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1. Nonlinear Z‐score modeling for improved detection of cognitive abnormality

Author

John Kornak, Julie Fields, Walter Kremers, Sara Farmer, Hilary W. Heuer, Leah Forsberg, Danielle Brushaber, Amy Rindels, Hiroko Dodge, Sandra Weintraub, Lilah Besser, Brian Appleby, Yvette Bordelon, Jessica Bove, Patrick Brannelly, Christina Caso, Giovanni Coppola, Reilly Dever, Christina Dheel, Bradford Dickerson, Susan Dickinson, Sophia Dominguez, Kimiko Domoto‐Reilly, Kelley Faber, Jessica Ferrall, Ann Fishman, Jamie Fong, Tatiana Foroud, Ralitza Gavrilova, Deb Gearhart, Behnaz Ghazanfari, Nupur Ghoshal, Jill Goldman, Jonathan Graff‐Radford, Neill Graff‐Radford, Ian M. Grant, Murray Grossman, Dana Haley, John Hsiao, Robin Hsiung, Edward D. Huey, David Irwin, David Jones, Lynne Jones, Kejal Kantarci, Anna Karydas, Daniel Kaufer, Diana Kerwin, David Knopman, Ruth Kraft, Joel Kramer, Walter Kukull, Maria Lapid, Irene Litvan, Peter Ljubenkov, Diane Lucente, Codrin Lungu, Ian Mackenzie, Miranda Maldonado, Masood Manoochehri, Scott McGinnis, Emily McKinley, Mario Mendez, Bruce Miller, Namita Multani, Chiadi Onyike, Jaya Padmanabhan, Alexander Pantelyat, Rodney Pearlman, Len Petrucelli, Madeline Potter, Rosa Rademakers, Eliana Marisa Ramos, Katherine Rankin, Katya Rascovsky, Erik D. Roberson, Emily Rogalski‐Miller, Pheth Sengdy, Les Shaw, Adam M. Staffaroni, Margaret Sutherland, Jeremy Syrjanen, Carmela Tartaglia, Nadine Tatton, Joanne Taylor, Arthur Toga, John Trojanowski, Ping Wang, Bonnie Wong, Zbigniew Wszolek, Brad Boeve, Adam Boxer, Howard Rosen, and ARTFL/LEFFTDS Consortium

Subjects
Generalized additive models, Heterogenous variance modeling, Neuropsychological testing scores, Nonlinear Z‐score correction, Shape constrained additive models, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Introduction Conventional Z‐scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these “adjusted” Z‐scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z‐scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency. Methods In this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance). Results Corrected Z‐scores based on nonlinear shape constrained additive models provide improved adjustment for age, sex, and education, as indicated by higher adjusted‐R2. Discussion Nonlinearly corrected Z‐scores with respect to age, sex, and education with age‐varying residual standard deviation allow for improved detection of non‐normative extreme cognitive scores.

Published
2019
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2. Resting-State Functional Connectivity Is Associated With Cerebrospinal Fluid Levels of the Synaptic Protein NPTX2 in Non-demented Older Adults

Author

Anja Soldan, Abhay Moghekar, Keenan A. Walker, Corinne Pettigrew, Xirui Hou, Hanzhang Lu, Michael I. Miller, Alfonso Alfini, Marilyn Albert, Desheng Xu, Mei-Fang Xiao, Paul Worley, The BIOCARD Research Team, John Csernansky, David Holtzman, David Knopman, Walter Kukull, Kevin Grimm, John Hsiao, Laurie Ryan, Constantine Lyketsos, Carlos Pardo, Gerard Schellenberg, Leslie Shaw, Madhav Thambisetty, and John Trojanowski

