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1. Investigation of the genetic aetiology of Lewy body diseases with and without dementia

Author

Wu, Lesley Yue, Real, Raquel, Martinez-Carrasco, Alejandro, Chia, Ruth, Lawton, Michael A, Shoai, Maryam, Bresner, Catherine, Blauwendraat, Cornelis, Singleton, Andrew B, Ryten, Mina, Abramzon, Yevgeniya, Ahmed, Sarah, Alba, Camille, Albert, Marilyn S, Bacikova, Dagmar, Barrett, Matthew J, Beach, Thomas G, Bennett, David A, Besser, Lilah M, Bigio, Eileen H, Boeve, Bradley F, Bohannan, Ryan C, Caraway, Chad A, Palma, Jose-Alberto, Dalgard, Clifton L, Dickson, Dennis, Ding, Jinhui, Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, Gibbs, J Raphael, Goate, Alison, Goldstein, David, Graff-Radford, Neill R, Hu, Heng-Chen, Hupalo, Daniel, Kaiser, Scott M, Kaufmann, Horacio, Kim, Ronald C, Klein, Gregory, Kukull, Walter, Kuzma, Amanda, Leverenz, James, Lopez, Grisel, Mao, Qinwen, Martinez-McGrath, Elisa, Masliah, Eliezer, Monuki, Ed, Newell, Kathy L, Norcliffe-Kaufmann, Lucy, Perkins, Matthew, Pletnikova, Olga, Renton, Alan E, Resnick, Susan M, Ross, Owen A, Sabir, Marya S, Scherzer, Clemens R, Scholz, Sonja W, Serrano, Geidy, Shakkotai, Vikram, Sidransky, Ellen, Tanaka, Toshiko, Tayebi, Nahid, Traynor, Bryan J, Troncoso, Juan C, Viollet, Coralie, Walton, Ronald L, Woltjer, Randy, Wszolek, Zbigniew K, Black, Sandra E, Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Ferrari, Raffaele, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Reynolds, Regina H, Thomas, Alan J, Tilley, Bension S, Troakes, Claire, Brett, Francesca, Brice, Alexis, and Duyckaerts, Charles

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Genetics, Prevention, Aging, Lewy Body Dementia, Brain Disorders, Dementia, Alzheimer's Disease Related Dementias (ADRD), Parkinson's Disease, Human Genome, Acquired Cognitive Impairment, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Neurological, International Lewy Body Dementia Genomics Consortium, APOE, Lewy body diseases, dementia, genome-wide association studies, Clinical sciences, Biological psychology
Abstract

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

Published
2024

2. Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson’s disease

Author

Hop, Paul J., Lai, Dongbing, Keagle, Pamela J., Baron, Desiree M., Kenna, Brendan J., Kooyman, Maarten, Shankaracharya, Halter, Cheryl, Straniero, Letizia, Asselta, Rosanna, Bonvegna, Salvatore, Soto-Beasley, Alexandra I., Wszolek, Zbigniew K., Uitti, Ryan J., Isaias, Ioannis Ugo, Pezzoli, Gianni, Ticozzi, Nicola, Ross, Owen A., Veldink, Jan H., Foroud, Tatiana M., Kenna, Kevin P., and Landers, John E.

Published
2024
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3. Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction

Author

Schormair, Barbara, Zhao, Chen, Bell, Steven, Didriksen, Maria, Nawaz, Muhammad S., Schandra, Nathalie, Stefani, Ambra, Högl, Birgit, Dauvilliers, Yves, Bachmann, Cornelius G., Kemlink, David, Sonka, Karel, Paulus, Walter, Trenkwalder, Claudia, Oertel, Wolfgang H., Hornyak, Magdolna, Teder-Laving, Maris, Metspalu, Andres, Hadjigeorgiou, Georgios M., Polo, Olli, Fietze, Ingo, Ross, Owen A., Wszolek, Zbigniew K., Ibrahim, Abubaker, Bergmann, Melanie, Kittke, Volker, Harrer, Philip, Dowsett, Joseph, Chenini, Sofiene, Ostrowski, Sisse Rye, Sørensen, Erik, Erikstrup, Christian, Pedersen, Ole B., Topholm Bruun, Mie, Nielsen, Kaspar R., Butterworth, Adam S., Soranzo, Nicole, Ouwehand, Willem H., Roberts, David J., Danesh, John, Burchell, Brendan, Furlotte, Nicholas A., Nandakumar, Priyanka, Earley, Christopher J., Ondo, William G., Xiong, Lan, Desautels, Alex, Perola, Markus, Vodicka, Pavel, Dina, Christian, Stoll, Monika, Franke, Andre, Lieb, Wolfgang, Stewart, Alexandre F. R., Shah, Svati H., Gieger, Christian, Peters, Annette, Rye, David B., Rouleau, Guy A., Berger, Klaus, Stefansson, Hreinn, Ullum, Henrik, Stefansson, Kari, Hinds, David A., Di Angelantonio, Emanuele, Oexle, Konrad, and Winkelmann, Juliane

Published
2024
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4. Examining Associations Between Smartphone Use and Clinical Severity in Frontotemporal Dementia: Proof-of-Concept Study

Author

Paolillo, Emily W, Casaletto, Kaitlin B, Clark, Annie L, Taylor, Jack C, Heuer, Hilary W, Wise, Amy B, Dhanam, Sreya, Sanderson-Cimino, Mark, Saloner, Rowan, Kramer, Joel H, Kornak, John, Kremers, Walter, Forsberg, Leah, Appleby, Brian, Bayram, Ece, Bozoki, Andrea, Brushaber, Danielle, Darby, R Ryan, Day, Gregory S, Dickerson, Bradford C, Domoto-Reilly, Kimiko, Elahi, Fanny, Fields, Julie A, Ghoshal, Nupur, Graff-Radford, Neill, Hall, Matthew GH, Honig, Lawrence S, Huey, Edward D, Lapid, Maria I, Litvan, Irene, Mackenzie, Ian R, Masdeu, Joseph C, Mendez, Mario F, Mester, Carly, Miyagawa, Toji, Naasan, Georges, Pascual, Belen, Pressman, Peter, Ramos, Eliana Marisa, Rankin, Katherine P, Rexach, Jessica, Rojas, Julio C, VandeVrede, Lawren, Wong, Bonnie, Wszolek, Zbigniew K, Boeve, Bradley F, Rosen, Howard J, Boxer, Adam L, Staffaroni, Adam M, and Consortium, ALLFTD

Subjects
Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Neurosciences, Alzheimer's Disease, Frontotemporal Dementia (FTD), Behavioral and Social Science, Neurodegenerative, Clinical Research, Acquired Cognitive Impairment, Dementia, Brain Disorders, Alzheimer's Disease Related Dementias (ADRD), Basic Behavioral and Social Science, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Mental Health, Aging, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Neurological, Mental health, Humans, Female, Male, Middle Aged, Frontotemporal Dementia, Smartphone, Aged, Severity of Illness Index, Proof of Concept Study, Adult, Longitudinal Studies, Neuropsychological Tests, Mobile Applications, digital, technology, remote, monitoring, cognition, neuropsychology, cognitive impairment, neurodegenerative, screening, clinical trials, mobile phone, ALLFTD Consortium, Clinical sciences, Biomedical engineering, Health services and systems
Abstract

BackgroundFrontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged

Published
2024

5. Network Connectivity Alterations across the MAPT Mutation Clinical Spectrum

Author

Zhang, Liwen, Flagan, Taru M, Häkkinen, Suvi, Chu, Stephanie A, Brown, Jesse A, Lee, Alex J, Pasquini, Lorenzo, Mandelli, Maria Luisa, Gorno‐Tempini, Maria Luisa, Sturm, Virginia E, Yokoyama, Jennifer S, Appleby, Brian S, Cobigo, Yann, Dickerson, Bradford C, Domoto‐Reilly, Kimiko, Geschwind, Daniel H, Ghoshal, Nupur, Graff‐Radford, Neill R, Grossman, Murray, Hsiung, Ging‐Yuek Robin, Huey, Edward D, Kantarci, Kejal, Lago, Argentina Lario, Litvan, Irene, Mackenzie, Ian R, Mendez, Mario F, Onyike, Chiadi U, Ramos, Eliana Marisa, Roberson, Erik D, Tartaglia, Maria Carmela, Toga, Arthur W, Weintraub, Sandra, Wszolek, Zbigniew K, Forsberg, Leah K, Heuer, Hilary W, Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Miller, Bruce L, Seeley, William W, Lee, Suzee E, and Consortia, the ARTFL LEFFTDS ALLFTD

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Dementia, Brain Disorders, Alzheimer's Disease Related Dementias (ADRD), Clinical Research, Frontotemporal Dementia (FTD), Mental Health, Alzheimer's Disease, Rare Diseases, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Acquired Cognitive Impairment, Neurodegenerative, Biomedical Imaging, 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, Cross-Sectional Studies, tau Proteins, Brain, Mutation, Gray Matter, Magnetic Resonance Imaging, Frontotemporal Dementia, Biomarkers, ARTFL/LEFFTDS/ALLFTD Consortia, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveMicrotubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers.MethodsWe compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles.ResultsSymptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline.InterpretationNetwork connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632-646.

Published
2023

6. Role of GBA variants in Lewy body disease neuropathology

Author

Walton, Ronald L., Koga, Shunsuke, Beasley, Alexandra I., White, Launia J., Griesacker, Teresa, Murray, Melissa E., Kasanuki, Koji, Hou, Xu, Fiesel, Fabienne C., Springer, Wolfdieter, Uitti, Ryan J., Fields, Julie A., Botha, Hugo, Ramanan, Vijay K., Kantarci, Kejal, Lowe, Val J., Jack, Clifford R., Ertekin-Taner, Nilufer, Savica, Rodolfo, Graff-Radford, Jonathan, Petersen, Ronald C., Parisi, Joseph E., Reichard, R. Ross, Graff-Radford, Neill R., Ferman, Tanis J., Boeve, Bradley F., Wszolek, Zbigniew K., Dickson, Dennis W., Ross, Owen A., and Heckman, Michael G.

Published
2024
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7. Differences in Motor Features of C9orf72, MAPT, or GRN Variant Carriers With Familial Frontotemporal Lobar Degeneration.

Author

Tipton, Philip Wade, Deutschlaender, Angela B, Savica, Rodolfo, Heckman, Michael G, Brushaber, Danielle E, Dickerson, Bradford C, Gavrilova, Ralitza H, Geschwind, Daniel H, Ghoshal, Nupur, Graff-Radford, Jonathan, Graff-Radford, Neill R, Grossman, Murray, Hsiung, Ging-Yuek R, Huey, Edward D, Irwin, David John, Jones, David T, Knopman, David S, McGinnis, Scott M, Rademakers, Rosa, Ramos, Eliana Marisa, Forsberg, Leah K, Heuer, Hilary W, Onyike, Chiadi, Tartaglia, Carmela, Domoto-Reilly, Kimiko, Roberson, Erik D, Mendez, Mario F, Litvan, Irene, Appleby, Brian S, Grant, Ian, Kaufer, Daniel, Boxer, Adam L, Rosen, Howard J, Boeve, Brad F, and Wszolek, Zbigniew K

Subjects
C9orf72 Protein: genetics, Frontotemporal Dementia: diagnosis, genetics, Frontotemporal Lobar Degeneration: genetics, Granulins: genetics, Humans, Mutation: genetics, Progranulins: genetics, Quality of Life, Supranuclear Palsy, Progressive, tau Proteins: genetics
Abstract

Familial frontotemporal lobar degeneration (f-FTLD) is a phenotypically heterogeneous spectrum of neurodegenerative disorders most often caused by variants within chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), or granulin (GRN). The phenotypic association with each of these genes is incompletely understood. We hypothesized that the frequency of specific clinical features would correspond with different genes.We screened the Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)/ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium for symptomatic carriers of pathogenic variants in C9orf72, MAPT, or GRN. We assessed for clinical differences among these 3 groups based on data recorded as part of a detailed neurologic examination, the Progressive Supranuclear Palsy Rating Scale, Progressive Supranuclear Palsy-Quality of Life Rating Scale, Unified Parkinson's Disease Rating Scale Part III (motor items), and the Amyotrophic Lateral Sclerosis Functional Rating Scale, revised version. Data were analyzed using Kruskal-Wallis and Wilcoxon rank-sum tests and Fisher exact test.We identified 184 symptomatic participants who had a single pathogenic variant in C9orf72 (n = 88), MAPT (n = 53), or GRN (n = 43). Motor symptom age at onset was earliest in the MAPT participants followed by C9orf72, whereas the GRN pathogenic variant carriers developed symptoms later. C9orf72 participants more often had fasciculations, muscle atrophy, and weakness, whereas parkinsonism was less frequent. Vertical oculomotor abnormalities were more common in the MAPT cohort, whereas apraxia and focal limb dystonia occurred more often in participants with GRN variants.We present a large comparative study of motor features in C9orf72, MAPT, and GRN pathogenic variant carriers with symptomatic f-FTLD. Our findings demonstrate characteristic phenotypic differences corresponding with specific gene variants that increase our understanding of the genotype-phenotype relationship in this complex spectrum of neurodegenerative disorders.NCT02365922, NCT02372773, and NCT04363684.

Published
2022

9. Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy

Author

Chadarevian, Jean Paul, Hasselmann, Jonathan, Lahian, Alina, Capocchi, Joia K., Escobar, Adrian, Lim, Tau En, Le, Lauren, Tu, Christina, Nguyen, Jasmine, Kiani Shabestari, Sepideh, Carlen-Jones, William, Gandhi, Sunil, Bu, Guojun, Hume, David A., Pridans, Clare, Wszolek, Zbigniew K., Spitale, Robert C., Davtyan, Hayk, and Blurton-Jones, Mathew

Published
2024
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10. Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups.

Author

Kaivola, Karri, Shah, Zalak, Chia, Ruth, Black, Sandra E, Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A, Hodges, Angela K, Love, Seth, McKeith, Ian G, Morris, Christopher M, Morris, Huw R, Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J, Troakes, Claire, Albert, Marilyn S, Barrett, Matthew J, Beach, Thomas G, Bekris, Lynn M, Bennett, David A, Boeve, Bradley F, Dalgard, Clifton L, Dawson, Ted M, Dickson, Dennis W, Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E, Foroud, Tatiana M, Ghetti, Bernardino, Gibbs, J Raphael, Goate, Alison, Goldstein, David S, Graff-Radford, Neill R, Kaufmann, Horacio, Kukull, Walter A, Leverenz, James B, Mao, Qinwen, Masliah, Eliezer, Monuki, Edwin, Newell, Kathy L, Palma, Jose Alberto, Pletnikova, Olga, Renton, Alan E, Resnick, Susan M, Rosenthal, Liana S, Ross, Owen A, Scherzer, Clemens R, Serrano, Geidy E, Shakkottai, Vikram G, Sidransky, Ellen, Tanaka, Toshiko, Topol, Eric, Torkamani, Ali, Troncoso, Juan C, Woltjer, Randy, Wszolek, Zbigniew K, and Scholz, Sonja W

