Network-selective vulnerability of the human cerebellum to Alzheimer's disease and frontotemporal dementia

Abstract

SEE SCHMAHMANN DOI101093/BRAIN/AWW064 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Neurodegenerative diseases are associated with distinct and distributed patterns of atrophy in the cerebral cortex. Emerging evidence suggests that these atrophy patterns resemble intrinsic connectivity networks in the healthy brain, supporting the network-based degeneration framework where neuropathology spreads across connectivity networks. An intriguing yet untested possibility is that the cerebellar circuits, which share extensive connections with the cerebral cortex, could be selectively targeted by major neurodegenerative diseases. Here we examined the structural atrophy in the cerebellum across common types of neurodegenerative diseases, and characterized the functional connectivity patterns of these cerebellar atrophy regions. Our results showed that Alzheimer's disease and frontotemporal dementia are associated with distinct and circumscribed atrophy in the cerebellum. These cerebellar atrophied regions share robust and selective intrinsic connectivity with the atrophied regions in the cerebral cortex. These findings for the first time demonstrated the selective vulnerability of the cerebellum to common neurodegenerative disease, extending the network-based degeneration framework to the cerebellum. Our work also has direct implications on the cerebellar contribution to the cognitive and affective processes that are compromised in neurodegeneration as well as the practice of using the cerebellum as reference region for ligand neuroimaging studies.

Keywords: cerebellum; intrinsic connectivity; neurodegeneration; selective vulnerability.

See Schmahmann (doi: 10.1093/brain/aww064 ) for a scientific commentary on this article. Atrophy patterns in neurodegenerative diseases reflect disruptions of intrinsic connectivity networks in the cerebral cortex. Guo et al . show that circumscribed and distinct atrophy is also present in the cerebellum, following the topographic organization of intrinsic cerebro-cerebellar connectivity. Network-based degeneration may be a universal framework underlying pathogenesis in the ageing brain.

Figure 1

Statistical maps of structural atrophy in the cerebellum in ( A ) Alzheimer’s disease (AD), ( B ) bvFTD, ( C ) nfvPPA and ( D ) svPPA, and their overlays with the Buckner 7-network atlas. ( E ) The corresponding 7-network atlas in the cerebrum (only left hemisphere is shown). P < 0.001 (Alzheimer’s disease and bvFTD) or 0.005 (nfvPPA and svPPA) for peak height and FWE-corrected P < 0.05 for spatial extent. Purple regions in the cerebellum are all part of the salience network, as the visual network, colour-coded as dark purple, does not have a cerebellar counterpart (Buckner et al. , 2011). HC = healthy control.

Figure 2

Intrinsic connectivity patterns of cerebral ( top row ) and cerebellar ( bottom row ) atrophy regions in Alzheimer’s disease ( A ) and bvFTD ( B ). Seed regions are signified by yellow arrowhead. Additional anatomical landmarks are signified by white/grey arrowheads to assist visual inspection.

Figure 3

Correlation between cerebral and cerebellar atrophy in patients with Alzheimer’s disease ( A , AD) and behavioural variant FTD ( B ). Grey matter volumes from the cerebral and cerebellar seed regions for the default mode network and salience network are plotted against each other. Significant correlations (Bonferroni-corrected for multiple comparisons) are plotted in black and non-significant correlations are plotted in grey.