TY - JOUR
T1 - Prospective natural history study of C9orf72 ALS clinical characteristics and biomarkers
AU - Cammack, Alexander J.
AU - Atassi, Nazem
AU - Hyman, Theodore
AU - Van Den Berg, Leonard H.
AU - Harms, Matthew
AU - Baloh, Robert H.
AU - Brown, Robert H.
AU - Van Es, Michael A.
AU - Veldink, Jan H.
AU - De Vries, Balint S.
AU - Rothstein, Jeffrey D.
AU - Drain, Caroline
AU - Jockel-Balsarotti, Jennifer
AU - Malcolm, Amber
AU - Boodram, Sonia
AU - Salter, Amber
AU - Wightman, Nicholas
AU - Yu, Hong
AU - Sherman, Alexander V.
AU - Esparza, Thomas J.
AU - McKenna-Yasek, Diane
AU - Owegi, Margaret A.
AU - Douthwright, Catherine
AU - McCampbell, Alexander
AU - Ferguson, Toby
AU - Cruchaga, Carlos
AU - Cudkowicz, Merit
AU - Miller, Timothy M.
N1 - Funding Information:
Funding provided by Biogen Inc., the ALS Association, the Muscular Dystrophy Association, the Knight Alzheimer’s Disease Research Center at Washington University, and C9ID foundation. Other support provided by USPHS grant 5UL1 RR024992-02. Unexpanded control data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (NIH grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and the following: AbbVie; Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the NIH (fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. A.J.C. was supported by grant 5T32GM008151-32 and by the Lucille P. Markey Special Emphasis Pathway in Human Pathobiology at Washington University. R.H. Baloh was supported by NIH R01 NS097545 and the Robert and Louis Schwab Family. R.H. Brown receives support from NINDS (R01 NS088689, R01 NS073873, R01 NS104022), the ALS Association, ALS Finding a Cure, ALS ONE, the Angel Fund for ALS Research, and Project ALS. T.M.M. was supported by NINDS R01 NS078398. Industry sponsor: Biogen Inc.
Publisher Copyright:
© 2019 American Academy of Neurology.
PY - 2019/10/22
Y1 - 2019/10/22
N2 - ObjectiveTo define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies.MethodsWe prospectively collected clinical and demographic data from 116 symptomatic C9ALS and 12 non-amyotrophic lateral sclerosis (ALS) full expansion carriers across 7 institutions in the United States and the Netherlands. In addition, we collected blood samples for DNA repeat size assessment, CSF samples for biomarker identification, and autopsy samples for dipeptide repeat protein (DPR) size determination. Finally, we collected retrospective clinical data via chart review from 208 individuals with C9ALS and 450 individuals with singleton ALS.ResultsThe mean age at onset in the symptomatic prospective cohort was 57.9 ± 8.3 years, and median duration of survival after onset was 36.9 months. The monthly change was -1.8 ± 1.7 for ALS Functional Rating Scale-Revised and -1.4% ± 3.24% of predicted for slow vital capacity. In blood DNA, we found that G4C2 repeat size correlates positively with age. In CSF, we observed that concentrations of poly(GP) negatively correlate with DNA expansion size but do not correlate with measures of disease progression. Finally, we found that size of poly(GP) dipeptides in the brain can reach large sizes similar to that of their DNA repeat derivatives.ConclusionsWe present a thorough investigation of C9ALS natural history, providing the basis for C9ALS clinical trial design. We found that clinical features of this genetic subset are less variant than in singleton ALS. In addition, we identified important correlations of C9ALS patient pathologies with clinical and demographic data.
AB - ObjectiveTo define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies.MethodsWe prospectively collected clinical and demographic data from 116 symptomatic C9ALS and 12 non-amyotrophic lateral sclerosis (ALS) full expansion carriers across 7 institutions in the United States and the Netherlands. In addition, we collected blood samples for DNA repeat size assessment, CSF samples for biomarker identification, and autopsy samples for dipeptide repeat protein (DPR) size determination. Finally, we collected retrospective clinical data via chart review from 208 individuals with C9ALS and 450 individuals with singleton ALS.ResultsThe mean age at onset in the symptomatic prospective cohort was 57.9 ± 8.3 years, and median duration of survival after onset was 36.9 months. The monthly change was -1.8 ± 1.7 for ALS Functional Rating Scale-Revised and -1.4% ± 3.24% of predicted for slow vital capacity. In blood DNA, we found that G4C2 repeat size correlates positively with age. In CSF, we observed that concentrations of poly(GP) negatively correlate with DNA expansion size but do not correlate with measures of disease progression. Finally, we found that size of poly(GP) dipeptides in the brain can reach large sizes similar to that of their DNA repeat derivatives.ConclusionsWe present a thorough investigation of C9ALS natural history, providing the basis for C9ALS clinical trial design. We found that clinical features of this genetic subset are less variant than in singleton ALS. In addition, we identified important correlations of C9ALS patient pathologies with clinical and demographic data.
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U2 - 10.1212/WNL.0000000000008359
DO - 10.1212/WNL.0000000000008359
M3 - Article
C2 - 31578300
AN - SCOPUS:85073664635
VL - 93
SP - E1605-E1617
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 17
ER -