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1. Prognostic performance of blood neurofilament light chain protein in hospitalized COVID-19 patients without major central nervous system manifestations: an individual participant data meta-analysis

Author

Abdelhak, Ahmed, Barba, Lorenzo, Romoli, Michele, Benkert, Pascal, Conversi, Francesco, D’Anna, Lucio, Masvekar, Ruturaj R, Bielekova, Bibiana, Prudencio, Mercedes, Petrucelli, Leonard, Meschia, James F, Erben, Young, Furlan, Roberto, De Lorenzo, Rebecca, Mandelli, Alessandra, Sutter, Raoul, Hert, Lisa, Epple, Varenka, Marastoni, Damiano, Sellner, Johann, Steinacker, Petra, Aamodt, Anne Hege, Heggelund, Lars, Dyrhol-Riise, Anne Margarita, Virhammar, Johan, Fällmar, David, Rostami, Elham, Kumlien, Eva, Blennow, Kaj, Zetterberg, Henrik, Tumani, Hayrettin, Sacco, Simona, Green, Ari J, Otto, Markus, Kuhle, Jens, Ornello, Raffaele, Foschi, Matteo, and Abu-Rumeileh, Samir

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Good Health and Well Being, Adult, Male, Humans, Middle Aged, Aged, Aged, 80 and over, Female, Prognosis, COVID-19, Biomarkers, Intermediate Filaments, Central Nervous System, Neurofilament Proteins, Biomarker, NfL, Neurosciences, Neurology & Neurosurgery, Clinical sciences
Abstract

Background and aimsTo investigate the prognostic value of blood neurofilament light chain protein (NfL) levels in the acute phase of coronavirus disease 2019 (COVID-19).MethodsWe conducted an individual participant data (IPD) meta-analysis after screening on MEDLINE and Scopus to May 23rd 2022. We included studies with hospitalized adult COVID-19 patients without major COVID-19-associated central nervous system (CNS) manifestations and with a measurement of blood NfL in the acute phase as well as data regarding at least one clinical outcome including intensive care unit (ICU) admission, need of mechanical ventilation (MV) and death. We derived the age-adjusted measures NfL Z scores and conducted mixed-effects modelling to test associations between NfL Z scores and other variables, encompassing clinical outcomes. Summary receiver operating characteristic curves (SROCs) were used to calculate the area under the curve (AUC) for blood NfL.ResultsWe identified 382 records, of which 7 studies were included with a total of 669 hospitalized COVID-19 cases (mean age 66.2 ± 15.0 years, 68.1% males). Median NfL Z score at admission was elevated compared to the age-corrected reference population (2.37, IQR: 1.13-3.06, referring to 99th percentile in healthy controls). NfL Z scores were significantly associated with disease duration and severity. Higher NfL Z scores were associated with a higher likelihood of ICU admission, need of MV, and death. SROCs revealed AUCs of 0.74, 0.80 and 0.71 for mortality, need of MV and ICU admission, respectively.ConclusionsBlood NfL levels were elevated in the acute phase of COVID-19 patients without major CNS manifestations and associated with clinical severity and poor outcome. The marker might ameliorate the performance of prognostic multivariable algorithms in COVID-19.

Published
2023

2. HDGFL2 cryptic proteins report presence of TDP-43 pathology in neurodegenerative diseases

Author

Calliari, Anna, Daughrity, Lillian M., Albagli, Ellen A., Castellanos Otero, Paula, Yue, Mei, Jansen-West, Karen, Islam, Naeyma N., Caulfield, Thomas, Rawlinson, Bailey, DeTure, Michael, Cook, Casey, Graff-Radford, Neill R., Day, Gregory S., Boeve, Bradley F., Knopman, David S., Petersen, Ronald C., Josephs, Keith A., Oskarsson, Björn, Gitler, Aaron D., Dickson, Dennis W., Gendron, Tania F., Prudencio, Mercedes, Ward, Michael E., Zhang, Yong-Jie, and Petrucelli, Leonard

Published
2024
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4. Abundant transcriptomic alterations in the human cerebellum of patients with a C9orf72 repeat expansion

Author

Udine, Evan, DeJesus-Hernandez, Mariely, Tian, Shulan, das Neves, Sofia Pereira, Crook, Richard, Finch, NiCole A., Baker, Matthew C., Pottier, Cyril, Graff-Radford, Neill R., Boeve, Bradley F., Petersen, Ronald C., Knopman, David S., Josephs, Keith A., Oskarsson, Björn, Da Mesquita, Sandro, Petrucelli, Leonard, Gendron, Tania F., Dickson, Dennis W., Rademakers, Rosa, and van Blitterswijk, Marka

Published
2024
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6. Temporal order of clinical and biomarker changes in familial frontotemporal dementia

Author

Staffaroni, Adam M, Quintana, Melanie, Wendelberger, Barbara, Heuer, Hilary W, Russell, Lucy L, Cobigo, Yann, Wolf, Amy, Goh, Sheng-Yang Matt, Petrucelli, Leonard, Gendron, Tania F, Heller, Carolin, Clark, Annie L, Taylor, Jack Carson, Wise, Amy, Ong, Elise, Forsberg, Leah, Brushaber, Danielle, Rojas, Julio C, VandeVrede, Lawren, Ljubenkov, Peter, Kramer, Joel, Casaletto, Kaitlin B, Appleby, Brian, Bordelon, Yvette, Botha, Hugo, Dickerson, Bradford C, Domoto-Reilly, Kimiko, Fields, Julie A, Foroud, Tatiana, Gavrilova, Ralitza, Geschwind, Daniel, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathon, Graff-Radford, Neill, Grossman, Murray, Hall, Matthew G. H, Hsiung, Ging-Yuek, Huey, Edward D, Irwin, David, Jones, David T, Kantarci, Kejal, Kaufer, Daniel, Knopman, David, Kremers, Walter, Lago, Argentina Lario, Lapid, Maria I, Litvan, Irene, Lucente, Diane, Mackenzie, Ian R, Mendez, Mario F, Mester, Carly, Miller, Bruce L, Onyike, Chiadi U, Rademakers, Rosa, Ramanan, Vijay K, Ramos, Eliana Marisa, Rao, Meghana, Rascovsky, Katya, Rankin, Katherine P, Roberson, Erik D, Savica, Rodolfo, Tartaglia, M. Carmela, Weintraub, Sandra, Wong, Bonnie, Cash, David M, Bouzigues, Arabella, Swift, Imogen J, Peakman, Georgia, Bocchetta, Martina, Todd, Emily G, Convery, Rhian S, Rowe, James B, Borroni, Barbara, Galimberti, Daniela, Tiraboschi, Pietro, Masellis, Mario, Finger, Elizabeth, van Swieten, John C, Seelaar, Harro, Jiskoot, Lize C, Sorbi, Sandro, Butler, Chris R, Graff, Caroline, Gerhard, Alexander, Langheinrich, Tobias, Laforce, Robert, Sanchez-Valle, Raquel, de Mendonça, Alexandre, Moreno, Fermin, Synofzik, Matthis, Vandenberghe, Rik, Ducharme, Simon, Le Ber, Isabelle, Levin, Johannes, Danek, Adrian, Otto, Markus, Pasquier, Florence, Santana, Isabel, and Kornak, John

