Review
Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging

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Summary

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.

Introduction

Cerebral small vessel disease (SVD) is the term commonly used to describe a syndrome of clinical, cognitive, neuroimaging, and neuropathological findings thought to arise from disease affecting the perforating cerebral arterioles, capillaries, and venules, and the resulting brain damage in the cerebral white and deep grey matter.1 These perforating vessels are essential to maintain optimum functioning of the brain's most metabolically active nuclei and complex white matter networks.2

In the past 15 years, SVD has been recognised as a serious problem. The disease is very common and causes substantial cognitive,3 psychiatric,4 and physical disabilities,5, 6 is responsible for about a fifth of all strokes worldwide,7 more than doubles the future risk of stroke,8, 9 and contributes to up to 45% of dementias.10 The cost to society is huge. Because the cause of disease is unknown, prevention and treatment (still mostly empirical) are probably suboptimum11, 12 or even dangerous.13 This unawareness could have resulted from attention being given to other stroke mechanisms (ie, cortical atherothromboembolic and cardioembolic stroke), the cognitive component being overshadowed by Alzheimer's disease, and because most research has focused on individual features of SVD and did not recognise the combined components as one disorder.

Why is so little known about such an important disease? Small vessels are difficult to image and investigate in vivo.14 The clinical manifestations are diverse and include: sudden-onset stroke symptoms or syndromes; covert neurological symptoms that include mild, largely ignored, neurological symptoms and signs;15 self-reported cognitive difficulties;16 progressive cognitive decline;6 dementia; depression;4 and physical disabilities.5 Reliance on clinical features and CT scanning to differentiate between lacunar and non-lacunar stroke is imprecise and has probably confounded epidemiological and observational studies of risk factor associations.17 Many trials have not explicitly differentiated ischaemic stroke subtypes, and might have overlooked any differences in treatment responses between patients with different subtypes of stroke.18 Death resulting directly from lacunar stroke is rare, so most pathology shows late-stage disease.19 Only a few studies of human lacunar stroke pathology have been done19 and few studies compared imaging and pathology findings.20 To backtrack from a late-stage scar to the initial pathology is difficult. Much of SVD is clinically silent and late, and experimental models are limited by lack of a mechanism to mimic.21, 22 Terminology for clinical features, imaging,23 and the pathology24 of SVD is highly varied. Standardisation of terminology for imaging features is the subject of an international collaboration of experts; their report is due in 2013.25 Until the terminology has been standardised, we use some traditional terms because these were used in the reports that formed the basis of this Review. We focus on common sporadic SVD and do not discuss any of the rare hereditary forms of SVD (eg, CADASIL, CARASIL, COL4AI, Fabry's, and HERNS) except where these diseases have immediate relevance to sporadic SVD. For space reasons, we do not discuss details of amyloid-associated angiopathy (ie, cerebral amyloid angiopathy) because this has been the subject of recent reviews.26

In this Review, we will discuss traditional perceived mechanisms for SVD and then focus on a novel pathway that may provide a better fit with available data and testable predictions for future study. To achieve this, we will focus on the pathogenesis of the microvascular and brain abnormality, which is undetermined in most cases of SVD. We define SVD as a sporadic intrinsic process affecting small cerebral arterioles, capillaries, and sometimes venules. Features of SVD probably develop over many years before they become clinically evident. The main mechanism underlying SVD-related brain injury is usually assumed to be ischaemia, which acts through narrowed arteries or structural or functional occlusion (eg, vasospasm, impaired autoregulation, or hypotension). However, arteriolar occlusion might be a late-stage phenomenon and does not explain the early pathology of the disease. We discuss specific SVD imaging features to help put the commonest suspected mechanisms into perspective, then focus on what we consider to be a key problem: diffuse cerebrovascular endothelial failure. We summarise evidence suggesting that endothelial damage leads to increased permeability with leakage of material into the vessel wall and perivascular tissue, damage to the vessel wall, inflammation, demyelination, glial scarring, thickening and stiffness of the vessel wall, impaired autoregulation, and at a late stage, luminal narrowing and occlusion, precipitating discrete focal brain parenchymal ischaemia and infarction.

