臺灣博碩士論文加值系統

背景：
巴金森病(Parkinson’s disease, PD)為僅次於阿滋海默病的常見神經退化性疾病，除了一般所熟知的肢體僵硬、靜止型顫抖及步態不穩等運動症狀之外，認知功能障礙在PD患者亦相當常見。在診斷超過二十年以上的患者中，高達八成以上都會得到失智症。在過去的臨床病理研究中發現，巴金森病合併失智症(Parkinson’s disease with dementia, 簡稱PDD)的病患中，除了廣泛分佈在邊緣系統與大腦皮質區的路易氏體(Lewy bodies)之外，還有程度不一的含有類澱粉蛋白(β-amyloid, Aβ) 與神經纖維纏結(neurofibrillary tangles)的神經炎斑塊 (neuritic plaques)。但在這些病人發生認知功能障礙的原因與確切病理機轉，目前仍未有明確的解釋。
目的：
本研究希望從正常心智功能的PD患者、伴隨輕度認知功能障礙PD患者(Parkinson’s disease with mild cognitive impairment, PD-MCI)與PDD病人，其臨床症狀與神經心理功能評估，合併檢驗血漿中的致病蛋白質濃度, 了解這些致病蛋白質對PD病人產生失智症的影響與關聯，進一步找尋協助早期診斷PDD的可能生物指標。
方法：
由臨床心理師為約各20位年齡與教育程度比對之健康受試者、20位正常認知PD患者(Parkinson’s disease, not demented, PDND)、10位PD-MCI與20位PDD病人，進行完整認知功能、神經精神症狀的評估，作為臨床症狀之分析；並藉由近年來新發展的超導磁減量技術(Immunomagnetic reduction assay), 敏感的定量受試者血漿中的Amyloid-β1-42 (Aβ42), Tau蛋白質與α-synuclein等生物指標，比較這些臨床症狀與生物指標在這四組受試者之間的差異；並分析致病蛋白濃度與病人認知功能評估之間的相關性。
結果：
在PD的非運動症狀中，以幻覺、憂鬱與焦慮等症狀在PDD病人裡最嚴重且合併出現比例也最高；運動症狀中則以肢體僵硬、步態不穩與平衡功能不佳在PDD組別與PDND組有顯著的差異。認知功能評估中，MMSE(Mini-Mental State Examination)總分、執行功能、注意力、記憶功能與視覺空間功能等各項分測驗在PDD組的表現都顯著的要比其他組別的受試者差。而三種血漿蛋白幾乎都有隨著患者認知功能下降而濃度上昇的趨勢，其中α-synuclein與Tau在PDD組的濃度要比HC組的受試者顯著的升高。在多變項迴歸分析中發現，教育程度在9.7年以上與Hoehn and Yahr stage為1的受試者，對Modified card sorting test-category(MCST-C)分數有顯著正向的預測性；而受試者年齡越大、使用左旋多巴胺劑量越高與PD得病時間越長則有顯著負向的預測性，進一步檢驗各共變項的交互作用，發現認知功能障礙時間在2.5個月以上再乘上α-synuclein濃度之後，對MCST-C有相當顯著的負向預測性(p<0.0001, R=0.8519)。
結論：
我們的研究發現PD患者的幻覺與焦慮等非運動症狀，與僵硬、步態不穩與平衡不佳，都在PDD患者上更為明顯且症狀更嚴重，血漿中α-synuclein與Tau濃度在PDD患者也明顯升高，而PD患者一旦認知障礙時間在2.5個月以上，隨著血漿中α-synuclein濃度越高，在預測MCST-C的得分會有高達72.6%的解釋力。

