Immunolocalization of platelet-derived growth factor receptor-ß (PDGFR-ß) and pericytes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

AIMS: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is identified by aggregates of NOTCH3 extracellular domain (N3ECD) along capillaries and the deposition of granular osmiophilic material (GOM). We assessed the pattern of distribution of pericytes in relation to N3ECD deposits in cerebral microvessels of CADASIL subjects. METHODS: We assessed post mortem brains from (n = 50) subjects with CADASIL, cerebral small vessel disease, and similar-age cognitively normal and older controls. Immunohistochemical and immunofluorescent staining methods were used to study the distribution and quantify immunoreactivities of the platelet-derived growth factor receptor-ß (PDGFR-ß) (for pericytes) and microvascular markers in the frontal cortex and white matter. RESULTS: PDGFR-ß antibody stained cells typical of pericytes in capillaries and small arterioles in both the grey and white matter. PDGFR-ß reactive pericytes adopted 'crescent' morphology wrapped closely around capillary walls readily evident in cross-sections. We noted considerable overlap between PDGFR-ß and N3ECD imunoreactivities in capillaries. Quantitative analysis of PDGFR-ß immunoreactivity revealed significant differences in PDGFR-ß %A in CADASIL compared with young controls (P < 0.05). PDGFR-ß %A was further positively correlated with the basement membrane marker collagen IV (r = 0.529, P = 0.009), but was not associated with GLUT-1, the marker for endothelial cells. CONCLUSIONS: Our results suggest increased expression of PDGFR-ß immunoreactive pericytes in cerebral microvessels in CADASIL compared with similar age controls. While we cannot confirm whether PDGFR-ß-expressing pericytes produce N3ECD and hence GOM, our findings demonstrate that up-regulation of pericyte-like cells is associated with microvascular changes, including loss of vascular smooth muscle cells in CADASIL.

White matter pathology and disconnection in the frontal lobe in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

BACKGROUND: Magnetic resonance imaging indicates diffuse white matter (WM) changes are associated with cognitive impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We examined whether the distribution of axonal abnormalities is related to microvascular pathology in the underlying WM. METHODS: We used post-mortem brains from CADASIL subjects and similar age cognitively normal controls to examine WM axonal changes, microvascular pathology, and glial reaction in up to 16 different regions extending rostro-caudally through the cerebrum. Using unbiased stereological methods, we estimated length densities of affected axons immunostained with neurofilament antibody SMI32. Standard immunohistochemistry was used to assess amyloid precursor protein immunoreactivity per WM area. To relate WM changes to microvascular pathology, we also determined the sclerotic index (SI) in WM arterioles. RESULTS: The degree of WM pathology consistently scored higher across all brain regions in CADASIL subjects (P<0.01) with the WM underlying the primary motor cortex exhibiting the most severe change. SMI32 immunoreactive axons in CADASIL were invariably increased compared with controls (P<0.01), with most prominent axonal abnormalities observed in the frontal WM (P<0.05). The SIs of arterioles in CADASIL were increased by 25-45% throughout the regions assessed, with the highest change in the mid-frontal region (P=0.000). CONCLUSIONS: Our results suggest disruption of either cortico-cortical or subcortical-cortical networks in the WM of the frontal lobe that may explain motor deficits and executive dysfunction in CADASIL. Widespread WM axonal changes arise from differential stenosis and sclerosis of arterioles in the WM of CADASIL subjects, possibly affecting some axons of projection neurones connecting to targets in the subcortical structures.