Published
2022

9. 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

12. TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains

Author

Estades Ayuso, Virginia, Pickles, Sarah, Todd, Tiffany, Yue, Mei, Jansen-West, Karen, Song, Yuping, González Bejarano, Jesús, Rawlinson, Bailey, DeTure, Michael, Graff-Radford, Neill R., Boeve, Bradley F., Knopman, David S., Petersen, Ronald C., Dickson, Dennis W., Josephs, Keith A., Petrucelli, Leonard, and Prudencio, Mercedes

Published
2023
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13. TDP-43 represses cryptic exon inclusion in the FTD–ALS gene UNC13A

Author

Ma, X Rosa, Prudencio, Mercedes, Koike, Yuka, Vatsavayai, Sarat C, Kim, Garam, Harbinski, Fred, Briner, Adam, Rodriguez, Caitlin M, Guo, Caiwei, Akiyama, Tetsuya, Schmidt, H Broder, Cummings, Beryl B, Wyatt, David W, Kurylo, Katherine, Miller, Georgiana, Mekhoubad, Shila, Sallee, Nathan, Mekonnen, Gemechu, Ganser, Laura, Rubien, Jack D, Jansen-West, Karen, Cook, Casey N, Pickles, Sarah, Oskarsson, Björn, Graff-Radford, Neill R, Boeve, Bradley F, Knopman, David S, Petersen, Ronald C, Dickson, Dennis W, Shorter, James, Myong, Sua, Green, Eric M, Seeley, William W, Petrucelli, Leonard, and Gitler, Aaron D

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Rare Diseases, Stem Cell Research - Nonembryonic - Human, Dementia, Neurosciences, Brain Disorders, Acquired Cognitive Impairment, Human Genome, Stem Cell Research, Neurodegenerative, ALS, 2.1 Biological and endogenous factors, Aetiology, Neurological, Amyotrophic Lateral Sclerosis, DNA-Binding Proteins, Exons, Frontotemporal Dementia, Genome-Wide Association Study, Humans, Motor Neurons, Nerve Tissue Proteins, General Science & Technology
Abstract

A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord1. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing2-4. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies5,6, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function.

Published
2022

14. Demographic and psychosocial factors associated with the decision to learn mutation status in familial frontotemporal dementia and the impact of disclosure on mood

Author

Bajorek, Lynn P, Kiekhofer, Rachel, Hall, Matthew, Taylor, Joanne, Lucente, Diane E, Brushaber, Danielle, Appleby, Brian, Coppolla, Giovanni, Bordelon, Yvette M, Botha, Hugo, Dickerson, Brad C, Dickson, Dennis W, Domoto‐Reilly, Kimiko, Fagan, Anne M, Fields, Julie A, Fong, Jamie C, Foroud, Tatiana M, Forsberg, Leah K, Galasko, Doug R, Gavrilova, Ralitza H, Geschwind, Daniel H, Ghoshal, Nupur, Goldman, Jill, Graff‐Radford, Neill R, Graff‐Radford, Jonathan, Grant, Ian, Grossman, Murray, Heuer, Hilary W, Hsiung, Ging‐Yuek Robin, Huang, Eric J, Huey, Edward D, Irwin, David J, Jones, David T, Kantarci, Kejal, Kornak, John, Kremers, Walter K, Lapid, Maria I, Leger, Gabriel C, Litvan, Irene, Ljubenkov, Peter A, Mackenzie, Ian R, Masdeu, Joseph C, McMillan, Corey, Mendez, Mario, Miller, Bruce L, Miyagawa, Toji, Onyike, Chiadi U, Pascual, Belen, Pedraza, Otto, Petrucelli, Leonard, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine P, Rascovsky, Katya, Rexach, Jessica E, Ritter, Aaron, Roberson, Erik D, Savica, Rodolfo, Rojas, Julio C, Seeley, William W, Tartaglia, Maria Carmela, Toga, Arthur W, Weintraub, Sandra, Wong, Bonnie, Wszolek, Zbigniew, Vandevrede, Lawren, Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Staffaroni, Adam M, and Consortium, ALLFTD

Subjects
Clinical Trials and Supportive Activities, Aging, Dementia, Genetics, Neurodegenerative, Clinical Research, Prevention, Acquired Cognitive Impairment, Mental Health, Depression, Brain Disorders, Clinical Sciences, Neurosciences, Geriatrics
Abstract

BACKGROUND: Up to 30% of frontotemporal dementia (FTD) cases are due to known pathogenic mutations (f-FTD). Little is known about the factors that predict who will choose to learn their results. Upcoming clinical trials in f-FTD may require disclosure prior to enrollment, even before symptom onset, and thus characterizing this sample is important. Furthermore, understanding the mood impacts of genetic disclosure may guide genetic counseling practice. METHOD: F-FTD participants (n=568) from families with a known pathogenic mutation (MAPT, C9orf72, GRN) were enrolled through the ARTFL/LEFFTDS Longitudinal FTD Study (ALLFTD) and provided the opportunity for disclosure. Independent-sample t-tests compared demographic and psychosocial factors between participants who did and did not receive their results. In participants who were asymptomatic at baseline and follow up (n=199,177 with follow-up), linear mixed effects modeling was used to investigate pre- to post-disclosure changes in the 15-item Geriatric Depression Scale (GDS). RESULT: Of participants from families with a known pathogenic genetic mutation, 47% received genetic disclosure. Of the asymptomatic subset (n=386), 36% know their mutation status. Of these asymptomatic learners, 46% received disclosure through the study, and the remainder learned their genetic status prior to study enrollment. None of the analyzed demographic or psychosocial factors (i.e., sex, age, education, having children) differed between learners and non-learners (p's > 0.05). In the longitudinal analysis of asymptomatic participants, learners showed a pre- to post-increase of 0.31 GDS points/year (95%CI: -0.08, 0.69, p = 0.12), whereas non-learners showed a slight decline (-0.15 points/year, 95%CI: -0.36, 0.06, p = 0.16). This difference between slopes was statistically significant (0.46, 95%CI: 0.02, 0.89, p=0.04) but represents a small clinical effect. In asymptomatic learners, slopes did not differ based on mutation status (0.28, 95%CI: -0.66, 1.20, p=0.55). Conclusions were based on the estimates and full range of confidence intervals. CONCLUSION: The majority of asymptomatic research participants do not know their genetic status, which will be a consideration for clinical trials that require disclosure. No considered demographic factors were strongly associated with the decision to receive disclosure. The findings suggest that disclosure in asymptomatic participants has minimal impact on depressive symptoms regardless of genetic results.

