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Research paper
Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis
  1. David J Irwin1–3,
  2. Corey T McMillan2,3,
  3. Johannes Brettschneider1,4,
  4. David J Libon3,5,
  5. John Powers2,3,
  6. Katya Rascovsky2,3,
  7. Jon B Toledo1,
  8. Ashley Boller2,3,
  9. Jonathan Bekisz1,
  10. Keerthi Chandrasekaran2,3,
  11. Elisabeth McCarty Wood1,3,
  12. Leslie M Shaw1,
  13. John H Woo6,
  14. Philip A Cook6,
  15. David A Wolk2,
  16. Steven E Arnold1,2,7,
  17. Vivianna M Van Deerlin1,
  18. Leo F McCluskey2,
  19. Lauren Elman2,
  20. Virginia M-Y Lee1,3,
  21. John Q Trojanowski1,3,
  22. Murray Grossman2,3
  1. 1Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Alzheimer's Disease Core Center, Institute on Aging, Philadelphia, Pennsylvania, USA
  2. 2Department of Neurology, Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania, USA
  3. 3Penn Frontotemporal Degeneration Center, Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania, USA
  4. 4Department of Neurology, University of Ulm, 89081 Ulm, Germany
  5. 5Department of Neurology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
  6. 6Department of Radiology, Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania, USA
  7. 7Department of Psychiatry, Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania, USA
  1. Correspondence to Dr Murray Grossman, Department of Neurology Perelman School of Medicine at the University of Pennsylvania Hospital of the University of Pennsylvania 3400 Spruce Street, Philadelphia, PA 19104, USA; mgrossma{at}mail.med.upenn.edu

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.

  • Cognitive Neuropsychology
  • Neurogenetics
  • Frontal Lobe
  • Mri
  • Motor Neuron Disease

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