Subjects
Genetics, Lewy Body Dementia, Neurodegenerative, Aging, Brain Disorders, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Alzheimer's Disease, Acquired Cognitive Impairment, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Alzheimer Disease, Apolipoprotein E4, Genome-Wide Association Study, Humans, Lewy Body Disease, alpha-Synuclein, International LBD Genomics Consortium, APOE, Alzheimer’s disease, co-pathology, dementia with Lewy bodies, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

The APOE locus is strongly associated with risk for developing Alzheimer's disease and dementia with Lewy bodies. In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for dementia with Lewy bodies in patients without APOE ε4 (P = 6.58 × 10-9, OR = 3.41, 95% CI = 2.25-5.17), but not with dementia with Lewy bodies with APOE ε4 (P = 0.034, OR = 1.87, 95%, 95% CI = 1.05-3.37). We then divided 495 neuropathologically examined dementia with Lewy bodies cases into three groups based on the extent of concomitant Alzheimer's disease co-pathology: pure dementia with Lewy bodies (n = 88), dementia with Lewy bodies with intermediate Alzheimer's disease co-pathology (n = 66) and dementia with Lewy bodies with high Alzheimer's disease co-pathology (n = 341). In each group, we tested the association of the APOE ε4 against the 2928 neurologically healthy controls. Our examination found that APOE ε4 was associated with dementia with Lewy bodies + Alzheimer's disease (P = 1.29 × 10-32, OR = 4.25, 95% CI = 3.35-5.39) and dementia with Lewy bodies + intermediate Alzheimer's disease (P = 0.0011, OR = 2.31, 95% CI = 1.40-3.83), but not with pure dementia with Lewy bodies (P = 0.31, OR = 0.75, 95% CI = 0.43-1.30). In conclusion, although deep clinical data were not available for these samples, our findings do not support the notion that APOE ε4 is an independent driver of α-synuclein pathology in pure dementia with Lewy bodies, but rather implicate GBA as the main risk gene for the pure dementia with Lewy bodies subgroup.

Published
2022

11. Sensitivity of the Social Behavior Observer Checklist to Early Symptoms of Patients With Frontotemporal Dementia.

Author

Toller, Gianina, Cobigo, Yann, Ljubenkov, Peter A, Appleby, Brian S, Dickerson, Bradford C, Domoto-Reilly, Kimiko, Fong, Jamie C, Forsberg, Leah K, Gavrilova, Ralitza H, Ghoshal, Nupur, Heuer, Hilary W, Knopman, David S, Kornak, John, Lapid, Maria I, Litvan, Irene, Lucente, Diane E, Mckenzie, Ian R, McGinnis, Scott M, Miller, Bruce L, Pedraza, Otto, Rojas, Julio C, Staffaroni, Adam M, Wong, Bonnie, Wszolek, Zbigniew K, Boeve, Brad F, Boxer, Adam L, Rosen, Howard J, Rankin, Katherine P, and ALLFTD research consortium

Subjects
ALLFTD research consortium, Social Behavior Observer Checklist, behavior, behavioral variant frontotemporal dementia, clinical trials, neurodegenerative disease, social cognition, Aging, Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Clinical Research, Dementia, Behavioral and Social Science, Frontotemporal Dementia (FTD), Alzheimer's Disease, Clinical Trials and Supportive Activities, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Rare Diseases, Neurosciences, Basic Behavioral and Social Science, Prevention, Neurological, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Background and objectivesChanges in social behavior are common symptoms of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease syndromes. For early identification of individual patients and differential diagnosis, sensitive clinical measures are required that are able to assess patterns of behaviors and detect syndromic differences in both asymptomatic and symptomatic stages. We investigated whether the examiner-based Social Behavior Observer Checklist (SBOCL) is sensitive to early behavior changes and reflects disease severity within and between neurodegenerative syndromes.MethodsAsymptomatic individuals and neurodegenerative disease patients were selected from the multisite ALLFTD cohort study. In a sample of participants with at least one timepoint of SBOCL data, we investigated whether the Disorganized, Reactive, and Insensitive subscales of the SBOCL change as a function of disease stage within and between these syndromes. In a longitudinal subsample with both SBOCL and neuroimaging data, we examined whether change over time on each subscale corresponds to progressive gray matter atrophy.Results1082 FTLD mutation carriers and non-carriers were enrolled (282 asymptomatic, 341 behavioral variant frontotemporal dementia, 114 semantic and 95 non-fluent variant primary progressive aphasia, 137 progressive supranuclear palsy, 113 Alzheimer's clinical syndrome). The Disorganized score increased between asymptomatic to very mild (p=0.016, estimate=-1.10, 95%CI=[-1.99, -0.22]), very mild to mild (p=0.013, -1.17, [-2.08, -0.26]), and mild to moderate/severe (p

Published
2022

12. Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons

Author

Al-Dalahmah, Osama, Lam, Matti, McInvale, Julie J., Qu, Wenhui, Nguyen, Trang, Mun, Jeong-Yeon, Kwon, Sam, Ifediora, Nkechime, Mahajan, Aayushi, Humala, Nelson, Winters, Tristan, Angeles, Ellen, Jakubiak, Kelly A., Kühn, Rebekka, Kim, Yoon A., De Rosa, Maria Caterina, Doege, Claudia A., Paryani, Fahad, Flowers, Xena, Dovas, Athanassios, Mela, Angeliki, Lu, Hong, DeTure, Michael A., Vonsattel, Jean Paul, Wszolek, Zbigniew K., Dickson, Dennis W., Kuhlmann, Tanja, Zaehres, Holm, Schöler, Hans R., Sproul, Andrew A., Siegelin, Markus D., De Jager, Philip L., Goldman, James E., Menon, Vilas, Canoll, Peter, and Hargus, Gunnar

Published
2024
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13. MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study