Subjects
resting-state functional connectivity, magnetic resonance imaging, cerebrospinal fluid, NPTX2, synaptic function, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Intrinsic functional connectivity of large-scale brain networks has been shown to change with aging and Alzheimer’s disease (AD). These alterations are thought to reflect changes in synaptic function, but the underlying biological mechanisms are poorly understood. This study examined whether Neuronal Pentraxin 2 (NPTX2), a synaptic protein that mediates homeostatic strengthening of inhibitory circuits to control cortical excitability, is associated with functional connectivity as measured by resting-state functional magnetic resonance imaging (rsfMRI) in five large-scale cognitive brain networks. In this cross-sectional study, rsfMRI scans were obtained from 130 older individuals (mean age = 69 years) with normal cognition (N = 113) and Mild Cognitive Impairment (N = 17); NPTX2 was measured in the same individuals in cerebrospinal fluid (CSF). Higher levels of NPTX2 in CSF were associated with greater functional connectivity in the salience/ventral attention network, based on linear regression analysis. Moreover, this association was stronger among individuals with lower levels of cognitive reserve, as measured by a composite score (comprised of years of education, reading, and vocabulary measures). Additionally, higher connectivity in the salience/ventral attention network was related to better performance on a composite measure of executive function. Levels of NPTX2 were not associated with connectivity in other networks (executive control, limbic, dorsal attention, and default-mode). Findings also confirmed prior reports that individuals with MCI have lower levels of NPTX2 compared to those with normal cognition. Taken together, the results suggest that NPTX2 mechanisms may play a central role among older individuals in connectivity within the salience/ventral attention network and for cognitive tasks that require modulation of attention and response selection.

Published
2019
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3. Portuguese version of the CDR plus NACC FTLD: Validation studies

Author

Marisa, Lima, Miguel, Tábuas-Pereira, João, Durães, Pedro, Faustino, Mário R, Simões, Walter, Kukull, David S, Knopman, and Isabel, Santana

Subjects
Psychiatry and Mental health, Neurology (clinical)
Abstract

The CDR Dementia Staging Instrument PLUS National Alzheimer's Coordinating Center (CDR plus NACC FTLD) was developed by adding to the standard CDR two extra domains focused on the main features of frontotemporal lobar degeneration (FTLD): language and behavior/personality. We intended to perform the validation studies for the European-Portuguese population.A total of 105 participants matched for age, education, and disease staging (35 bvFTD, 35 AD, and 35 controls) were included. A translated-version of the CDR and the two added domains was administered by a neuropsychologist who was blinded to the diagnosis.The bvFTD group had higher baseline CDR plus NACC FTLD scores compared to the AD and controls. Only the sum-of-boxes (SB) score, the behavior/personality, and language domains were able to distinguish between clinical groups. Logistic regression analyses showed that adding the behavior/personality domain with or without language significantly enhanced the discriminating ability.Results show that the CDR plus NACC FTLD is a reliable tool in the diagnostic process of bvFTD patients and has an added value in distinguishing them from patients with AD.

Published
2022
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4. Trajectories of Cognitive Decline in Brain Donors With Autopsy-Confirmed Alzheimer Disease and Cerebrovascular Disease

Author

Brandon Frank, Madeline Ally, Yorghos Tripodis, Christian Puzo, Caroline Labriola, Landon Hurley, Brett Martin, Joseph Palmisano, Lawrence Chan, Eric Steinberg, Katherine Turk, Andrew Budson, Maureen O’Connor, Rhoda Au, Wei Qiao Qiu, Lee Goldstein, Walter Kukull, Neil Kowall, Ronald Killiany, Robert Stern, Thor Stein, Ann McKee, Jesse Mez, and Michael Alosco

Subjects
Cerebrovascular Disorders, Alzheimer Disease, Brain, Humans, Bayes Theorem, Cognitive Dysfunction, Neurology (clinical), Autopsy, Neuropsychological Tests, Research Article
Abstract

