認知功能障礙所影響的認知功能層面包括學習、記憶、感知、語言、專注力及問題解決能力。嚴重程度可能從輕微認知功能障礙、輕度至重度失智症。成因可能來自原發性腦退化性疾病、腦部相關疾患、身體系統性影響腦部功能，比如感染、發炎、內分泌、營養、藥物等因素。而化療藥物所引發之認知功能障礙 (chemotherapy-induced cognitive impairment, CICI) 為其中一藥物給予身體系統性影響腦部而導致之認知功能障礙，為一常見且越來越為人所認知之化療藥物的可能副作用。直至目前為止，其致病機轉尚未完全釐清，而不同化療藥物所誘發之認知功能疾患之致病機轉可能不同，但有動物實驗及人體影像證據顯示化療所導致之認知及情緒障礙可能與海馬迴受損相關。CICI病患在影像學研究上可見海馬迴萎縮，而阿茲海默症的研究及基因相關研究發現，神經新生之路徑影響可能影響海馬迴體積。因此，化療藥物誘發之腦部神經新生受損可能為CICI的其中一個致病機轉。在我們過去所做的文獻回顧發現，會影響神經新生相關的因素包含基因、環境、藥物等造成內生性路徑及外生性路徑的影響，其中包括神經再生滋養因子 (brain-derived neurotrophic factor, BDNF) 及發炎現象 (inflammation)。因此，在我們的動物研究模型中，我們探討神經新生現象在CICI所扮演的角色及其可能之分子機轉。首先，我們使用紫杉醇 (paclitaxel) 在小鼠上建立CICI模型，並證實神經新生受損確實造成CICI小鼠的記憶功能障礙及情緒障礙。我們同時發現CICI小鼠在紫杉醇注射後造成發炎細胞素(inflammatory cytokine)的改變。為進一步證實神經新生在 CICI我們同時也在CICI小鼠模型上進一步證實memantine將可能透過調整發炎現象及促進BDNF釋放而成為CICI的潛力治療方式，但不同memantine治療方式所導致對於發炎現象的調節效果不同，而造成情緒障礙治療效果不一。為了進一步將基礎實驗推進到人體實驗，我們進一步進行了前瞻性化療病患的收案計畫，並同步進行前瞻性中風病患的收案計畫作為比較，進一步探討癌症病患接受化療藥物後的認知功能曲線以及可能的影響因子，並以中風病患之認知功能數據作為比較。未來研究也將進一步探討memantine在化療病患認知功能的治療效益。

Cognitive disorders, also known as neurocognitive disorders, affect the ability of learning, memory, perceptual-motor function, language, attention, and problem solving. The severity of cognitive disorders is ranged from mild cognitive impairment, and mild to severe dementia. Cognitive disorders may be caused by primary neurologic, neuropsychiatric, systemic or medical conditions, including the effects of chronic infection, inflammation, metabolic, nutrition deficiency or drug exposure. Among these cognitive disorders due to various etiologies, chemotherapy-induced cognitive impairment (CICI), is recognized as a frequent adverse effect of cancer treatment. Until now, the definite mechanism of CICI has remained unclear, and various chemotherapeutic agents may lead to clinical symptoms of CICI through different mechanisms. An increasing body of literature from animal studies and neuroimaging studies in cancer patients suggests a possible relationship between chemotherapy induced hippocampal damage and the spectrum of neurocognitive deficits and mood alterations. Hippocampal atrophy may be observed in CICI patients. The evidence from previous Alzheimer’s disease (AD) model and genome-wide association analyses showed that neurogenesis-related pathways are also associated with changes in hippocampal volume. Therefore, the change of neurogenesis may play a role in CICI development. The evidence from our review study showed that genetic, environmental, and pharmacological factors may play a role in regulating adult hippocampal neurogenesis through multiple intrinsic and extrinsic factors. Among them, the expression pattern of neurotrophic growth factors and disease related inflammation may be a potent factor for the change of neurogenesis. Therefore, in our study, we aimed to characterize the role of neurogenesis in CICI and to elucidate the potential molecular mechanism by which chemotherapeutic agents induced impaired neurogenesis. In our basic study, we created a paclitaxel-treated mice as our CICI model and demonstrated the correlation between impaired neurogenesis and the clinical symptoms of CICI. The changes of inflammatory cytokine were also noted in our CICI model. In addition, we demonstrated that memantine may serve as a potential therapeutic agent for paclitaxel-induced CICI by modulating neurogenesis and inflammation. However, the treatment regimen may lead to variations in the treatment efficacy, especially in terms of mood dysfunction. Then, we further performed a prospective cohort study to observe the cognitive changes in fresh diagnosed cancer patients while receiving chemotherapy. For comparison, another prospective study was performed to enroll post-stroke patients for comparison. We hope to describe the cognitive trajectory in cancer patients receiving chemotherapy and to demonstrate the potential influencing factors on this cognitive trajectory. Further translational studies may be developed to evaluate the clinical efficacy of memantine in human CICI studies.

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