Author

Warner, Thomas T, Jaunmuktane, Zane, Boeve, Bradley F, Duara, Ranjan, Graff-Radford, Neill R, Josephs, Keith A, Knopman, David S, Koga, Shunsuke, Murray, Melissa E, Lyons, Kelly E, Pahwa, Rajesh, Petersen, Ronald C, Whitwell, Jennifer L, Grinberg, Lea T, Miller, Bruce, Schlereth, Athena, Spina, Salvatore, Grossman, Murray, Irwin, David J, Suh, EunRan, Trojanowski, John Q, Van Deerlin, Vivianna M, Wolk, David A, Connors, Theresa R, Dooley, Patrick M, Oakley, Derek H, Aldecoa, Iban, Balasa, Mircea, Gelpi, Ellen, Borrego-Écija, Sergi, Gascon-Bayarri, Jordi, Sánchez-Valle, Raquel, Sanz-Cartagena, Pilar, Piñol-Ripoll, Gerard, Bigio, Eileen H, Flanagan, Margaret E, Rogalski, Emily J, Weintraub, Sandra, Schneider, Julie A, Peng, Lihua, Zhu, Xiongwei, Chang, Koping, Troncoso, Juan C, Prokop, Stefan, Newell, Kathy L, Jones, Matthew, Richardson, Anna, Roncaroli, Federico, Snowden, Julie, Allinson, Kieren, Singh, Poonam, Serrano, Geidy E, Flowers, Xena E, Goldman, James E, Heaps, Allison C, Leskinen, Sandra P, Black, Sandra E, Masellis, Mario, King, Andrew, Al-Sarraj, Safa, Troakes, Claire, Hodges, John R, Kril, Jillian J, Kwok, John B, Piguet, Olivier, Roeber, Sigrun, Attems, Johannes, Thomas, Alan J, Evers, Bret M., Bieniek, Kevin F, Sieben, Anne A, Cras, Patrick P, De Vil, Bart B, Bird, Thomas, Castellani, Rudolph J, Chaffee, Ann, Franklin, Erin, Haroutunian, Vahram, Jacobsen, Max, Keene, Dirk, Latimer, Caitlin S, Metcalf, Jeff, Perrin, Richard J, Purohit, Dushyant P, Rissman, Robert A, Schantz, Aimee, Walker, Jamie, De Deyn, Peter P, Duyckaerts, Charles, Le Ber, Isabelle, Seilhean, Danielle, Turbant-Leclere, Sabrina, Ervin, John F, Nennesmo, Inger, Riehl, James, Nacmias, Benedetta, Finger, Elizabeth C, Blauwendraat, Cornelis, Nalls, Mike A, Singleton, Andrew B, Vitale, Dan, Cunha, Cristina, Wszolek, Zbigniew K, Valentino, Rebecca R, Scotton, William J, Roemer, Shanu F, Lashley, Tammaryn, Heckman, Michael G, Shoai, Maryam, Martinez-Carrasco, Alejandro, Tamvaka, Nicole, Walton, Ronald L, Baker, Matthew C, Macpherson, Hannah L, Real, Raquel, Soto-Beasley, Alexandra I, Mok, Kin, Revesz, Tamas, Christopher, Elizabeth A, DeTure, Michael, Seeley, William W, Lee, Edward B, Frosch, Matthew P, Molina-Porcel, Laura, Gefen, Tamar, Redding-Ochoa, Javier, Ghetti, Bernardino, Robinson, Andrew C, Kobylecki, Christopher, Rowe, James B, Beach, Thomas G, Teich, Andrew F, Keith, Julia L, Bodi, Istvan, Halliday, Glenda M, Gearing, Marla, Arzberger, Thomas, Morris, Christopher M, White, Charles L, 3rd, Mechawar, Naguib, Boluda, Susana, MacKenzie, Ian R, McLean, Catriona, Cykowski, Matthew D, Wang, Shih-Hsiu J, Graff, Caroline, Nagra, Rashed M, Kovacs, Gabor G, Giaccone, Giorgio, Neumann, Manuela, Ang, Lee-Cyn, Carvalho, Agostinho, Morris, Huw R, Rademakers, Rosa, Hardy, John A, Dickson, Dennis W, Rohrer, Jonathan D, and Ross, Owen A

Published
2024
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16. Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders

Author

Gendron, Tania F, Heckman, Michael G, White, Launia J, Veire, Austin M, Pedraza, Otto, Burch, Alexander R, Bozoki, Andrea C, Dickerson, Bradford C, Domoto-Reilly, Kimiko, Foroud, Tatiana, Forsberg, Leah K, Galasko, Douglas R, Ghoshal, Nupur, Graff-Radford, Neill R, Grossman, Murray, Heuer, Hilary W, Huey, Edward D, Hsiung, Ging-Yuek R, Irwin, David J, Kaufer, Daniel I, Leger, Gabriel C, Litvan, Irene, Masdeu, Joseph C, Mendez, Mario F, Onyike, Chiadi U, Pascual, Belen, Ritter, Aaron, Roberson, Erik D, Rojas, Julio C, Tartaglia, Maria Carmela, Wszolek, Zbigniew K, Rosen, Howard, Boeve, Bradley F, Boxer, Adam L, consortium, ALLFTD, Appleby, Brian S, Barmada, Sami, Bordelon, Yvette, Botha, Hugo, Brushaber, Danielle, Clark, David, Coppola, Giovanni, Darby, Ryan, Devick, Katrina, Dickson, Dennis, Faber, Kelley, Fagan, Anne, Fields, Julie A, Gavrilova, Ralitza, Geschwind, Daniel, Goldman, Jill, Graff-Radford, Jonathon, Grant, Ian, Jones, David T, Kantarci, Kejal, Kerwin, Diana, Knopman, David S, Kornak, John, Kremers, Walter, Lapid, Maria, Lago, Argentina Lario, Ljubenkov, Peter, Lucente, Diane, Mackenzie, Ian R, McGinnis, Scott, Mester, Carly, Miller, Bruce L, Pressman, Peter, Rademakers, Rosa, Ramanan, Vijay K, Ramos, E Marisa, Rankin, Katherine P, Rao, Meghana, Rascovsky, Katya, Savica, Rodolfo, Seeley, William, Staffaroni, Adam M, Syrjanen, Jeremy, Taylor, Jack, VandeVrede, Lawren, Weintraub, Sandra, Wong, Bonnie, and Petrucelli, Leonard

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Rare Diseases, Dementia, Brain Disorders, Prevention, Acquired Cognitive Impairment, Neurodegenerative, Frontotemporal Dementia (FTD), 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Good Health and Well Being, Cross-Sectional Studies, Frontotemporal Dementia, Humans, Intermediate Filaments, Neurofilament Proteins, Pick Disease of the Brain, Syndrome, ALLFTD consortium, Richardson’s syndrome, behavioral variant frontotemporal dementia, biomarker, corticobasal syndrome, neurofilament light, plasma, presymptomatic, primary progressive aphasia, progressive supranuclear palsy, Biomedical and clinical sciences
Abstract

Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations.

