer disease (AD), reflecting increasing vulnerability to decisional impairment. Clinicians and researchers working with MCI patients should give particular attention to the informed consent process when conversion to AD is suspected or confirmed.
Published: 2008
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29. Medical decision-making capacity in cognitively impaired Parkinson's disease patients without dementia

Author: Daniel C. Marson, Roy C. Martin, Alfred A. Bartolucci, Anthony P. Nicholas, H. Randall Griffith, Natividad Stover, David G. Clark, Kristen L. Triebel, Ray L. Watts, Lindy E. Harrell, Ozioma C. Okonkwo, and Joni Hill
Subjects: Male, medicine.medical_specialty, Parkinson's disease, Decision Making, Disease, Neuropsychological Tests, Article, Central nervous system disease, Degenerative disease, mental disorders, medicine, Humans, Dementia, Mental Competency, Aged, Retrospective Studies, Physician-Patient Relations, Informed Consent, Cognitive disorder, Parkinson Disease, Middle Aged, Medical decision making, medicine.disease, Neurology, Case-Control Studies, Physical therapy, Female, Neurology (clinical), Cognitively impaired, Cognition Disorders, Psychology
Abstract: Little is currently known about the higher order functional skills of patients with Parkinson disease and cognitive impairment. Medical decision-making capacity (MDC) was assessed in patients with Parkinson's disease (PD) with cognitive impairment and dementia. Participants were 16 patients with PD and cognitive impairment without dementia (PD-CIND), 16 patients with PD dementia (PDD), and 22 healthy older adults. All participants were administered the Capacity to Consent to Treatment Instrument (CCTI), a standardized capacity instrument assessing MDC under five different consent standards. Parametric and non-parametric statistical analyses were utilized to examine capacity performance on the consent standards. In addition, capacity outcomes (capable, marginally capable, or incapable outcomes) on the standards were identified for the two patient groups. Relative to controls, PD-CIND patients demonstrated significant impairment on the understanding treatment consent standard, clinically the most stringent CCTI standard. Relative to controls and PD-CIND patients, patients with PDD patients were impaired on the three clinical standards of understanding, reasoning, and appreciation. The findings suggest that impairment in decisional capacity is already present in cognitively impaired PD patients without dementia, and increases as these patients develop dementia. Clinicians and researchers should carefully assess decisional capacity in all PD patients with cognitive impairment.
Published: 2008
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30. 'Apperceptive' Alexia in Posterior Cortical Atrophy

Author: Jill S. Shapira, Mario F. Mendez, and David G. Clark
Subjects: Male, Reading disability, genetic structures, Cognitive Neuroscience, media_common.quotation_subject, Experimental and Cognitive Psychology, Context (language use), Dyslexia, Perceptual Disorders, Visual processing, Reference Values, Reading (process), medicine, Humans, Aged, media_common, Cerebral Cortex, Brain Diseases, Posterior cortical atrophy, Middle Aged, medicine.disease, Apperceptive agnosia, Neuropsychology and Physiological Psychology, Pattern Recognition, Visual, Reading, Agraphia, Visual Perception, Female, Atrophy, medicine.symptom, Psychology, Cognitive psychology
Abstract: The most common presenting complaint in posterior cortical atrophy (PCA) is reading difficulty. Although often described as an alexia without agraphia, alexia in PCA may have multiple causes, including a primary visuoperceptual etiology, attentional alexia, and central reading difficulty. This study evaluated 14 patients with early PCA and disturbances in reading ability in comparison to 14 normal controls. All 14 patients had a progressive disorder of complex visual functions and neuroimaging evidence of occipitoparietal dysfunction. They underwent a task requiring identification of single letters with and without flanking distractors. They also read single words consisting of regular English spelling or irregular grapheme-phoneme correspondence (irregular words) and pronounceable nonsense words (pseudowords). The PCA patients made errors in letter identification when letters were flanked by visually similar letters or numbers. They could read most single regular and irregular words but made visual errors and had particular trouble with pseudowords. They could not use a letter-by-letter reading strategy effectively. The PCA patients had similar difficulties on other visuoperceptual tests. These findings are consistent with an alexia manifested by perceptual and attentional difficulty on attempting serial visual processing of letters in the context of other letters. This “apperceptive alexia” results when the configuration of letters into words is impaired during letter-by-letter reading. Disproportionate difficulty reading pseudowords suggests an additional impairment in phonological processing. PCA patients have variable neuropathology and individual patients may have other contributions to their reading impairment.
Published: 2007
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31. Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals

Author: Lee-Way Jin, Rudolph E. Tanzi, Lisa L. Barnes, Neill R. Graff-Radford, Joel H. Kramer, Tatiana Foroud, John R. Gilbert, Wayne W. Poon, Philip L. De Jager, Lei Yu, John M. Ringman, James J. Lah, Marla Gearing, David A. Bennett, Susan M. McCurry, Kenneth B. Fallon, Clinton B. Wright, Deborah Blacker, Bradley T. Hyman, Patricia L. Kramer, Joseph F. Quinn, Alison Goate, Gail P. Jarvik, Allan I. Levey, Jennifer Williamson, Mary Ganguli, Carlos Cruchaga, Julie A. Schneider, Amanda Smith, Eric M. Reiman, Lon S. Schneider, Steven H. Ferris, Richard Mayeux, Randall L. Woltjer, Li-San Wang, Goldie S. Byrd, Malcolm B. Dick, Towfique Raj, Steven L. Carroll, Carol A. Miller, Bradley F. Boeve, John S. K. Kauwe, Elaine R. Peskind, Hugh C. Hendrie, R. C. Kim, Jonathan D. Glass, Helena C. Chui, Guiqing Cai, Deborah C. Mash, Gyungah Jun, James Bowen, Marilyn S. Albert, Kathryn L. Lunetta, Huntington Potter, Walter A. Kukull, Paul K. Crane, Neil W. Kowall, Mark W. Logue, Lindsay A. Farrer, Jean Paul G. Vonsattel, Chang-En Yu, Thomas G. Beach, Gary W. Beecham, Erik D. Roberson, John M Olichney, Gerard D. Schellenberg, Harry V. Vinters, Chiao-Feng Lin, Bruce L. Miller, Duane Beekly, Daniel H. Geschwind, Murray A. Raskind, Kara L. Hamilton-Nelson, Jill R. Murrell, Linda J. Van Eldik, Wendy J. Mack, A. Karydas, Douglas Galasko, Barry Reisberg, Thomas O. Obisesan, Aimee Pierce, Andrew McDavid, Salvatore Spina, M.-Marsel Mesulam, Steven T. DeKosky, Andrew P. Lieberman, Ann C. McKee, Robert Barber, Nigel J. Cairns, Roger L. Albin, Bernardino Ghetti, Nilufer Ertekin-Taner, Kathleen A. Welsh-Bohmer, James B. Leverenz, M. Michael Barmada, F. Yesim Demirci, Hakon Hakonarson, Rodney C.P. Go, Oscar L. Lopez, Joseph D. Buxbaum, Adam C. Naj, Frank Martiniuk, Charles DeCarli, Otto Valladares, Andrew J. Saykin, Kelley Faber, Christine M. Hulette, John C. Morris, M. Ilyas Kamboh, Eliezer Masliah, Christine Sato, Steven E. Arnold, James R. Burke, Daniel C. Marson, Edward H. Koo, Ronald C. Petersen, David G. Clark, William W. Seeley, Robert C. Green, Constantine G. Lyketsos, Rosalyn Lang-Walker, John Q. Trojanowski, Jeffrey Kaye, Eileen H. Bigio, Laura B. Cantwell, Matthew P. Frosch, Jonathan L. Haines, Debby W. Tsuang, Juan C. Troncoso, Joshua W. Miller, Denis A. Evans, Kathleen S. Hall, Frank M. LaFerla, Joseph E. Parisi, Elizabeth Crocco, Mary Sano, Mahdi Ghani, Patrick Griffith, Margaret A. Pericak-Vance, Ashok Raj, Christopher S. Carlson, Jennifer J. Manly, Sid Gilman, Thomas J. Montine, Chuanhai Cao, A. Boxer, Ekaterina Rogaeva, Steven G. Younkin, Ronald L. Hamilton, Rong Cheng, Vahram Haroutunian, Peter St George-Hyslop, Liana G. Apostolova, M. Daniele Fallin, Clinton T. Baldwin, Ruchita Rajbhandary, Robert S. Stern, Sandra Weintraub, David H. Cribbs, Lindy E. Harrell, Wayne C. McCormick, Ge Li, Christiane Reitz, Eric B. Larson, Thomas D. Bird, Gregory A. Jicha, Regina M. Carney, Badri N. Vardarajan, Joshua A. Sonnen, Lawrence S. Honig, Joseph H. Lee, John H. Growdon, and Vivianna M. Van Deerlin
Subjects: Genetics, Chicago, Indiana, business.industry, Haplotype, Homozygote, Case-control study, Single-nucleotide polymorphism, Genome-wide association study, Genes, Recessive, Runs of Homozygosity, Polymorphism, Single Nucleotide, Article, Black or African American, Alzheimer Disease, Case-Control Studies, SNP, Medicine, Humans, Neurology (clinical), business, Imputation (genetics), SNP array, Aged, Genome-Wide Association Study
Abstract: Importance Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. Objective To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. Design, Setting, and Participants Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer’s Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project–Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. Main Outcomes and Measures The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. Results The African American cohort had a low degree of inbreeding ( F ~ 0.006). In the Alzheimer’s Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb ( P = .004) or greater than 3 Mb ( P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project–Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. Conclusions and Relevance To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.
Published: 2015

