腦血管病變是台灣十大死因的第二位，也是引起老年人肢體殘障的主要原因。 此外，腦血管病變也會引起認知功能障礙及失智症，此為另一種型式的功能性障礙，罹病者往往造成家庭及社會極大的負擔。顱內動脈瘤破裂引起之蜘蛛膜下腔出血(subarachnoid hemorrhage)約佔所有腦血管病變的5–10%，是所有腦血管病變中預後最差的一型。即使患者幸運存活, 有10–20％的病患會有肢體殘障的後遺症，且有超過半數的病患有認知及記憶功能缺損。本篇研究首先運用台灣健保資料庫分析腦血管病變導致失智症的機率，結果顯示腦中風病患發生失智症的風險顯著增加，尤其以出血性腦中風及蜘蛛膜下腔出血的患者為最，所以，在後續的研究中，我嘗試尋找蜘蛛膜下腔出血可能的致病機轉及治療藥物。在蜘蛛膜下腔出血造成腦損傷的主要機轉分成兩部份，分別是急性期的缺血性腦傷及延遲性血管痙攣造成的次發性腦缺血。許多臨床研究及動物實驗已證實蜘蛛膜下出血在急性期會引起大量的麩胺酸(glutamate) 釋放，而引起細胞興奮性毒性反應; 且能夠減少神經型一氧化氮合成酶活性及過亞硝酸鹽(peroxynitrite)之生成，而達到降低氧化／硝化壓力的治療效果，最終memantine能夠減少蜘蛛膜下出血造成之神經損傷，而改善神經學症狀及預後。另一方面，memantine亦對於發生蜘蛛膜下腔出血後的神經血管單元有保護效果，不但可在急性期維持腦血管障壁的完整性，且可以在亞急性期回復內皮細胞及內皮型一氧化氮合成酶的功能，而減少血管痙攣的嚴重度。總括而論，蜘蛛膜下出血的預後不良，患者有極高比例會有嚴重的後遺症及失智症，而memantine是一種臨床上使用多年且安全的藥物，此藥物對於蜘蛛膜下腔出血有治療效果及神經血管保護作用，本研究的發現值得再做後續進一步的研究來探討。
之後的研究目標，是希望在不久的將來，能使用NMDA受體拮抗劑來進行臨床實驗，探討此類藥物在治療蜘蛛膜下腔出血患者的效果，使其能成為這類病患的另一治療選擇。

Cerebrovascular accidents are the major cause of disability and considerably increase the risk of dementia, which is another important cause of disability. Aneurysmal subarachnoid hemorrhage (SAH) represents 5–10% of all cerebrovascular accidents, and leads to the worst outcome among all strokes. Of the survivors, the rate of related permanent disability is estimated to be 10–20% and long-term cognitive dysfunction affects up to 50–60% of survivors.
The first section of my PhD research aimed to study the risk of dementia after stroke, using nationwide population-based cohort study. In comparison with non-stroke controls, patients with stroke had increased risk of dementia. Among various stroke subtypes, SAH and hemorrhagic stroke had higher impact on the development of dementia than ischemic stroke.
Thus I intend to find a new therapeutic option to improve the outcome of SAH. The underlying mechanism of brain injury after SAH is biphasic, acute brain injury and delayed vasospasm. Experimental and clinical studies have indicated that SAH causes cerebral ischemic injury via glutamatergic excitotoxicity at acute stage. Based on the excitotoxicity theory, the antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors may provide neuroprotection to limit secondary brain injury after SAH. However, high affinity NMDA antagonists will indiscriminately block physiologic effect of NMDA receptors and cause undesirable side effects. Memantine (1-amino-3,5-dimethyladamantane hydrochloride), with its characteristic of low affinity uncompetitive NMDA antagonist, has been used clinically for years as treatment of dementia and Parkinson’s disease without serious adverse effects. It has also been proven to reduce brain injury in several neurological diseases.
For this reason, using a SAH animal model, I investigated the pathophysiological mechanisms of SAH and the therapeutic potential of memantine in SAH. The results showed memantine suppressed SAH-induced apoptotic cascades. Moreover, up-regulated neuronal nitric oxide synthase activity, peroxynitrite formation, and subsequent oxidative/nitrosative stress after SAH were reduced by memantine treatment. Memantine finally rescued SAH-induced neuronal injury and improved neurobehavioral outcome. On the other hand, memantine also prevented the damage of neurovascular unit after SAH. It not only preserved blood-brain barrier integrity at acute stage, but also attenuated delayed vasospasm via restoring endothelial functionality. Taken together, SAH suggests increased risk of dementia. Memantine, which is a clinically tolerable drug, has therapeutic potential in experimental SAH and may help combat SAH-induced brain damage. These findings warrant further investigation in patients with SAH.
Afterward, I intend to conduct clinical trials targeting the treatment of SAH using NMDA receptor antagonists. I expect the NMDA-based therapy is a potential therapeutic option to improve the outcome of SAH.

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