Background and ObjectivesCerebrovascular disease (CBVD) is frequently comorbid with autopsy-confirmed Alzheimer disease (AD), but its contribution to the clinical presentation of AD remains unclear. We leveraged the National Alzheimer's Coordinating Center (NACC) uniform and neuropathology datasets to compare the cognitive and functional trajectories of AD+/CBVD+ and AD+/CBVD− brain donors.MethodsThe sample included NACC brain donors with autopsy-confirmed AD (Braak stage ≥3,Consortium to Establish a Registry for Alzheimer's Diseasescore ≥2) and complete Uniform Data Set (UDS) evaluations between 2005 and 2019, with the most recent UDS evaluation within 2 years of autopsy. CBVD was defined as moderate to severe arteriosclerosis or atherosclerosis. We used propensity score weighting to isolate the effects of comorbid AD and CBVD. This method improved the balance of covariates between the AD+/CBVD+ and AD+/CBVD− groups. Longitudinal mixed-effects models were assessed with robust bayesian estimation. UDS neuropsychological test and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores were primary outcomes.ResultsOf 2,423 brain donors, 1,476 were classified as AD+/CBVD+. Compared with AD+/CVBD− donors, the AD+/CBVD+ group had accelerated decline (i.e., group × time effects) on measures of processing speed (β = −0.93, 95% CI −1.35, −0.51, Bayes factor [BF] 130.75), working memory (β = 0.05, 95% CI 0.02, 0.07, BF 3.59), verbal fluency (β = 0.10, 95% CI 0.04, 0.15, BF 1.28), naming (β = 0.09, 95% CI 0.03, 0.16, BF = 0.69), and CDR-SB (β = −0.08, 95% CI −0.12, −0.05, BF 18.11). Effects ranged from weak (BFs DiscussionIn brain donors with autopsy-confirmed AD, comorbid CBVD was associated with an accelerated functional and cognitive decline, particularly on neuropsychological tests of attention, psychomotor speed, and working memory. CBVD magnified effects of AD neuropathology on semantic-related neuropsychological tasks. Findings support a prominent additive and more subtle synergistic effect for comorbid CBVD neuropathology in AD.

Published
2021

5. Neuropathological lesions and their contribution to dementia and cognitive impairment in a heterogeneous clinical population

Author

Dana Godrich, Eden R. Martin, Gerard Schellenberg, Margaret A. Pericak‐Vance, Michael Cuccaro, William K. Scott, Walter Kukull, Thomas Montine, and Gary W. Beecham

Subjects
Epidemiology, Health Policy, Brain, Neurofibrillary Tangles, Plaque, Amyloid, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Alzheimer Disease, Humans, Cognitive Dysfunction, Lewy Bodies, Neurology (clinical), Geriatrics and Gerontology
Abstract

Alzheimer disease (AD) and related dementias are characterized by damage caused by neuropathological lesions in the brain. These include AD lesions (plaques and tangles) and non-AD lesions such as vascular injury or Lewy bodies. We report here an assessment of lesion association to dementia in a large clinic-based population.We identified 5272 individuals with neuropathological data from the National Alzheimer's Coordinating Center. Individual lesions, as well as a neuropathological composite score (NPCS) were tested for association with dementia, and both functional and neurocognitive impairment using regression models.Most individuals exhibited mixed pathologies, especially AD lesions in combination with non-AD lesions. All lesion types were associated with one or more clinical outcomes; most even while controlling for AD pathology. The NPCS was also associated with clinical outcomes.These data suggest mixed-type pathologies are extremely common in a clinic-based population and may contribute to dementia and cognitive impairment.

