New Insight into the Pathogenesis of Cerebral Small-Vessel Diseases

Cerebral small-vessel diseases (SVD) are a common cause of vascular dementia and disability in the elderly. Apart from risk containment, little can be done to prevent or to treat SVD. Although most cases occur sporadically, hereditary forms of the disease provide the chance to elucidate the molecular and cellular mechanisms leading to microvascular pathology. Along this line, authoritative reviews on SVD have been published.1–3 Here, we would like to extend current concepts of SVD by highlighting a molecular pathway that seems to be involved in several well-defined SVD, some of which are hereditary. As a new piece of evidence, we will focus on incontinentia pigmenti (IP), which has recently been shown to be associated with microvascular pathology of the brain and retina.4,5 As will be elaborated below, IP is a SVD that does not present in the elderly but rather during infancy. The young age of onset and the nonprogressive microvascular pathology lead to a clinical picture that differs from other SVD. We suggest the term developmental SVD for this form of presentation. IP is caused by mutations in the NEMO gene (NF-kappaB essential modulator), an essential modulator of the transcription factor nuclear factor (NF)-κB.6 NEMO maintains the viability of brain endothelial cells and stabilizes the blood–brain barrier (BBB).5 In NEMO-deficient animals, there is rarefaction of cerebral capillaries and hypoperfusion of the central nervous system (CNS). Disruption of the transforming growth factor (TGF)-β–activated kinase (TAK1) upstream of NEMO produces a similar pathology.5 Interestingly, TGF-β has also been involved in the pathogenesis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and the vascular changes of Alzheimer disease (AD),7–11 suggesting disturbed TGF-β signaling as a common denominator of several forms of SVD. We will outline possible implications of this concept for sporadic SVD.