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Published on: November 6, 2017
Cortical neuronal apoptosis in CADASIL
Anand Viswanathan1, Francoise Gray, Marie-Germaine Bousser
1Department of Neurology, Assistance Publique-Hôpitaux de Paris (AP-HP) Hôpital Lariboisière-Université Paris VII, Paris, France.
Insights
Neuronal apoptosis, or programmed cell death, is implicated in cortical atrophy in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This process correlates with lesion burden and brain volume reduction.
Area of Science:
- Neuroscience
- Neuropathology
- Genetics
Background:
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder caused by NOTCH3 gene mutations.
- CADASIL serves as a key model for studying pure vascular dementia.
- Cortical atrophy is linked to cognitive decline in CADASIL, but its mechanism remains unclear.
Purpose of the Study:
- To investigate the potential role of neuronal apoptosis in cortical atrophy within CADASIL.
- To explore the relationship between apoptosis, subcortical ischemic lesions, and brain volume in CADASIL patients.
Main Methods:
- Analysis of brain tissue from 4 deceased CADASIL patients (2 demented) and 3 non-CADASIL controls.
- Immunohistochemistry using antibodies against activated caspase-3 to detect apoptosis.
- In situ end labeling assays to identify DNA fragmentation.
Main Results:
- Widespread neuronal apoptosis was observed in the cerebral cortex of all CADASIL patients, particularly in layers 3 and 5.
- No significant apoptosis was detected in control subjects.
- Apoptosis levels correlated positively with the extent of subcortical ischemic lesions and negatively with brain volume.
Conclusions:
- Neuronal apoptosis is likely involved in the cortical atrophy seen in CADASIL.
- The extent of apoptosis appears related to the burden of subcortical ischemic lesions.
- These findings suggest apoptosis as a potential therapeutic target for CADASIL and other small vessel diseases.
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.
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