Published
2022

22. Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Author

Soltis, Anthony R., Viollet, Coralie, Sukumar, Gauthaman, Alba, Camille, Lott, Nathaniel, McGrath Martinez, Elisa, Tuck, Meila, Singh, Jatinder, Bacikova, Dagmar, Zhang, Xijun, Hupalo, Daniel N., Adeleye, Adelani, Wilkerson, Matthew D., Pollard, Harvey B., Dalgard, Clifton L., Black, Sandra E., Gan-Or, Ziv, Keith, Julia, Masellis, Mario, Rogaeva, Ekaterina, Brice, Alexis, Lesage, Suzanne, Xiromerisiou, Georgia, Calvo, Andrea, Canosa, Antonio, Chio, Adriano, Logroscino, Giancarlo, Mora, Gabriele, Krüger, Reijko, May, Patrick, Alcolea, Daniel, Clarimon, Jordi, Fortea, Juan, Gonzalez-Aramburu, Isabel, Infante, Jon, Lage, Carmen, Lleó, Alberto, Pastor, Pau, Sanchez-Juan, Pascual, Brett, Francesca, Aarsland, Dag, Al-Sarraj, Safa, Attems, Johannes, Gentleman, Steve, Hardy, John A., Hodges, Angela K., Love, Seth, McKeith, Ian G., Morris, Christopher M., Morris, Huw R., Palmer, Laura, Pickering-Brown, Stuart, Ryten, Mina, Thomas, Alan J., Troakes, Claire, Albert, Marilyn S., Barrett, Matthew J., Beach, Thomas G., Bekris, Lynn M., Bennett, David A., Boeve, Bradley F., Dawson, Ted M., Dickson, Dennis W., Faber, Kelley, Ferman, Tanis, Ferrucci, Luigi, Flanagan, Margaret E., Foroud, Tatiana M., Ghetti, Bernardino, Gibbs, J. Raphael, Goate, Alison, Goldstein, David S., Graff-Radford, Neill R., Kaufmann, Horacio, Kukull, Walter A., Leverenz, James B., Lopez, Grisel, Mao, Qinwen, Masliah, Eliezer, Monuki, Edwin, Newell, Kathy L., Palma, Jose-Alberto, Perkins, Matthew, Pletnikova, Olga, Renton, Alan E., Resnick, Susan M., Rosenthal, Liana S., Ross, Owen A., Scherzer, Clemens R., Serrano, Geidy E., Shakkottai, Vikram G., Sidransky, Ellen, Tanaka, Toshiko, Tayebi, Nahid, Topol, Eric, Torkamani, Ali, Troncoso, Juan C., Woltjer, Randy, Wszolek, Zbigniew K., Scholz, Sonja W., Baloh, Robert H., Bowser, Robert, Broach, James, Camu, William, Chiò, Adriano, Cooper-Knock, John, Drepper, Carsten, Drory, Vivian E., Dunckley, Travis L., Feldman, Eva, Fratta, Pietro, Gerhard, Glenn, Gibson, Summer B., Glass, Jonathan D., Harms, Matthew B., Heiman-Patterson, Terry D., Jansson, Lilja, Kirby, Janine, Kwan, Justin, Laaksovirta, Hannu, Landers, John E., Landi, Francesco, Le Ber, Isabelle, Lumbroso, Serge, MacGowan, Daniel J.L., Maragakis, Nicholas J., Mouzat, Kevin, Myllykangas, Liisa, Orrell, Richard W., Ostrow, Lyle W., Pamphlett, Roger, Pioro, Erik, Pulst, Stefan M., Ravits, John M., Robberecht, Wim, Rothstein, Jeffrey D., Sendtner, Michael, Shaw, Pamela J., Sidle, Katie C., Simmons, Zachary, Stein, Thor, Stone, David J., Tienari, Pentti J., Traynor, Bryan J., Valori, Miko, Van Damme, Philip, Van Deerlin, Vivianna M., Van Den Bosch, Ludo, Zinman, Lorne, Kaivola, Karri, Chia, Ruth, Ding, Jinhui, Rasheed, Memoona, Fujita, Masashi, Menon, Vilas, Walton, Ronald L., Collins, Ryan L., Billingsley, Kimberley, Brand, Harrison, Talkowski, Michael, Zhao, Xuefang, Dewan, Ramita, Stark, Ali, Ray, Anindita, Solaiman, Sultana, Alvarez Jerez, Pilar, Malik, Laksh, Tienari, Pentti, Mazzini, Letizia, D'Alfonso, Sandra, Moglia, Cristina, and De Jager, Philip L.

Published
2023
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23. Development and characterization of phospho-ubiquitin antibodies to monitor PINK1-PRKN signaling in cells and tissue

Author

Watzlawik, Jens O., primary, Hou, Xu, additional, Richardson, Tyrique, additional, Lewicki, Szymon L., additional, Siuda, Joanna, additional, Wszolek, Zbigniew K., additional, Cook, Casey N., additional, Petrucelli, Leonard, additional, DeTure, Michael, additional, Dickson, Dennis W., additional, Antico, Odetta, additional, Muqit, Miratul M. K., additional, Fishman, Jordan B., additional, Pirani, Karima, additional, Kumaran, Ravindran, additional, Polinski, Nicole K., additional, Fiesel, Fabienne C., additional, and Springer, Wolfdieter, additional

Published
2024
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24. MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study

Author

Valentino, Rebecca R, primary, Scotton, William J, additional, Roemer, Shanu F, additional, Lashley, Tammaryn, additional, Heckman, Michael G, additional, Shoai, Maryam, additional, Martinez-Carrasco, Alejandro, additional, Tamvaka, Nicole, additional, Walton, Ronald L, additional, Baker, Matthew C, additional, Macpherson, Hannah L, additional, Real, Raquel, additional, Soto-Beasley, Alexandra I, additional, Mok, Kin, additional, Revesz, Tamas, additional, Christopher, Elizabeth A, additional, DeTure, Michael, additional, Seeley, William W, additional, Lee, Edward B, additional, Frosch, Matthew P, additional, Molina-Porcel, Laura, additional, Gefen, Tamar, additional, Redding-Ochoa, Javier, additional, Ghetti, Bernardino, additional, Robinson, Andrew C, additional, Kobylecki, Christopher, additional, Rowe, James B, additional, Beach, Thomas G, additional, Teich, Andrew F, additional, Keith, Julia L, additional, Bodi, Istvan, additional, Halliday, Glenda M, additional, Gearing, Marla, additional, Arzberger, Thomas, additional, Morris, Christopher M, additional, White, Charles L, additional, Mechawar, Naguib, additional, Boluda, Susana, additional, MacKenzie, Ian R, additional, McLean, Catriona, additional, Cykowski, Matthew D, additional, Wang, Shih-Hsiu J, additional, Graff, Caroline, additional, Nagra, Rashed M, additional, Kovacs, Gabor G, additional, Giaccone, Giorgio, additional, Neumann, Manuela, additional, Ang, Lee-Cyn, additional, Carvalho, Agostinho, additional, Morris, Huw R, additional, Rademakers, Rosa, additional, Hardy, John A, additional, Dickson, Dennis W, additional, Rohrer, Jonathan D, additional, Ross, Owen A, additional, Warner, Thomas T, additional, Jaunmuktane, Zane, additional, Boeve, Bradley F, additional, Duara, Ranjan, additional, Graff-Radford, Neill R, additional, Josephs, Keith A, additional, Knopman, David S, additional, Koga, Shunsuke, additional, Murray, Melissa E, additional, Lyons, Kelly E, additional, Pahwa, Rajesh, additional, Petersen, Ronald C, additional, Whitwell, Jennifer L, additional, Grinberg, Lea T, additional, Miller, Bruce, additional, Schlereth, Athena, additional, Spina, Salvatore, additional, Grossman, Murray, additional, Irwin, David J, additional, Suh, EunRan, additional, Trojanowski, John Q, additional, Van Deerlin, Vivianna M, additional, Wolk, David A, additional, Connors, Theresa R, additional, Dooley, Patrick M, additional, Oakley, Derek H, additional, Aldecoa, Iban, additional, Balasa, Mircea, additional, Gelpi, Ellen, additional, Borrego-Écija, Sergi, additional, Gascon-Bayarri, Jordi, additional, Sánchez-Valle, Raquel, additional, Sanz-Cartagena, Pilar, additional, Piñol-Ripoll, Gerard, additional, Bigio, Eileen H, additional, Flanagan, Margaret E, additional, Rogalski, Emily J, additional, Weintraub, Sandra, additional, Schneider, Julie A, additional, Peng, Lihua, additional, Zhu, Xiongwei, additional, Chang, Koping, additional, Troncoso, Juan C, additional, Prokop, Stefan, additional, Newell, Kathy L, additional, Jones, Matthew, additional, Richardson, Anna, additional, Roncaroli, Federico, additional, Snowden, Julie, additional, Allinson, Kieren, additional, Singh, Poonam, additional, Serrano, Geidy E, additional, Flowers, Xena E, additional, Goldman, James E, additional, Heaps, Allison C, additional, Leskinen, Sandra P, additional, Black, Sandra E, additional, Masellis, Mario, additional, King, Andrew, additional, Al-Sarraj, Safa, additional, Troakes, Claire, additional, Hodges, John R, additional, Kril, Jillian J, additional, Kwok, John B, additional, Piguet, Olivier, additional, Roeber, Sigrun, additional, Attems, Johannes, additional, Thomas, Alan J, additional, Evers, Bret M., additional, Bieniek, Kevin F, additional, Sieben, Anne A, additional, Cras, Patrick P, additional, De Vil, Bart B, additional, Bird, Thomas, additional, Castellani, Rudolph J, additional, Chaffee, Ann, additional, Franklin, Erin, additional, Haroutunian, Vahram, additional, Jacobsen, Max, additional, Keene, Dirk, additional, Latimer, Caitlin S, additional, Metcalf, Jeff, additional, Perrin, Richard J, additional, Purohit, Dushyant P, additional, Rissman, Robert A, additional, Schantz, Aimee, additional, Walker, Jamie, additional, De Deyn, Peter P, additional, Duyckaerts, Charles, additional, Le Ber, Isabelle, additional, Seilhean, Danielle, additional, Turbant-Leclere, Sabrina, additional, Ervin, John F, additional, Nennesmo, Inger, additional, Riehl, James, additional, Nacmias, Benedetta, additional, Finger, Elizabeth C, additional, Blauwendraat, Cornelis, additional, Nalls, Mike A, additional, Singleton, Andrew B, additional, Vitale, Dan, additional, Cunha, Cristina, additional, and Wszolek, Zbigniew K, additional