Published
2021

15. Gearing up for the future: Exploring facilitators and barriers to inform clinical trial design in frontotemporal lobar degeneration

Author

Banga, Yasmin B, Lai, Yujung, Kim, Priscilla, Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Forsberg, Leah K, Heuer, Hilary W, Brushaber, Danielle, Appleby, Brian, Biernacka, Joanna M, Bordelon, Yvette M, Botha, Hugo, Bozoki, Andrea C, Brannelly, Patrick, Dickerson, Brad C, Dickinson, Susan, Dickson, Dennis W, Domoto‐Reilly, Kimiko, Faber, Kelley, Fagan, Anne M, Fields, Julie A, Fishman, Ann, Foroud, Tatiana M, Galasko, Doug R, Gavrilova, Ralitza H, Gendron, Tania F, Geschwind, Daniel H, Ghoshal, Nupur, Goldman, Jill, Graff‐Radford, Jonathan, Graff‐Radford, Neill R, Grant, Ian, Grossman, Murray, Hsiung, Ging‐Yuek Robin, Huang, Eric J, Huey, Edward D, Irwin, David J, Jones, David T, Kantarci, Kejal, Karydas, Anna M, Kaufer, Daniel, Knopman, David S, Kramer, Joel H, Kremers, Walter K, Kornak, John, Kukull, Walter A, Lagone, Emma, Leger, Gabriel C, Litvan, Irene, Ljubenkov, Peter A, Lucente, Diane E, Mackenzie, Ian R, Manoochehri, Masood, Masdeu, Joseph C, McGinnis, Scott, Mendez, Mario F, Miller, Bruce L, Miyagawa, Toji, Nelson, Kevin M, Onyike, Chiadi U, Pantelyat, Alex, Pascual, Belen, Pearlman, Rodney, Petrucelli, Leonard, Pottier, Cyril P, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine P, Rascovsky, Katya, Rexach, Jessica E, Ritter, Aaron, Roberson, Erik D, Rojas, Julio C, Sabbagh, Marwan N, Salmon, David P, Savica, Rodolfo, Seeley, William W, Staffaroni, Adam M, Syrjanen, Jeremy A, Tartaglia, Maria Carmela, Tatton, Nadine, Taylor, Jack C, Toga, Arthur W, Weintraub, Sandra, Wheaton, Diana, Wong, Benjamin, Wszolek, Zbigniew, and Consortium, ALLFTD

Subjects
Frontotemporal Dementia (FTD), Rare Diseases, Behavioral and Social Science, Neurodegenerative, Acquired Cognitive Impairment, Basic Behavioral and Social Science, Brain Disorders, Clinical Research, Dementia, Aging, Biomedical Imaging, Clinical Trials and Supportive Activities, Neurological, Clinical Sciences, Neurosciences, Geriatrics
Abstract

BACKGROUND: Frontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imperative to explore facilitators and barriers for potential candidates. OBJECTIVE: The objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD. METHODS: Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) are observational studies focused on characterizing FTLD syndromes in preparation for clinical trials. The 584 participants enrolled across 18 research sites in the United States and Canada completed a survey assessing interest in clinical trial participation. RESULTS: 29% of respondents self-reported as patients (63±10 years), 26% self-reported as caregivers answering on behalf of patients (65±10 years), and 45% self-reported as healthy but at risk for FTLD (48±14 years). Travel reimbursement was the most common factor reported to positively influence participation (≧66%), with the healthy but at risk group showing the strongest endorsement (83%). Cost and time involved in travel were possible barriers for about half of the patients (48%) and healthy but at risk respondents (53%). The respondents value receiving feedback on the study findings (≧80%) and being informed of their individual disease progression (≧75%). Particularly, keeping participation confidential was very important for the healthy but at risk group (62%). In regard to research assessments, most participants demonstrated a high interest in physical and neurological exams at a research center (≧87%) whereas only half were interested in doing more invasive procedures such as the lumbar puncture (≧52%). Overall, respondents showed a positive attitude and support for research participation (≧77%) and trusted that their health information would remain confidential in a clinical trial (≧53%). CONCLUSIONS: Favorable attitudes and interest towards medical research exist among participants. To optimize participation, clinical trials should allocate funding for travel and involve participants in feedback about study results and their disease progression. Alternatives to invasive assessments may increase participation.

Published
2021

17. Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration

Author

Rojas, Julio C, Wang, Ping, Staffaroni, Adam M, Heller, Carolin, Cobigo, Yann, Wolf, Amy, Goh, Sheng-Yang M, Ljubenkov, Peter A, Heuer, Hilary W, Fong, Jamie C, Taylor, Joanne B, Veras, Eliseo, Song, Linan, Jeromin, Andreas, Hanlon, David, Yu, Lili, Khinikar, Arvind, Sivasankaran, Rajeev, Kieloch, Agnieszka, Valentin, Marie-Anne, Karydas, Anna M, Mitic, Laura L, Pearlman, Rodney, Kornak, John, Kramer, Joel H, Miller, Bruce L, Kantarci, Kejal, Knopman, David S, Graff-Radford, Neill, Petrucelli, Leonard, Rademakers, Rosa, Irwin, David J, Grossman, Murray, Ramos, Eliana Marisa, Coppola, Giovanni, Mendez, Mario F, Bordelon, Yvette, Dickerson, Bradford C, Ghoshal, Nupur, Huey, Edward D, Mackenzie, Ian R, Appleby, Brian S, Domoto-Reilly, Kimiko, Hsiung, Ging-Yuek R, Toga, Arthur W, Weintraub, Sandra, Kaufer, Daniel I, Kerwin, Diana, Litvan, Irene, Onyike, Chiadikaobi U, Pantelyat, Alexander, Roberson, Erik D, Tartaglia, Maria C, Foroud, Tatiana, Chen, Weiping, Czerkowicz, Julie, Graham, Danielle L, van Swieten, John C, Borroni, Barbara, Sanchez-Valle, Raquel, Moreno, Fermin, Laforce, Robert, Graff, Caroline, Synofzik, Matthis, Galimberti, Daniela, Rowe, James B, Masellis, Mario, Finger, Elizabeth, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Santana, Isabel, Ducharme, Simon, Butler, Chris R, Gerhard, Alexander, Levin, Johannes, Danek, Adrian, Otto, Markus, Sorbi, Sandro, Cash, David M, Convery, Rhian S, Bocchetta, Martina, Foiani, Martha, Greaves, Caroline V, Peakman, Georgia, Russell, Lucy, Swift, Imogen, Todd, Emily, Rohrer, Jonathan D, Boeve, Bradley F, Rosen, Howard J, Boxer, Adam L, and consortia, on behalf of the ALLFTD and GENFI

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Neurodegenerative, Genetics, Prevention, Dementia, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, Alzheimer's Disease, Frontotemporal Dementia (FTD), Aging, Acquired Cognitive Impairment, Clinical Trials and Supportive Activities, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Aged, 80 and over, Biomarkers, Cohort Studies, Disease Progression, Female, Frontotemporal Lobar Degeneration, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neurofilament Proteins, Predictive Value of Tests, Young Adult, ALLFTD and GENFI consortia, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ObjectiveWe tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression.MethodsBaseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables.ResultsIn both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers.ConclusionsPlasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials.Trial registration informationClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.Classification of evidenceThis study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.

