Understanding the Contribution of Basal Ganglia Pathology to Late-life Dementia and Motor Impairment

Introduction: Cerebral small vessel disease (CSVD) and Alzheimer’s disease (AD) pathology co-occur in the ageing brain, sharing mechanisms that mutually amplify neurodegeneration. The basal ganglia are an important but understudied site of CSVD pathology, yet the substrates of their vulnerability to cognitive and motor dysfunction remain uncharacterised. This thesis investigated whether CSVD-associated basal ganglia pathology contributes to dementia and motor impairment in late life.

Methods: Post-mortem tissue was obtained from the MRC Cognitive Function and Ageing Study (CFAS). Basal ganglia tissue (n=393) was scored for six CSVD lesion types and quantified for COLIV, ERG1, and SLC6A12 by immunohistochemistry, with associations with dementia and falls modelled by regression. Whole-transcriptome microarray on lentiform nucleus tissue (n=17 post-QC) stratified by arteriolosclerosis (ASC) severity, with KEGG enrichment via DAVID and neuroinflammatory findings validated immunohistochemically (n=113).

Results: CSVD lesions were highly prevalent and inter-associated. Enlarged perivascular space (ePVS) severity was independently associated with dementia risk; lacunar infarct burden was associated with tendency to fall. Microvascular markers varied with CSVD severity: COLIV co-elevated with ePVS, SLC6A12 was inversely associated with ePVS and rarefaction, and medium ERG1 conferred markedly elevated dementia odds (OR=4.34, 95% CI 1.33-14.20). Transcriptomic analysis identified 428 differentially expressed genes in high versus low ASC tissue, predominantly downregulated, implicating DNA replication, nucleotide excision repair, tight junction integrity, and cytokine signalling. CD163 was positively associated with ASC severity (p=0.016), consistent with alternative microglial activation.

Discussion: These findings support a unified framework in which chronic arteriolar insufficiency drives capillary dysfunction, glymphatic, creating compounding conditions for mixed vascular-neurodegenerative pathology. The strategic connectivity of the basal ganglia amplifies these consequences disproportionately. These results advance understanding of the substrates of late-life dementia and motor impairment, identify basal ganglia ePVS as a candidate imaging biomarker, and position the capillary dysfunction cascade as a target for future investigation.