Update on Vascular Cognitive Impairment Associated with Subcortical Small-Vessel Disease

Abstract

Subcortical small-vessel disease (SSVD) is a disorder well characterized from the clinical, imaging, and neuropathological viewpoints. SSVD is considered the most prevalent ischemic brain disorder, increasing in frequency with age. Vascular risk factors include hypertension, diabetes, hyperlipidemia, elevated homocysteine, and obstructive sleep apnea. Ischemic white matter lesions are the hallmark of SSVD; other pathological lesions include arteriolosclerosis, dilatation of perivascular spaces, venous collagenosis, cerebral amyloid angiopathy, microbleeds, microinfarcts, lacunes, and large infarcts. The pathogenesis of SSVD is incompletely understood but includes endothelial changes and blood-brain barrier alterations involving metalloproteinases, vascular endothelial growth factors, angiotensin II, mindin/spondin, and the mammalian target of rapamycin pathway. Metabolic and genetic conditions may also play a role but hitherto there are few conclusive studies. Clinical diagnosis of SSVD includes early executive dysfunction manifested by impaired capacity to use complex information, to formulate strategies, and to exercise self-control. In comparison with Alzheimer's disease (AD), patients with SSVD show less pronounced episodic memory deficits. Brain imaging has advanced substantially the diagnostic tools for SSVD. With the exception of cortical microinfarcts, all other lesions are well visualized with MRI. Diagnostic biomarkers that separate AD from SSVD include reduction of cerebrospinal fluid amyloid-β (Aβ)42 and of the ratio Aβ42/Aβ40 often with increased total tau levels. However, better markers of small-vessel function of intracerebral blood vessels are needed. The treatment of SSVD remains unsatisfactory other than control of vascular risk factors. There is an urgent need of finding targets to slow down and potentially halt the progression of this prevalent, but often unrecognized, disorder.

Keywords: Cerebral small vessel disease; cerebrospinal fluid; classification; cognitive impairment; diagnostic imaging; genetics; metabolism; pathology; pathophysiology; symptoms.

Fig.1

Newcastle categorization in six subtypes of different cerebrovascular pathologies associated with VCI. Post-stroke survivors are included in subtypes I–III. Cases with extensive WM disease in the absence of significant other features are included under SVD. Subtype I may result from large vessel occlusion (athero-thromboembolism), artery-to-artery embolism or cardioembolism. Subtype II usually involves arteriosclerosis, lipohyalinosis and hypertensive, arteriosclerotic, amyloid or collagen angiopathy. Subtypes I, II and V may result from aneurysms, arterial dissections, arteriovenous malformations and various forms of arteritis (vasculitis). AD, Alzheimer’s disease; CH, cerebral haemorrhage; CVD, cerebrovascular disease; MI, myocardial infarction; MID, multi-infarct dementia; LVD, large vessel disease; SIVD, subcortical ischemic vascular dementia; SVD, small vessel disease; VCI, vascular cognitive impairment; VaD, vascular dementia. From: Kalaria RN, 2016 [13].

Fig.2

Components of the pathology due to SSVD. A, B) Low power (A) and higher power (B) views of a histological section from a case of SSVD. The section has been stained for myelin (blue) (Luxol fast blue/cresyl violet stain). There is diffuse pallor of staining and, at the top left corner of the section in (A), the tissue is necrotic. B) Damaged white matter at higher power. The nuclei (purple) are chiefly those of infiltrating macrophages. C) Greatly dilated perivascular space (hematoxylin and eosin stain). D) Small artery with a grossly thickened wall in which collagen has replaced smooth muscle (hematoxylin and eosin stain). E) Normal white matter arterioles in which the deeper pink cells are smooth muscle cells. F) Severely fibrotic and stenosed arteriole from a case of SSVD (E and F, hematoxylin and eosin).

Fig.3

Executive Clock-Drawing Task (CLOX): The patient is instructed to draw a clock on a white sheet of paper. The instructions are as follows: “Draw a clock that says 1:45. Set the hands and numbers on the face of the clock so that even a child could read them.” The instructions can be repeated until they are clearly understood, but once the subject begins to draw no further assistance is allowed. This patient scored 7/15 points. The subject’s performance is scored as follows: Does figure resemble a clock? 1 point; Circular face present? 1 point; Dimensions >1 inch? 1 point; All numbers inside the perimeter? 1 point; No sectoring or tic marks? 1 point; Numbers 12, 6, 3, & 9 placed first? 1 point; Spacing Intact? (Symmetry on either side of 12 and 6 o’clock?) 1 point; Only Arabic numerals? 1 point; Only numbers 1 - 12 among the numerals present? 1 point; Sequence 1-12 intact? No omissions or intrusions. 1 point; Only two hands are present? 1 point; All hands represented as arrows? 1 point; Hour hand between 1 and 2 o’clock? 1 point; Minute hand obviously longer than hour? 1 point; 1 point if none of the following are present: 1) Hand pointing to 4 or 5 o’clock? 2) “1:45” present? 3) Any other notation (e.g., “ 9:00”)? 4) Any arrows point inward? 5) Intrusions from “hand” or “face” present? 6) Any letters, words or pictures? From: Royall et al., 1998 [116].

Fig.4

Examples of different features of small vessel disease, including white matter hyperintensities, as published by the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) study group. From: Wardlaw et al., 2013 [145].

Fig.5

Increase in global cerebral blood flow determined by arterial spin label MR imaging post-lumbar puncture in a patient with normal-pressure hydrocephalus. (Román GC and Fung S, unpublished data).