Published
2021

19. p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)

Author

Maor-Nof, Maya, Shipony, Zohar, Lopez-Gonzalez, Rodrigo, Nakayama, Lisa, Zhang, Yong-Jie, Couthouis, Julien, Blum, Jacob A, Castruita, Patricia A, Linares, Gabriel R, Ruan, Kai, Ramaswami, Gokul, Simon, David J, Nof, Aviv, Santana, Manuel, Han, Kyuho, Sinnott-Armstrong, Nasa, Bassik, Michael C, Geschwind, Daniel H, Tessier-Lavigne, Marc, Attardi, Laura D, Lloyd, Thomas E, Ichida, Justin K, Gao, Fen-Biao, Greenleaf, William J, Yokoyama, Jennifer S, Petrucelli, Leonard, and Gitler, Aaron D

Subjects
Biochemistry and Cell Biology, Biological Sciences, Stem Cell Research, Brain Disorders, ALS, Genetics, Frontotemporal Dementia (FTD), Neurodegenerative, Acquired Cognitive Impairment, Rare Diseases, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Stem Cell Research - Induced Pluripotent Stem Cell - Human, Dementia, Stem Cell Research - Induced Pluripotent Stem Cell, Neurosciences, 1.1 Normal biological development and functioning, Underpinning research, Aetiology, 2.1 Biological and endogenous factors, Neurological, Animals, Apoptosis Regulatory Proteins, Axons, C9orf72 Protein, Cell Death, Cells, Cultured, Cerebral Cortex, Chromatin, DNA Damage, DNA Repeat Expansion, Disease Models, Animal, Drosophila, Mice, Inbred C57BL, Nerve Degeneration, Protein Stability, Transcription, Genetic, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Mice, ATAC-seq, C9orf72, TDP-43, amyotrophic lateral sclerosis, axonal degeneration, neurodegeneration, p53, puma, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a GGGGCC repeat expansion in the C9orf72 gene. We developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons during degeneration. We provide evidence that neurons expressing the dipeptide repeat protein poly(proline-arginine), translated from the C9orf72 repeat expansion, activate a highly specific transcriptional program, exemplified by a single transcription factor, p53. Ablating p53 in mice completely rescued neurons from degeneration and markedly increased survival in a C9orf72 mouse model. p53 reduction also rescued axonal degeneration caused by poly(glycine-arginine), increased survival of C9orf72 ALS/FTD-patient-induced pluripotent stem cell (iPSC)-derived motor neurons, and mitigated neurodegeneration in a C9orf72 fly model. We show that p53 activates a downstream transcriptional program, including Puma, which drives neurodegeneration. These data demonstrate a neurodegenerative mechanism dynamically regulated through transcription-factor-binding events and provide a framework to apply chromatin accessibility and transcription program profiles to neurodegeneration.

Published
2021

20. Poly(GR) interacts with key stress granule factors promoting its assembly into cytoplasmic inclusions

Author

Park, Jinyoung, Wu, Yanwei, Shao, Wei, Gendron, Tania F., van der Spek, Sophie J.F., Sultanakhmetov, Grigorii, Basu, Avik, Castellanos Otero, Paula, Jones, Caroline J., Jansen-West, Karen, Daughrity, Lillian M., Phanse, Sadhna, del Rosso, Giulia, Tong, Jimei, Castanedes-Casey, Monica, Jiang, Lulu, Libera, Jenna, Oskarsson, Björn, Dickson, Dennis W., Sanders, David W., Brangwynne, Clifford P., Emili, Andrew, Wolozin, Benjamin, Petrucelli, Leonard, and Zhang, Yong-Jie

Published
2023
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22. Premature termination codon readthrough upregulates progranulin expression and improves lysosomal function in preclinical models of GRN deficiency

Author

Frew, Jonathan, Baradaran-Heravi, Alireza, Balgi, Aruna D, Wu, Xiujuan, Yan, Tyler D, Arns, Steve, Shidmoossavee, Fahimeh S, Tan, Jason, Jaquith, James B, Jansen-West, Karen R, Lynn, Francis C, Gao, Fen-Biao, Petrucelli, Leonard, Feldman, Howard H, Mackenzie, Ian R, Roberge, Michel, and Nygaard, Haakon B

Subjects
Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Stem Cell Research, Genetics, Stem Cell Research - Induced Pluripotent Stem Cell, Neurosciences, Frontotemporal Dementia (FTD), Stem Cell Research - Induced Pluripotent Stem Cell - Human, Acquired Cognitive Impairment, Neurodegenerative, Dementia, Alzheimer's Disease Related Dementias (ADRD), 2.1 Biological and endogenous factors, Aetiology, Neurological, Animals, Cells, Cultured, Codon, Nonsense, Codon, Terminator, Frontotemporal Lobar Degeneration, Gene Expression, Gentamicins, HEK293 Cells, Humans, Lysosomes, Mice, Neurons, Progranulins, Up-Regulation, Progranulin, GRN, Frontotemporal lobar degeneration, Nonsense mutation, Premature termination codon, Readthrough, G418, Induced pluripotent stem cell, Clinical Sciences, Neurology & Neurosurgery
Abstract

BackgroundFrontotemporal lobar degeneration (FTLD) is a devastating and progressive disorder, and a common cause of early onset dementia. Progranulin (PGRN) haploinsufficiency due to autosomal dominant mutations in the progranulin gene (GRN) is an important cause of FTLD (FTLD-GRN), and nearly a quarter of these genetic cases are due to a nonsense mutation. Premature termination codons (PTC) can be therapeutically targeted by compounds allowing readthrough, and aminoglycoside antibiotics are known to be potent PTC readthrough drugs. Restoring endogenous PGRN through PTC readthrough has not previously been explored as a therapeutic intervention in FTLD.MethodsWe studied whether the aminoglycoside G418 could increase PGRN expression in HEK293 and human induced pluripotent stem cell (hiPSC)-derived neurons bearing the heterozygous S116X, R418X, and R493X pathogenic GRN nonsense mutations. We further tested a novel substituted phthalimide PTC readthrough enhancer in combination with G418 in our cellular models. We next generated a homozygous R493X knock-in hiPSC isogenic line (R493X-/- KI), assessing whether combination treatment in hiPSC-derived neurons and astrocytes could increase PGRN and ameliorate lysosomal dysfunction relevant to FTLD-GRN. To provide in vivo proof-of-concept of our approach, we measured brain PGRN after intracerebroventricular administration of G418 in mice expressing the V5-tagged GRN nonsense mutation R493X.ResultsThe R418X and R493X mutant GRN cell lines responded to PTC readthrough with G418, and treatments increased PGRN levels in R493X-/- KI hiPSC-derived neurons and astrocytes. Combining G418 with a PTC readthrough enhancer increased PGRN levels over G418 treatment alone in vitro. PGRN deficiency has been shown to impair lysosomal function, and the mature form of the lysosomal protease cathepsin D is overexpressed in R493X-/- KI neurons. Increasing PGRN through G418-mediated PTC readthrough normalized this abnormal lysosomal phenotype in R493X-/- KI neuronal cultures. A single intracerebroventricular injection of G418 induced GRN PTC readthrough in 6-week-old AAV-GRN-R493X-V5 mice.ConclusionsTaken together, our findings suggest that PTC readthrough may be a potential therapeutic strategy for FTLD caused by GRN nonsense mutations.

