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.

Cerebellar atrophy in neurodegeneration—a meta-analysis

“…In addition, our combined plot showed that there exists some overlap in atrophy patterns. These findings suggest that cerebellar changes are highly disease-specific and correspond to the cortical or subcortical changes characteristically reported in each disease 10. Lobular overlap between ALS and FTD in Crus I/II further corroborates this notion as both diseases lie on a spectrum.…”

“…Regions of Crus I/II identified here share major connections with prefrontal and parietal areas as part of the DMN and ECN,40 resulting in coactivation during executive functioning, memory and emotion processing 48. This may explain the relationship between cerebellar atrophy and specific cortical changes in FTD 10. The atrophied regions in Crus I may also be involved in the SN, which has been recognised to be affected by degeneration in FTD 10…”

“…Regions of atrophy in the cerebellum are intrinsically connected with atrophied areas in cerebral cortex in AD and FTD, suggesting that atrophy spreads through brain networks 10. Clearly, the relationship between cerebellar atrophy and AD symptomatology warrants further study in the future.…”

The cerebellum shrinks faster than normal ageing in Alzheimer's disease but not in mild cognitive impairment

“…However, the cerebellum can be parsed functionally and morphologically into different subdivisions and it is likely that AD pathology targets each subdivision differently. Previous voxel-based morphometric studies showed bilateral lower gray matter density in lobule VI (Colloby, et al, 2014) and Crus I/II (Guo, et al, 2016) in AD compared with CN, suggesting that network-selective vulnerability underlies the cerebellar neurodegeneration(Guo, et al, 2016). Regardless of selective or non-selective volume loss in the cerebellum and its subregions, cross-sectional approach needs to be affirmed by tracking atrophy in a longitudinal approach.…”

Modafinil-Induced Changes in Functional Connectivity in the Cortex and Cerebellum of Healthy Elderly Subjects

“…Interestingly, recent data indicate that AD-related neurodegeneration is present, beyond the cortex, also in the Crus I and II cerebellar regions (Guo et al, 2016). In that respect, it is conceivable that the modafinil FC effects we have found in these cerebellar areas may be of some help and exert a compensatory role.…”