Cortical neuronal apoptosis in CADASIL.
OBJECTIVE
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations of the NOTCH3 gene and is a model of pure vascular dementia. Cortical atrophy has been reported to be associated with cognitive decline in the disease, although the underlying mechanism is unknown. We postulated that apoptosis may be involved in this process.


METHODS
We report the clinical history, magnetic resonance imaging findings, and pathologic examinations of 4 patients (2 of whom were demented) who died from complications of the disease. Apoptosis was evaluated in brain tissue using antibodies against activated caspase3 and in situ end labeling assays for DNA fragmentation.


RESULTS
Widespread neuronal apoptosis in the cerebral cortex (predominantly in layers 3 and 5) was observed in all patients. This was not seen in 3 non-CADASIL controls. Semiquantitative analysis suggested that apoptosis was more extensive in the presence of larger load of subcortical ischemic lesions and smaller brain volumes.


CONCLUSIONS
Neuronal apoptosis may be involved in cortical atrophy in CADASIL and appears related to the burden of subcortical ischemic lesions. These findings may have important implications in other small vessel diseases and may provide a potential target for future therapeutic interventions.
Viswanathan
Anand
A
Department of Neurology, Assistance Publique-Hôpitaux de Paris (AP-HP) Hôpital Lariboisière-Université Paris VII, Paris, France.
Gray
Francoise
F
Bousser
Marie-Germaine
MG
Baudrimont
Marielle
M
Chabriat
Hugues
H
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics*; D046589:CADASIL / Q000235:genetics* / Q000473:pathology*; D002540:Cerebral Cortex / Q000473:pathology*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000473:pathology*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics
C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch