Functional cerebrovascular abnormalities in CADASIL

Abstract

CADASIL is a hereditary small vessel disease related to NOTCH3 mutations. Main vascular characteristics include: vascular smooth muscle cell degeneration, deposition of the extracellular domain of the Notch3 receptor, and deposition of electron dense material within the arterial wall. SPECT, PET, and perfusion MRI studies have demonstrated a reduction in cerebral blood flow (CBF) and cerebral blood volume (CBV) particularly within white matter regions that are hyperintense on T2-weighed images. Consistent with these findings, doppler sonography reveals diminished mean flow velocities in the MCA. These changes might in part relate to a rarefication of the microvascular tree. Several studies found an impaired cerebrovascular reactivity. Thus, for example, the vasodilatory response to C02 and acetazolamide was found to be reduced whereas the vasodilatory response to L-Arginine was significantly enhanced in cerebral blood vessels. Again, altered cerebrovascular reactivity was most pronounced within WML. Treatment with statins over two months had no significant effect on cerebrovascular CO2 reactivity and the response to L-Arginine. Isolated peripheral blood vessels from CADASIL patients show an enhanced vasoconstrictor response to angiotensin II and reduced tachyphylaxis in the presence of a normal vasodilatory response to acetylcholine and bradykinin. Both structural and functional vascular alterations might contribute to the occurence of subcortical lesions. Yet, the exact mechanisms underlying such lesions in CADASIL are still unknown.