Published
2021

6. Pathogenic huntingtin repeat expansions in patients with frontotemporal dementia and amyotrophic lateral sclerosis

Author

Ramita Dewan, Ruth Chia, Jinhui Ding, Richard A. Hickman, Thor D. Stein, Yevgeniya Abramzon, Sarah Ahmed, Marya S. Sabir, Makayla K. Portley, Arianna Tucci, Kristina Ibáñez, F.N.U. Shankaracharya, Pamela Keagle, Giacomina Rossi, Paola Caroppo, Fabrizio Tagliavini, Maria L. Waldo, Per M. Johansson, Christer F. Nilsson, James B. Rowe, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Edwin Jabbari, Coralie Viollet, Jonathan D. Glass, Andrew B. Singleton, Vincenzo Silani, Owen A. Ross, Mina Ryten, Ali Torkamani, Toshiko Tanaka, Luigi Ferrucci, Susan M. Resnick, Stuart Pickering-Brown, Christopher B. Brady, Neil Kowal, John A. Hardy, Vivianna Van Deerlin, Jean Paul Vonsattel, Matthew B. Harms, Huw R. Morris, Raffaele Ferrari, John E. Landers, Adriano Chiò, J. Raphael Gibbs, Clifton L. Dalgard, Sonja W. Scholz, Bryan J. Traynor, Adelani Adeleye, Camille Alba, Dagmar Bacikova, Daniel N. Hupalo, Elisa McGrath Martinez, Harvey B. Pollard, Gauthaman Sukumar, Anthony R. Soltis, Meila Tuck, Xijun Zhang, Matthew D. Wilkerson, Bradley N. Smith, Nicola Ticozzi, Claudia Fallini, Athina Soragia Gkazi, Simon D. Topp, Jason Kost, Emma L. Scotter, Kevin P. Kenna, Jack W. Miller, Cinzia Tiloca, Caroline Vance, Eric W. Danielson, Claire Troakes, Claudia Colombrita, Safa Al-Sarraj, Elizabeth A. Lewis, Andrew King, Daniela Calini, Viviana Pensato, Barbara Castellotti, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, Peter C. Sapp, Diane McKenna-Yasek, Russell L. McLaughlin, Meraida Polak, Seneshaw Asress, Jesús Esteban-Pérez, José Luis Muñoz-Blanco, Zorica Stevic, Sandra D’Alfonso, Letizia Mazzini, Giacomo P. Comi, Roberto Del Bo, Mauro Ceroni, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Wouter van Rheenen, Frank P. Diekstra, Rosa Rademakers, Marka van Blitterswijk, Kevin B. Boylan, Giuseppe Lauria, Stefano Duga, Stefania Corti, Cristina Cereda, Lucia Corrado, Gianni Sorarù, Kelly L. Williams, Garth A. Nicholson, Ian P. Blair, Claire Leblond-Manry, Guy A. Rouleau, Orla Hardiman, Karen E. Morrison, Jan H. Veldink, Leonard H. van den Berg, Ammar Al-Chalabi, Hardev Pall, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Franco Taroni, Alberto García-Redondo, Zheyang Wu, Cinzia Gellera, Antonia Ratti, Robert H. Brown, Christopher E. Shaw, John C. Ambrose, Prabhu Arumugam, Emma L. Baple, Marta Bleda, Freya Boardman-Pretty, Jeanne M. Boissiere, Christopher R. Boustred, H. Brittain, Mark J. Caulfield, Georgia C. Chan, Clare E.H. Craig, Louise C. Daugherty, Anna de Burca, Andrew Devereau, Greg Elgar, Rebecca E. Foulger, Tom Fowler, Pedro Furió-Tarí, Joanne M. Hackett, Dina Halai, Angela Hamblin, Shirley Henderson, James E. Holman, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Dalia Kasperaviciute, Melis Kayikci, Lea Lahnstein, Kay Lawson, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Joanne Mason, Ellen M. McDonagh, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Chris A. Odhams, Christine Patch, Daniel Perez-Gil, Dimitris Polychronopoulos, John Pullinger, Tahrima Rahim, Augusto Rendon, Pablo Riesgo-Ferreiro, Tim Rogers, Kevin Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, Alexander Sieghart, Damian Smedley, Katherine R. Smith, Alona Sosinsky, William Spooner, Helen E. Stevens, Alexander Stuckey, Razvan Sultana, Ellen R.A. Thomas, Simon R. Thompson, Carolyn Tregidgo, Emma Walsh, Sarah A. Watters, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, Magdalena Zarowiecki, Sampath Arepalli, Pavan Auluck, Robert H. Baloh, Robert Bowser, Alexis Brice, James Broach, William Camu, John Cooper-Knock, Philippe Corcia, Carsten Drepper, Vivian E. Drory, Travis L. Dunckley, Faraz Faghri, Jennifer Farren, Eva Feldman, Mary Kay Floeter, Pietro Fratta, Glenn Gerhard, Summer B. Gibson, Stephen A. Goutman, Terry D. Heiman-Patterson, Dena G. Hernandez, Ben Hoover, Lilja Jansson, Freya Kamel, Janine Kirby, Neil W. Kowall, Hannu Laaksovirta, Francesco Landi, Isabelle Le Ber, Serge Lumbroso, Daniel JL. MacGowan, Nicholas J. Maragakis, Gabriele Mora, Kevin Mouzat, Liisa Myllykangas, Mike A. Nalls, Richard W. Orrell, Lyle W. Ostrow, Roger Pamphlett, Erik Pioro, Stefan M. Pulst, John M. Ravits, Alan E. Renton, Wim Robberecht, Ian Robey, Ekaterina Rogaeva, Jeffrey D. Rothstein, Michael Sendtner, Katie C. Sidle, Zachary Simmons, David J. Stone, Pentti J. Tienari, John Q. Trojanowski, Juan C. Troncoso, Miko Valori, Philip Van Damme, Ludo Van Den Bosch, Lorne Zinman, Diego Albani, Barbara Borroni, Alessandro Padovani, Amalia Bruni, Jordi Clarimon, Oriol Dols-Icardo, Ignacio Illán-Gala, Alberto Lleó, Adrian Danek, Daniela Galimberti, Elio Scarpini, Maria Serpente, Caroline Graff, Huei-Hsin