Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebral small vessel disease caused by mutations in NOTCH3, is characterized by recurrent stroke without vascular risk factors, mood disturbances, and dementia. MRI imaging shows cerebral white matter (WM) hyperintensity, particularly in the external capsule and temporal pole. Missense mutations related to a cysteine residue in the 34 EGFr on the NOTCH3 extracellular domain (N3ECD) are a typical mutation of CADASIL. On the other hand, atypical mutations including cysteine sparing mutation, null mutation, homozygous mutation, and other associate genes are also reported. From the viewpoint of gain of function apart from Notch signaling or loss of function of Notch signaling, we review the research article about CADASIL and summarized the pathogenesis of small vessel, stroke, and dementia in this disease.

We propose the new criteria of high sensitivity, which will help physicians to assess the need for genetic testing.

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Background: Reduced cerebrovascular reactivity (CVR) is an important step in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The present study utilized quantitative single photon emission computed tomography (SPECT) with the autoradiographic (ARG) method and reactive hyperemia peripheral arterial tonometry (RH-PAT) to assess vasoreactivity in intracranial arteries and in peripheral arteries in patients with CADASIL. Methods: Quantitative SPECT studies were conducted in eight patients with CADASIL, while RH-PAT analysis was conducted in eight CADASIL patients and in eight age-matched normal subjects. Quantitative SPECT studies with the ARG method were performed at baseline and after administration of acetazolamide. Regional cerebral blood flow (rCBF) values were measured using stereotactic extraction estimation (SEE) methods. The rCBF of CADASIL patients was averaged in the bilateral frontal, temporal, parietal, and occipital lobes as well as in the limbic system, cerebellar hemisphere, whole cerebral cortex and basal ganglia. The CVR index from acetazolamide stress of intracranial arteries was calculated in each area. Vasoreactivity of peripheral arteries was estimated by the reactive hyperemia index (RHI) measured with a PAT device before and after interruption of arterial flow. Results: Average RHI after post-deflation was lower in CADASIL patients than in normal subjects. RHI correlated significantly with CVR in all brain areas in CADASIL patients. Conclusions: Vasoreactivity is reduced in peripheral arteries and in intracranial arteries in patients with CADASIL.

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