Small vessel disease: mechanisms and clinical implications

Summary

Small vessel disease is a disorder of cerebral microvessels that causes white matter hyperintensities and several other common abnormalities (eg, recent small subcortical infarcts and lacunes) seen on brain imaging. Despite being a common cause of stroke and vascular dementia, the underlying pathogenesis is poorly understood. Research in humans has identified several manifestations of cerebral microvessel endothelial dysfunction including blood–brain barrier dysfunction, impaired vasodilation, vessel stiffening, dysfunctional blood flow and interstitial fluid drainage, white matter rarefaction, ischaemia, inflammation, myelin damage, and secondary neurodegeneration. These brain abnormalities are more dynamic and widespread than previously thought. Relationships between lesions and symptoms are highly variable but poorly understood. Major challenges are the determination of which vascular dysfunctions are most important in pathogenesis, which abnormalities are reversible, and why lesion progression and symptomatology are so variable. This knowledge will help to identify potential targets for intervention and improve risk prediction for individuals with small vessel disease.

Introduction

Small vessel disease is a disorder of the brain's small perforating arterioles, capillaries, and probably venules¹ that causes various lesions that are seen on pathological examination or brain imaging with MRI or CT. Typical small vessel disease lesions are white matter hyperintensities of presumed vascular origin, lacunes, microbleeds, superficial siderosis, perivascular spaces, and microinfarcts (panel).2, 3 These lesions might be clinically silent individually, and many affected people do not have symptoms, but increasing numbers of individual lesion types and combinations of lesion types are associated with cognitive impairment, dementia, depression, mobility problems, increased risk of stroke,⁴ and worse outcome after stroke.⁵ Other typical small vessel disease lesions are recent small subcortical (or lacunar) infarcts and intracerebral haemorrhage, which typically present with stroke.² These varied clinical presentations have usually been considered separately in research and in the clinic, and patients have been referred to separate stroke, cognition, or mobility clinics. However, small vessel disease causes about a quarter of ischaemic strokes and most haemorrhagic strokes, is the commonest cause of vascular dementia, often occurs with Alzheimer's disease, and worsens the resulting cognitive impairment,6, 7 thus contributing to about 50% of dementias worldwide, a massive health burden of stroke and dementia.4, 7

Small vessel disease-related brain damage is not confined to the visible lesions. More sensitive MRI methods show that pathological changes occur in the so-called normal appearing white matter and grey matter, which worsen as the small vessel disease lesions increase,8, 9 and that white matter fibres passing through visible lesions can die back, leading to secondary degeneration in distant cortex or the brain stem and resulting in global brain effects.8, 9, 10 Some MRI methods are exquisitely sensitive to small changes in fluid content, and studies8, 11 suggest that white matter hyperintensities, at least partly or in their early stages, represent areas of increased interstitial fluid, not just demyelination.

Small vessel disease is recognised as being increasingly diverse, including rare familial and common sporadic (ie, non-familial) forms, with apparently different subtypes, even among sporadic forms. For example, cerebral amyloid angiopathy with microbleeds and superficial siderosis has different pathology to predominantly non-haemorrhagic small vessel diseases.¹²

In this Review, we discuss sporadic (ie, non-familial) small vessel disease, the commonest clinically recognised form, focusing on causes and implications of white matter hyperintensities, lacunes, recent small subcortical infarcts, and subvisible findings. Microinfarcts and haemorrhagic small vessel diseases (cerebral amyloid angiopathy, microbleeds, and superficial siderosis) have been reviewed elsewhere.3, 12, 13 We review the evidence that sporadic small vessel disease starts in the endothelium, and discuss how it causes focal lesions that are more dynamic than traditionally thought, and how it affects the whole brain. We consider potential explanations for the different clinical effects of small vessel disease and highlight potential therapeutic targets and interventions.