Fibrosis and Stenosis of the Long Penetrating Cerebral Arteries: the Cause of the White Matter Pathology in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

In cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) the vascular smooth muscle cells are destroyed and granular osmiophilic material is deposited followed by fibrosis of the arterial wall. To verify whether true stenosis of the fibrotic white matter arteries is a key pathogenic event in CADASIL, we analyzed the thickness of walls (expressed as sclerotic index) and luminal diameters of penetrating arterioles in both grey matter and white matter of four CADASIL patients due to the C475T (R133C) mutation in the Notch3 gene and in 9 age-matched controls. We also reconstructed 9 arterioles from 1000 serial sections in two CADASIL patients. The thickness of the arteriolar walls in both grey matter and white matter was significantly increased in the CADASIL patients compared with controls. Furthermore, in CADASIL patients the arteriolar walls were significantly thicker in the white matter than in the grey matter. The distribution curve of arteriolar internal diameters in CADASIL patients shifted towards smaller sizes. In serial sections, the marked increase in the thickness of the white matter penetrating arterioles or their branches did not occur until the internal diameters had decreased to about 20 to 30 pm and external diameters to about 100 to 130 microm. In conclusion, long penetrating arterioles and their branches supplying subcortical structures in CADASIL are stenosed and their walls are thickened. This conforms to the abundance of infarcts and primary ischemic damage in CADASIL patients' white matter.