Published
2020

23. Studying the natural history of frontotemporal lobar degeneration (FTLD): The ARTFL LEFFTDS longitudinal FTLD (ALLFTD) protocol

Author

Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Forsberg, Leah K, Heuer, Hilary W, Brushaber, Danielle, Appleby, Brian, Biernacka, Joanna M, Bordelon, Yvette M, Botha, Hugo, Brannelly, Patrick, Dickerson, Brad C, Dickson, Dennis W, Kimiko, Domoto‐Reilly, Faber, Kelley, Fagan, Anne, Fields, Julie A, Fishman, Ann, Foroud, Tatiana M, Galasko, Doug R, Gavrilova, Ralitza H, Gendron, Tania F, Geschwind, Daniel H, Ghoshal, Nupur, Goldman, Jill, Graff‐Radford, Jonathan, Graff‐Radford, Neill R, Grant, Ian, Grossman, Murray, Hsiung, Ging‐Yuek Robin, Huang, Eric J, Huey, Edward, Irwin, David J, Jones, David T, Kantarci, Kejal, Karydas, Anna M, Kaufer, Daniel, Knopman, David S, Kramer, Joel H, Kremers, Walter K, Kornak, John, Kukull, Walter A, Lagone, Emma, Leger, Gabriel C, Litvan, Irene, Ljubenkov, Peter A, Lucente, Diane E, Mackenzie, Ian R, Manoochehri, Masood, Masdeu, Joseph C, McGinnis, Scott, Mendez, Mario F, Miller, Bruce L, Miyagawa, Toji, Nelson, Kevin M, Onyike, Chiadi U, Pantelyat, Alex, Pascual, Belen, Pearlman, Rodney, Petrucelli, Leonard, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine, Rascovsky, Katya, Rexach, Jessica E, Ritter, Aaron, Roberson, Erik D, Rojas, Julio C, Sabbagh, Marwan N, Salmon, David P, Savica, Rodolfo, Seeley, William W, Staffaroni, Adam M, Syrjanen, Jeremy, Tartaglia, Carmela, Tatton, Nadine, Taylor, Joanne, Toga, Arthur W, Weintraub, Sandra, Wheaton, Diana, Wong, Bonnie, and Wszolek, Zbigniew

Subjects
Brain Disorders, Rare Diseases, Acquired Cognitive Impairment, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Trials and Supportive Activities, Clinical Research, Frontotemporal Dementia (FTD), Alzheimer's Disease Related Dementias (ADRD), Genetics, Neurosciences, Dementia, 2.1 Biological and endogenous factors, Geriatrics, Clinical Sciences
Published
2020

24. Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72

Author

Zhu, Qiang, Jiang, Jie, Gendron, Tania F, McAlonis-Downes, Melissa, Jiang, Lulin, Taylor, Amy, Diaz Garcia, Sandra, Ghosh Dastidar, Somasish, Rodriguez, Maria J, King, Patrick, Zhang, Yongjie, La Spada, Albert R, Xu, Huaxi, Petrucelli, Leonard, Ravits, John, Da Cruz, Sandrine, Lagier-Tourenne, Clotilde, and Cleveland, Don W

Subjects
Genetics, Neurosciences, Neurodegenerative, Aging, Orphan Drug, Dementia, Rare Diseases, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Alzheimer's Disease Related Dementias (ADRD), Frontotemporal Dementia (FTD), ALS, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Neurological, Amyotrophic Lateral Sclerosis, Animals, C9orf72 Protein, DNA Repeat Expansion, Female, Frontotemporal Dementia, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Hexanucleotide expansions in C9orf72, which encodes a predicted guanine exchange factor, are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although repeat expansion has been established to generate toxic products, mRNAs encoding the C9ORF72 protein are also reduced in affected individuals. In this study, we tested how C9ORF72 protein levels affected repeat-mediated toxicity. In somatic transgenic mice expressing 66 GGGGCC repeats, inactivation of one or both endogenous C9orf72 alleles provoked or accelerated, respectively, early death. In mice expressing a C9orf72 transgene with 450 repeats that did not encode the C9ORF72 protein, inactivation of one or both endogenous C9orf72 alleles exacerbated cognitive deficits, hippocampal neuron loss, glial activation and accumulation of dipeptide-repeat proteins from translation of repeat-containing RNAs. Reduced C9ORF72 was shown to suppress repeat-mediated elevation in autophagy. These efforts support a disease mechanism in ALS/FTD resulting from reduced C9ORF72, which can lead to autophagy deficits, synergizing with repeat-dependent gain of toxicity.

Published
2020

25. Utility of the global CDR® plus NACC FTLD rating and development of scoring rules: Data from the ARTFL/LEFFTDS Consortium

Author

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

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Dementia, Frontotemporal Dementia (FTD), Neurosciences, Neurodegenerative, Acquired Cognitive Impairment, Clinical Trials and Supportive Activities, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Brain Disorders, Aged, Aphasia, Primary Progressive, Cross-Sectional Studies, Female, Frontotemporal Lobar Degeneration, Humans, Male, Mental Status and Dementia Tests, Middle Aged, behavior, comportment, personality, CDR, CDR plus NACC FTLD, frontotemporal lobar degeneration, global rating, language, CDR®, behavior, comportment, and personality, Clinical Sciences, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionWe 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.MethodsThe 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.ResultsThe 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.DiscussionThe 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
2020

26. Tracking white matter degeneration in asymptomatic and symptomatic MAPT mutation carriers

Author

Chen, Qin, Boeve, Bradley F, Schwarz, Christopher G, Reid, Robert, Tosakulwong, Nirubol, Lesnick, Timothy G, Bove, Jessica, Brannelly, Patrick, Brushaber, Danielle, Coppola, Giovanni, Dheel, Christina, Dickerson, Bradford C, Dickinson, Susan, Faber, Kelley, Fields, Julie, Fong, Jamie, Foroud, Tatiana, Forsberg, Leah, Gavrilova, Ralitza H, Gearhart, Debra, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathan, Graff-Radford, Neill R, Grossman, Murray, Haley, Dana, Heuer, Hilary W, Hsiung, Ging-Yuek R, Huey, Edward, Irwin, David J, Jack, Clifford R, Jones, David T, Jones, Lynne, Karydas, Anna M, Knopman, David S, Kornak, John, Kramer, Joel, Kremers, Walter, Kukull, Walter A, Lapid, Maria, Lucente, Diane, Lungu, Codrin, Mackenzie, Ian RA, Manoochehri, Masood, McGinnis, Scott, Miller, Bruce L, Pearlman, Rodney, Petrucelli, Leonard, Potter, Madeline, Rademakers, Rosa, Ramos, Eliana M, Rankin, Katherine P, Rascovsky, Katya, Sengdy, Pheth, Shaw, Leslie, Syrjanen, Jeremy, Tatton, Nadine, Taylor, Joanne, Toga, Arthur W, Trojanowski, John, Weintraub, Sandra, Wong, Bonnie, Boxer, Adam L, Rosen, Howie, Wszolek, Zbigniew, Kantarci, Kejal, and Consortium, LEFFTDS