Chiang, Behzad Khoshnood, Linn Öijerstedt, Christopher M. Morris, Benedetta Nacmias, Sandro Sorbi, Jorgen E. Nielsen, Lynne E. Hjermind, Valeria Novelli, Annibale A. Puca, Pau Pastor, Ignacio Alvarez, Monica Diez-Fairen, Miquel Aguilar, Robert Perneczky, Janine Diehl-Schimd, Mina Rossi, Agustin Ruiz, Mercè Boada, Isabel Hernández, Sonia Moreno-Grau, Johannes C. Schlachetzki, Dag Aarsland, Marilyn S. Albert, Johannes Attems, Matthew J. Barrett, Thomas G. Beach, Lynn M. Bekris, David A. Bennett, Lilah M. Besser, Eileen H. Bigio, Sandra E. Black, Bradley F. Boeve, Ryan C. Bohannan, Francesca Brett, Maura Brunetti, Chad A. Caraway, Jose-Alberto Palma, Andrea Calvo, Antonio Canosa, Dennis Dickson, Charles Duyckaerts, Kelley Faber, Tanis Ferman, Margaret E. Flanagan, Gianluca Floris, Tatiana M. Foroud, Juan Fortea, Ziv Gan-Or, Steve Gentleman, Bernardino Ghetti, Jesse Raphael Gibbs, Alison Goate, David Goldstein, Isabel González-Aramburu, Neill R. Graff-Radford, Angela K. Hodges, Heng-Chen Hu, Daniel Hupalo, Jon Infante, Alex Iranzo, Scott M. Kaiser, Horacio Kaufmann, Julia Keith, Ronald C. Kim, Gregory Klein, Rejko Krüger, Walter Kukull, Amanda Kuzma, Carmen Lage, Suzanne Lesage, James B. Leverenz, Giancarlo Logroscino, Grisel Lopez, Seth Love, Qinwen Mao, Maria Jose Marti, Elisa Martinez-McGrath, Mario Masellis, Eliezer Masliah, Patrick May, Ian McKeith, Marek-Marsel Mesulam, Edwin S. Monuki, Kathy L. Newell, Lucy Norcliffe-Kaufmann, Laura Palmer, Matthew Perkins, Olga Pletnikova, Laura Molina-Porcel, Regina H. Reynolds, Eloy Rodríguez-Rodríguez, Jonathan D. Rohrer, Pascual Sanchez-Juan, Clemens R. Scherzer, Geidy E. Serrano, Vikram Shakkottai, Ellen Sidransky, Nahid Tayebi, Alan J. Thomas, Bension S. Tilley, Ronald L. Walton, Randy Woltjer, Zbigniew K. Wszolek, Georgia Xiromerisiou, Chiara Zecca, Hemali Phatnani, Justin Kwan, Dhruv Sareen, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Neil A. Shneider, Ernest Fraenkel, Noah Zaitlen, James D. Berry, Andrea Malaspina, Gregory A. Cox, Leslie M. Thompson, Steve Finkbeiner, Efthimios Dardiotis, Timothy M. Miller, Siddharthan Chandran, Suvankar Pal, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos.A. Patsopoulos, Oleg Butovsky, Joshua Dubnau, Avindra Nath, Matt Harms, Eleonora Aronica, Mary Poss, Jennifer Phillips-Cremins, John Crary, Nazem Atassi, Dale J. Lange, Darius J. Adams, Leonidas Stefanis, Marc Gotkine, Suma Babu, Towfique Raj, Sabrina Paganoni, Ophir Shalem, Colin Smith, Bin Zhang, Brent Harris, Iris Broce, Vivian Drory, John Ravits, Corey McMillan, Vilas Menon, Lani Wu, Steven Altschuler, Khaled Amar, Neil Archibald, Oliver Bandmann, Erica Capps, Alistair Church, Jan Coebergh, Alyssa Costantini, Peter Critchley, Boyd CP. Ghosh, Michele T.M. Hu, Christopher Kobylecki, P. Nigel Leigh, Carl Mann, Luke A. Massey, Uma Nath, Nicola Pavese, Dominic Paviour, Jagdish Sharma, Jenny Vaughan, HUS Neurocenter, Neurologian yksikkö, Department of Neurosciences, Clinicum, Pentti Tienari / Principal Investigator, Parkinson's UK, Human Genetics, ARD - Amsterdam Reproduction and Development, ANS - Complex Trait Genetics, Pathology, ANS - Cellular & Molecular Mechanisms, AII - Inflammatory diseases, Universidad de Cantabria, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Huntington's Disease, Pathology, amyotrophic lateral sclerosis, Huntingtin, Neurology, 1702 Cognitive Sciences, International ALS/FTD Genomics Consortium, Neurodegenerative, frontotemporal dementia, 3124 Neurology and psychiatry, 0302 clinical medicine, Medicine, 2.1 Biological and endogenous factors, Psychology, Amyotrophic lateral sclerosis, Aetiology, Alzheimer's Disease Related Dementias (ADRD), NYGC ALS Consortium, Huntingtin Protein, DNA Repeat Expansion, General Neuroscience, Frontotemporal Dementia (FTD), International FTD Genetics Consortium, whole-genome sequencing, Frontotemporal Dementia, Neurological, Cognitive Sciences, Lewy body dementia, huntingtin, repeat expansions, Amyotrophic Lateral Sclerosis, Humans, Mutation, Whole Genome Sequencing, Frontotemporal dementia, Huntington’s disease, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, FALS Sequencing Consortium, Article, 03 medical and health sciences, Atrophy, Rare Diseases, American Genome Center, Clinical Research, mental disorders, Genetics, Acquired Cognitive Impairment, Dementia, PROSPECT Consortium, Neurology & Neurosurgery, Lewy body, business.industry, International LBD Genomics Consortium, Neurosciences, 3112 Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), nutritional and metabolic diseases, medicine.disease, Brain Disorders, nervous system diseases, 030104 developmental biology, Genomics England Research Consortium, 1701 Psychology, ALS, business, 1109 Neurosciences, 030217 neurology & neurosurgery
Abstract

