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Journal article
Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis
Journal of neurology, neurosurgery and psychiatry, v 84(2), pp 163-169
01 Feb 2013
PMID: 23117491
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Background Significant heterogeneity in clinical features of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) cases with the pathogenic C9orf72 expansion (C9P) have been described. To clarify this issue, we compared a large C9P cohort with carefully matched non-expansion (C9N) cases with a known or highly-suspected underlying TAR DNA-binding protein 43 (TDP-43) proteinopathy. Methods A retrospective case-control study was carried out using available cross-sectional and longitudinal clinical and neuropsychological data, MRI voxel-based morphometry (VBM) and neuropathological assessment from 64 C9P cases (ALS=31, FTLD=33) and 79 C9N cases (ALS=36, FTLD=43). Results C9P cases had an earlier age of onset (p=0.047) and, in the subset of patients who were deceased, an earlier age of death (p=0.014) than C9N. C9P had more rapid progression than C9N: C9P ALS cases had a shortened survival (2.6±0.3 years) compared to C9N ALS (3.8±0.4 years; log-rank λ2=4.183, p=0.041), and C9P FTLD showed a significantly greater annualised rate of decline in letter fluency (4.5±1.3 words/year) than C9N FTLD (1.4±0.8 words/year, p=0.023). VBM revealed greater atrophy in the right frontoinsular, thalamus, cerebellum and bilateral parietal regions for C9P FTLD relative to C9N FTLD, and regression analysis related verbal fluency scores to atrophy in frontal and parietal regions. Neuropathological analysis found greater neuronal loss in the mid-frontal cortex in C9P FTLD, and mid-frontal cortex TDP-43 inclusion severity correlated with poor letter fluency performance. Conclusions C9P cases may have a shorter survival in ALS and more rapid rate of cognitive decline related to frontal and parietal disease in FTLD. C9orf72 genotyping may provide useful prognostic and diagnostic clinical information for patients with ALS and FTLD.
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- Title
- Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis
- Creators
- David J Irwin - National Institutes of HealthCorey T McMillan - University of PennsylvaniaJohannes Brettschneider - Institute on AgingDavid J Libon - Drexel UniversityJohn Powers - University of PennsylvaniaKatya Rascovsky - University of PennsylvaniaJon B Toledo - Institute on AgingAshley Boller - University of PennsylvaniaJonathan Bekisz - Institute on AgingKeerthi Chandrasekaran - University of PennsylvaniaElisabeth McCarty Wood - University of PennsylvaniaLeslie M Shaw - Institute on AgingJohn H Woo - University of PennsylvaniaPhilip A Cook - University of PennsylvaniaDavid A Wolk - University of PennsylvaniaSteven E Arnold - University of PennsylvaniaVivianna M Van Deerlin - Institute on AgingLeo F McCluskey - University of PennsylvaniaLauren Elman - University of PennsylvaniaVirginia M-Y Lee - University of PennsylvaniaJohn Q Trojanowski - University of PennsylvaniaMurray Grossman - University of Pennsylvania
- Publication Details
- Journal of neurology, neurosurgery and psychiatry, v 84(2), pp 163-169
- Publisher
- British Medical Journal (BMJ)
- Resource Type
- Journal article
- Language
- English
- Web of Science ID
- WOS:000313554700010
- Scopus ID
- 2-s2.0-84872677920
- Other Identifier
- 991021901315104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Clinical Neurology
- Psychiatry
- Surgery