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Dementia, Neurodegenerative, Aging, Acquired Cognitive Impairment, Biomedical Imaging, Neurosciences, Clinical Trials and Supportive Activities, Clinical Research, Brain Disorders, 2.1 Biological and endogenous factors, Adult, Aged, Diffusion Magnetic Resonance Imaging, Diffusion Tensor Imaging, Disease Progression, Female, Frontotemporal Dementia, Gray Matter, Heterozygote, Humans, Male, Middle Aged, Mutation, Neurodegenerative Diseases, Neuropsychological Tests, White Matter, tau Proteins, Diffusion tensor image, MAPT, Asymptomatic, Frontotemporal dementia, Longitudinal, LEFFTDS Consortium, Neurology & Neurosurgery, Biological psychology
Abstract

Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed. Asymptomatic MAPT mutation carriers had higher MD in entorhinal WM, which propagated to the limbic tracts and frontotemporal projections in the symptomatic stage compared with noncarriers. Reduced fractional anisotropy and increased MD in the entorhinal WM were associated with the proximity to estimated and actual age of symptom onset. The annualized change of entorhinal MD on serial DTI was accelerated in MAPT mutation carriers compared with noncarriers. Entorhinal WM diffusion abnormalities precede the symptom onset and track with disease progression in MAPT mutation carriers. Our cross-sectional and longitudinal data showed a potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials.

Published
2019

28. 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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29. Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial

Author

Babu, Suma, primary, Nicholson, Katharine A, additional, Rothstein, Jeffrey D, additional, Swenson, Andrea, additional, Sampognaro, Paul J, additional, Pant, Pravin, additional, Macklin, Eric A, additional, Spruill, Susan, additional, Paganoni, Sabrina, additional, Gendron, Tania F, additional, Prudencio, Mercedes, additional, Petrucelli, Leonard, additional, Nix, Darrell, additional, Landrette, Sean, additional, Nkrumah, Esther, additional, Fandrick, Keith, additional, Edwards, Joan, additional, and Young, Peter R, additional

Published
2024
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30. 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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32. 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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33. P2‐314: THE MULTIDOMAIN IMPAIRMENT RATING (MIR) SCALE: INITIAL RELIABILITY DATA ON A MULTIDIMENSIONAL SCALE DESIGNED FOR FTLD SPECTRUM DISORDERS

Author

Forsberg, Leah K, Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Kornak, John, Heuer, Hilary W, Fields, Julie A, Brushaber, Danielle, Machulda, Mary M, Sturm, Virginia, Staffaroni, Adam M, Ljubenkov, Peter A, Denver, Reilly, Ong, Elise, Appleby, Brian, Bordelon, Yvette M, Brannelly, Patrick, Coppola, Giovanni, Dickerson, Brad C, Dickinson, Susan, Kimiko, Domoto-Reilly, Faber, Kelley, Fong, Jamie, Foroud, Tatiana M, Gavrilova, Ralitza H, Gearhart, Debra, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathan, Graff-Radford, Neil R, Grossman, Murray, Hsiung, Ging-Yuek Robin, Huey, Edward D, Irwin, David, Jones, David T, Kantarci, Kejal, Karydas, Anna M, Kaufer, Daniel, Kerwin, Diana R, Knopman, David S, Kraft, Ruth A, Kramer, Joel H, Kremers, Walter K, Kukull, Walter A, Litvan, Irene, Lucente, Diane E, Lungu, Codrin, Mackenzie, Ian R, McGinnis, Scott M, Mendez, Mario F, Miller, Bruce L, Onyike, Chiadi U, Pantelyat, Alex, Pearlman, Rodney, Petrucelli, Leonard, Potter, Madeline, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine, Rascovsky, Katya, Roberson, Erik D, Rogalski, Emily J, Shaw, Leslie M, Sutherland, Marg, Syrjanen, Jeremy, Tartaglia, Carmela, Tatton, Nadine, Taylor, Joanne, Toga, Arthur W, Trojanowski, John Q, Weintraub, Sandra, Wong, Bonnie, and Wszolek, Zbigniew

Subjects
Clinical Sciences, Neurosciences, Geriatrics
Published
2019

34. Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

Author

Pottier, Cyril, Ren, Yingxue, Perkerson, Ralph B, Baker, Matt, Jenkins, Gregory D, van Blitterswijk, Marka, DeJesus-Hernandez, Mariely, van Rooij, Jeroen GJ, Murray, Melissa E, Christopher, Elizabeth, McDonnell, Shannon K, Fogarty, Zachary, Batzler, Anthony, Tian, Shulan, Vicente, Cristina T, Matchett, Billie, Karydas, Anna M, Hsiung, Ging-Yuek Robin, Seelaar, Harro, Mol, Merel O, Finger, Elizabeth C, Graff, Caroline, Öijerstedt, Linn, Neumann, Manuela, Heutink, Peter, Synofzik, Matthis, Wilke, Carlo, Prudlo, Johannes, Rizzu, Patrizia, Simon-Sanchez, Javier, Edbauer, Dieter, Roeber, Sigrun, Diehl-Schmid, Janine, Evers, Bret M, King, Andrew, Mesulam, M Marsel, Weintraub, Sandra, Geula, Changiz, Bieniek, Kevin F, Petrucelli, Leonard, Ahern, Geoffrey L, Reiman, Eric M, Woodruff, Bryan K, Caselli, Richard J, Huey, Edward D, Farlow, Martin R, Grafman, Jordan, Mead, Simon, Grinberg, Lea T, Spina, Salvatore, Grossman, Murray, Irwin, David J, Lee, Edward B, Suh, EunRan, Snowden, Julie, Mann, David, Ertekin-Taner, Nilufer, Uitti, Ryan J, Wszolek, Zbigniew K, Josephs, Keith A, Parisi, Joseph E, Knopman, David S, Petersen, Ronald C, Hodges, John R, Piguet, Olivier, Geier, Ethan G, Yokoyama, Jennifer S, Rissman, Robert A, Rogaeva, Ekaterina, Keith, Julia, Zinman, Lorne, Tartaglia, Maria Carmela, Cairns, Nigel J, Cruchaga, Carlos, Ghetti, Bernardino, Kofler, Julia, Lopez, Oscar L, Beach, Thomas G, Arzberger, Thomas, Herms, Jochen, Honig, Lawrence S, Vonsattel, Jean Paul, Halliday, Glenda M, Kwok, John B, White, Charles L, Gearing, Marla, Glass, Jonathan, Rollinson, Sara, Pickering-Brown, Stuart, Rohrer, Jonathan D, Trojanowski, John Q, Van Deerlin, Vivianna, Bigio, Eileen H, Troakes, Claire, Al-Sarraj, Safa, Asmann, Yan, Miller, Bruce L, Graff-Radford, Neill R, Boeve, Bradley F, and Seeley, William W

