Cerebellar dysfunction in frontotemporal dementia: intra-cerebellar pathology and cerebellar network degeneration

Abstract

Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share overlapping clinical, genetic, and neuroimaging features; a spectrum of conditions commonly referred to as the ALS-FTD continuum. The majority of imaging studies focus on supratentorial pathology, and phenotype-defining motor, cognitive, and behavioural profiles are often exclusively attributed to supratentorial degeneration overlooking the contribution of cerebellar pathology.

Methods: A multimodal neuroimaging study was conducted to evaluate phenotype-associated cerebello-cerebral connectivity profiles in ALS-FTD, behavioural variant frontotemporal dementia (bvFTD), non-fluent variant (nfvPPA), and semantic variant primary progressive aphasia (svPPA). Structural connectivity, functional connectivity, and volumetric analyses were conducted.

Results: Radial diffusivity analyses detected impaired bilateral cerebello-frontal, cerebello-parietal, and cerebello-temporal connectivity in all study groups along the ALS-FTD spectrum. Cerebello-occipital disconnection was captured in ALS-FTD and nfvPPA. Spinocerebellar disconnection was detected in C9orf72 negative ALS-FTD and nfvPPA. C9orf72 positive ALS-FTD patients exhibited both anterior and posterior lobe cerebellar volume loss, while bvFTD and nfvPPA patients showed posterior cerebellar atrophy. Flocculonodular degeneration was observed in nfvPPA and cerebellar crura atrophy in bvFTD. Bilateral corticospinal tract and corpus callosum degeneration was detected in ALS-FTD, bvFTD, and nfvPPA. Primary motor cortex volume reductions were captured in both ALS-FTD and nfvPPA.

Conclusions: Our analyses capture significant cerebro-cerebellar disconnection in frontotemporal dementia. Corticospinal tract and motor cortex degeneration can be readily detected in non-ALS phenotypes. Intra-cerebellar pathology, coupled with the degeneration of cerebellar projections and the ensuing dysfunction of cerebro-cerebellar networks likely contribute to phenotype-defining clinical profiles in frontotemporal dementia. Infratentorial disease burden and cerebellar network dysfunction should, therefore, be carefully considered in FTD, and phenotype-defining neuropsychological profiles should not be solely attributed to supratentorial degeneration.

Keywords: Amyotrophic lateral sclerosis; Cerebellum; Frontotemporal dementia; Magnetic resonance imaging; Motor neuron disease; Neuroimaging.

Fig. 1

Representative tractography outputs of cerebellar projections. Representative sagittal, coronal, and axial views are shown for each tract

Fig. 2

Structural and functional connectivity profiles in the study groups. bvFTD behavioural variant frontotemporal dementia (pink colour), C9NEG sporadic, C9orf72 negative patients with ALS-FTD (orange colour), C9POS ALS-FTD patients with GGGGCC hexanucleotide repeat expansions C9orf72 (blue colour), FC Functional connectivity, HC healthy controls (turquoise colour), Lt Left hemisphere, nfvPPA non-fluent variant primary progressive aphasia (neon green colour), RD Radial diffusivity as a proxy of “structural connectivity” Rt Right hemisphere, svPPA semantic variant primary progressive aphasia (yellow colour). Only representative contrasts are shown in one hemisphere and only radial diffusivity profiles are shown for diffusivity analyses; full statistical details are provided in Table 2 which presents statistics for all imaging metrics in both hemispheres. Significant differences compared to controls are highlighted by horizontal arrows

Fig. 3

The volumetric profiles of the study groups. bvFTD behavioural variant frontotemporal dementia (pink colour), C9NEG sporadic, C9orf72 negative patients with ALS-FTD (orange colour), C9POS ALS-FTD patients with GGGGCC hexanucleotide repeat expansions C9orf72 (blue colour), HC healthy controls (turquoise colour), nfvPPA non-fluent variant primary progressive aphasia (neon green colour), svPPA semantic variant primary progressive aphasia (yellow colour). Significant differences compared to controls are highlighted by horizontal arrows with asterisks