Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging

Abstract

The term cerebral small vessel disease (SVD) describes a range of neuroimaging, pathological, and associated clinical features. Clinical features range from none, to discrete focal neurological symptoms (eg, stroke), to insidious global neurological dysfunction and dementia. The burden on public health is substantial. The pathogenesis of SVD is largely unknown. Although the pathological processes leading to the arteriolar disease are associated with vascular risk factors and are believed to result from an intrinsic cerebral arteriolar occlusive disease, little is known about how these processes result in brain disease, how SVD lesions contribute to neurological or cognitive symptoms, and the association with risk factors. Pathology often shows end-stage disease, which makes identification of the earliest stages difficult. Neuroimaging provides considerable insights; although the small vessels are not easily seen themselves, the effects of their malfunction on the brain can be tracked with detailed brain imaging. We discuss potential mechanisms, detectable with neuroimaging, that might better fit the available evidence and provide testable hypotheses for future study.

Figure 1

Key imaging characteristics of features of SVD. A) diffusion-weighted image of an acute small deep (‘lacunar’) infarct (arrow): <2cm diameter, hyperintense on diffusion imaging, FLAIR and T2-weighted imaging, hypointense on T1-weighted imaging. B) Lacune on FLAIR imaging: a CSF-containing cavity, >3mm and <1.5cm diameter, in white or deep grey matter or brainstem, signal characteristics of CSF on other sequences. C) WMH on FLAIR imaging: hyperintense areas on FLAIR and T2 in white and deep grey matter and brainstem, occasionally hypointense on T1 but often not visible, may coalesce when numerous. D) Perivascular spaces on T2-weighted imaging, hyperintense due to containing CSF-like fluid, <3mm diameter, round or linear in white or deep grey matter, visible on T1-weighted imaging when prominent.

Figure 2

An acute small deep (lacunar) infarct on diffusion imaging (serial axial views from basal ganglia to centrum semiovale, left to right) and T1-weighted imaging (coronal view, right). Note the tubular shape in the coronal plane as the infarct follows the line of a perforating arteriole. A wider range of examples of acute small deep (lacunar) infarcts is shown in Supplementary Figure 1.

Figure 3

Illustrating common late sequelae of acute small deep (lacunar) infarcts. Acute stage DWI (left column), FLAIR (middle column) and about one year later FLAIR (right column). These can: disappear (top), look like a WMH indefinitely (middle), or cavitate to create a lacune (bottom).

Figure 4

Examples of perivascular spaces (PVS) on MRI and histology. (a) 72 year old asymptomatic subject, right, T2-weighted image shows linear PVS in the plane of the image, and on left FLAIR shows WMH around the PVS; (b) 49 year old man with left internal capsule acute small deep infarct (not shown) on T2-weighted imaging shows a perivascular space extending from the periventricular to subcortical tissues and (c) on the corresponding FLAIR image, one WMH running longitudinally around the PVS. (d) PVS on histology (H&E x40) showing parenchymal tissue retraction from around small perforating vessels; these have been dismissed as a processing artefact but are typically seen in ageing brain sections, and often associated with SVD.

Figure 5

Histological appearances typical of arterioles affected by SVD pathology, from early arteriolosclerosis through to fibrinoid necrosis (all H&E x200). a) Arterioles where the smooth muscle is being replaced by collagenous tissue and there are small clusters of perivascular inflammatory cells. B) Lipohyalinosis with collagenous thickening of the vessel wall, foamy macrophage deposition and inflammatory cell infiltrate; the residual lumen contains some post mortem thrombus. C) Fibrinoid necrosis with segmental vessel wall destruction and prominent surrounding inflammation; the endothelium is not visible and there is some aneurysmal vessel wall dilatation. d) Severely disrupted arteriole with evidence of previous occlusion and recanalisation, arrows.

Figure 6

Schematic diagram of the basal ganglia and superficial perforating arterioles showing key features of the arteriolar and capillary wall. Perforating arterioles show a branching pattern that resembles that of poplar trees rather than oak trees. Arterioles have a smooth muscle layer and are surrounded by perivascular spaces that are delineated by membranes related to pial membranes: there are two layers around basal ganglia arterioles but one layer around superficial perforating arterioles.^, The capillary endothelium forms the blood-brain barrier and is closely related via pericytes, microglia, astrocytes and glial cells to neurons; the endothelium continues in the arterioles but at the arteriolar level, the endothelial cell tight junctions are less ‘tight’ than at the capillary level. Hence arteriolar walls are less protected from the consequences of endothelial failure than are capillary walls; tissue around the basal ganglia arterioles is more protected from the effects of vascular disease than is tissue around the superficial perforating arterioles. The figure was prepared by Antonia Weingart, Institute for Stroke and Dementia Research, University of Munich.

Figure 7

MR imaging of cerebrovascular endothelial permeability. Top row: 56 year old patient with a right thalamic lacunar infarct: A) DWI, B) FLAIR two days after symptom onset. C) Two months later, FLAIR image after iv. gadolinium (Gd) showing Gd in the perivascular spaces (arrowheads) and sulci (arrows) and (D) inset magnified image of (C). Bottom row: Older patient with left internal capsule lacunar infarct (not shown): E) colour mapping of cerebrovascular permeability following intravenous Gd and F) corresponding FLAIR images showing WMH. Blue indicates low cerebral vascular endothelial permeability, yellow and red indicate increasing permeability. Permeability changes are diffuse. (E) courtesy of Dr Maria Valdes Hernandez.