Cerebellar atrophy in pathological subtypes of Alzheimer’s disease and related dementias

Abstract

AbstractBackgroundThe cerebellum is differentially affected in various neurodegenerative diseases (Gellersen et al., 2017), but associations of cerebellar atrophy with specific neuropathologies have not been systematically analyzed. We used brain imaging to examine cerebellar grey matter volume with patients with all major pathological subtypes of Alzheimer’s disease and related dementias (ADRD).MethodWe applied voxel‐based morphometry to the earliest structural magnetic resonance imaging scans of autopsy‐proven ADRD cases (n = 309), and age‐, sex‐, and education‐matched healthy controls (n = 80). Seventy‐seven AD cases, 74 cases with mixed Lewy body disease and AD (LBD‐AD), and 158 frontotemporal lobar degeneration (FTLD) cases were included in this study. Patients with FTLD were further classified into FTLD major molecular classes and subtypes: FTLD‐TDP [FTLD‐TDP type A (TDP‐A) (n = 21), FTLD‐TDP type B (TDP‐B) (n = 21), FTLD‐TDP type C (TDP‐C) (n = 26)] and FTLD‐tau [Pick’s disease (n = 25), corticobasal degeneration (CBD) (n = 32), progressive supranuclear palsy (PSP) (n = 33)]. Clinical function was assessed with the Clinical Dementia Rating Scale (CDR) (Morris, 1993; Hughes et al., 1982) at the time of MRI scan, with global score ranging from 0 (normal), 0.5 (very mildly impaired), 1 (mildly impaired), 2 (moderately impaired) to 3 (severely impaired).ResultsCompared with controls, distinct patterns of cerebellar atrophy were observed in all pathological subtypes spanning bilateral hemispheres and vermis (PFWE‐corr<0.05, >100 contiguous voxels). Significant cerebellar grey matter changes were even found in the early stage (CDR ≦ 1) of all subtypes, with the exception of TDP‐B, and in the very early stage (CDR 0‐0.5) of AD, LBD‐AD, TDP‐A and PSP. Degree of cortical atrophy positively predicted degree of cerebellar atrophy in all subtypes.ConclusionThis study is the first to identify distinct early patterns of cerebellar atrophy across pathological subtypes of ADRD, and to show a direct relationship between cerebellar and cortical grey matter volume. These results clarify the cerebellar involvement in ADRD and underscore the potential for cerebellar neuroimaging to be a non‐invasive biomarker for differential diagnosis among pathologies and disease monitoring.