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Published
2020
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7. Utility of the global CDR

Author

Toji, Miyagawa, Danielle, Brushaber, Jeremy, Syrjanen, Walter, Kremers, Julie, Fields, Leah K, Forsberg, Hilary W, Heuer, David, Knopman, John, Kornak, Adam, Boxer, Howard J, Rosen, Bradley F, Boeve, Brian, Appleby, Yvette, Bordelon, Jessica, Bove, Patrick, Brannelly, Christina, Caso, Giovanni, Coppola, Reilly, Dever, Christina, Dheel, Bradford, Dickerson, Susan, Dickinson, Sophia, Dominguez, Kimiko, Domoto-Reilly, Kelley, Faber, Jessica, Ferrell, Ann, Fishman, Jamie, Fong, Tatiana, Foroud, Ralitza, Gavrilova, Debra, Gearhart, Behnaz, Ghazanfari, Nupur, Ghoshal, Jill S, Goldman, Jonathan, Graff-Radford, Neill, Graff-Radford, Ian, Grant, Murray, Grossman, Dana, Haley, Robin, Hsiung, Edward, Huey, David, Irwin, David, Jones, Lynne, Jones, Kejal, Kantarci, Anna, Karydas, Daniel, Kaufer, Diana, Kerwin, Ruth, Kraft, Joel, Kramer, Walter, Kukull, Irene, Litvan, Diane, Lucente, Codrin, Lungu, Ian, Mackenzie, Miranda, Maldonado, Masood, Manoochehri, Scott, McGinnis, Emily, McKinley, Mario F, Mendez, Bruce, Miller, Namita, Multani, Chiadi, Onyike, Jaya, Padmanabhan, Alexander, Pantelyat, Rodney, Pearlman, Leonard, Petrucelli, Madeline, Potter, Rosa, Rademakers, Eliana M, Ramos, Kate, Rankin, Katya, Rascovsky, Erik D, Roberson, Emily, Rogalski, Pheth, Sengdy, Leslie, Shaw, Maria C, Tartaglia, Nadine, Tatton, Joanne, Taylor, Arthur, Toga, John Q, Trojanowski, Ping, Wang, Sandra, Weintraub, Bonnie, Wong, and Zbigniew, Wszolek

