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阿茲海默症的診斷

越來越多的失智病例被診斷為阿茲海默症(Alzheimer’s disease, AD)，它是一種神經退化性疾病，其病因到目前為止還不明確[1]<ref>Global prevalence of dementia: a Delphi consensus study.。AD的發病機制可能涉及大腦中的β-類澱粉(β-Amyloid)與過度磷酸化的tau-p蛋白斑塊相繼作用造成的短期記憶消失。在臨床上AD患者會出現難以記住最近發生的事件，嚴重一點的患者甚至會出現記憶喪失症狀[2]<ref>Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiology of aging.。由於腦部β-類澱粉與tau-p 蛋白糾結在一起，很難釋放到血液中，所以不易直接由血液中檢測出來，故而AD的診斷方式大多基於臨床使用認知功能障礙篩檢量表(MMSE)[3]<ref>The mini-mental state examination: a comprehensive review.、簡易心智狀態問卷調查表(SPMSQ)[4]<ref>A short portable mental status questionnaire for the assessment of organic brain deficit in elderly patients.等。事實上，這些量表的評分診斷出來已經確定為失智，但這些診斷方式並不能準確的檢測到患者失智的早期階段，甚至無法明確區分出患者為AD神經退化性失智或血管性失智。進一步，也必須由影像學儀器來診斷，包括電腦斷層掃描儀(CT)、磁振造影檢查儀(MRI)分析來判斷腦部的萎縮狀況[5, 6]<ref>Depression in Taiwanese patients with Alzheimer's disease determined by the National Institutes of Mental Health Provisional Criteria<ref>Symptoms in Parkinson's Disease Dementia Are More Similar to Alzheimer's Disease than Dementia with Lewy Bodies: A Case-Control Study.。雖然有些科學家也陸續開發出一些血液生化值來做臨床檢驗，但是準確值仍然有很多改善空間，甚至無法做為早期AD的追蹤。

氧化態GAPDH與AD的關係

目前關於許多AD研究學術期刊證明，氧化態甘油醛3-磷酸脫氫酶(oxidative Glyceraldehyde-3-Phosphate Dehydrogenase, GAPDH)與AD腦部的神經斑塊嚴重性有高度相關，並且發現AD腦部中有許多氧化態的GAPDH濃度含量[7, 8]<ref>An increase in S-glutathionylated proteins in the Alzheimer's disease inferior parietal lobule, a proteomics approach.<ref>of nitrated proteins in Alzheimer's disease brain using a redox proteomics approach. 。而林佳靜教授率領研究團隊發現在正常情況下血液中並不存在氧化態的GAPDH，因此進一步深入研究探討關於氧化態GAPDH在血液中的濃度與AD疾病的進展關係。團隊在人體試驗中發現被醫師判定為嚴重的AD患者，其血液中氧化態的GAPDH濃度明顯高於相同年齡的正常對照組，並且可以透過血液中氧化態的GAPDH濃度來評估AD進展過程中導致神經凋亡的程度[9]<ref>An investigation of the correlation between the S-glutathionylated GAPDH levels in blood and Alzheimer's disease progression.。

氧化態GAPDH含量與正常對照組比較

林佳靜教授與研究團隊解釋：原本正常的GAPDH是細胞中進行糖解作用(Glycolysis)過程中重要的酵素，一般在科學界被認為是不會改變表現量的家管基因(House keeping gene)[10]<ref>Glyceraldehyde-3-phosphate Dehydrogenase Aggregates Accelerate Amyloid-beta Amyloidogenesis in Alzheimer Disease.，但是在近期的研究中發現在AD患者的大腦中大量存在著GAPDH以氧化形式與Aβ和tau-p斑塊聚集在一起，並且失序的GAPDH氧化態已在AD海馬部位中被大量發現，而氧化態GAPDH的含量與正常對照組相比較卻高出了7倍之多[7, 8]<ref>An increase in S-glutathionylated proteins in the Alzheimer's disease inferior parietal lobule, a proteomics approach.<ref>of nitrated proteins in Alzheimer's disease brain using a redox proteomics approach.。這些功能失調形式的GAPDH可能會導致AD大腦中的神經元功能喪失和神經變性及凋亡。

氧化態GAPDH濃度與AD的關係

當GAPDH在粒線體中累積以改變線粒體膜的通透性時，它具有誘導細胞凋亡的能力，因此它也被認為是一種促進凋亡因子[11]<ref>a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization.。而正常型式的GAPDH存在於細胞質而不是血液中，所以在正常人的血漿中未檢測的到，但當神經元因AD病程中死亡時，氧化態的GAPDH會被釋放到血漿中，AD患者的血漿中可以檢測到氧化態的GAPDH濃度，濃度愈高代表神經凋亡數愈多。因此，在這項研究中，血液中氧化態的GAPDH與AD進展呈現正相關，但與年齡和性別無關。只要血液中有數值，代表目前神經細胞就有凋亡的現象，數值愈高代表凋亡的神經細胞數量愈多。當長期神經細胞死亡持續10-20年至出現認知功能障礙時，此時才容易由門診神經病學診所的MMSE、CT和/或MRI綜合檢查做出診斷[5, 6]<ref>Depression in Taiwanese patients with Alzheimer's disease determined by the National Institutes of Mental Health Provisional Criteria<ref>Symptoms in Parkinson's Disease Dementia Are More Similar to Alzheimer's Disease than Dementia with Lewy Bodies: A Case-Control Study.。然而，在大量腦神經元凋亡的過程中應該可以在早期階段就進行拯救，以免於惡化。

