Perivascular spaces (PVS) are compartments surrounding cerebral blood vessels that become visible on MRI when enlarged. Enlarged PVS (EPVS) are commonly seen in patients with cerebral small vessel... Show morePerivascular spaces (PVS) are compartments surrounding cerebral blood vessels that become visible on MRI when enlarged. Enlarged PVS (EPVS) are commonly seen in patients with cerebral small vessel disease (CSVD) and have been suggested to reflect dysfunctional perivascular clearance of soluble waste products from the brain. In this study, we investigated histopathological correlates of EPVS and how they relate to vascular amyloid-beta (A beta) in cerebral amyloid angiopathy (CAA), a form of CSVD that commonly co-exists with Alzheimer's disease (AD) pathology. We used ex vivo MRI, semi-automatic segmentation and validated deep-learning-based models to quantify EPVS and associated histopathological abnormalities. Severity of MRI-visible PVS during life was significantly associated with severity of MRI-visible PVS on ex vivo MRI in formalin fixed intact hemispheres and corresponded with PVS enlargement on histopathology in the same areas. EPVS were located mainly around the white matter portion of perforating cortical arterioles and their burden was associated with CAA severity in the overlying cortex. Furthermore, we observed markedly reduced smooth muscle cells and increased vascular A beta accumulation, extending into the WM, in individually affected vessels with an EPVS. Overall, these findings are consistent with the notion that EPVS reflect impaired outward flow along arterioles and have implications for our understanding of perivascular clearance mechanisms, which play an important role in the pathophysiology of CAA and AD. Show less
Onkenhout, L.; Appelmans, N.; Kappelle, L.J.; Koek, D.; Exalto, L.; Bresser, J. de; ... ; Utrecht VCI Study Grp 2020
Background: Cerebral small vessel disease (SVD) lesions on MRI are common in patients with cognitive impairment. It has been suggested that cerebral hypoperfusion is involved in the etiology of... Show moreBackground: Cerebral small vessel disease (SVD) lesions on MRI are common in patients with cognitive impairment. It has been suggested that cerebral hypoperfusion is involved in the etiology of these lesions. Objective: The aim of the study was to determine the relationship between cerebral blood flow (CBF) and SVD burden in patients referred to a memory clinic with SVD on MRI. Method: We included 132 memory clinic patients (mean age 73 +/- 10, 56% male) with SVD on MRI. We excluded patients with large non-lacunar cortical infarcts. Global CBF (mL/min per 100 mL of brain tissue) was derived from 2-dimensional phase-contrast MRI focused on the internal carotid arteries and the basilar artery. SVD burden was defined as the sum of (each 1 point): white matter hyperintensities (WMHs) Fazekas 1 or more, lacunes, microbleeds (MBs), or enlarged perivascular spaces (PVS) presence, and each SVD feature separately. Linear regression analyses were performed to study the association between CBF and SVD burden, age- and sex-adjusted. Results: Median SVD burden score was 2, 36.4% of patients had MBs, 35.6% lacunar infarcts, 48.4% intermediate to severe enlarged PVS, and 57.6% a WMH Fazekas score 2 or more. Median WMH volume was 21.4 mL (25% quartile: 9.6 mL, 75% quartile: 32.5 mL). Mean CBF +/- SD was 44.0 +/- 11.9 mL/min per 100 mL brain. There was no relation between CBF and overall SVD burden (CBF difference per burden score point [95% CI]: -0.5 [-2.4; 1.4] mL/min/100 mL brain, p = 0.9). CBF did also not differ according to presence or absence or an high burden of any of the individual SVD features. Moreover, there was no significant relation between WMH volume and CBF (CBF difference per ml increase in WMH [95% CI] -0.6 [-1.5; 0.3] mL/min/100 mL brain p = 0.2). Conclusion: Global CBF was not related to overall SVD burden or with individual SVD features in this memory clinic cohort, indicating that in this setting these lesions were not primarily due to cerebral hypoperfusion. Show less
