Cerebral Small Vessel Disease-Related Dementia: More Questions Than Answers

Abstract

Cerebral small vessel disease (CSVD) has emerged as a common factor driving age-dependent diseases, including stroke and dementia. CSVD-related dementia will affect a growing fraction of the aging population, requiring improved recognition, understanding, and treatments. This review describes evolving criteria and imaging biomarkers for the diagnosis of CSVD-related dementia. We describe diagnostic challenges, particularly in the context of mixed pathologies and the absence of highly effective biomarkers for CSVD-related dementia. We review evidence regarding CSVD as a risk factor for developing neurodegenerative disease and potential mechanisms by which CSVD leads to progressive brain injury. Finally, we summarize recent studies on the effects of major classes of cardiovascular medicines relevant to CSVD-related cognitive impairment. Although many key questions remain, the increased attention to CSVD has resulted in a sharper vision for what will be needed to meet the upcoming challenges imposed by this disease.

Keywords: Alzheimer disease; biomarker; blood-brain barrier; dementia; magnetic resonance imaging.

Figure 1.

Neuroimaging in CSVD-VCID. (A) subcortical and periventricular white matter hyperintensities (WMH) on T2/FLAIR (fluid-attenuated inversion recovery) sequences. (B) Lacunar stroke a cavity with a rim of hyperintensity on FLAIR. (C) Enlarged perivascular spaces (ePVS) on T1 sequence, can appear both as streak-like spaces as well as punctate. (D) Subcortical microhemorrhages on T2* SWI (susceptibility weighted imaging) sequence. (E) Cortical microhemorrhages on T2* SWI sequence. (F) Superficial siderosis on T2* SWI sequence.

Figure 2.

Histopathological features of CSVD. Common histopathological features include arterial wall thickening, vascular cell loss, and protein accumulation in a laminar pattern. The top photo shows a normal appearing white matter artery stained with hematoxylin and eosin (H&E). The middle row shows markedly thickened small arteries in a patient with CADASIL, an inherited CSVD. On the left is a vessel after Miller’s staining, which shows massive vessel thickening and fraying elastin fibers of the intimal/medial function. Cell loss is demonstrated in the H&E stained CADASIL artery on the right. The lower panel illustrates layered protein accumulation in a patient with CADASIL. The left photo shows staining for all collagens using a collagen binding peptide probe (B-CHP) that stains all three layers of the vessel (adventitia, media, and intima). The middle photo shows staining with a NOTCH3 neo-epitope antibody that principally highlights the media; in CAA, the media accumulates Aβ. The right photo shows staining for COL4A that localizes predominantly to the intima. Scale bar span 40 microns for rows 1–2 and 100 microns for row 3.