氧化態GAPDH可以做為檢測阿茲海默失智症早期的風險指標

目前林佳靜教授與研究團隊將氧化態的GAPDH濃度作為一種易於檢測阿茲海默失智早期的風險指標(Alzheimer's Disease Risk Index, ADRI )，這項指標可用來診斷評估AD出現前10-20年大腦神經凋亡及腦部惡化的進展情況，此項研究已經榮獲美國、歐盟、日本、大陸、中華民國、香港等國際性發明專利，並且發表SCI 的科學期刊[9]<ref>An investigation of the correlation between the S-glutathionylated GAPDH levels in blood and Alzheimer's disease progression.。

ADRI精準且易檢測

。ADRI是一項精準並且簡易的檢測，ADRI 值與阿茲海默失智症的敏感度為95.74％；專一性92.67％[9]<ref>An investigation of the correlation between the S-glutathionylated GAPDH levels in blood and Alzheimer's disease progression.。 。目前努力推廣失智症早期風險檢測，及早發現、及早預防。

Reference

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2. Braak H, Braak E. Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiology of aging. 1995;16(3):271-8; discussion 8-84. doi: 10.1016/0197-4580(95)00021-6. PubMed PMID: 7566337.Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiology of aging. [https://pubmed.ncbi.nlm.nih.gov/7566337/ Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiology of aging.

3. Tombaugh TN, McIntyre NJ. The mini-mental state examination: a comprehensive review. Journal of the American Geriatrics Society. 1992;40(9):922-35. doi: 10.1111/j.1532-5415.1992.tb01992.x. PubMed PMID: 1512391. The mini-mental state examination: a comprehensive review.

4. Pfeiffer E. A short portable mental status questionnaire for the assessment of organic brain deficit in elderly patients. Journal of the American Geriatrics Society. 1975;23(10):433-41. doi: 10.1111/j.1532-5415.1975.tb00927.x. PubMed PMID: 1159263. A short portable mental status questionnaire for the assessment of organic brain deficit in elderly patients.

5. Chiu PY, Steffens D, Chen PK, Hsu YC, Huang HT, Lai TJ. Depression in Taiwanese patients with Alzheimer's disease determined by the National Institutes of Mental Health Provisional Criteria. International psychogeriatrics. 2012;24(8):1299-305. doi: 10.1017/S1041610211002262. PubMed PMID: 22333495. Depression in Taiwanese patients with Alzheimer's disease determined by the National Institutes of Mental Health Provisional Criteria

6. Chiu PY, Tsai CT, Chen PK, Chen WJ, Lai TJ. Neuropsychiatric Symptoms in Parkinson's Disease Dementia Are More Similar to Alzheimer's Disease than Dementia with Lewy Bodies: A Case-Control Study. PloS one. 2016;11(4):e0153989. doi: 10.1371/journal.pone.0153989. PubMed PMID: 27101140; PubMed Central PMCID: PMC4839640. Symptoms in Parkinson's Disease Dementia Are More Similar to Alzheimer's Disease than Dementia with Lewy Bodies: A Case-Control Study.

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8. Sultana R, Poon HF, Cai J, Pierce WM, Merchant M, Klein JB, et al. Identification of nitrated proteins in Alzheimer's disease brain using a redox proteomics approach. Neurobiology of disease. 2006;22(1):76-87. doi: 10.1016/j.nbd.2005.10.004. PubMed PMID: 16378731. of nitrated proteins in Alzheimer's disease brain using a redox proteomics approach.

9. Tsai CW, Tsai CF, Lin KH, Chen WJ, Lin MS, Hsieh CC, et al. An investigation of the correlation between the S-glutathionylated GAPDH levels in blood and Alzheimer's disease progression. PloS one. 2020;15(5):e0233289. doi: 10.1371/journal.pone.0233289. PubMed PMID: 32469899; PubMed Central PMCID: PMC7259681. An investigation of the correlation between the S-glutathionylated GAPDH levels in blood and Alzheimer's disease progression.

10. Itakura M, Nakajima H, Kubo T, Semi Y, Kume S, Higashida S, et al. Glyceraldehyde-3-phosphate Dehydrogenase Aggregates Accelerate Amyloid-beta Amyloidogenesis in Alzheimer Disease. The Journal of biological chemistry. 2015;290(43):26072-87. doi: 10.1074/jbc.M115.669291. PubMed PMID: 26359500; PubMed Central PMCID: PMC4646260. Glyceraldehyde-3-phosphate Dehydrogenase Aggregates Accelerate Amyloid-beta Amyloidogenesis in Alzheimer Disease.

11. Tarze A, Deniaud A, Le Bras M, Maillier E, Molle D, Larochette N, et al. GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization. Oncogene. 2007;26(18):2606-20. doi: 10.1038/sj.onc.1210074. PubMed PMID: 17072346. a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization.