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.

Cerebellar neuronal loss in amyotrophic lateral sclerosis cases with ATXN2 intermediate repeat expansions

“…The finding of no significant neuronal loss across cerebellar functional zones in sporadic ALS cases appears contrary to previous in vivo findings identified with structural neuroimaging. 13 FIGURE 2: Mean ( 6 SE) neuron density of Purkinje neurons (A and C) and granule neurons (B and C) quantified in the lateral cerebellar hemispheres (cerebrocerebellum) and vermis (spinocerebellum) of ALS cases with C9ORF72 and ATXN2 expansions presented as a % of mean neuron density in controls. *p < 0.05 compared to controls or across groups marked.…”

“…39 A loss in these fibers, which arises from the vulnerable brainstem and spinal cord, 40 is consistent with the cerebellar white matter degeneration identified in sporadic ALS 41 and may contribute to the gray matter structural changes previously observed in vivo. 13 Alternatively, because routine screening for ATXN2 repeat expansions in ALS is still not common, whether ALS cases with ATXN2 expansions underscore some of the changes previously reported using magnetic resonance imaging remains to be addressed. 13,[42][43][44][45] In both the cerebro-and spinocerebellar regions of ALS, PMA, and controls, no significant difference in cerebellar neuron numbers was observed.…”

“…13 Alternatively, because routine screening for ATXN2 repeat expansions in ALS is still not common, whether ALS cases with ATXN2 expansions underscore some of the changes previously reported using magnetic resonance imaging remains to be addressed. 13,[42][43][44][45] In both the cerebro-and spinocerebellar regions of ALS, PMA, and controls, no significant difference in cerebellar neuron numbers was observed. This suggests that cerebellar neuronal degeneration is not affected by upper and/or lower motor neuron degeneration, and that the cerebellar degeneration presently observed in intermediate ATXN2-ALS carriers occurs independently of motor system degeneration.…”

“…Using structural neuroimaging in ALS, we recently identified gray matter degeneration in the posterior lateral cerebellar hemispheres and vermis of sporadic cases. 13 Whether these cerebellar changes indicate underlying neuronal degeneration, and whether they initiated, co-occurred, or occurred subsequent to motor system degeneration in ALS, is unclear. In order to address these questions, quantitative assessment of cerebellar neurons in different forms of ALS is needed.…”

Measuring the progression of upper motor neuron disease using diffusion MRI and its correlation with Clinical phenotype

“…The majority of studies involving ALS subjects did not test cognition; it is therefore possible that the extramotor abnormalities found on DTI in ALS are due to a subset of patients with clinical features of extra-motor disease such as cognitive impairment, which is found in some patients with ALS (Lillo, Savage et al 2012). As well as cognitive impairment, some ALS patients have other extra-motor features such as sensory disturbance (Pugdahl, Fuglsang-Frederiksen et al 2007), autonomic disturbance (Baltadzhieva, Gurevich et al 2005) and cerebellar disturbance (Tan, Devenney et al 2014). In some patients there is thought to be an ALS plus syndrome, with prominent extra-motor features.…”