Published
2024
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26. Neurofilament light chain and vaccination status associate with clinical outcomes in severe COVID-19

Author

Erben, Young, Prudencio, Mercedes, Marquez, Christopher P., Jansen-West, Karen R., Heckman, Michael G., White, Launia J., Dunmore, Judith A., Cook, Casey N., Lilley, Meredith T., Qosja, Neda, Song, Yuping, Hanna Al Shaikh, Rana, Daughrity, Lillian M., Bartfield, Jordan L., Day, Gregory S., Oskarsson, Björn, Nicholson, Katharine A., Wszolek, Zbigniew K., Hoyne, Jonathan B., Gendron, Tania F., Meschia, James F., and Petrucelli, Leonard

Published
2022
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27. Mitochondrial genomic variation in dementia with Lewy bodies: association with disease risk and neuropathological measures

Author

Valentino, Rebecca R., Ramnarine, Chloe, Heckman, Michael G., Johnson, Patrick W., Soto-Beasley, Alexandra I., Walton, Ronald L., Koga, Shunsuke, Kasanuki, Koji, Murray, Melissa E., Uitti, Ryan J., Fields, Julie A., Botha, Hugo, Ramanan, Vijay K., Kantarci, Kejal, Lowe, Val J., Jack, Clifford R., Ertekin-Taner, Nilufer, Savica, Rodolfo, Graff-Radford, Jonathan, Petersen, Ronald C., Parisi, Joseph E., Reichard, R. Ross, Graff-Radford, Neill R., Ferman, Tanis J., Boeve, Bradley F., Wszolek, Zbigniew K., Dickson, Dennis W., and Ross, Owen A.

Published
2022
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29. Evidence of cerebellar TDP-43 loss of function in FTLD-TDP

Author

Pickles, Sarah, Gendron, Tania F., Koike, Yuka, Yue, Mei, Song, Yuping, Kachergus, Jennifer M., Shi, J., DeTure, Michael, Thompson, E. Aubrey, Oskarsson, Björn, Graff-Radford, Neill R., Boeve, Bradley F., Petersen, Ronald C., Wszolek, Zbigniew K., Josephs, Keith A., Dickson, Dennis W., Petrucelli, Leonard, Cook, Casey N., and Prudencio, Mercedes

Published
2022
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30. Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders

Author

Appleby, Brian S., Barmada, Sami, Bordelon, Yvette, Botha, Hugo, Brushaber, Danielle, Clark, David, Coppola, Giovanni, Darby, Ryan, Devick, Katrina, Dickson, Dennis, Faber, Kelley, Fagan, Anne, Fields, Julie A., Gavrilova, Ralitza, Geschwind, Daniel, Goldman, Jill, Graff-Radford, Jonathon, Grant, Ian, Jones, David T., Kantarci, Kejal, Kerwin, Diana, Knopman, David S., Kornak, John, Kremers, Walter, Lapid, Maria, Lago, Argentina Lario, Ljubenkov, Peter, Lucente, Diane, Mackenzie, Ian R., McGinnis, Scott, Mester, Carly, Miller, Bruce L., Pressman, Peter, Rademakers, Rosa, Ramanan, Vijay K., Ramos, E. Marisa, Rankin, Katherine P., Rao, Meghana, Rascovsky, Katya, Savica, Rodolfo, Seeley, William, Staffaroni, Adam M., Syrjanen, Jeremy, Taylor, Jack, VandeVrede, Lawren, Weintraub, Sandra, Wong, Bonnie, Gendron, Tania F., Heckman, Michael G., White, Launia J., Veire, Austin M., Pedraza, Otto, Burch, Alexander R., Bozoki, Andrea C., Dickerson, Bradford C., Domoto-Reilly, Kimiko, Foroud, Tatiana, Forsberg, Leah K., Galasko, Douglas R., Ghoshal, Nupur, Graff-Radford, Neill R., Grossman, Murray, Heuer, Hilary W., Huey, Edward D., Hsiung, Ging-Yuek R., Irwin, David J., Kaufer, Daniel I., Leger, Gabriel C., Litvan, Irene, Masdeu, Joseph C., Mendez, Mario F., Onyike, Chiadi U., Pascual, Belen, Ritter, Aaron, Roberson, Erik D., Rojas, Julio C., Tartaglia, Maria Carmela, Wszolek, Zbigniew K., Rosen, Howard, Boeve, Bradley F., Boxer, Adam L., and Petrucelli, Leonard

Published
2022
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31. Global Presence and Penetrance of CSF1R-Related Disorder.

Author

Dulski, Jaroslaw, Baker, Matthew, Banks, Samantha A., Bayat, Michael, Bruffaerts, Rose, Cruz, Gabriela Ortiz, Disserol, Caio C., Fisher, Kristen S., Jose, Jainy N., Kalman, Bernadette, Kantarci, Orhun H., Maltsev, Dmytro, Middleton, Catherine, Novotni, Gabriela, Plaseska-Karanfilska, Dijana, Raskin, Salmo, Souza, Josiane, Teive, Helio A., and Wszolek, Zbigniew K.

Published
2024
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32. Dopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa‐Induced Dyskinesia.

Author

Sosero, Yuri L., Bandres‐Ciga, Sara, Ferwerda, Bart, Tocino, Maria T.P., Belloso, Dìaz R., Gómez‐Garre, Pilar, Faouzi, Johann, Taba, Pille, Pavelka, Lukas, Marques, Tainà M., Gomes, Clarissa P.C., Kolodkin, Alexey, May, Patrick, Milanowski, Lukasz M., Wszolek, Zbigniew K., Uitti, Ryan J., Heutink, Peter, van Hilten, Jacobus J., Simon, David K., and Eberly, Shirley

Abstract

Background: Levodopa‐induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2. Objectives: Our goal was to investigate the effects of genetic variants on risk and time to LID. Methods: We performed a genome‐wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID. Results: We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21–2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09–1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile = 1.27; 95% CI, 1.03–1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile = 1.38; 95% CI, 1.07–1.79; P = 0.0128; HRfourth_quartile = 1.38; 95% CI = 1.06–1.78; P = 0.0147). Conclusions: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Published
2024
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33. Structural and Functional Characterization of the Most Frequent Pathogenic PRKN Substitution p.R275W.

Author

Bustillos, Bernardo A., Cocker, Liam T., Coban, Mathew A., Weber, Caleb A., Bredenberg, Jenny M., Boneski, Paige K., Siuda, Joanna, Slawek, Jaroslaw, Puschmann, Andreas, Narendra, Derek P., Graff-Radford, Neill R., Wszolek, Zbigniew K., Dickson, Dennis W., Ross, Owen A., Caulfield, Thomas R., Springer, Wolfdieter, and Fiesel, Fabienne C.

