[Subcortical ischemic vascular dementia: lesson from hereditary cerebral small vessel disease].

Subcortical ischemic vascular dementia (SIVD) is a main subgroup of vascular dementia related to cerebral small vessel disease. Risk factors for SIVD include hypertension, ageing, and diabetes mellitus, but the specific contribution of each factor to the development of cerebral small vessel disease remains obscure. This is mainly because SIVD in the elderly might be affected by many factors related to the ageing process. Hereditary cerebral small vessel diseases, including cerebral autosomal-dominant or autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL or CARASIL) and cerebral amyloid angiopathy, are affected by different pathomechanisms, but these diseases indicate a clear a role of the cerebral small vessel on subcortical dementia. CADASIL is caused by a cysteine residue-related mutation in the EGF-like repeat on the extracellular domain of Notch3. Pathological examination of a CADASIL brain indicated abnormal accumulation of the extracellular domain of Notch3 with extracellular matrix proteins, including tissue inhibitor of metalloproteinase 3 and vitronectin, around vascular smooth muscle cells. CARASIL is caused by a mutation in HTAR1, a serine protease that regulates transforming growth factor (TGF)-beta signaling. The mutation in HTAR1 related to CARASIL fails to repress TGF-beta signaling and induces the accumulation of extracellular matrix, including the extra domain-A region of fibronectin and versican. The individual and common pathomechanisms of hereditary cerebral small vessel disease are discussed in this review.