Subjects
Male, nutritional and metabolic diseases, Middle Aged, Mental Status and Dementia Tests, Article, nervous system diseases, Aphasia, Primary Progressive, Cross-Sectional Studies, nervous system, mental disorders, Humans, Female, Frontotemporal Lobar Degeneration, Aged
Abstract

INTRODUCTION: We created global rating scoring rules for the CDR® plus NACC FTLD to detect and track early frontotemporal lobar degeneration (FTLD) and to conduct clinical trials in FTLD. METHODS: The CDR plus NACC FTLD rating was applied to 970 sporadic and familial participants from the baseline visit of Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Each of the eight domains of the CDR plus NACC FTLD was equally weighed in determining the global score. An interrater reliability study was completed for 40 participants. RESULTS: The CDR plus NACC FTLD showed very good interrater reliability. It was especially useful in detecting clinical features of mild non‐fluent/agrammatic variant primary progressive aphasia participants. DISCUSSION: The global CDR plus NACC FTLD score could be an attractive outcome measure for clinical trials in symptomatic FTLD, and may be useful in natural history studies and clinical trials in FTLD spectrum disorders.

Published
2019

8. Sex-specific genetic predictors of Alzheimer's disease biomarkers

Author

Yuetiva, Deming, Logan, Dumitrescu, Lisa L, Barnes, Madhav, Thambisetty, Brian, Kunkle, Katherine A, Gifford, William S, Bush, Lori B, Chibnik, Shubhabrata, Mukherjee, Philip L, De Jager, Walter, Kukull, Matt, Huentelman, Paul K, Crane, Susan M, Resnick, C Dirk, Keene, Thomas J, Montine, Gerard D, Schellenberg, Jonathan L, Haines, Henrik, Zetterberg, Kaj, Blennow, Eric B, Larson, Sterling C, Johnson, Marilyn, Albert, Abhay, Moghekar, Jorge L, Del Aguila, Maria Victoria, Fernandez, John, Budde, Jason, Hassenstab, Anne M, Fagan, Matthias, Riemenschneider, Ronald C, Petersen, Lennart, Minthon, Michael J, Chao, Vivianna M, Van Deerlin, Virginia M-Y, Lee, Leslie M, Shaw, John Q, Trojanowski, Elaine R, Peskind, Gail, Li, Lea K, Davis, Julia M, Sealock, Nancy J, Cox, Alison M, Goate, David A, Bennett, Julie A, Schneider, Angela L, Jefferson, Carlos, Cruchaga, and Yi, Zhao

Subjects
0301 basic medicine, Apolipoprotein E, Male, Genotype, Physiology, Muscle Proteins, Genome-wide association study, Locus (genetics), tau Proteins, Neuropathology, Article, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Apolipoproteins E, Sex Factors, Alzheimer Disease, medicine, Humans, Serpins, Aged, 80 and over, Amyloid beta-Peptides, business.industry, Alzheimer's disease biomarkers, Brain, Amyloidosis, medicine.disease, Genetic architecture, Peptide Fragments, 030104 developmental biology, Endophenotype, Claudins, Mutation, Female, Neurology (clinical), Alzheimer's disease, business, 030217 neurology & neurosurgery, Biomarkers, Genome-Wide Association Study, Transcription Factors
Abstract

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer’s disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = − 0.03, p = 4.25 × 10−8; β = 0.03, p = 3.97 × 10−8) than males (β = − 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10−10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD’s genetic architecture.