Background:
Cognitive impairment is a frequent and devastating non-motor symptom of Parkinson''s disease (PD). Impaired cognition has a major impact on either quality of life or mortality in patients with PD. Clinicopathological studies have reported varying amounts of neuritic plaques containing β-amyloid (Aβ) and neurofibrillary tangles in Parkinson’s disease with dementia (PDD) in addition to widespread limbic and cortical Lewy bodies (α-synuclein aggregates). But the relationship among these neuropathological features and the development of dementia in PD remains uncertain.
Aim:
The purpose of this study is to identify the association with optimal biomarkers including clinical neuropsychological examination results, cognitive profile, and plasma biomarkers. Hopefully it will further help determine prediction of progression of cognitive decline in patients with PD.
Methods:
We enrolled each of 20 gender-, age-, and education-matched healthy control subjects (HC, healthy control), patients of PD with intact cognition (PDND, Parkinson’s disease, not demented), 20 patients of Parkinson’s disease with mild cognitive impairment (PD-MCI), and 20 patients of PDD. All study subjects underwent complete neuropsychological, and neuro-psychiatric assessments. In addition, peripheral blood samples were collected for plasma biomarkers of α-synuclein, Tau, and Amyloid-β1-42 (Aβ42) by means of immunomagnetic reduction (IMR) assays.
Results:
PDD group is significantly associated with longer dementia diagnosis duration and more advance Hoehn and Yahr stage. Meanwhile, PDD group also has more prominent both non-motor (hallucination, depression, and anxiety) and motor symptoms (rigidity, gait disturbance and postural imbalance). Plasma α-synuclein and Tau concentration is significantly higher in PDD group than HC subjects (α-synuclein: PDD: 1.447±1.054 (pg/mL), HC: 0.577±0.45(pg/mL); Tau: PDD: 29.073±11.6 (pg/mL), HC: 19.133± 11.179 (pg/mL), p<0.05). PDD patients also perform much worse in executive, attention, memory, and visuospatial function than the rest 3 groups. By means of multivariate analysis of predictors for Modified card sorting test-category(MCST-C) score, patient age, education, and dementia duration longer than 2.5 months cross plasma α-synuclein concentration can best predict the score(p<0.0001, R=0.8519).
Conclusion:
Both the severity of motor and nonmotor symptoms were much more prominent in PDD patient. Plasma α-synuclein and Tau concentration is also significantly higher in PDD patient in comparison with control groups. The score of MCST-C can be fairly predicted by patient age, education, and dementia duration longer than 2.5 months combined with plasma α-synuclein level via multivariate analysis.

口試委員會審定書…………………………………………………………………….ii
誌謝……………………………………………………………………………………iii
中文摘要………………………………………………………………………………iv
英文摘要………………………………………………………………………………vi
圖目錄………………………………………………………………………………….x
表目錄………………………………………………………………………………….xi
第一章 緒論…………………………………………………………………………...1
1.1 巴金森病的流行病學與目前診斷上的瓶頸………………………………..1
1.2 巴金森病的非運動症狀: 從輕度認知功能障礙到失智症………………...2
1.3 巴金森病的神經病理研究與不正常蛋白質的堆疊聚集…………………..4
1.4 腦脊髓液與血漿中生物標記之間的關聯…………………………………..4
1.5 目前的血漿生物標記檢測方式……………………………………………..6
第二章 研究方法與材料……………………………………………………………...7
2. 1 病患的收集及診斷方式…………………………………………………….7
2.2 臨床評估檢查與流行病學資料之獲取…………………………………….7
2.3 神經心理學心智功能評估(Neuropsychological test, NPT)………………..8
2.4 血漿檢體樣品收集與準備………………………………………………….8
2.5 免疫磁減量檢測(Immunomagnetic reduction assay, IMR assay)………….9
2.6 統計分析……………………………………………………………………10
第三章 研究結果…………………………………………………………………….12
3.1 流行病學分析………………………………………………………………12
3.2 MDS-UPDRS (Movement Disorder Society–sponsored revision of the Unified Parkinson’s Disease Rating Scale)的評估分數結果……………………12
3.3 血漿生物標記與心智功能評估……………………………………………13
3.4 利用多變項分析看各個共變項與心智功能與非運動症狀之間的關聯…14
第四章 討論………………………………………………………………………….15
4.1 臨床症狀與在巴金森患者產生認知功能障礙之間的關聯………………15
4.2 三種血漿生物標記與認知功能的關聯……………………………………16
4.3 多變項分析對臨床指標的運用……………………………………………17
第五章 展望………………………………………………………………………….18
參考文獻……………………………………………………………………………….19

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