Abstract
摘要:阿茲海默症,特別是偶發性,是由多重病因造成,基因、營養、代謝、環境、甚至於社交運動都影響其發生與惡化。目前流行病學的研究結果顯示,某些微量與巨量營養元素可以減緩知能減退與阿茲海默症的惡化;綜合分析多項研究報告,相對於健康老人,阿茲海默症患者血漿中的葉酸與維生素B12顯著降低。維生素B群是體內單炭代謝的重要輔助因子,缺乏即造成同半胱氨酸增加;同半胱氨酸過高會經由刺激NMDA受體引發細胞過度激發毒性、從而形成凋零死亡;附基因調控也被認為是阿茲海默症一項重要成因,SAH/homocysteine所導致DNA 去甲基化,已被證實會影響APP、PS1及BACE這些基因的啟動子功能,而造成乙型類澱粉蛋白的增生。阿茲海默症病患需要這些特殊營養素的補充,除了本身體內缺乏之外,病理機轉的對應需求也是重要因素。愈來愈多證據顯示阿茲海默症患者腦中的白質病變與其臨床症狀有關,我們研究團隊之前即發表過利用核磁共振的彌散張量成像,顯示輕度智能障礙與輕度阿茲海默症患者在胼胝體與腦室周圍有白質病變。亦有研究報告指出,血漿葉酸值與智能表現及整體腦中白質病變有顯著負相關;而維生素B12缺乏,除了廣為熟知的周邊神經病變之外,也被報告與腦中白質病變、特別是腦室周圍白質有關;且其關聯性都和同半胱氨酸無關。也就是與同半胱氨酸及腦血管病理變化非同步變化,推論葉酸/維生素B12有另外途徑可以影響白質神經髓鞘的功能,而非透過同半胱氨酸的血管性傷害;但確切機轉仍待釐清。我們之前完成的葉酸-阿茲海默症系列研究,我們發現在阿茲海默症基因轉植鼠(3xTg-AD)腦中白質神經髓鞘有剝離變形的情況,但透過葉酸補充可加以改善。因此我們設計這個前瞻性世代研究,來探討輕度阿茲海默症患者、或甚至更早期的失憶性輕度知能障礙及自覺記憶減退個案,其血中葉酸/維生素B12濃度,是否會影響中樞及周邊神經系統白質神經髓鞘的完整性;因為是極早期的研究個案,所以分別選用更靈敏的核磁共振彌散張量成像與神經興奮度測試的測量方式,以取代早期的體積定量化影像分析與傳統神經傳導方法。此外,我們也同時安排動物實驗,操控飲食中葉酸/維生素B12的缺乏或補充,直接以電鏡觀察其神經髓鞘變化、並分析其可能機制。.
Abstract: Alzheimer’s disease (AD), especially sporadic type, is a multifactorial disease. Genetic, nutritional, metabolic, environmental and social factors are associated with onset and progression of the disease. Current epidemiological data are in favor of a protective role of certain micronutrients and macronutrients in the prevention of cognitive decline and AD. Meta-analysis has shown significantly lower plasma levels of folate and vitamin B12 in patients with AD compared with cognitively intact elderly controls. B vitamins are essential cofactors of homocysteine metabolism, also called one-carbon metabolism. Hyperhomocysteinemia promotes excitotoxicity via stimulation of NMDA receptors and damages neuronal DNA, thereby triggering apoptosis. Epigenetic changes triggered by these dietary nutrients have also an important role in the pathogenesis of Alzheimer’s disease. SAH/homocysteine-dependent DNA hypomethylation - which is an activating input on the promoter region - has already been demonstrated for APP, PS1 and BACE leading to increased formation of ß-amyloid. A nutrient intake needed to compensate for the lower nutrient status in AD and concurrently meeting the higher nutrient needs resulting from the pathophysiological processes.White matter damage and its contribution to clinical manifestations in patients with Alzheimer dementia have been increasingly recognized. We also have report diffusion tensor change in the periventricular area and corpus callosum in MCI and AD patients. Several studies reported an association between low plasma folate and worse cognitive performance and greater severity of total brain white matter lesions, which appeared independent of homocysteine concentration. Except the well-known peripheral neuropathy, deficiency of vitamin B12 has been also reported to have significantly association with greater severity of white-matter lesions, in particular periventricular white-matter lesions. Because of independence of homocysteine and not invariably associated with cerebrovascular pathology, folate/vitamin B12 themselves might be another factors influencing the integrity of white matter. In our previous Folate-Alzheimer serial projects, we have shown the deformed myelin sheath of central white matter in AD transgenic mice (3xTg-AD); and the folate supplement could alleviate the destruction of myelination. Therefore, we launch this prospective cohort study to investigate the interaction of plasma folate/vitamin B12 with the myelination in central and peripheral nervous systems in the mild stage of Alzheimer’s patients and even the possible preclinical subjects – i.e. amnesic MCI and subjective memory complaints. Diffuse Tensor image and nerve excitation measurements have been selected as more sensitive tools to detect the trivial destruction of myelination as compared with the tradition structure MRI and nerve conductive study. In addition, we also design an animal model adjusted with deficiency or supplement of folate/Vit.B12, and then seen the pathological change directly via electron microscopy and seek the possible mechanism.
Keyword(s)
阿茲海默症
神經髓鞘
葉酸
維生素B12
彌散張量成像
神經興奮度測試
Alzheimer
Myelination
Folate
Vitamin B12
Diffuse tensor image
Nerve excitability measurement