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

We performed a clinicopathological study to assess the burden of small vessel disease (SVD) type of pathological changes in elderly demented subjects, who had clinical evidence of autonomic dysfunction, either carotid sinus hypersensitivity or orthostatic hypotension or both or had exhibited unexpected repeated falls. Clinical and neuropathological diagnoses in 112 demented subjects comprised dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), Alzheimer's disease (AD), Mixed dementia (mostly AD-DLB) and vascular dementia (VaD). Of these, 12 DLB subjects had no recorded unexpected falls in life and therefore no evidence of concomitant autonomic dysfunction. A further 17 subjects were assessed as aging controls without significant pathology or signs of autonomic dysfunction. We quantified brain vascular pathological changes and determined severities of neurodegenerative lesions including α-synuclein pathology. We found moderate-severe vascular changes and high-vascular pathology scores (P < 0.01) in all neurodegenerative dementias and as expected in VaD compared to similar age controls. Arteriolosclerosis, perivascular spacing and microinfarcts were frequent in the basal ganglia and frontal white matter (WM) across all dementias, whereas small infarcts (<5 mm) were restricted to VaD. In a sub-set of demented subjects, we found that vascular pathology scores were correlated with WM hyperintensity volumes determined by MRI in life (P < 0.02). Sclerotic index values were increased by ~50% in both the WM and neocortex in all dementias compared to similar age controls. We found no evidence for increased α-synuclein deposition in subjects with autonomic dysfunction. Our findings suggest greater SVD pathological changes occur in the elderly diagnosed with neurodegenerative dementias including DLB and who develop autonomic dysfunction. SVD changes may not necessarily manifest in clinically overt symptoms but they likely confound motor or cognitive dysfunction. We propose dysautonomia promotes chronic cerebral hypoperfusion to impact upon aging-related neurodegenerative disorders and characterize their end-stage clinical syndromes.

White matter capillaries in vascular and neurodegenerative dementias.

Previous studies suggest white matter (WM) integrity is vulnerable to chronic hypoperfusion during brain ageing. We assessed ~ 0.7 million capillary profiles in the frontal lobe WM across several dementias comprising Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease with dementia, vascular dementia, mixed dementias, post-stroke dementia as well as post-stroke no dementia and similar age ageing and young controls without significant brain pathology. Standard histopathological methods were used to determine microvascular pathology and capillary width and densities in 153 subjects using markers of the basement membrane (collagen IV; COL4) and endothelium (glucose transporter-1; GLUT-1). Variable microvascular pathology including coiled, tortuous, collapsed and degenerated capillaries as well as occasional microaneurysms was present in all dementias. As expected, WM microvascular densities were 20-49% lower than in the overlying cortex. This differential in density between WM and cortex was clearly demonstrated by COL4, which was highly correlated with GLUT-1 densities (Spearman's rho = 0.79, P = 0.000). WM COL4 immunopositive microvascular densities were decreased by ~ 18% across the neurodegenerative dementias. However, we found WM COL4 densities were increased by ~ 57% in post-stroke dementia versus ageing and young controls and other dementias. Using three different methods to measure capillary diameters, we found WM capillaries to be significantly wider by 19-45% compared to those in overlying neocortex apparent with both COL4 and GLUT-1. Remarkably, WM capillary widths were increased by ~ 20% across all dementias compared to ageing and young controls (P < 0.01). We also noted mean WM pathology scores incorporating myelin loss, arteriolosclerosis and perivascular spacing were correlated with COL4 immunopositive capillary widths (Pearson's r = 0.71, P = 0.032). Our key finding indicates that WM capillaries are wider compared to those in the overlying neocortex in controls but they dilate further during dementia pathogenesis. We suggest capillaries undergo restructuring in the deep WM in different dementias. This reflects compensatory changes to retain WM perfusion and integrity during hypoperfusive states in ageing-related dementias.