Cerebellar integrity in the amyotrophic lateral sclerosis-frontotemporal dementia continuum

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.

Figure 1. The human cerebellum with lobules I–X labelled from the probabilistic atlas template (SUIT) of the human cerebellum (http://www.icn.ucl.ac.uk/motorcontrol/imaging/propatlas.htm).

L Left Hemisphere; R Right Hemisphere.

Figure 2. Voxel-based morphometry (VBM) findings for ALS, ALS-bvFTD and bvFTD in comparison to controls.

VBM findings are shown in red-yellow; coloured voxels show regions that were significant in the analysis at p<0.05 family-wise error (FEW) corrected. All clusters reported t>3.50. Clusters are overlaid on the MNI standard brain with a mask for lobule VII (crus 1, 2 and VIIb) shown in blue and a mask for the vermis shown in light blue. - No significance; L Left Hemisphere; R Right Hemisphere.

Figure 3. Unique cerebellar grey matter atrophy across patient groups.

Voxel-based morphometry findings contrasting grey matter atrophy in the a) lobules; b) crus; c) vermis across groups. Clusters are overlaid on the MNI standard brain with a mask for lobule VII (crus 1, 2 and VIIb) shown in blue and a mask for the vermis shown in light blue. Coloured voxels show regions that were significant in the analysis for p<0.05 family-wise error (FEW) corrected. NA Not applicable; - No significance; L Left Hemisphere; R Right Hemisphere.

Figure 4. Correlation between cerebellar grey matter volume and a) ACE-R (green); b) CBI-R (light blue); c) ALSFRS-R (red) scores.

Clusters are overlaid on the MNI standard brain with a mask for lobule VII (crus 1, 2 and VIIb) shown in blue and a mask for the vermis shown in light blue. Coloured voxels show regions that were significant in the analysis for p<0.05 family-wise error (FEW) corrected. L Left Hemisphere; R Right Hemisphere.