32. Early-Onset Dementia: Frequency and Causes Compared to Late-Onset Dementia

Author: Mario F. Mendez, Aaron McMurtray, Dianne Christine, and David G. Clark
Subjects: Lewy Body Disease, Male, medicine.medical_specialty, Pediatrics, Cognitive Neuroscience, Late onset, Neuropsychological Tests, Central nervous system disease, Alzheimer Disease, mental disorders, Epidemiology, Prevalence, medicine, Humans, Mass Screening, Dementia, Age of Onset, Psychiatry, Aged, business.industry, Dementia, Vascular, Incidence, Incidence (epidemiology), Cognitive disorder, Parkinson Disease, social sciences, Middle Aged, medicine.disease, humanities, Alcoholism, Psychiatry and Mental health, Huntington Disease, Brain Injuries, Female, Geriatrics and Gerontology, Age of onset, Alzheimer's disease, Cognition Disorders, business
Abstract: Background: Research on the epidemiology of dementia has focused on the elderly. Few investigations have studied differences in etiologic frequencies between early-onset dementia (EOD), with onset at an age of less than 65 years old, and the more common late-onset disorder. Objectives: To determine relative frequencies and characteristics of EOD versus late-onset dementia (LOD; age of onset ≧65 years) diagnosed in a large memory disorders program over a 4-year period. Methods: We reviewed medical records, including an extensive neurobehavioral and neurological evaluation, of all patients seen at a large Veteran’s Affairs Medical Center Memory Disorders clinic between 2001 and 2004 and assessed demographic variables, final diagnoses, presence of dementia, and differential diagnosis of dementing illnesses. Results: Among 1,683 patients presenting for evaluation of an acquired decline in memory or cognition, 948 (56%) met established clinical criteria for a dementing illness. About 30% (n = 278) of these had an age of onset of Conclusions: This study, conducted at a Veterans Affairs Hospital, is the largest series to date on EOD, and found a previously unexpectedly large number of patients below the age of 65 with cognitive deficits and impaired functioning consequent to head trauma, alcohol abuse, and HIV. These findings highlight the differential distribution and importance of preventable causes of dementia in the young.
Published: 2006
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33. Fluent versus nonfluent primary progressive aphasia: A comparison of clinical and functional neuroimaging features

Author: Bruce L. Miller, Jill S. Shapira, Mario F. Mendez, David G. Clark, and Anthony Charuvastra
Subjects: Male, Linguistics and Language, Cognitive Neuroscience, Semantic dementia, Experimental and Cognitive Psychology, Language and Linguistics, Lateralization of brain function, Primary progressive aphasia, Speech and Hearing, Aphasia, Wernicke, Functional neuroimaging, Communication disorder, Aphasia, medicine, Humans, Language disorder, Aged, Tomography, Emission-Computed, Single-Photon, Aphasia, Broca, Neuropsychology, Middle Aged, respiratory system, medicine.disease, Positron-Emission Tomography, Dementia, Female, medicine.symptom, Psychology, Cognitive psychology
Abstract: To better characterize fluent and nonfluent variants of primary progressive aphasia (PPA). Although investigators have recognized both fluent and nonfluent patients with PPA, the clinical and neuroimaging features of these variants have not been fully defined. We present clinical and neuropsychological data on 47 PPA patients comparing the fluent (n=21) and nonfluent (n=26) subjects. We further compared language features with PET/SPECT data available on 39 of these patients. Compared to the nonfluent PPA patients, those with fluent PPA had greater impairment of confrontational naming and loss of single word comprehension. They also exhibited semantic paraphasic errors and loss of single word comprehension. Patients with nonfluent PPA were more likely to be female, were more often dysarthric, and exhibited phonological speech errors in the absence of semantic errors. No significant differences were seen with regard to left hemisphere abnormalities, suggesting that both variants result from mechanisms that overlap frontal, temporal, and parietal regions. Of the language measures, only semantic paraphasias were strongly localized, in this case to the left temporal lobe. Fluent and nonfluent forms of PPA are clinically distinguishable by letter fluency, single word comprehension, object naming, and types of paraphasic errors. Nevertheless, there is a large amount of overlap between dysfunctional anatomic regions associated with these syndromes.
Published: 2005
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34. Regulation of Methylbenzoate Emission after Pollination in Snapdragon and Petunia Flowers

