Small vessel disease pathological changes in neurodegenerative and vascular dementias concomitant with autonomic dysfunction

Autonomic dysfunction may affect brain blood flow and result in intermittent cerebral hypoperfusion, which is recognised as a cause of cognitive impairment and dementia. We assessed the burden of small vessel disease pathology in elderly subjects who had clinical evidence of autonomic dysfunction and had developed neurodegenerative dementias or vascular dementia (VaD). Clinical and neuropathological diagnosis in 118 subjects comprised dementia with Lewy bodies (DLB), Parkinson’s disease with dementia, Alzheimer’s disease (AD), Mixed dementia (mostly AD and DLB), VaD and ageing controls without significant pathology. Autonomic dysfunction was diagnosed in demented subjects who had clinical evidence of carotid sinus hypersensitivity or orthostatic hypotension or both. A subgroup of elderly demented subjects, who were reported to have unexplained falls in life were also analysed in parallel. Post-mortem brain tissues were stained using routine histopathological and immunocytochemical methods to quantify brain vascular and neurodegenerative lesions including hyperphosphorylated tau and α-synuclein. The frontal lobe grey and white matter (WM) in all cases was further assessed to quantify the degree of arteriolosclerosis using the sclerotic index (SI), microvascular density and capillary width using markers of the basement membrane (collagen IV; COL4) and the endothelium (glucose transporter-1; GLUT-1). We found moderate to severe vascular lesions and high vascular pathology scores (P<0.01) in all neurodegenerative dementias and as expected in VaD. Perivascular spacing and microinfarcts were frequently present in the basal ganglia and frontal WM across all dementias whereas lacunes and small infarcts being largely restricted to VaD. We also noted that vascular pathology scores were correlated with WM hyperintensity volumes in dementia subjects who were MR scanned in life (P<0.01). Compared to similar age controls, SI values were increased by ~50% in both the WM and neocortex in all dementias. Whereas COL4 and GLUT-1 immunopositive microvascular densities were decreased in the WM and the cortex of dementia subjects, we found that capillaries were significantly wider by 20-25% in the WM compared to the neocortex irrespective of the type of dementia. Compered to ageing controls, WM capillary widths were remarkably increased in all dementias with autonomic dysfunction (P<0.01). Previous studies suggested that α-synuclein pathology is a strong factor in autonomic dysfunction but we found no clear evidence for this in neurodegenerative dementias or VaD, especially that the burden of α-synuclein pathology in AD and VaD subjects with clinical evidence of autonomic dysfunction was rather low. Overall, our findings demonstrate the presence of widespread small vessel disease (SVD) type of changes in elderly subjects with autonomic dysfunction who develop neurodegenerative dementia. These SVD changes do not necessarily manifest as overt neurological signs but likely confound motor function as well as contribute to the dementia syndrome. Autonomic dysfunction may promote chronic cerebral hypoperfusion to also impact on ongoing neurodegenerative processes and produce the end-stage clinical syndrome