Correlations in post‐mortem imaging‐histopathology studies of sporadic human cerebral small vessel disease: A systematic review

Abstract

Aims Sporadic human cerebral small vessel disease (SVD) commonly causes stroke and dementia but its pathogenesis is poorly understood. There are recognised neuroimaging and histopathological features. However, relatively few studies have examined the relationship between the radiological and pathological correlates of SVD; better correlation would promote greater insight into the underlying biological changes. Methods We performed a systematic review to collate and appraise the information derived from studies that correlated histological with neuroimaging‐defined SVD lesions. We searched for studies describing post‐mortem imaging and histological tissue examination in adults, extracted data from published studies, categorised the information and compiled this narrative. Results We identified 38 relevant studies, including at least 1146 subjects, 342 of these with SVD: 29 studies focussed on neuroradiological white matter lesions (WML), six on microinfarcts and three on dilated perivascular spaces (PVS) and lacunes. The histopathology terminology was diverse with few robust definitions. Reporting and methodology varied widely between studies, precluding formal meta‐analysis. PVS and ‘oedema’ were frequent findings in WML, being described in at least 94 and 18 radiological WML, respectively, in addition to myelin pallor. Histopathological changes extended beyond the radiological lesion margins in at least 33 radiological WML. At least 43 radiological lesions not seen pathologically and at least 178 histological lesions were not identified on imaging. Conclusions Histopathological assessment of human SVD is hindered by inconsistent methodological approaches and unstandardised definitions. The data from this systematic review will help to develop standardised definitions to promote consistency in human SVD research.

An intrinsic endothelial dysfunction causes cerebral small vessel disease

“…These changes are more frequent in KO animals ( Fig. 2G ), indicating EC dysfunction at an ultrastructural level, consistent with structural abnormalities seen in small perforating brain blood vessels in human SVD(27). Not all blood vessels are affected, with heterogeneity between vessels even within animals ( Fig.…”

“…Not all blood vessels are affected, with heterogeneity between vessels even within animals ( Fig. 2H ), highlighting the well-recognised focal nature of SVD as found in humans(27).…”

“…2E ), suggesting that EC-secreted factors change in how they affect oligodendroglia over time, possibly reflecting some compensation. In human SVD, subtle diffuse WM changes are seen by MRI(31, 32), but pathological white matter changes are usually described as focal around blood vessels(27) and so we quantified the PLP-positive immunofluorescence pixels in a 10µm concentric ring around small vessels of the deep white matter, with the hypothesis that there would be less myelin nearer to blood vessels. Surprisingly, there was a significant increase in the number of PLP-positive pixels found near these vessels in the Atp11b KO adults ( Fig.…”

Superficial white matter microstructure affects processing speed in cerebral small vessel disease

“…Using these conventional diffusion measures, previous studies have suggested that potential pathological processes underlying WMH may be related to demyelination and reduced axonal density (Wardlaw, Valdés Hernández and Muñoz-Maniega, 2015; Muñoz Maniega et al ., 2017). Furthermore, recent studies indicate that an increase of extracellular free-water (FW) (Pasternak et al ., 2009), measured using dMRI, may be an early pathological process in CSVD (Duering et al ., 2018; Wardlaw, Smith and Dichgans, 2019; Humphreys, Smith and Wardlaw, 2021) and is a sensitive marker of cognitive performance in aging (Maillard et al ., 2019). While associations between white matter microstructure and cognitive performance are found throughout the white matter in CSVD (Table 1), thus far the superficial white matter microstructure has not been specifically investigated.…”

“…First, the effect of WMH is widespread. A recent review summarizes postmortem histological and MR imaging studies of CSVD, which have reported extensive white matter lesions with SWM involvement (Humphreys, Smith and Wardlaw, 2021). In addition, progression of WMH is known to spread from deeper to more superficial white matter regions during the course of CSVD (Lambert et al ., 2016; van Leijsen et al ., 2018).…”