Author: Florence Negre, Christine M. Kish, David G. Clark, Natalia Dudareva, Jennifer Boatright, Kenichi Shibuya, Conrad Wagner, and Beverly A. Underwood
Subjects: S-Adenosylmethionine, DNA, Complementary, Ethylene, Pollination, Molecular Sequence Data, Flowers, Plant Science, medicine.disease_cause, Benzoates, Methylation, Petunia, Gene Expression Regulation, Enzymologic, chemistry.chemical_compound, Gene Expression Regulation, Plant, Pollen, Botany, Antirrhinum, medicine, Plant Proteins, Benzoic acid, biology, Reproduction, Gene Expression Regulation, Developmental, Methyltransferases, Sequence Analysis, DNA, Cell Biology, Benzoic Acid, Ethylenes, biology.organism_classification, chemistry, Floral scent, Odorants, Pollen tube, Research Article
Abstract: The molecular mechanisms responsible for postpollination changes in floral scent emission were investigated in snapdragon cv Maryland True Pink and petunia cv Mitchell flowers using a volatile ester, methylbenzoate, one of the major scent compounds emitted by these flowers, as an example. In both species, a 70 to 75% pollination-induced decrease in methylbenzoate emission begins only after pollen tubes reach the ovary, a process that takes between 35 and 40 h in snapdragon and approximately 32 h in petunia. This postpollination decrease in emission is not triggered by pollen deposition on the stigma. Petunia and snapdragon both synthesize methylbenzoate from benzoic acid and S-adenosyl-l-methionine (SAM); however, they use different mechanisms to downregulate its production after pollination. In petunia, expression of the gene responsible for methylbenzoate synthesis is suppressed by ethylene. In snapdragon, the decrease in methylbenzoate emission is the result of a decrease in both S-adenosyl-l-methionine:benzoic acid carboxyl methyltransferase (BAMT) activity and the ratio of SAM to S-adenosyl-l-homocysteine ("methylation index") after pollination, although the BAMT gene also is sensitive to ethylene.
Published: 2003
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35. Latent Information in Fluency Lists Predicts Functional Decline in Persons at Risk for Alzheimer Disease

Author: Thomas P. DeRamus, David S. Geldmacher, K. Lokken, P. Kapur, David G. Clark, John C. Brockington, Anthony P. Nicholas, Daniel C. Marson, Lindy E. Harrell, and P.D. Blanton
Subjects: Male, Risk, medicine.medical_specialty, Cognitive Neuroscience, Experimental and Cognitive Psychology, Audiology, Semantics, Article, Speech Disorders, Fluency, Alzheimer Disease, Artificial Intelligence, medicine, Dementia, Humans, Speech, Cognitive Dysfunction, Functional decline, Cognitive neuropsychology, Aged, Semantic fluency, Reproducibility of Results, Middle Aged, medicine.disease, Random forest, Neuropsychology and Physiological Psychology, ROC Curve, Area Under Curve, Case-Control Studies, Female, Alzheimer's disease, Psychology, Cognitive psychology
Abstract: We constructed random forest classifiers employing either the traditional method of scoring semantic fluency word lists or new methods. These classifiers were then compared in terms of their ability to diagnose Alzheimer disease (AD) or to prognosticate among individuals along the continuum from cognitively normal (CN) through mild cognitive impairment (MCI) to AD.Semantic fluency lists from 44 cognitively normal elderly individuals, 80 MCI patients, and 41 AD patients were transcribed into electronic text files and scored by four methods: traditional raw scores, clustering and switching scores, "generalized" versions of clustering and switching, and a method based on independent components analysis (ICA). Random forest classifiers based on raw scores were compared to "augmented" classifiers that incorporated newer scoring methods. Outcome variables included AD diagnosis at baseline, MCI conversion, increase in Clinical Dementia Rating-Sum of Boxes (CDR-SOB) score, or decrease in Financial Capacity Instrument (FCI) score. Receiver operating characteristic (ROC) curves were constructed for each classifier and the area under the curve (AUC) was calculated. We compared AUC between raw and augmented classifiers using Delong's test and assessed validity and reliability of the augmented classifier.Augmented classifiers outperformed classifiers based on raw scores for the outcome measures AD diagnosis (AUC .97 vs. .95), MCI conversion (AUC .91 vs. .77), CDR-SOB increase (AUC .90 vs. .79), and FCI decrease (AUC .89 vs. .72). Measures of validity and stability over time support the use of the method.Latent information in semantic fluency word lists is useful for predicting cognitive and functional decline among elderly individuals at increased risk for developing AD. Modern machine learning methods may incorporate latent information to enhance the diagnostic value of semantic fluency raw scores. These methods could yield information valuable for patient care and clinical trial design with a relatively small investment of time and money.
Published: 2014

36. [Untitled]

Author: Kathleen M. Brown, Solveig Lind-Iversen, David G. Clark, Zoe Hilioti, and Christina Richards
Subjects: Gynoecium, Ethylene, biology, Plant Science, General Medicine, Pelargonium, medicine.disease_cause, biology.organism_classification, chemistry.chemical_compound, Abscission, chemistry, Complementary DNA, Pollen, Geranium, Botany, Genetics, medicine, Petal, Agronomy and Crop Science
Abstract: Self-pollination of diploid zonal geranium (Pelargonium × hortorum L.H. Bailey) florets leads to a dramatic rise in ethylene production, followed by abscission within 4 h. Neither wounding of the stigma, pollination with tetraploid pollen, nor heat-killed self pollen could elicit as much ethylene production and petal abscission as self-pollination. A cDNA sharing sequence identity with ACC synthase (GACS2) and three different cDNAs sharing sequence identity with ACC oxidase (GACO1, GACO2, GACO3) were isolated from geranium pistils. Transcripts hybridizing with these probes increased slightly in response to self-pollination, but the degree of accumulation in response to various treatments did not correlate with ethylene production. When calculated on a per-plant-part basis, transcripts hybridizing with GACS2 were equally distributed among the stigma+style, sterile ovary, and ovary tissues, but transcripts hybridizing with the three ACC oxidase clones were differentially distributed. All transcripts were differentially expressed among the other tissues of the plant, with GACO1 being the most widely distributed. Ethylene production in geranium pistils was not autocatalytic. Propylene failed to induce ethylene production and ethylene did not induce the accumulation of ACC synthase or ACC oxidase transcripts. ACC accumulated in the stigma and style, and to a smaller extent in the sterile ovary, after pollination. These data support a model of pollination-induced ethylene production by post-transcriptional regulation of ethylene biosynthetic gene expression.
Published: 1997
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37. Basal ganglia volume in unmedicated patients with schizophrenia is associated with treatment response to antipsychotic medication

