摘要:腦部小血管疾病是造成腦中風及失智症的重要原因,也會導致步態障礙、無症狀性腦梗塞或腦出血。體顯性腦動脈血管病變合併皮質下腦梗塞及腦白質病變(CADASIL)乃是單一基因(NOTCH3)突變造成的遺傳性腦部小血管疾病,可作為此類疾病的模型。我們的研究發現台灣病患其基因突變好發位點與西方人不同,臨床特色除了缺血性中風,也很容易腦出血,導致用藥治療上的困難。至今,腦部小血管疾病除了控制已知的危險因子(如高血壓)或給予抗血栓藥物以外,治療上並無太大突破,找到可介入的危險因子至為關鍵。血脂異常是導致大動脈粥狀硬化的重要成因,其中陰電性低密度膽固醇(L5 LDL)與致病機轉有密切的關係,但其是否會影響腦部小血管疾病,目前尚未定論。本研究明確目標: 本研究希望透過遺傳性疾病CADASIL作為研究模板,從基礎及臨床兩層面探討血脂異常對腦部小血管疾病的影響,並發展未來可能的臨床診斷及藥物應用。具體研究方向: (1)長期追蹤台灣CADASIL病人之血脂數值與認知功能、腦部影像、中風事件的關係。(2)藉由CADASIL小鼠模型探討高脂肪飲食刺激或Statin治療之下,其認知與行為能力、病理變化的比較。第一年進度: 研究血脂與腦部小血管疾病表徵之關聯性。於多醫學中心收納150位CADASIL病患及100位健康受試者,分析基線上血脂數值(包括LDL, non-HDL, L5 LDL)與臨床與影像的關聯,對適合個案給予Statin治療。動物實驗則培植NOTCH3突變之小鼠,分別為台灣(R544C)與歐美好發(R170C)之兩株基因型,給予高脂肪飲食、Statin治療、以及對照組。第二年進度: 追蹤血脂數值與腦部小血管疾病表徵之變化。多收案50位病患及100位健康受試者,並繼續收錄臨床資料。小鼠實驗每六個月記錄其行為功能,在12個月及24個月時分別犧牲一批、研究其解剖下病理變化,比較不同種刺激與基因型小鼠之差異。第三年進度: 確認血脂數值與腦部小血管疾病表徵之角色。所有病患在兩年後有認知功能、腦部影像的追蹤,腦部影像是否有新增的為出血點或腦梗塞,臨床則紀錄是否有新發生中風事件(按研究估計已中風者年復發率為8%,則200位病患可能有32個新發事件),進行統計分析。小鼠實驗則持續補齊樣本數不足之處。預期成果: 結合基礎與臨床,探討血脂異常是否為遺傳性腦部小血管疾病嚴重程度及預後的重要因子。
Abstract: Cerebral small vessel disease (CSVD) is one of the major cause for stroke and dementia, and it also leads to gait disturbance, silent brain infarcts or microbleeds. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) caused by mutations at NOTCH3 gene is a hereditary cause of ischemic stroke (IS) and vascular dementia, and can be used as a disease model of CSVD. In Taiwan, a substantial proportion of CADASIL patients may also suffer from intracerebral hemorrhage (ICH), posing a treatment dilemma in these patients.The treatment strategy against CSVD is limited, and finding potential target for intervention is critical. Dyslipidemia is a known risk factor for large artery atherosclerosis, and L5 low density lipoprotein (LDL) is most atherogenic subfractions of LDL which strongly ties with the disease mechanism. The effects of dyslipidemia on CSVD, however, is uncertain and inconclusive yet.Specific Aim: Using CADASIL as a disease model to decipher the effects of dyslipidemia on CSVD via clinical and basic research, and to develop potential diagnosis and treatment strategy.Objectives: (1) Clinical part: investigate the associations between lipid profile and stroke events, cognitive function, and neuroimaging features in a longitudinal cohort of CADASIL patients. (2) Basic part: compare the behavior, cognitive, and pathology change in mice model of CADASIL under high fat diet and/or statin treatment.Year 1: To study the associations between lipid profile (including LDL, non-HDL and L5 LDL) and manifestations of CSVD. We will recruit 150 CADASIL patients and 100 healthy control in a multi-center cohort study, and analyze the associations. Besides, mice with knock-in NOTCH3 mutation at R544C (Taiwan strain) and R170C (Caucasian strain) will be prepared and bread with high fat diet, statin, or sham control.Year 2: To investigate the change in lipid profile and manifestations of CSVD. We expect to recruit 50 more CADASIL patients and 100 controls, and continue to collect data in all patients. The expected phenotype in mice will appear at 20-22 months. The behavior and cognitive function of the mice will be recorded every 6 months. First half of the mice will be sacrificed to see the pathological change at 12 months, and the second half at 24 months. The differences between two strains and different lipid challenge groups will be compared.Year 3: To confirm the role of dyslipidemia in CSVD. All CADASIL patients will have their cognitive function, neuroimaging (especially incident lacunes and cerebral microbleeds), and clinical stroke events recorded annually till 2 years. The estimated recurrent stroke risk in CADASIL patients is 8.1/100 person-year, making a maximal number of stroke case of 32, for further statistical analysis. Animal study will be continued until the target number is reached.Implications: This project combining basic and clinical parts will elucidate whether dyslipidemia is an important risk factor for the severity and outcome in the hereditary CSVD, providing evidence for further treatment and clinical trials.