期刊
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
卷 84, 期 2, 页码 163-169出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jnnp-2012-303507
关键词
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资金
- NIH [P30AG010124, P01 AG017586, R01 NS44266, R01 AG15116, P01 AG32953, P01 NS53488, R21 NS06311, T32-AG000255, R01 AG037376, R01 MH086492, K23 AG028018, P30 AG010124]
- Wyncote Foundation
- Deutsche Forschungsgemeinschaft DFG [AOBJ586910]
- Alfonso Martin Escudero Foundation
- GE Healthcare
- Pfizer, Inc.
- Penn licenses
- AstraZeneca
- BMS
- American College of Radiology Imaging Network
- Pfizer
- Alzheimer's Disease Neuroimaging Initiative
- Johnson Johnson
- National Institute of Drug Abuse
- Neuronetrix
- National Institute of Mental Health
- Eli Lilly
- [HD060406]
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 lambda 2=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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