皮質下性認知症の現代的捉え方—遺伝性脳小血管病からの解析

Subcortical Ischemic Vascular Dementia: Lesson from Hereditary Cerebral Small Vessel Disease

高齢で発症する小血管病を基盤とする皮質下性認知症は発症過程の解析が難しい。CADASIL，CARASIL，脳アミロイド血管症などの遺伝性脳小血管病は血管性認知症の発症機序を考えるうえで重要な疾患である。CADASILでは変異notch3，CARASILではTGFβシグナル亢進，脳アミロイド血管症ではアミロイドβ蛋白蓄積により，異常蛋白凝集体，細胞外基質が血管周囲に蓄積して小血管病変，認知症へ進展する機序を考察する。

Abstract

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.