Author: Nathan L. Hutcheson, Adrienne C. Lahti, David G. Clark, David White, and Mark Bolding
Subjects: Adult, Male, Time Factors, Adolescent, medicine.drug_class, medicine.medical_treatment, Neuroscience (miscellaneous), Caudate nucleus, Atypical antipsychotic, Globus Pallidus, Severity of Illness Index, Basal Ganglia, Article, Basal Ganglia Diseases, Basal ganglia, Severity of illness, medicine, Humans, Radiology, Nuclear Medicine and imaging, Antipsychotic, Basal ganglia disease, Risperidone, Putamen, Organ Size, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Psychiatry and Mental health, Anesthesia, Schizophrenia, Female, Caudate Nucleus, Psychology, medicine.drug, Antipsychotic Agents
Abstract: We investigated the relationship between basal ganglia volume and treatment response to the atypical antipsychotic medication risperidone in unmedicated patients with schizophrenia. Basal ganglia volumes included the bilateral caudate, putamen, and pallidum and were measured using the Freesurfer automated segmentation pipeline in 23 subjects. Also, baseline symptom severity, duration of illness, age, gender, time off medication, and exposure to previous antipsychotic were measured. Treatment response was significantly correlated with all three regions of the bilateral basal ganglia (caudate, putamen, and pallidum), baseline symptom severity, duration of illness, and age but not gender, time off antipsychotic medication, or exposure to previous antipsychotic medication. The caudate volume was the basal ganglia region that demonstrated the strongest correlation with treatment response and was significantly negatively correlated with patient age. Caudate volume was not significantly correlated with any other measure. We demonstrated a novel finding that the caudate volume explains a significant amount of the variance in treatment response over the course of six-weeks of risperidone pharmacotherapy even when controlling for baseline symptom severity and duration of illness.
Published: 2013

38. Diagnosis and Grading of Alzheimer’s Disease via Automatic Classification of FDG-PET Scans

Author: Vijay V. Raghavan, David G. Clark, Ryan Benton, Suresh Choubey, and Tom Johnsten
Subjects: medicine.medical_specialty, medicine.diagnostic_test, business.industry, Disease, computer.software_genre, Thresholding, Support vector machine, Clinical trial, Neuroimaging, Positron emission tomography, Surface projection, medicine, Medical physics, Data mining, business, computer, Grading (tumors)
Abstract: Clinical trials for interventions that seek to delay the onset of Alzheimer's disease (AD) are hampered by inadequate methods for selecting study subjects who are at risk, and who may therefore benefit from the interventions being studied. Automated monitoring tools may facilitate clinical research and thereby reduce the impact of AD on individuals, caregivers, society at large, and government healthcare infrastructure. We studied the 18F-deoxyglucose positron emission tomography (FDG-PET) scans of research subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI), using a Machine Learning technique. Three hundred ninety-four FDG-PET scans were obtained from the ADNI database. An automated procedure was used to extract measurements from 31 regions of each PET surface projection. These data points were used to evaluate the sensitivity and specificity of support vector machine (SVM) classifiers and to compare both Linear and Radial-Basis SVM techniques against a classic thresholding method used in earlier work.
Published: 2013
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39. Assessment of the genetic variance of late-onset Alzheimer's disease

Author: Perry G. Ridge, Kaitlyn B. Hoyt, Kevin Boehme, Shubhabrata Mukherjee, Paul K. Crane, Jonathan L. Haines, Richard Mayeux, Lindsay A. Farrer, Margaret A. Pericak-Vance, Gerard D. Schellenberg, John S.K. Kauwe, Perrie M. Adams, Marilyn S. Albert, Roger L. Albin, Liana G. Apostolova, Steven E. Arnold, Sanjay Asthana, Craig S. Atwood, Clinton T. Baldwin, Robert C. Barber, Michael M. Barmada, Lisa L. Barnes, Sandra Barral, Thomas G. Beach, James T. Becker, Gary W. Beecham, Duane Beekly, David A. Bennett, Eileen H. Bigio, Thomas D. Bird, Deborah Blacker, Bradley F. Boeve, James D. Bowen, Adam Boxer, James R. Burke, Jeffrey M. Burns, Joseph D. Buxbaum, Nigel J. Cairns, Laura B. Cantwell, Chuanhai Cao, Chris S. Carlson, Cynthia M. Carlsson, Regina M. Carney, Minerva M. Carrasquillo, Steven L. Carroll, Helena C. Chui, David G. Clark, Jason Corneveaux, David H. Cribbs, Elizabeth A. Crocco, Carlos Cruchaga, Philip L. De Jager, Charles DeCarli, F. Yesim Demirci, Malcolm Dick, Dennis W. Dickson, Rachelle S. Doody, Ranjan Duara, Nilufer Ertekin-Taner, Denis A. Evans, Kelley M. Faber, Thomas J. Fairchild, Kenneth B. Fallon, David W. Fardo, Martin R. Farlow, Steven Ferris, Tatiana M. Foroud, Matthew P. Frosch, Douglas R. Galasko, Marla Gearing, Daniel H. Geschwind, Bernardino Ghetti, John R. Gilbert, Alison M. Goate, Neill R. Graff-Radford, Robert C. Green, John H. Growdon, Hakon Hakonarson, Ronald L. Hamilton, Kara L. Hamilton-Nelson, John Hardy, Lindy E. Harrell, Lawrence S. Honig, Ryan M. Huebinger, Matthew J. Huentelman, Christine M. Hulette, Bradley T. Hyman, Gail P. Jarvik, Gregory A. Jicha, Lee-Way Jin, Gyungah Jun, M. Ilyas Kamboh, Anna Karydas, Mindy J. Katz, Jeffrey A. Kaye, Ronald Kim, Neil W. Kowall, Joel H. Kramer, Walter A. Kukull, Brian W. Kunkle, Frank M. LaFerla, James J. Lah, Eric B. Larson, James B. Leverenz, Allan I. Levey, Ge Li, Andrew P. Lieberman, Chiao-Feng Lin, Richard B. Lipton, Oscar L. Lopez, Kathryn L. Lunetta, Constantine G. Lyketsos, Wendy J. Mack, Daniel C. Marson, Eden R. Martin, Frank Martiniuk, Deborah C. Mash, Eliezer Masliah, Wayne C. McCormick, Susan M. McCurry, Andrew N. McDavid, Ann C. McKee, Marsel Mesulam, Bruce L. Miller, Carol A. Miller, Joshua W. Miller, Thomas J. Montine, John C. Morris, Jill R. Murrell, Amanda J. Myers, Adam C. Naj, Sid O'Bryant, John M. Olichney, Vernon S. Pankratz, Joseph E. Parisi, Amanda Partch, Henry L. Paulson, William Perry, Elaine Peskind, Ronald C. Petersen, Aimee Pierce, Wayne W. Poon, Huntington Potter, Joseph F. Quinn, Ashok Raj, Murray Raskind, Eric M. Reiman, Barry Reisberg, Joan S. Reisch, Christiane Reitz, John M. Ringman, Erik D. Roberson, Ekaterina Rogaeva, Howard J. Rosen, Roger N. Rosenberg, Donald R. Royall, Mark A. Sager, Mary Sano, Andrew J. Saykin, Julie A. Schneider, Lon S. Schneider, William W. Seeley, Amanda G. Smith, Joshua A. Sonnen, Salvatore Spina, Peter St George-Hyslop, Robert A. Stern, Russell H. Swerdlow, Rudolph E. Tanzi, Tricia A. Thornton-Wells, John Q. Trojanowski, Juan C. Troncoso, Debby W. Tsuang, Otto Valladares, Vivianna M. Van Deerlin, Linda J. Van Eldik, Badri N. Vardarajan, Harry V. Vinters, Jean Paul Vonsattel, Li-San Wang, Sandra Weintraub, Kathleen A. Welsh-Bohmer, Jens R. Wendland, Kirk C. Wilhelmsen, Jennifer Williamson, Thomas S. Wingo, Ashley R. Winslow, Sarah Wishnek, Randall L. Woltjer, Clinton B. Wright, Chuang-Kuo Wu, Steven G. Younkin, Chang-En Yu, and Lei Yu
Subjects: 0301 basic medicine, Male, Risk, Aging, Neuroscience(all), Clinical Neurology, Datasets as Topic, Genome-wide association study, Single-nucleotide polymorphism, Receptors, Cell Surface, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Amyloid beta-Protein Precursor, 0302 clinical medicine, Alzheimer Disease, Genetic variation, medicine, Genetics, Humans, Allele, Receptors, Immunologic, Genetic variance, Aged, Aged, 80 and over, Membrane Glycoproteins, TREM2, General Neuroscience, Genetic disorder, Genetic Variation, Alzheimer's disease, Explained variation, medicine.disease, Genetic architecture, 3. Good health, Ageing, 030104 developmental biology, Female, Neurology (clinical), Geriatrics and Gerontology, Netrin Receptors, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract: Alzheimer's disease (AD) is a complex genetic disorder with no effective treatments. More than 20 common markers have been identified, which are associated with AD. Recently, several rare variants have been identified in Amyloid Precursor Protein (APP), Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Unc-5 Netrin Receptor C (UNC5C) that affect risk for AD. Despite the many successes, the genetic architecture of AD remains unsolved. We used Genome-wide Complex Trait Analysis to (1) estimate phenotypic variance explained by genetics; (2) calculate genetic variance explained by known AD single nucleotide polymorphisms (SNPs); and (3) identify the genomic locations of variation that explain the remaining unexplained genetic variance. In total, 53.24% of phenotypic variance is explained by genetics, but known AD SNPs only explain 30.62% of the genetic variance. Of the unexplained genetic variance, approximately 41% is explained by unknown SNPs in regions adjacent to known AD SNPs, and the remaining unexplained genetic variance outside these regions.
Published: 2016
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40. 971a Inflammation Modulates the Sphingosine-1-Phosphate Pathway in Inflammatory Bowel Disease (IBD)