Subjects
PARKINSON'S disease, UBIQUITIN, FIBROBLASTS, FUNCTIONAL analysis, FLOW cytometry
Abstract

Mutations in the PINK1 and PRKN genes are the most frequent genetic cause of early-onset Parkinson disease. The pathogenic p.R275W substitution in PRKN is the most frequent substitution observed in patients, and thus far has been characterized mostly through overexpression models that suggest a possible gain of toxic misfunction. However, its effects under endogenous conditions are largely unknown. We used patient fibroblasts, isogenic neurons, and post-mortem human brain samples from carriers with and without PRKN p.R275W to assess functional impact. Immunoblot analysis and immunofluorescence were used to study mitophagy activation, and mitophagy execution was analyzed by flow cytometry of the reporter mitoKeima. The functional analysis was accompanied by structural investigation of PRKN p.R275W. We observed lower PRKN protein in fibroblasts with compound heterozygous p.R275W mutations. Isogenic neurons showed an allele-dose dependent decrease in PRKN protein. Lower PRKN protein levels were accompanied by diminished phosphorylated ubiquitin and decreased MFN2 modification. Mitochondrial degradation was also allele-dose dependently impaired. Consistently, PRKN protein levels were drastically reduced in human brain samples from p.R275W carriers. Finally, structural simulations showed significant changes in the closed form of PRKN p.R275W. Our data suggest that under endogenous conditions the p.R275W mutation results in a loss-of-function by destabilizing PRKN. [ABSTRACT FROM AUTHOR]

Published
2024
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34. Specific Biomarkers in Spinocerebellar Ataxia Type 3: A Systematic Review of Their Potential Uses in Disease Staging and Treatment Assessment.

Author

Soto-Piña, Alexandra E., Pulido-Alvarado, Caroline C., Dulski, Jaroslaw, Wszolek, Zbigniew K., and Magaña, Jonathan J.

Subjects
SPINOCEREBELLAR ataxia, BODY fluids, THERAPEUTICS, DISEASE progression, OXIDATIVE stress
Abstract

Spinocerebellar ataxia type 3 (SCA3) is the most common type of disease related to poly-glutamine (polyQ) repeats. Its hallmark pathology is related to the abnormal accumulation of ataxin 3 with a longer polyQ tract (polyQ-ATXN3). However, there are other mechanisms related to SCA3 progression that require identifying trait and state biomarkers for a more accurate diagnosis and prognosis. Moreover, the identification of potential pharmacodynamic targets and assessment of therapeutic efficacy necessitates valid biomarker profiles. The aim of this review was to identify potential trait and state biomarkers and their potential value in clinical trials. Our results show that, in SCA3, there are different fluid biomarkers involved in neurodegeneration, oxidative stress, metabolism, miRNA and novel genes. However, neurofilament light chain NfL and polyQ-ATXN3 stand out as the most prevalent in body fluids and SCA3 stages. A heterogeneity analysis of NfL revealed that it may be a valuable state biomarker, particularly when measured in plasma. Nonetheless, since it could be a more beneficial approach to tracking SCA3 progression and clinical trial efficacy, it is more convenient to perform a biomarker profile evaluation than to rely on only one. [ABSTRACT FROM AUTHOR]

Published
2024
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35. Apolipoprotein E regulates lipid metabolism and α-synuclein pathology in human iPSC-derived cerebral organoids

Author

Zhao, Jing, Lu, Wenyan, Ren, Yingxue, Fu, Yuan, Martens, Yuka A., Shue, Francis, Davis, Mary D., Wang, Xue, Chen, Kai, Li, Fuyao, Liu, Chia-Chen, Graff-Radford, Neill R., Wszolek, Zbigniew K., Younkin, Steven G., Brafman, David A., Ertekin-Taner, Nilüfer, Asmann, Yan W., Dickson, Dennis W., Xu, Ziying, Pan, Meixia, Han, Xianlin, Kanekiyo, Takahisa, and Bu, Guojun

Published
2021
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36. Neurofilament light chain and vaccination status associate with clinical outcomes in severe COVID-19

Author

Erben, Young, primary, Prudencio, Mercedes, additional, Marquez, Christopher P., additional, Jansen-West, Karen R., additional, Heckman, Michael G., additional, White, Launia J., additional, Dunmore, Judith A., additional, Cook, Casey N., additional, Lilley, Meredith T., additional, Qosja, Neda, additional, Song, Yuping, additional, Al Shaikh, Rana Hanna, additional, Daughrity, Lillian M., additional, Bartfield, Jordan L., additional, Day, Gregory S., additional, Oskarsson, Björn, additional, Nicholson, Katharine A., additional, Wszolek, Zbigniew K., additional, Hoyne, Jonathan B., additional, Gendron, Tania F., additional, Meschia, James F., additional, and Petrucelli, Leonard, additional

Published
2024
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37. Enhancing outcomes in deep brain stimulation: a comparative study of direct targeting using 7T versus 3T MRI

Author

Middlebrooks, Erik H., primary, Tipton, Philip W., additional, Greco, Elena, additional, Okromelidze, Lela, additional, Patel, Vishal, additional, Wszolek, Zbigniew K., additional, Zhou, Xiangzhi, additional, Tao, Shengzhen, additional, Westerhold, Erin M., additional, Straub, Sina, additional, Uitti, Ryan J., additional, Sandhu, Sukhwinder Johnny Singh, additional, Quiñones-Hinojosa, Alfredo, additional, and Grewal, Sanjeet S., additional

Published
2024
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39. Correction to: Apolipoprotein E regulates lipid metabolism and α‑synuclein pathology in human iPSC‑derived cerebral organoids

Author

Zhao, Jing, Lu, Wenyan, Ren, Yingxue, Fu, Yuan, Martens, Yuka A., Shue, Francis, Davis, Mary D., Wang, Xue, Chen, Kai, Li, Fuyao, Liu, Chia-Chen, Graff-Radford, Neill R., Wszolek, Zbigniew K., Younkin, Steven G., Brafman, David A., Ertekin-Taner, Nilüfer, Asmann, Yan W., Dickson, Dennis W., Xu, Ziying, Pan, Meixia, Han, Xianlin, Kanekiyo, Takahisa, and Bu, Guojun

Published
2022
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40. Secretome from iPSC-derived MSCs exerts proangiogenic and immunosuppressive effects to alleviate radiation-induced vascular endothelial cell damage.

Author

Gupta, Kshama, Perkerson III, Ralph B., Parsons, Tammee M., Angom, Ramacharan, Amerna, Danilyn, Burgess, Jeremy D., Ren, Yingxue, McLean, Pamela J., Mukhopadhyay, Debabrata, Vibhute, Prasanna, Wszolek, Zbigniew K., Zubair, Abba C., Quiñones-Hinojosa, Alfredo, and Kanekiyo, Takahisa

Subjects
VASCULAR endothelial cells, ANDROGEN receptors, GENE expression, STEM cells, PREMATURE aging (Medicine), RNA metabolism, DNA repair
Abstract