Subjects
Biomedical and Clinical Sciences, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, Brain Disorders, Rare Diseases, Human Genome, Alzheimer's Disease Related Dementias (ADRD), Dementia, Prevention, Genetics, Frontotemporal Dementia (FTD), Neurodegenerative, Acquired Cognitive Impairment, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Aged, DNA Repeat Expansion, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Female, Frontal Lobe, Frontotemporal Lobar Degeneration, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-DQ Antigens, Humans, Intracellular Signaling Peptides and Proteins, Loss of Function Mutation, Male, Middle Aged, Nerve Tissue Proteins, Potassium Channels, Progranulins, Protein Serine-Threonine Kinases, Proteins, RNA, Messenger, Risk Factors, Sequence Analysis, RNA, Societies, Scientific, TDP-43 Proteinopathies, White People, Whole-genome sequencing FTLD-TDP, TBK1, DPP6, UNC13A, HLA, Immunity, Clinical Sciences, Neurology & Neurosurgery
Abstract

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

Published
2019

35. 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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37. CRISPR/Cas9-mediated excision of ALS/FTD-causing hexanucleotide repeat expansion in C9ORF72 rescues major disease mechanisms in vivo and in vitro

Author

Meijboom, Katharina E., Abdallah, Abbas, Fordham, Nicholas P., Nagase, Hiroko, Rodriguez, Tomás, Kraus, Carolyn, Gendron, Tania F., Krishnan, Gopinath, Esanov, Rustam, Andrade, Nadja S., Rybin, Matthew J., Ramic, Melina, Stephens, Zachary D., Edraki, Alireza, Blackwood, Meghan T., Kahriman, Aydan, Henninger, Nils, Kocher, Jean-Pierre A., Benatar, Michael, Brodsky, Michael H., Petrucelli, Leonard, Gao, Fen-Biao, Sontheimer, Erik J., Brown, Robert H., Zeier, Zane, and Mueller, Christian

Published
2022
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38. 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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39. Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy

Author

Khalil, Bilal, Chhangani, Deepak, Wren, Melissa C., Smith, Courtney L., Lee, Jannifer H., Li, Xingli, Puttinger, Christian, Tsai, Chih-Wei, Fortin, Gael, Morderer, Dmytro, Gao, Junli, Liu, Feilin, Lim, Chun Kim, Chen, Jingjiao, Chou, Ching-Chieh, Croft, Cara L., Gleixner, Amanda M., Donnelly, Christopher J., Golde, Todd E., Petrucelli, Leonard, Oskarsson, Björn, Dickson, Dennis W., Zhang, Ke, Shorter, James, Yoshimura, Shige H., Barmada, Sami J., Rincon-Limas, Diego E., and Rossoll, Wilfried

Published
2022
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40. TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau

Author

Ash, Peter E. A., Lei, Shuwen, Shattuck, Jenifer, Boudeau, Samantha, Carlomagno, Yari, Medalla, Maria, Mashimo, Bryce L., Socorro, Guillermo, Al-Mohanna, Louloua F. A., Jiang, Lulu, Öztürk, Muhammet M., Knobel, Mark, Ivanov, Pavel, Petrucelli, Leonard, Wegmann, Susanne, Kanaan, Nicholas M., and Wolozin, Benjamin

Published
2021

41. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study

Author

Pottier, Cyril, Zhou, Xiaolai, Perkerson, Ralph B, Baker, Matt, Jenkins, Gregory D, Serie, Daniel J, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, de Munain, Adolfo López, Zulaica, Miren, Moreno, Fermin, Le Ber, Isabelle, Pasquier, Florence, Hannequin, Didier, Sánchez-Valle, Raquel, Antonell, Anna, Lladó, Albert, Parsons, Tammee M, Finch, NiCole A, Finger, Elizabeth C, Lippa, Carol F, Huey, Edward D, Neumann, Manuela, Heutink, Peter, Synofzik, Matthis, Wilke, Carlo, Rissman, Robert A, Slawek, Jaroslaw, Sitek, Emilia, Johannsen, Peter, Nielsen, Jørgen E, Ren, Yingxue, van Blitterswijk, Marka, DeJesus-Hernandez, Mariely, Christopher, Elizabeth, Murray, Melissa E, Bieniek, Kevin F, Evers, Bret M, Ferrari, Camilla, Rollinson, Sara, Richardson, Anna, Scarpini, Elio, Fumagalli, Giorgio G, Padovani, Alessandro, Hardy, John, Momeni, Parastoo, Ferrari, Raffaele, Frangipane, Francesca, Maletta, Raffaele, Anfossi, Maria, Gallo, Maura, Petrucelli, Leonard, Suh, EunRan, Lopez, Oscar L, Wong, Tsz H, van Rooij, Jeroen GJ, Seelaar, Harro, Mead, Simon, Caselli, Richard J, Reiman, Eric M, Sabbagh, Marwan Noel, Kjolby, Mads, Nykjaer, Anders, Karydas, Anna M, Boxer, Adam L, Grinberg, Lea T, Grafman, Jordan, Spina, Salvatore, Oblak, Adrian, Mesulam, M-Marsel, Weintraub, Sandra, Geula, Changiz, Hodges, John R, Piguet, Olivier, Brooks, William S, Irwin, David J, Trojanowski, John Q, Lee, Edward B, Josephs, Keith A, Parisi, Joseph E, Ertekin-Taner, Nilüfer, Knopman, David S, Nacmias, Benedetta, Piaceri, Irene, Bagnoli, Silvia, Sorbi, Sandro, Gearing, Marla, Glass, Jonathan, Beach, Thomas G, Black, Sandra E, Masellis, Mario, Rogaeva, Ekaterina, Vonsattel, Jean-Paul, Honig, Lawrence S, Kofler, Julia, Bruni, Amalia C, Snowden, Julie, Mann, David, and Pickering-Brown, Stuart

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Frontotemporal Dementia (FTD), Neurodegenerative, Dementia, Genetics, Aging, Prevention, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Alzheimer's Disease Related Dementias (ADRD), Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Neurological, Age of Onset, Aged, Case-Control Studies, Cerebellum, Female, Frontotemporal Lobar Degeneration, Genetic Predisposition to Disease, Genome-Wide Association Study, Glial Cell Line-Derived Neurotrophic Factor Receptors, Humans, Male, Middle Aged, Mutation, Progranulins, RNA, Messenger, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundLoss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers.MethodsThe study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p