Author: David G. Clark, Fiona Scott, Joshua D. Boyer, En-hui Behrens, Gor Sarkisyan, Paul Jedlicka, Lauren Gima, Giorgos Bamias, Marisol Veny, Thangaraj Karuppuchamy, Robert Peach, Pedro J. Gonzalez-Cabrera, Jesus Rivera-Nieves, and Hugh Rosen
Subjects: chemistry.chemical_compound, Hepatology, chemistry, business.industry, Immunology, Gastroenterology, medicine, Inflammation, Sphingosine-1-phosphate, medicine.symptom, medicine.disease, business, Inflammatory bowel disease
Published: 2016
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41. Predicting missing biomarker data in a longitudinal study of Alzheimer disease

Author: Mary M. Laubinger, Po H. Lu, M. Saleem Ismail, Alan J. Lerner, Paul Malloy, Daniel C. Marson, Pierre N. Tariot, Adam S. Fleisher, Neill R Graff-Radford Mbbch, Vernice Bates, Jeffrey M. Burns, Robert B. Santulli, Maria Kataki, Kris A. Johnson, Henry Rusinek, Nick C. Fox, Ronald C. Petersen, Matt A. Bernstein, Heather Anderson, Janet S. Cellar, Godfrey D. Pearlson, Mark A. Mintun, Karen Crawford, Stephen Salloway, Owen Carmichael, Kaycee M. Sink, Howard Chertkow, Jeff D. Williamson, Ann Marie Hake, Teresa Villena, Scott Turner, George Marzloff, Daniel Varon, Anil Nair, Martin R. Farlow, Yaakov Stern, Javier Villanueva-Meyer, Kathleen Johnson, Martha G. MacAvoy, Daniel H.S. Silverman, Marjorie E. Marenberg, Jacobo Mintzer, Ranjan Duara, Ronald A. Cohen, Munir Chowdhury, Bruce L. Miller, Charles DeCarli, Dzintra Celmins, Stephen Correia, Sonia Pawluczyk, Paul S. Aisen, Heather Johnson, Gaby Thai, Paul J. Wang, William J. Jagust, Anthony Gamst, Adrian Preda, Jaimie Toroney, Allyson C. Rosen, Chris Hosein, Michele Assaly, Neil Buckholtz, Christopher M. Clark, Hillel Grossman, Stephanie Reeder, Ging-Yuek Robin Hsiung, John A. Rogers, Wes Ashford, Scott C. Neu, Jennifer Richard, Karen S. Anderson, Michael Borrie, George Bartzokis, Marilyn S. Albert, Brian R. Ott, Barry A. Hendin, Dick Trost, Michael D. Devous, Ramon Diaz-Arrastia, Chuang-Kuo Wu, Helen Vanderswag, Jeffrey R. Petrella, Susan De Santi, Jeffrey Kaye, Randall Griffith, Howard Feldman, Catherine Mc-Adams-Ortiz, Bryan M. Spann, Donald Connor, Francine Parfitt, Ruth A. Mulnard, P. Murali Doraiswamy, Raj C. Shah, M.-Marsel Mesulam, Howard J. Rosen, Donna Munic, Marilyn Aiello, Robert C. Green, Laurel A. Beckett, Cynthia M. Carlsson, Marwan N. Sabbagh, Michael C. Donohue, John C. Morris, Donna M. Simpson, Peter A. Hardy, James B. Brewer, Charles Bernick, Cheuk Y. Tang, Leon Hudson, Sanjay Asthana, Alice D. Brown, Kristen Martin-Cook, David G. Clark, Amanda L. Benincasa, T-Y Lee, Seema Mirje, Charles D. Smith, Lon S. Schneider, Nancy Collins Johnson, Christopher H. van Dyck, Joseph F. Quinn, Steven G. Potkin, Sandra Jacobson, Ronald G. Thomas, Kelly E. Behan, Barry W. Rovner, Anders M. Dale, Norbert Schuff, Howard Bergman, Arthur W. Toga, Andrew Kertesz, Horacio Capote, Keith A. Johnson, Mony J. de Leon, Sandra E. Black, Dan Bandy, Karen L. Bell, Leylade Toledo-Morrell, Allan I. Levey, Connie Brand, Paul M. Thompson, Julia Pedroso, Scott Herring, Dana Nguyen, Oscar L. Lopez, Judith L. Heidebrink, Curtis A. Given, Reisa A. Sperling, Simon P. Graham, Danielle J Harvey, Earl A. Zimmerman, Sara Dolen, John Kornak, Walter Martinez, Ronald J. Killiany, Smita Kittur, Holly Soares, Paula Ogrocki, Joanne L. Lord, Jared R. Tinklenberg, Lawrence S. Honig, Kewei Chen, Carl H. Sadowsky, Joel P. Felmlee, Magdalena Korecka, Jessica Englert, Peggy Roberts, Michelle Rainka, Clifford R. Jack, Annapurni Jayam-Trouth, Alexander Norbash, Sterling C. Johnson, Curtis B. Caldwell, MaryAnn Oakley, Gene E. Alexander, Dorene M. Rentz, Tatiana Foroud, James J. Lah, Cassie Pham, Virginia M.-Y. Lee, Franklin Watkins, T. J. Montine, Douglas W. Scharre, Sam Gandy, Thomas O. Obisesan, Steven Potkin, Li Shen, Jessica Nunez, Andrew J. Saykin, Raymond Y. Lo, Evan Fletcher, Sarah Walter, Stacy Schneider, Rob Bartha, and Rachelle S. Doody
Subjects: Oncology, medicine.medical_specialty, Longitudinal study, Patient Dropouts, tau Proteins, Neuropsychological Tests, Logistic regression, Developmental psychology, Cohort Studies, Alzheimer Disease, Fluorodeoxyglucose F18, Risk Factors, Internal medicine, mental disorders, medicine, Dementia, Humans, Cognitive Dysfunction, Longitudinal Studies, Homocysteine, Amyloid beta-Peptides, Dementia, Vascular, medicine.disease, Missing data, Magnetic Resonance Imaging, Peptide Fragments, Logistic Models, Research Design, Positron-Emission Tomography, Biomarker (medicine), Neurology (clinical), Alzheimer's disease, Psychology, Biomarkers, Alzheimer's Disease Neuroimaging Initiative, Cohort study
Abstract: Objective: To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD). Methods: The Alzheimer9s 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 Aβ 42 . 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

42. Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases

Author: Jason Lee, Ranjan Duara, Michael A. Slifer, Kenneth B. Fallon, Thomas J. Montine, Beth A. Dombroski, Peter St George-Hyslop, Debby W. Tsuang, Patricia L. Kramer, Duane Beekly, Ronald C. Petersen, Carl W. Cotman, Helena C. Chui, Alison Goate, Michelle K. Lupton, Sid Gilman, Thomas G. Beach, A. Karydas, Andrew McDavid, Susan M. McCurry, William G. Ellis, Bradley T. Hyman, Badri N. Vardarajan, Joshua A. Sonnen, Neill R. Graff-Radford, Robert Barber, Elisavet Preza, Paul Gallins, Lawrence S. Honig, Adam C. Naj, Frank Martiniuk, Jacek Biernat, Christopher S. Carlson, Richard J. Caselli, Huntington Potter, Chris Zarow, Christine M. Hulette, Hakon Hakonarson, Oscar L. Lopez, Alexandra I. Soto-Ortolaza, Eric Klein, Margaret A. Pericak-Vance, Ashok Raj, Marla Gearing, Kathryn L. Lunetta, Adam L. Boxer, Gerard D. Schellenberg, John H. Growdon, Ramon Diaz-Arrastia, Wayne W. Poon, James R. Burke, Michael D. Geschwind, Douglas Galasko, Ruchita Rajbhandary, Eric M. Reiman, Gregory A. Jicha, Steven L. Carroll, Robert S. Stern, Vivianna M. Van Deerlin, Murray A. Raskind, Carol A. Miller, Ekaterina Rogaeva, Carlos Cruchaga, Joshua W. Miller, Matthew J. Huentelman, Joseph E. Parisi, Charles C. DeCarli, Eliezer Masliah, Didier Hannequin, Deborah Blacker, Michael L. Shelanski, Roger L. Albin, Mary Sano, Paul K. Crane, David G. Clark, Jean Paul G. Vonsattel, Mary Ganguli, John Hardy, John Powell, Charles DeCarli, Ronald C. Kim, Charles D. Smith, Jonathan D. Glass, M. Ilyas Kamboh, Steven E. Arnold, Gyungah Jun, Gail P. Jarvik, Anna Karydas, Suzee E. Lee, Carol F. Lippa, Allan I. Levey, Eckhard Mandelkow, Petra Nowotny, Dennis W. Dickson, Jennifer Williamson, John Q. Trojanowski, Isabelle Le Ber, Zbigniew K. Wszolek, Jeffrey Kaye, Eric B. Larson, Matthew P. Frosch, Harry V. Vinters, David A. Bennett, Joseph D. Buxbaum, Sandra Weintraub, Charles L. White, Lindy E. Harrell, Jonathan L. Haines, Minerva M. Carrasquillo, Robert O. Kenet, Lindsay A. Farrer, Robert C. Green, Wayne C. McCormick, Richard Mayeux, Denis A. Evans, Erik D. Roberson, Bruno Giordani, Liana G. Apostolova, Virginia M.-Y. Lee, Elizabeth Finger, Subashchandrabose Chinnathambi, Clinton T. Baldwin, Satish Kumar, Christiane Reitz, Steven H. Ferris, Randall L. Woltjer, Li-San Wang, Elaine R. Peskind, Thomas D. Bird, Eden R. Martin, Ryan J. Uitti, Martin R. Farlow, Amanda J. Myers, Jason J. Corneveaux, Gary W. Beecham, James D. Bowen, Juan C. Troncoso, Daniel H. Geschwind, Ann C. McKee, Roger N. Rosenberg, Bruce L. Miller, Daniel C. Marson, Jeffrey L. Cummings, Salvatore Spina, Regina M. Carney, Lee-Way Jin, Yvette Bordelon, Jean Paul Vonsattel, John R. Gilbert, Simon Lovestone, Kelley Faber, Mario F. Mendez, Laura B. Cantwell, Philip L. De Jager, John M. Ringman, Elizabeth Head, Wendy J. Mack, Giovanni Coppola, Nigel J. Cairns, Nilufer Ertekin-Taner, Nancy Johnson, Jacqueline L. Buros, Wallace W. Tourtellotte, Julie A. Schneider, Rosa Rademakers, Malcolm B. Dick, Ian R. A. Mackenzie, Andrew J. Saykin, Bradley F. Boeve, John S. K. Kauwe, Neil W. Kowall, Eva Maria Mandelkow, Andrew Kertesz, Lon S. Schneider, Joseph F. Quinn, F. Yesim Demirci, John C. Morris, Barry Reisberg, Andrew P. Lieberman, Bernardino Ghetti, Kathleen A. Welsh-Bohmer, Edward H. Koo, Alden Y. Huang, Walter A. Kukull, Alexis Brice, Eileen H. Bigio, M.-Marsel Mesulam, Steven T. DeKosky, Jorge L. Juncos, Neil Graff-Radford, M. Michael Barmada, Rudolph E. Tanzi, Owen A. Ross, Jason Karlawish, Tatiana Foroud, William W. Seeley, James J. Lah, Deborah C. Mash, Chuanhai Cao, Daniel P. Perl, A. Boxer, Matt Baker, Steven G. Younkin, Ronald L. Hamilton, Renee L. Sears, Jessica Lane, and Alzheimer's Dis Genetics Consortiu
Subjects: Risk, Genotype, epidemiology [Alzheimer Disease], Tau protein, epidemiology [Frontotemporal Dementia], Locus (genetics), genetics [Alzheimer Disease], MAPT protein, human, tau Proteins, Disease, Progressive supranuclear palsy, Alzheimer Disease, ddc:570, Genetic variation, Rare mutations, mental disorders, Genetics, medicine, Humans, Genetic Predisposition to Disease, Molecular Biology, Gene, Biology, genetics [Frontotemporal Dementia], Genetics (clinical), Aged, biology, Association Studies Articles, Genetic Variation, General Medicine, Middle Aged, medicine.disease, eye diseases, nervous system diseases, Chemistry, genetics [tau Proteins], Haplotypes, Clinical diagnosis, Frontotemporal Dementia, biology.protein, Human medicine
Abstract: Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
Published: 2012
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43. Storage Costs and Heuristics Interact to Produce Patterns of Aphasic Sentence Comprehension Performance

Author: David G. Clark
Subjects: Computer science, lcsh:BF1-990, computer.software_genre, Cognitive resource theory, Aphasia, medicine, Psychology, Set (psychology), syntax, semantics, General Psychology, Original Research, business.industry, Heuristic, Locality, Syntax, aphasia, lcsh:Psychology, sentence comprehension, Artificial intelligence, medicine.symptom, business, Heuristics, computer, Natural language processing, Sentence
Abstract: Background: Despite general agreement that aphasic individuals exhibit difficulty understanding complex sentences, the nature of sentence complexity itself is unresolved. In addition, aphasic individuals appear to make use of heuristic strategies for understanding sentences. This research is a comparison of predictions derived from two approaches to the quantification of sentence complexity, one based on the hierarchical structure of sentences, and the other based on dependency locality theory (DLT). Complexity metrics derived from these theories are evaluated under various assumptions of heuristic use. Method: A set of complexity metrics was derived from each general theory of sentence complexity and paired with assumptions of heuristic use. Probability spaces were generated that summarized the possible patterns of performance across 16 different sentence structures. The maximum likelihood of comprehension scores of 42 aphasic individuals was then computed for each probability space and the expected scores from the best-fitting points in the space were recorded for comparison to the actual scores. Predictions were then compared using measures of fit quality derived from linear mixed effects models. Results: All three of the metrics that provide the most consistently accurate predictions of patient scores rely on storage costs based on the DLT. Patients appear to employ an Agent–Theme heuristic, but vary in their tendency to accept heuristically generated interpretations. Furthermore, the ability to apply the heuristic may be degraded in proportion to aphasia severity. Conclusion: DLT-derived storage costs provide the best prediction of sentence comprehension patterns in aphasia. Because these costs are estimated by counting incomplete syntactic dependencies at each point in a sentence, this finding suggests that aphasia is associated with reduced availability of cognitive resources for maintaining these dependencies.
Published: 2012
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44. US-guided automated large-core breast biopsy

Author: J G Price, K K Johnson, Steve H. Parker, J E Truell, David G. Clark, A B Kortz, Wayne F. Yakes, M A Dennis, A T Stavros, and W E Jobe
Subjects: Breast biopsy, medicine.medical_specialty, Percutaneous, medicine.diagnostic_test, business.industry, Needle breast biopsy, Biopsy, Needle, Ultrasound, Breast Neoplasms, Biopsy, Large core, Humans, Medicine, Mammography, Female, Radiology, Nuclear Medicine and imaging, Breast, Ultrasonography, Mammary, Tubular carcinoma, Radiology, business
Abstract: To evaluate the efficacy of ultrasound (US)-guided automated large-core percutaneous needle breast biopsy, biopsy of 181 ultrasonographically suspicious breast lesions was performed by using a long-throw biopsy gun and 14-gauge needles with continuous US guidance. A "freehand" technique with either 5.0- or 7.5-MHz linear-array transducers was used. Needle core diagnoses were compared with surgical diagnoses in the 49 lesions subsequently surgically excised. The remaining 132 cases were followed for 12-36 months. Agreement between needle-core and surgical diagnoses in the 49 lesions was 100%. This group included 34 cancers (28 infiltrating ductal, two mucinous, one mixed infiltrating ductal and lobular, and one each of intraductal, infiltrating lobular, and tubular carcinoma). To date, no cancers have been found in the other 132 cases. The procedure time averaged 20 minutes, and no complications occurred. With an accuracy approaching that of excisional biopsy, US-guided needle core biopsy provides an alternative to surgery.
Published: 1993
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45. Ethylene Signal Transduction in Fruits and Flowers

Author: David G. Clark and Harry J. Klee
Subjects: Ethylene signal transduction, medicine.anatomical_structure, Abscission, Histidine kinase, Cell, medicine, Context (language use), Ripening, Biology, Signal transduction, Hormone, Cell biology
Abstract: Persons reading this book will appreciate that phytohormones have vital roles in assimilating many aspects of plant growth and development. While it is well established that hormonal action is regulated at the level of synthesis, many developmental processes are also regulated at the level of hormone perception (8). Sensitivity to hormones is regulated both spatially and temporally during growth and development. For example, adjacent cell layers respond differentially to hormones during organ abscission. Likewise, sensitivity of an organ can change over time as occurs during fruit ripening. How such alterations in hormone responses are regulated is not well understood. However, as the individual components of signaling pathways are identified, a basic understanding of hormone responsiveness is emerging. In the context of this article, the term “sensitivity” refers to the response of a tissue or organ to the hormone. A change in sensitivity indicates that the concentration of hormone that is able to initiate a set response is altered.
Published: 2010
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46. Declining financial capacity in mild cognitive impairment: A 1-year longitudinal study

Author: Roy C. Martin, John C. Brockington, Daniel C. Marson, Lindy E. Harrell, David G. Clark, Ozioma C. Okonkwo, Kristen L. Triebel, Alfred A. Bartolucci, Janice C. Marceaux, and H. R. Griffith
Subjects: Male, Longitudinal study, Aging, Activities of daily living, Psychometrics, Financial Management, Decision Making, Neuropsychological Tests, behavioral disciplines and activities, Severity of Illness Index, Cohort Studies, Disability Evaluation, mental disorders, Severity of illness, Activities of Daily Living, medicine, Dementia, Humans, Mental Competency, Longitudinal Studies, Geriatric Assessment, Problem Solving, Aged, Finance, Psychiatric Status Rating Scales, business.industry, Cognitive disorder, Articles, Middle Aged, medicine.disease, Disease Progression, Female, Neurology (clinical), business, Psychology, Cognition Disorders, human activities, Bank statement, Mathematics, Cohort study
Abstract: Objective: To investigate 1-year change in financial capacity in relation to conversion from amnestic mild cognitive impairment (MCI) to dementia. Methods: Seventy-six cognitively healthy older controls, 25 patients with amnestic MCI who converted to Alzheimer-type dementia during the study period (MCI converters), and 62 patients with MCI who did not convert to dementia (MCI nonconverters) were administered the Financial Capacity Instrument (FCI) at baseline and 1-year follow-up. Performance on the FCI domain and global scores was compared within and between groups using multivariate repeated-measures analyses. Results: At baseline, controls performed better than MCI converters and nonconverters on almost all FCI domains and on both FCI total scores. MCI converters performed below nonconverters on domains of financial concepts, cash transactions, bank statement management, and bill payment and on both FCI total scores. At 1-year follow-up, MCI converters showed significantly greater decline than controls and MCI nonconverters for the domain of checkbook management and for both FCI total scores. The domain of bank statement management showed a strong trend. For both the checkbook and bank statement domains, MCI converters showed declines in procedural skills, such as calculating the correct balance in a checkbook register, but not in conceptual understanding of a checkbook or a bank statement. Conclusions: Declining financial skills are detectable in patients with mild cognitive impairment (MCI) in the year before their conversion to Alzheimer disease. Clinicians should proactively monitor patients with MCI for declining financial skills and advise patients and families about appropriate interventions.
Published: 2009

