Clinicopathological and genetic studies of two further Italian families with cerebral autosomal dominant arteriopathy

Abstract

We report on two Italian families with an early-adult onset autosomal dominant disorder, characterized by leukoencephalopathy, migraine, psychiatric disturbances, stroke and dementia. These findings fulfill the diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome. Moreover, to confirm the CADASIL gene location to 19p12, we performed a linkage analysis with four microsatellite markers. The results of the genetic study gave positive but not significant lod scores, indicating only weak evidence of a linkage with 19p12. In one autopsy case, we found extensive ischemic changes due to the selective involvement of the small muscular arteries of the cerebral white matter. The lesions consisted of a thickening of the media with deposition of granular eosinophilic material. Ultrastructural examination of the arterial walls showed graded damage to smooth muscle cells, mostly of the longitudinal layer, and an abnormal proliferation of basal lamina components. Immunocytochemical analysis showed strong reactivity using antibodies to collagen IV and smooth myosin proteins. The results suggest a primary involvement of the smooth muscle cells of small cerebral arteries, with a secondary alteration of basal lamina components and elastic tissue.

Correlations Between Clinical Findings and Magnetization Transfer Imaging Metrics of Tissue Damage in Individuals With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

“…Our findings agree with previous pathological reports showing the presence of subtle cortical changes, such as neuronal rarefaction and fibrillary gliosis, in individuals with CADASIL. 2,42,43 Interestingly, MTR of the NAGM was found to be normal in patients with subcortical atherosclerotic encephalopathy, 28 who have conventional MRI abnormalities similar to those found with CADASIL. Admittedly, the role of subtle white and gray matter pathology in CADASIL warrants further elucidation.…”

An Animal Model for the Molecular Genetics of CADASIL

“…8,10 -12 Immunohistological staining patterns indicate that these deposits may contain collagen IV and smooth muscle myosin, 11 as would be expected after repeated cycles of smooth muscle cell degeneration and proliferation.…”

“…8 The arterial lesions occur throughout the arterial tree, including arteries and arterioles within muscle, skin, 9 and peripheral nerve. 10 These arterial lesions are neither arteriosclerotic nor amyloid, 8,11 and affected families rarely have vascular risk factors or hypertension. 4 Nevertheless, the arterial lesions are characterized by a marked thickening of the arterial wall associated with the proliferation of vascular smooth muscle cells and accumula-…”

Comparison between Multiple Lacunar Infarcted Patients with and without Dementia in Nursing Homes in Shimane Prefecture, Japan

“…Cases with multiple lacunar infarctions and control subjects were selected from this collection, and divided into three groups (VD, non-D and control group) [17]. There were no cases diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [18,19]. The multiple lacunar infarctions were distributed in the basal ganglia and the white matter in both the VD and the non-D group.…”