Prospective natural history study of C9orf72 ALS clinical characteristics and biomarkers

Alzheimer's Disease Neuroimaging Initiative

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: To define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies. METHODS: We 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. RESULTS: The 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. CONCLUSIONS: We 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.

Original languageEnglish (US)
Pages (from-to)e1605-e1617
JournalNeurology
Volume93
Issue number17
DOIs
StatePublished - Oct 22 2019

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Amyotrophic Lateral Sclerosis
Natural History
Biomarkers
Dipeptides
DNA
Demography
Motor Neuron Disease
Clinical Pathology
Vital Capacity
Age of Onset
Netherlands
Disease Progression
Autopsy
Clinical Trials
Pathology
Survival
Brain

ASJC Scopus subject areas

  • Clinical Neurology

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Prospective natural history study of C9orf72 ALS clinical characteristics and biomarkers. / Alzheimer's Disease Neuroimaging Initiative.

In: Neurology, Vol. 93, No. 17, 22.10.2019, p. e1605-e1617.

Research output: Contribution to journalArticle

Alzheimer's Disease Neuroimaging Initiative. / Prospective natural history study of C9orf72 ALS clinical characteristics and biomarkers. In: Neurology. 2019 ; Vol. 93, No. 17. pp. e1605-e1617.
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abstract = "OBJECTIVE: To define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies. METHODS: We 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. RESULTS: The 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. CONCLUSIONS: We 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.",
author = "{Alzheimer's Disease Neuroimaging Initiative} and Cammack, {Alexander J.} and Nazem Atassi and Theodore Hyman and {van den Berg}, {Leonard H.} and Matthew Harms and Baloh, {Robert H.} and Brown, {Robert H.} and {van Es}, {Michael A.} and Veldink, {Jan H.} and {de Vries}, {Balint S.} and Rothstein, {Jeffrey D.} and Caroline Drain and Jennifer Jockel-Balsarotti and Amber Malcolm and Sonia Boodram and Amber Salter and Nicholas Wightman and Hong Yu and Sherman, {Alexander V.} and Esparza, {Thomas J.} and Diane McKenna-Yasek and Owegi, {Margaret A.} and Catherine Douthwright and Alexander McCampbell and Toby Ferguson and Carlos Cruchaga and Merit Cudkowicz and Miller, {Timothy M.}",
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T1 - Prospective natural history study of C9orf72 ALS clinical characteristics and biomarkers

AU - Alzheimer's Disease Neuroimaging Initiative

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.

PY - 2019/10/22

Y1 - 2019/10/22

N2 - OBJECTIVE: To define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies. METHODS: We 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. RESULTS: The 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. CONCLUSIONS: We 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 - OBJECTIVE: To define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies. METHODS: We 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. RESULTS: The 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. CONCLUSIONS: We 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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