Section snippets

History of ideas about SVD pathophysiology

Modern ideas about aetiology and pathogenesis come from the seminal post-mortem work of C Miller Fisher done between 1955 and 1973. His work was based on detailed clinicopathological and vascular post-mortem examinations of 20 patients in whom he studied between one and 50 individual lesions (lacunes, lacunar infarcts, and perforating arterioles).27, 28, 29, 30, 31 After the introduction of CT scanning in 1973, pathological examination of the brain in patients with lacunar stroke almost

Features of SVD on MRI

The main imaging features of SVD (now recognised to be inter-related) visible on conventional MRI at 1·5T or 3T include acute lacunar (or small subcortical) infarcts or haemorrhages, lacunes (fluid-filled cavities thought to show old infarcts, many clinically silent),9 white matter hyperintensities (in which many investigators include small deep grey matter hyperintensities, mostly clinically silent),32 visible perivascular spaces,33 microbleeds,34 and brain atrophy (figure 1).35 Other emerging

Mechanisms underlying lacunar infarcts, lacunes, and white matter hyperintensities

The commonest abnormality described pathologically19, 27, 30, 31 is a diffuse, intrinsic disease of the small (40–200 μm diameter) arterioles, referred to by Fisher as arteriolosclerosis, lipohyalinosis, or fibrinoid necrosis (depending on severity of the abnormality), which he thought largely to result from hypertension. The vessel wall changes include infiltration of plasma components and inflammatory cells into the vessel wall and perivascular tissue with resulting vessel wall and

Other mechanisms

Some years ago, we observed that an abnormal perforating arteriole could sometimes be seen in the centre of an acute symptomatic lacunar infarct.14 The arteriolar wall appeared thickened as it passed through the infarct not proximal to it (as might be expected with a typical cortical atherothromboembolic infarct), with a signal that indicated thrombus in the lumen and blood products in and around the arteriole wall. This led to scrutiny of Fisher's original descriptions of the microvascular

Proposed role of early endothelial failure

Since first postulated, more evidence has accumulated for the hypothesis that early endothelial failure is a main precipitant of sporadic SVD. At the capillary level, the endothelium forms a key part of the blood–brain barrier,110 a phylogenetically important structure for conservation of neuronal function that is present in drosophila to human beings.111 Because the blood–brain barrier impedes the passage of many drugs into the brain, and thereby limits potential therapeutic approaches, this

Why does the endothelium fail?

The cerebrovascular endothelium becomes increasingly permeable with age:123 patients aged 70–80 years have an almost two times more permeable blood–brain barrier compared with patients younger than 70 years. Up to the age of 60 years, the increase in permeability of the blood–brain barrier per decade is probably less marked than in people older than 60 years, suggesting that, as with many ageing-related features, loss of endothelial integrity can start in different people at different ages and

Insights from pathology of SVD

In the study of SVD so far, pathology has had a minor although pivotal role. Patients rarely die in the acute phase of SVD, and the disease pathology is often observed at post mortem almost as an incidental finding (figure 5). Subacute lesions are rarely observed (appendix), on the basis of size and in the absence of any substantial relevant clinical dysfunction in life, are assumed to be asymptomatic lacunes (appendix). Imaging correlation is rarely available. The need for a unified approach

Other mechanisms suspected from imaging

Few studies have measured cerebral blood flow in patients with SVD, and those that have have produced conflicting results. Cerebral blood flow and blood flow velocities decrease as people get older. Reduced cerebral blood flow was observed with MRI in patients with more white matter hyperintensities in some,160 but not other161 studies; both studies found associations between cerebral blood flow and atrophy suggesting that a fall in cerebral blood flow might happen secondary to tissue loss. Old

Future directions and conclusions

Until more is known about the mechanism of SVD, we should continue with careful clinical management of vascular risk factors, particularly hypertension.142 Many combined antiplatelet agents should be used cautiously in patients with pure SVD without other large-artery risk factors.18 Until we understand the cause of white matter hyperintensities, instead of being referred to as ischaemic, perhaps these intensities should be called white matter hyperintensities, ageing-related white matter

Search strategy and selection criteria

We used systematic reviews where available, searched Medline and Embase (from inception to September 2012) extensively for papers on lacunar stroke, for all small vessel disease components in imaging or pathology studies, on the role of reduced blood flow and inflammation, the endothelium, other potential mechanisms, risk factors, in human and animal studies, population-based, cohort studies, and clinical trials. We used the key words “lacunar”, “small vessel disease”, “white matter lesions”,

References (163)

  • WM van der Flier et al.

    Small vessel disease and general cognitive function in nondisabled elderly: the LADIS study

    Stroke

    (2005)
  • LL Herrmann et al.

    White matter hyperintensities in late life depression: a systematic review

    J Neurol Neurosurg Psychiatry

    (2008)
  • KF de Laat et al.

    Loss of white matter integrity is associated with gait disorders in cerebral small vessel disease

    Brain

    (2011)
  • D Inzitari et al.

    Changes in white matter as determinant of global functional decline in older independent outpatients: three year follow-up of LADIS (leukoaraiosis and disability) study cohort

    BMJ

    (2009)
  • CLM Sudlow et al.

