Quantitative vascular pathology and phenotyping familial and sporadic cerebral small vessel diseases.

We quantified vascular changes in the frontal lobe and basal ganglia of four inherited small vessel diseases (SVDs) including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), hereditary multi-infarct dementia of Swedish type (Swedish hMID), and hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Vascular pathology was most severe in CADASIL, and varied with marginally greater severity in the basal ganglia compared to the frontal lobe. The overall sclerotic index values in frontal lobe were in the order CADASIL ≥ HERNS > PADMAL > Swedish hMID > sporadic SVD, and in basal ganglia CADASIL > HERNS > Swedish hMID > PADMAL> sporadic SVD. The subcortical white matter was almost always more affected than any gray matter. We observed glucose transporter-1 (GLUT-1) protein immunoreactivities were most affected in the white matter indicating capillary degeneration whereas collagen IV (COL4) immunostaining was increased in PADMAL cases in all regions and tissue types. Overall, GLUT-1 : COL4 ratios were higher in the basal ganglia indicating modifications in capillary density compared to the frontal lobe. Our study shows that the extent of microvascular degeneration varies in these genetic disorders exhibiting common end-stage pathologies but is the most aggressive in CADASIL.