Published Online
on September 28, 2006

A more recent version of this article appeared on November 1, 2006

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Submitted on July 18, 2006
Accepted on August 9, 2006

Cortical Neuronal Apoptosis in CADASIL

Anand Viswanathan MD, PhD; Francoise Gray MD^*; Marie-Germaine Bousser MD; Marielle Baudrimont MD; and Hugues Chabriat MD, PhD

From Department of Neurology (A.V., M.-G.B., H.C.) and Neuropathology (F.G., M.B.), Assistance Publique-Hôpitaux de Paris (AP-HP) Hôpital Lariboisière-Université Paris VII, Paris, France; Department of Neurology and Clinical Trials Unit (A.V.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: francoise.gray{at}lrb.ap-hop-paris.fr.

Background and Purpose--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.

Key words: apoptosis • CADASIL • cortex • cortical atrophy • lacunar infarction • white matter damage

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