Published
2018

9. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium

Author

Etsuro Mori, Daniel Weintraub, Pietro Tiraboschi, Bradley F. Boeve, David J. Burn, Masahito Yamada, Debby W. Tsuang, Glenda M. Halliday, David P. Salmon, Omar M. A. El-Agnaf, James B. Leverenz, Pamela J. McLean, Melissa E. Murray, Owen A. Ross, Stephen N. Gomperts, Kenji Kosaka, Laura Bonanni, Simon J.G. Lewis, Alan Thomas, Lawrence S. Honig, Ashley Bayston, Dennis W. Dickson, Daniel I. Kaufer, Nicolaas Bohnen, John E. Duda, Ronald B. Postuma, Jon B. Toledo, Zuzana Walker, Dag Aarsland, Jose Bras, Andrew B. Singleton, Johannes Attems, Tanis J. Ferman, Alice Chen-Plotkin, Virginia M.Y. Lee, Carol F. Lippa, John T. O'Brien, Thomas G. Beach, Alex Iranzo, Hiroshige Fujishiro, Angela Lunde, Frédéric Blanc, Dominic Ffytche, Ian G. McKeith, Clive Ballard, James E. Galvin, Patrik Brundin, Angela Taylor, Emilio Moreno, Brit Mollenhauer, Thomas J. Montine, Neill R. Graff-Radford, M Masellis, Shankar Ramaswamy, Jennifer G. Goldman, Eliezer Masliah, John Q. Trojanowski, Howard Feldman, Sotoshi Orimo, Douglas Galasko, John-Paul Taylor, Kejal Kantarci, Walter Kukull, O'Brien, John [0000-0002-0837-5080], Apollo - University of Cambridge Repository, Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, and Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Lewy Body Disease, medicine.medical_specialty, Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC], Consensus, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Clinical Sciences, Disease, REM sleep behavior disorder, law.invention, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, Randomized controlled trial, law, mental disorders, medicine, Humans, Intensive care medicine, Psychiatry, Neurology & Neurosurgery, Views & Reviews, Dementia with Lewy bodies, business.industry, Neurosciences, medicine.disease, 3. Good health, Clinical trial, 030104 developmental biology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Practice Guidelines as Topic, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cognitive Sciences, Dementia, Lewy Bodies, Neurology (clinical), Alzheimer's disease, business, Neurocognitive, 030217 neurology & neurosurgery, Biomarkers
Abstract

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Published
2017
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10. Drinking water aluminum and bioavailability

Author

Perri Standish-Lee, Steve Reiber, and Walter Kukull

Subjects
inorganic chemicals, Human gut, Chemistry, Environmental chemistry, General Chemistry, Solubility, Water pollution, complex mixtures, Intestinal absorption, Water Science and Technology, Bioavailability, Biological availability
Abstract

This article discusses chemical considerations relative to aluminum uptake in the body and reviews aluminum concentrations, species, and distribution in natural and treated waters. The issues of bioavailability and the likelihood that aluminum in drinking water is more readily assimilated than other forms of aluminum is reviewed and rejected based on issues of solubility and likely chemical transformations that take place in the human gut.

Published
1995
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11. GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers

Author

Eric M, Reiman, Jennifer A, Webster, Amanda J, Myers, John, Hardy, Travis, Dunckley, Victoria L, Zismann, Keta D, Joshipura, John V, Pearson, Diane, Hu-Lince, Matthew J, Huentelman, David W, Craig, Keith D, Coon, Winnie S, Liang, RiLee H, Herbert, Thomas, Beach, Kristen C, Rohrer, Alice S, Zhao, Doris, Leung, Leslie, Bryden, Lauren, Marlowe, Mona, Kaleem, Diego, Mastroeni, Andrew, Grover, Christopher B, Heward, Rivka, Ravid, Joseph, Rogers, Michael L, Hutton, Stacey, Melquist, Ron C, Petersen, Gene E, Alexander, Richard J, Caselli, Walter, Kukull, Andreas, Papassotiropoulos, and Dietrich A, Stephan

Subjects
Brain Chemistry, Genetic Markers, Apolipoprotein E4, DNA Mutational Analysis, Brain, Neurofibrillary Tangles, tau Proteins, Polymorphism, Single Nucleotide, Article, Gene Expression Regulation, Gene Frequency, Haplotypes, Alzheimer Disease, Risk Factors, Cell Line, Tumor, Mutation, Humans, Genetic Predisposition to Disease, Genetic Testing, Phosphorylation, Adaptor Proteins, Signal Transducing
Abstract

The apolipoprotein E (APOE) epsilon4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In epsilon4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 x 10(-11)) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE epsilon4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimer's neuropathology.

Published
2007

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