White matter hyperintensities are associated with post-stroke cognitive dysfunction, but the underlying mechanisms are unclear. Chen et al. provide evidence from human and experimental studies that clasmatodendrosis – a marker of irreversible astrocyte damage – and gliovascular abnormalities are increased in the frontal white matter of subjects who succumb to vascular dementia.

Advances in molecular genetics have enabled identification of several monogenic conditions involving small vessels predisposing to ischaemic and haemorrhagic strokes and diffuse white matter disease. With emphasis on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we review the molecular pathogenesis of recently characterized disorders including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and the Collagen type IV, alpha 1 (COL4A1)-related disorders. CADASIL remains the most common hereditary small vessel disease (SVD) caused by >190 different mutations in the NOTCH3 gene, which encodes a cell-signalling receptor. Mutant NOTCH3 instigates degeneration of vascular smooth muscle cells in small arteries and arterioles leading to recurrent lacunar infarcts. Mutations in the serine protease HTRA1 gene are associated with CARASIL. Aberrant HTRA1 activity results in increased transforming growth factor-β signalling provoking multiple actions including vascular fibrosis and extracellular matrix synthesis. The RVCL disorders characterized by profound retinopathy are associated with mutations in TREX1, which encodes an abundant 3'-5' DNA-specific exonuclease. TREX1 mutations lead to detrimental gain-of-function or insufficient quantities of enzyme. The COL4A1-related disorders are highly variable comprising four major phenotypes with overlapping systemic and central nervous system features including SVD with cerebral haemorrhages in children and adults. Mutant COL4A1 likely disrupts the extracellular matrix resulting in fragile vessel walls. The hereditary SVDs albeit with variable phenotypes demonstrate how effects of different defective genes converge to produce the characteristic arteriopathy and microvascular disintegration leading to vascular cognitive impairment.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of familial brain arteriopathy, is associated with deposition of granular osmiophilic material (GOM). We used immunohistochemistry and immunogold electron microscopy (EM) to examine the distribution of GOM and NOTCH3 ectodomain (N3ECD) protein in microvasculature of brain gray matter and white matter in patients with CADASIL, non-CADASIL hereditary small-vessel disease and sporadic age-related degenerative disease, and comparable-age controls. We observed intense immunostaining patterns with 2 different anti-N3ECD antibodies in CADASIL but not in young and older controls or other small-vessel disease patients. In addition, CADASIL samples exhibited immunoreactivity in arterial walls and in most capillaries. Electron microscopy revealed profound and widespread extracellular distribution of 0.2- to 2-μm GOM deposits associated with meningeal vessels and perforating arteries and arterioles. Granular osmiophilic material was adjacent to capillaries even within white matter. Immunogold EM with antibody A1-1 to N3ECD revealed abundant particles in GOM within microvessels, vascular smooth muscle cell membranes, and perivascular cells. Granular osmiophilic material did not exhibit immunogold labeling for smooth muscle α-actin or collagen IV. These results showed the specificity of the antibodies and confirm the predominant localization of N3ECD within GOM deposits. The extensive distribution of N3ECD-GOM complexes within meninges, arteries, arterioles, and particularly capillaries in the brains of CADASIL patients suggests that NOTCH3 fragments are major components of GOM deposits, which may be eliminated via perivascular routes.