    Comparable studies of the incidence of stroke and its pathological types. Results from an international collaboration

    Stroke

    (1997)
  • S Debette et al.

    The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis

    BMJ

    (2010)
  • PB Gorelick et al.

    Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association

    Stroke

    (2011)
  • R Weber et al.

    Telmisartan on top of antihypertensive treatment does not prevent progression of cerebral white matter lesions in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) MRI substudy

    Stroke

    (2012)
  • VH ten Dam et al.

    Effect of pravastatin on cerebral infarcts and white matter lesions

    Neurology

    (2005)
  • Effects of clopidogrel added to aspirin in patients with recent lacunar stroke

    N Engl J Med

    (2012)
  • JM Wardlaw et al.

    Imaging appearance of the symptomatic perforating artery in patients with lacunar infarction: occlusion or other vascular pathology?

    Ann Neurol

    (2001)
  • M Saini et al.

    Silent stroke: not listened to rather than silent

    Stroke

    (2012)
  • G Potter et al.

    Associations of clinical stroke misclassification (‘clinical-imaging dissociation’) in acute ischemic stroke

    Cerebrovasc Dis

    (2010)
  • S Palacio et al.

    Effect of addition of clopidogrel to aspirin on mortality: systematic review of randomized trials

    Stroke

    (2012)
  • EL Bailey et al.

    Pathology of lacunar ischaemic stroke in humans—a systematic review

    Brain Pathol

    (2012)
  • AA Gouw et al.

    Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations

    J Neurol Neurosurg Psychiatry

    (2011)
  • EL Bailey et al.

    Potential animal models of lacunar stroke: a systematic review

    Stroke

    (2009)
  • AH Hainsworth et al.

    Do in vivo experimental models reflect human cerebral small vessel disease? A systematic review

    J Cereb Blood Flow Metab

    (2008)
  • GM Potter et al.

    Wide variation in definition, detection, and description of lacunar lesions on imaging

    Stroke

    (2010)
  • A united approach to vascular disease and neurodegeneration

    Lancet Neurol

    (2012)
  • A Viswanathan et al.

    Cerebral amyloid angiopathy in the elderly

    Ann Neurol

    (2011)
  • CM Fisher

    Lacunes: small, deep cerebral infarcts

    Neurology

    (1965)
  • CM Fisher

    The arterial lesions underlying lacunes

    Acta Neuropathol

    (1969)
  • CM Fisher

    Capsular infarcts: the underlying vascular lesions

    Arch Neurol

    (1979)
  • CM Fisher

    Lacunar strokes and infarcts: a review

    Neurology

    (1982)
  • CM Fisher

    Lacunar infarcts: a review

    Cerebrovasc Dis

    (1991)
  • NS Rost et al.

    White matter hyperintensity volume is increased in small vessel stroke subtypes

    Neurology

    (2010)
  • FN Doubal et al.

    Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease

    Stroke

    (2010)
  • C Cordonnier et al.

    Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting

    Brain

    (2007)
  • BS Aribisala et al.

    Brain atrophy associations with white matter lesions in the ageing brain: the Lothian Birth Cohort 1936

    Eur Radiol

    (2012)
  • M Brundel et al.

    Cerebral microinfarcts: a systematic review of neuropathological studies

    J Cereb Blood Flow Metab

    (2012)
  • M O'Sullivan

    Imaging small vessel disease: lesion topography, networks, and cognitive deficits investigated with MRI

    Stroke

    (2010)
  • AMJ MacLullich et al.

    Higher systolic blood pressure is associated with increased water diffusivity in normal-appearing white matter

    Stroke

    (2009)
  • M Duering et al.

    Incident subcortical infacts induce focal thinning in connected cortical regions

    Neurology

    (2012)
  • GA Donnan et al.

    Subcortical infarction: classification and terminology

    Cerebrovasc Dis

    (1993)
  • CL Franke et al.

    Residual lesions on computed tomography after intracerebral hemorrhage

    Stroke

    (1991)
  • JM Wardlaw et al.

    Visible infarction on computed tomography is an independent predictor of poor functional outcome after stroke, and not of haemorrhagic transformation

    J Neurol Neurosurg Psychiatry

    (2003)
  • FN Doubal et al.

    Characteristics of patients with minor ischaemic strokes and negative MRI: a cross sectional study

    J Neurol Neurosurg Psychiatry

    (2011)
  • OY Bang et al.

    The course of patients with lacunar infarcts and a parent arterial lesion: similarities to large artery vs small artery disease

    Arch Neurol

    (2004)
  • GA Donnan et al.

    The stroke syndrome of striatocapsular infarction

    Brain

    (1991)
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