Cerebellar integrity in the amyotrophic lateral sclerosis-frontotemporal dementia continuum

PLoS One. 2014 Aug 21;9(8):e105632. doi: 10.1371/journal.pone.0105632. eCollection 2014.

Abstract

Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) are multisystem neurodegenerative disorders that manifest overlapping cognitive, neuropsychiatric and motor features. The cerebellum has long been known to be crucial for intact motor function although emerging evidence over the past decade has attributed cognitive and neuropsychiatric processes to this structure. The current study set out i) to establish the integrity of cerebellar subregions in the amyotrophic lateral sclerosis-behavioural variant frontotemporal dementia spectrum (ALS-bvFTD) and ii) determine whether specific cerebellar atrophy regions are associated with cognitive, neuropsychiatric and motor symptoms in the patients. Seventy-eight patients diagnosed with ALS, ALS-bvFTD, behavioural variant frontotemporal dementia (bvFTD), most without C9ORF72 gene abnormalities, and healthy controls were investigated. Participants underwent cognitive, neuropsychiatric and functional evaluation as well as structural imaging using voxel-based morphometry (VBM) to examine the grey matter subregions of the cerebellar lobules, vermis and crus. VBM analyses revealed: i) significant grey matter atrophy in the cerebellum across the whole ALS-bvFTD continuum; ii) atrophy predominantly of the superior cerebellum and crus in bvFTD patients, atrophy of the inferior cerebellum and vermis in ALS patients, while ALS-bvFTD patients had both patterns of atrophy. Post-hoc covariance analyses revealed that cognitive and neuropsychiatric symptoms were particularly associated with atrophy of the crus and superior lobule, while motor symptoms were more associated with atrophy of the inferior lobules. Taken together, these findings indicate an important role of the cerebellum in the ALS-bvFTD disease spectrum, with all three clinical phenotypes demonstrating specific patterns of subregional atrophy that associated with different symptomology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / pathology
  • Amyotrophic Lateral Sclerosis* / physiopathology
  • C9orf72 Protein
  • Cerebellum* / pathology
  • Cerebellum* / physiopathology
  • Female
  • Frontotemporal Dementia* / genetics
  • Frontotemporal Dementia* / pathology
  • Frontotemporal Dementia* / physiopathology
  • Humans
  • Male
  • Middle Aged
  • Proteins / genetics*

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • Proteins

Grant support

R. H. T. gratefully acknowledges funding support from Motor Neurone Disease Research Institute of Australia (MNDRIA), the Mick Rodger Benalla MND Research Grant and The Ian Potter Foundation. G. M. H. is a NHMRC Senior Principal Research Fellow (#630434). M. K. is supported by the National Health Medical Research Council #630440. J. R. H. and M. H. are supported by the Australian Research Council (DP110104202 to M. H. and FF0776229 to J. R. H.). This research was performed under Forefront, a collaborative research partnership in Australia funded by the NHMRC Program Grant (#1037746). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.