47. Genetic Contributions to Clinical Pain and Analgesia: Avoiding Pitfalls in Genetic Research

Author: Raymond A. Dionne, Hyungsuk Kim, and David G. Clark
Subjects: medicine.medical_specialty, Genotype, Clinical pain, Analgesic, Individualized treatment, Pain, Bioinformatics, Models, Biological, Polymorphism, Single Nucleotide, Article, Strength of evidence, medicine, Ethnicity, Animals, Humans, Genetic Predisposition to Disease, Intensive care medicine, business.industry, Perspective (graphical), Racial Groups, Genetic Variation, Sequence Analysis, DNA, Anesthesiology and Pain Medicine, Phenotype, Neurology, Haplotypes, Neurology (clinical), Analgesia, business, Genome-Wide Association Study
Abstract: Understanding the genetic basis of human variations in pain is critical to elucidating the molecular basis of pain sensitivity, variable responses to analgesic drugs, and, ultimately, to individualized treatment of pain and improved public health. With the help of recently accumulated knowledge and advanced technologies, pain researchers hope to gain insight into genetic mechanisms of pain and eventually apply this knowledge to pain treatment. Perspective We critically reviewed the published literature to examine the strength of evidence supporting genetic influences on clinical and human experimental pain. Based on this evidence and the experience of false associations that have occurred in other related disciplines, we provide recommendations for avoiding pitfalls in pain genetic research.
Published: 2009

48. Awareness of deficits in financial abilities in patients with mild cognitive impairment: going beyond self-informant discrepancy

Author: John C. Brockington, Virginia G. Wadley, Sara Lanza, Katherine Belue, Rema Raman, Daniel C. Marson, H. Randall Griffith, David G. Clark, Edward Zamrini, Lindy E. Harrell, and Ozioma C. Okonkwo
Subjects: Self-assessment, Male, Self-Assessment, Financial Management, Cross-sectional study, Article, Financial management, Alzheimer Disease, mental disorders, medicine, Humans, Geriatric Assessment, Depression (differential diagnoses), Aged, Finance, Observer Variation, Memory Disorders, business.industry, Anosognosia, Gold standard, Reproducibility of Results, Cognition, Awareness, medicine.disease, Psychiatry and Mental health, Cross-Sectional Studies, Case-Control Studies, Alabama, Objective test, Female, Geriatrics and Gerontology, business, Psychology, Cognition Disorders
Abstract: Objective Self and informant reports of functional abilities are weighted heavily in diagnostic decision making regarding mild cognitive impairment (MCI). However, it is unclear whether patients with MCI are fully aware and provide reliable estimates of their functional status. In this study, the authors used three different approaches to examine accuracy of self-report of financial abilities among patients with MCI. Design Cross-sectional, case-comparison group study. Setting University medical center. Participants Seventy-four patients with MCI and their informants, and 73 cognitively healthy older adults and their informants. Measurements The authors compared MCI patients' report of their financial abilities with their performance on an objective measure of financial capacity. The authors also compared informant reports of patients' abilities with patients' objective test performance, and informant reports with patients' self-report. Results The authors found that the discrepancy between self-report and objective performance was higher among MCI patients compared with the cognitively healthy older adults on the financial domains of Checkbook Management, Bank Statement Management, and Bill Payment, and on overall financial capacity. The authors also found that MCI patients with poorer global cognition overestimated their financial abilities whereas those with higher depressive symptoms underestimated their financial abilities. Overall, MCI patients were better at estimating their financial abilities than their informants. Conclusions Patients with MCI are not fully aware of deficits in their financial abilities. Both cognitive impairment and depression impact MCI patients' self-reported functioning. In addition, MCI informants misestimate patients' financial abilities. This raises concerns about the widespread use of informant report as the gold standard against which to evaluate patient self-report of functioning.
Published: 2008

49. From Atheist to Apologist

Author: David G. Clark
Subjects: History, medicine, Religious studies, medicine.disease, Humanities, Trench fever
Published: 2008
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50. Cognitive models of medical decision-making capacity in patients with mild cognitive impairment

Author: Daniel C. Marson, David G. Clark, Katherine Belue, John C. Brockington, Edward Zamrini, Lindy E. Harrell, Ozioma C. Okonkwo, Stephanie T. Lanza, Rema Raman, and H. R. Griffith
Subjects: Male, Multivariate analysis, Decision Making, Neuropsychological Tests, Alzheimer Disease, Memory, Reference Values, medicine, Humans, Attention, Mental Competency, Aged, Cognitive reserve, medicine.diagnostic_test, Verbal Behavior, business.industry, General Neuroscience, Case-control study, Neuropsychology, Cognition, Neuropsychological test, Middle Aged, Stepwise regression, Psychiatry and Mental health, Clinical Psychology, Case-Control Studies, Multivariate Analysis, Visual Perception, Female, Neurology (clinical), Verbal memory, Cognition Disorders, business, Clinical psychology
Abstract: This study investigated cognitive predictors of medical decision-making capacity (MDC) in patients with amnestic mild cognitive impairment (MCI). A total of 56 healthy controls, 60 patients with MCI, and 31 patients with mild Alzheimer's disease (AD) were administered the Capacity to Consent to Treatment Instrument (CCTI) and a neuropsychological test battery. The CCTI assesses MDC across four established treatment consent standards--S1 (expressing choice), S3 (appreciation), S4 (reasoning), and S5 (understanding)--and one experimental standard [S2] (reasonable choice). Scores on neuropsychological measures were correlated with scores on each CCTI standard. Significant bivariate correlates were subsequently entered into stepwise regression analyses to identity group-specific multivariable predictors of MDC across CCTI standards. Different multivariable cognitive models emerged across groups and consent standards. For the MCI group, measures of short-term verbal memory were key predictors of MDC for each of the three clinically relevant standards (S3, S4, and S5). Secondary predictors were measures of executive function. In contrast, in the mild AD group, measures tapping executive function and processing speed were primary predictors of S3, S4, and S5. MDC in patients with MCI is supported primarily by short-term verbal memory. The findings demonstrate the impact of amnestic deficits on MDC in patients with MCI.
Published: 2008
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