Background: Radiation therapy is the standard of care for central nervous system tumours. Despite the success of radiation therapy in reducing tumour mass, irradiation (IR)-induced vasculopathies and neuroinflammation contribute to late-delayed complications, neurodegeneration, and premature ageing in long-term cancer survivors. Mesenchymal stromal cells (MSCs) are adult stem cells that facilitate tissue integrity, homeostasis, and repair. Here, we investigated the potential of the iPSC-derived MSC (iMSC) secretome in immunomodulation and vasculature repair in response to radiation injury utilizing human cell lines. Methods: We generated iPSC-derived iMSC lines and evaluated the potential of their conditioned media (iMSC CM) to treat IR-induced injuries in human monocytes (THP1) and brain vascular endothelial cells (hCMEC/D3). We further assessed factors in the iMSC secretome, their modulation, and the molecular pathways they elicit. Results: Increasing doses of IR disturbed endothelial tube and spheroid formation in hCMEC/D3. When IR-injured hCMEC/D3 (IR ≤ 5 Gy) were treated with iMSC CM, endothelial cell viability, adherence, spheroid compactness, and proangiogenic sprout formation were significantly ameliorated, and IR-induced ROS levels were reduced. iMSC CM augmented tube formation in cocultures of hCMEC/D3 and iMSCs. Consistently, iMSC CM facilitated angiogenesis in a zebrafish model in vivo. Furthermore, iMSC CM suppressed IR-induced NFκB activation, TNF-α release, and ROS production in THP1 cells. Additionally, iMSC CM diminished NF-kB activation in THP1 cells cocultured with irradiated hCMEC/D3, iMSCs, or HMC3 microglial lines. The cytokine array revealed that iMSC CM contains the proangiogenic and immunosuppressive factors MCP1/CCL2, IL6, IL8/CXCL8, ANG (Angiogenin), GROα/CXCL1, and RANTES/CCL5. Common promoter regulatory elements were enriched in TF-binding motifs such as androgen receptor (ANDR) and GATA2. hCMEC/D3 phosphokinome profiling revealed increased expression of pro-survival factors, the PI3K/AKT/mTOR modulator PRAS40 and β-catenin in response to CM. The transcriptome analysis revealed increased expression of GATA2 in iMSCs and the enrichment of pathways involved in RNA metabolism, translation, mitochondrial respiration, DNA damage repair, and neurodevelopment. Conclusions: The iMSC secretome is a comodulated composite of proangiogenic and immunosuppressive factors that has the potential to alleviate radiation-induced vascular endothelial cell damage and immune activation. [ABSTRACT FROM AUTHOR]

Published
2024
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41. Recent Bibliometrics of the Journal and Thank You to Our Reviewers.

Author

Wszolek, Zbigniew K., Stolarczyk, Łukasz, and Sławek, Jarosław

Subjects
COVID-19, NEUROLOGICAL disorders, PROGRESSIVE supranuclear palsy, PLATELET lymphocyte ratio, NEUROLOGIC manifestations of general diseases, MYOCLONUS
Abstract

This article discusses recent bibliometric measurements of the Neurologia i Neurochirurgia Polska (Polish Journal of Neurology and Neurosurgery) and expresses gratitude to the journal's reviewers. Despite the COVID-19 pandemic, the journal's Impact Factor (IF) remains stable at 2.9, which is noteworthy as many highly cited journals have experienced a decrease in their IF score. The journal has also moved from Q3 level to Q2 level and has seen an increase in its Scopus CiteScore. The article highlights the importance of the journal's reviewers and provides a list of the most cited articles published in the journal. Additionally, there is a separate document acknowledging and thanking the reviewers for their contributions, which includes references to previous articles published in the journal on the genetics of Parkinson's disease in the Polish population and the use of cannabidiol in the treatment of epilepsy. [Extracted from the article]

Published
2024
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43. Basal activity of PINK1 and PRKN in cell models and rodent brain.

Author

Watzlawik, Jens O., Fiesel, Fabienne C., Fiorino, Gabriella, Bustillos, Bernardo A., Baninameh, Zahra, Markham, Briana N., Hou, Xu, Hayes, Caleb S., Bredenberg, Jenny M., Kurchaba, Nicholas W., Fričová, Dominika, Siuda, Joanna, Wszolek, Zbigniew K., Noda, Sachiko, Sato, Shigeto, Hattori, Nobutaka, Prasad, Asheeta A., Kirik, Deniz, Fox, Howard S., and Stauch, Kelly L.

Subjects
PARKINSON'S disease, CELL culture, RODENTS, FUNCTIONAL magnetic resonance imaging, UBIQUITIN, CLINICAL trials
Abstract

The ubiquitin kinase-ligase pair PINK1-PRKN recognizes and transiently labels damaged mitochondria with ubiquitin phosphorylated at Ser65 (p-S65-Ub) to mediate their selective degradation (mitophagy). Complete loss of PINK1 or PRKN function unequivocally leads to early-onset Parkinson disease, but it is debated whether impairments in mitophagy contribute to disease later in life. While the pathway has been extensively studied in cell culture upon acute and massive mitochondrial stress, basal levels of activation under endogenous conditions and especially in vivo in the brain remain undetermined. Using rodent samples, patient-derived cells, and isogenic neurons, we here identified age-dependent, brain region-, and cell type-specific effects and determined expression levels and extent of basal and maximal activation of PINK1 and PRKN. Our work highlights the importance of defining critical risk and therapeutically relevant levels of PINK1-PRKN signaling which will further improve diagnosis and prognosis and will lead to better stratification of patients for future clinical trials. [ABSTRACT FROM AUTHOR]

Published
2024
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45. miRNA family miR-29 inhibits PINK1-PRKN dependent mitophagy via ATG9A

Author

Markham, Briana N, primary, Ramnarine, Chloe, additional, Kim, Songeun, additional, Grever, William E, additional, Soto-Beasley, Alexandra I, additional, Heckman, Michael, additional, Ren, Yingxue, additional, Osborne, Andrew C, additional, Bhagwate, Aditya V, additional, Liu, Yuanhang, additional, Wang, Chen, additional, Kim, Jungsu, additional, Wszolek, Zbigniew K, additional, Ross, Owen A, additional, Springer, Wolfdieter, additional, and Fiesel, Fabienne C, additional

Published
2024
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46. TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia

Author

Marks, Jordan D., primary, Ayuso, Virginia Estades, additional, Carlomagno, Yari, additional, Yue, Mei, additional, Todd, Tiffany W., additional, Hao, Ying, additional, Li, Ziyi, additional, McEachin, Zachary T., additional, Shantaraman, Anantharaman, additional, Duong, Duc M., additional, Daughrity, Lillian M., additional, Jansen-West, Karen, additional, Shao, Wei, additional, Calliari, Anna, additional, Bejarano, Jesus Gonzalez, additional, DeTure, Michael, additional, Rawlinson, Bailey, additional, Casey, Monica Castanedes, additional, Lilley, Meredith T., additional, Donahue, Megan H., additional, Jawahar, Vidhya Maheswari, additional, Boeve, Bradley F., additional, Petersen, Ronald C., additional, Knopman, David S., additional, Oskarsson, Björn, additional, Graff-Radford, Neill R., additional, Wszolek, Zbigniew K., additional, Dickson, Dennis W., additional, Josephs, Keith A., additional, Qi, Yue A., additional, Seyfried, Nicholas T., additional, Ward, Michael E., additional, Zhang, Yong-Jie, additional, Prudencio, Mercedes, additional, Petrucelli, Leonard, additional, and Cook, Casey N., additional

Published
2024
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47. Diagnostic utility of 7T neuromelanin imaging of the substantia nigra in Parkinson’s disease

Author

Lakhani, Dhairya A., primary, Zhou, Xiangzhi, additional, Tao, Shengzhen, additional, Patel, Vishal, additional, Wen, Sijin, additional, Okromelidze, Lela, additional, Greco, Elena, additional, Lin, Chen, additional, Westerhold, Erin M., additional, Straub, Sina, additional, Wszolek, Zbigniew K., additional, Tipton, Philip W., additional, Uitti, Ryan J., additional, Grewal, Sanjeet S., additional, and Middlebrooks, Erik H., additional

Published
2024
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