Published
2018

42. Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Author

Meeter, Lieke HH, Gendron, Tania F, Sias, Ana C, Jiskoot, Lize C, Russo, Silvia P, Kaat, Laura Donker, Papma, Janne M, Panman, Jessica L, van der Ende, Emma L, Dopper, Elise G, Franzen, Sanne, Graff, Caroline, Boxer, Adam L, Rosen, Howard J, Sanchez‐Valle, Raquel, Galimberti, Daniela, Pijnenburg, Yolande AL, Benussi, Luisa, Ghidoni, Roberta, Borroni, Barbara, Laforce, Robert, del Campo, Marta, Teunissen, Charlotte E, van Minkelen, Rick, Rojas, Julio C, Coppola, Giovanni, Geschwind, Dan H, Rademakers, Rosa, Karydas, Anna M, Öijerstedt, Linn, Scarpini, Elio, Binetti, Giuliano, Padovani, Alessandro, Cash, David M, Dick, Katrina M, Bocchetta, Martina, Miller, Bruce L, Rohrer, Jonathan D, Petrucelli, Leonard, van Swieten, John C, and Lee, Suzee E

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Research, Neurodegenerative, Dementia, Brain Disorders, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurological, Clinical Sciences, Clinical and health psychology
Abstract

ObjectiveTo evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72-associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume.MethodsWe measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel-wise analyses.ResultsPoly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.InterpretationThis study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72-associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

Published
2018

43. Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration

Author

Saloner, Rowan, primary, Staffaroni, Adam, additional, Dammer, Eric, additional, Johnson, Erik C.B., additional, Paolillo, Emily, additional, Wise, Amy, additional, Heuer, Hilary, additional, Forsberg, Leah, additional, Lago, Argentina Lario, additional, Webb, Julia, additional, Vogel, Jacob, additional, Santillo, Alexander, additional, Hansson, Oskar, additional, Kramer, Joel, additional, Miller, Bruce, additional, Li, Jingyao, additional, Loureiro, Joseph, additional, Sivasankaran, Rajeev, additional, Worringer, Kathleen, additional, Seyfried, Nicholas, additional, Yokoyama, Jennifer, additional, Seeley, William, additional, Spina, Salvatore, additional, Grinberg, Lea, additional, VandeVrede, Lawren, additional, Ljubenkov, Peter, additional, Bayram, Ece, additional, Bozoki, Andrea, additional, Brushaber, Danielle, additional, Considine, Ciaran, additional, Day, Gregory, additional, Dickerson, Bradford, additional, Domoto-Reilly, Kimiko, additional, Faber, Kelley, additional, Galasko, Douglas, additional, Geschwind, Daniel, additional, Ghoshal, Nupur, additional, Graff-Radford, Neill, additional, Hales, Chadwick, additional, Honig, Lawrence, additional, Hsiung, Ging-Yuek, additional, Huey, Edward, additional, Kornak, John, additional, Kremers, Walter, additional, Lapid, Maria, additional, Lee, Suzee, additional, Litvan, Irene, additional, McMillan, Corey, additional, Mendez, Mario, additional, Miyagawa, Toji, additional, Pantelyat, Alexander, additional, Pascual, Belen, additional, Paulson, Henry, additional, Petrucelli, Leonard, additional, Pressman, Peter, additional, Ramos, Eliana, additional, Rascovsky, Katya, additional, Roberson, Erik, additional, Savica, Rodolfo, additional, Snyder, Allison, additional, Sullivan, A. Campbell, additional, Tartaglia, Carmela, additional, Vandebergh, Marijne, additional, Boeve, Bradley, additional, Rosen, Howie, additional, Rojas, Julio, additional, Boxer, Adam, additional, and Casaletto, Kaitlin, additional

Published
2024
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44. Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats

Author

Tseng, Yi-Ju, primary, Krans, Amy, additional, Malik, Indranil, additional, Deng, Xiexiong, additional, Yildirim, Evrim, additional, Ovunc, Sinem, additional, Tank, Elizabeth M H, additional, Jansen-West, Karen, additional, Kaufhold, Ross, additional, Gomez, Nicolas B, additional, Sher, Roger, additional, Petrucelli, Leonard, additional, Barmada, Sami J, additional, and Todd, Peter K, additional

Published
2024
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45. Mis-spliced transcripts generate de novo proteins in TDP-43–related ALS/FTD

Author

Seddighi, Sahba, primary, Qi, Yue A., additional, Brown, Anna-Leigh, additional, Wilkins, Oscar G., additional, Bereda, Colleen, additional, Belair, Cedric, additional, Zhang, Yong-Jie, additional, Prudencio, Mercedes, additional, Keuss, Matthew J., additional, Khandeshi, Aditya, additional, Pickles, Sarah, additional, Kargbo-Hill, Sarah E., additional, Hawrot, James, additional, Ramos, Daniel M., additional, Yuan, Hebao, additional, Roberts, Jessica, additional, Sacramento, Erika Kelmer, additional, Shah, Syed I., additional, Nalls, Mike A., additional, Colón-Mercado, Jennifer M., additional, Reyes, Joel F., additional, Ryan, Veronica H., additional, Nelson, Matthew P., additional, Cook, Casey N., additional, Li, Ziyi, additional, Screven, Laurel, additional, Kwan, Justin Y., additional, Mehta, Puja R., additional, Zanovello, Matteo, additional, Hallegger, Martina, additional, Shantaraman, Anantharaman, additional, Ping, Lingyan, additional, Koike, Yuka, additional, Oskarsson, Björn, additional, Staff, Nathan P., additional, Duong, Duc M., additional, Ahmed, Aisha, additional, Secrier, Maria, additional, Ule, Jernej, additional, Jacobson, Steven, additional, Reich, Daniel S., additional, Rohrer, Jonathan D., additional, Malaspina, Andrea, additional, Dickson, Dennis W., additional, Glass, Jonathan D., additional, Ori, Alessandro, additional, Seyfried, Nicholas T., additional, Maragkakis, Manolis, additional, Petrucelli, Leonard, additional, Fratta, Pietro, additional, and Ward, Michael E., additional

Published
2024
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46. Deep vein thrombosis and pulmonary embolism among hospitalized coronavirus disease 2019–positive patients predicted for higher mortality and prolonged intensive care unit and hospital stays in a multisite healthcare system

Author

Erben, Young, Franco-Mesa, Camila, Gloviczki, Peter, Stone, William, Quinones-Hinojoas, Alfredo, Meltzer, Andrew J., Lin, Michelle, Greenway, Melanie R.F., Hamid, Osman, Devcic, Zlatko, Toskich, Beau, Ritchie, Charles, Lamb, Christopher J., De Martino, Randall R., Siegel, Jason, Farres, Houssan, Hakaim, Albert G., Sanghavi, Devang K., Li, Yupeng, Rivera, Candido, Moreno-Franco, Pablo, O'Keefe, Nancy L., Gopal, Neethu, Marquez, Christopher P., Huang, Josephine F., Kalra, Manju, Shields, Raymond, Prudencio, Mercedes, Gendron, Tania, McBane, Robert, Park, Myung, Hoyne, Jonathan B., Petrucelli, Leonard, O'Horo, John C., and Meschia, James F.

Published
2021
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48. 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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