Cerebral small vessel disease: Recent advances and future directions

Abstract

Cerebral small vessel disease (SVD) causes lacunar stroke and intracerebral hemorrhage, and is the most common pathology underlying vascular cognitive impairment. Increasingly, the importance of other clinical features of SVD is being recognized including motor impairment, (vascular) parkinsonism, impaired balance, falls, and behavioral symptoms, such as depression, apathy, and personality change. Epidemiological data show a high prevalence of the characteristic magnetic resonance imaging (MRI) features of white matter hyperintensities and lacunar infarcts in community studies, and recent data suggest that it is also a major health burden in low- and middle-income countries. In this review, we cover advances in diagnosis, imaging, clinical presentations, pathogenesis, and treatment.The two most common pathologies underlying SVD are arteriolosclerosis caused by aging, hypertension, and other conventional vascular risk factors, and cerebral amyloid angiopathy (CAA) caused by vascular deposition of β-amyloid. We discuss the revised Boston criteria of CAA based on MRI features, which have been recently validated. Imaging is providing important insights into pathogenesis, including improved detection of tissue damage using diffusion tensor imaging (DTI) leading to its use to monitor progression and surrogate endpoints in clinical trials. Advanced MRI techniques can demonstrate functional or dynamic abnormalities of the blood vessels, while the high spatial resolution provided by ultrahigh field MRI at 7 T allows imaging of individual perforating arteries for the first time, and the measurement of flow velocity and pulsatility within these arteries. DTI and structural network analysis have highlighted the importance of network disruption in mediating the effect of different SVD pathologies in causing a number of symptoms, including cognitive impairment, apathy, and gait disturbance.Despite the public health importance of SVD, there are few proven treatments. We review the evidence for primary prevention, and recent data showing how intensive blood pressure lowering reduces white matter hyperintensities (WMH) progression and delays the onset of cognitive impairment. There are few treatments for secondary prevention, but a number of trials are currently evaluating novel treatment approaches. Recent advances have implicated molecular processes related to endothelial dysfunction, nitric oxide synthesis, blood-brain barrier integrity, maintenance and repair of the extracellular matrix, and inflammation. Novel treatment approaches are being developed to a number of these targets. Finally, we highlight the importance of large International collaborative initiatives in SVD to address important research questions and cover a number which have recently been established.

Keywords: Cerebral small vessel disease; lacunar stroke; vascular cognitive impairment; white matter hypersensitivities.

Figure 1.

Imaging appearances of age-related non-amyloid SVD. (a) Acute lacunar infarct in right thalamus on DWI. (b) Old cavitated lacune in posterior limb of left internal capsule on FLAIR. (c) Confluent white matter hyperintensities on FLAIR. (d) Deep CMB on gradient echo scan. (e) Enlarged PVS intracerebral. (f) Basal ganglia hemorrhage on CT. Copyright Hugh Markus.

Figure 2.

Imaging appearances of CAA. (a) Enlarged PVS (arrowed) and old right frontal ICH on T2 scan. (b) Superficial siderosis in right frontal region on susceptibility-weighted scan. (c) Cortical microbleeds in CAA on susceptibility-weighted scan. (d) Multiple cortical ICHs. (e) Lobar hemorrhage on CT. Copyright Hugh Markus.

Figure 3.

Cortical cerebral microinfarcts on 3T MRI. They are defined as hypointense cortical lesion found on T1-weighted images ((a) sagittal, (b) coronal, and (c) axial views) explored further as (d) hyperintense or isointense on FLAIR and (e) T2-weighted images. This was further confirmed by the absence of hypointense signal on (f) susceptibility-weighted image due to hemorrhagic lesion or vessel. Kindly provided by Saima Hila Copyright Saima Hilal.