最近一項尸檢研究表明，使用血管緊張素受體拮抗劑（ARB）類的降壓藥與腦內(nèi)阿爾茨海默病樣病理出現(xiàn)少相關。研究者發(fā)現(xiàn)采用CERAD制定的神經(jīng)病理學標準，生前服用ARB類降壓藥的AD患者與服用其它降壓藥的患者相比（37% vs. 54%，P=0.005），病理表現(xiàn)較輕。在校正年齡、性別、APOE分型和血壓等變量后，生前服用ARB類降壓藥的AD患者與服用其它降壓的患者尸檢AD病理變化的OR為0.47（95%CI,0,27-0.81）。該研究在線發(fā)表于最新一期的《神經(jīng)病學文獻》（Archives of Neurology）。

    之前曾有觀察性研究表明ARB類藥物治療高血壓具有保護認知的功能，動物研究顯示這類藥物可以減少腦內(nèi)與AD相關的病理性標志物Aβ集聚。ARB類藥物如何作用于Aβ的機制尚不清楚。

    于是，研究者們對全國阿爾茨海默病中心登記的890位患者進行研究，該中心匯集了全國29個阿爾茨海默病中心的數(shù)據(jù)庫的數(shù)據(jù)，研究包括神經(jīng)病理學及臨床資料方面的分析?；颊吲R床資料包括病史、藥物治療史，神經(jīng)精神病學史等，其中包含MMSE和臨床癡呆量表等多種測驗結(jié)果。對尸檢神經(jīng)病理方面的評估主要采用CREAD評分。另外，對患者進行Braak評分以評估不同部位神經(jīng)變性的程度。納入研究的患者中，80%接受過抗高血壓藥物治療，15%患者使用ARB類藥物，64%服用其它類型降壓藥。

    研究發(fā)現(xiàn)，與接受非ARB類降壓藥物治療患者及不服藥的患者相比，使用ARB類降壓藥的患者其死亡年齡更大（P<0.001），邏輯記憶測驗及MMSE得分更高，癡呆評定量表得分更低，這表明他們的認知功能更好。

    研究者稱，根據(jù)阿爾茨海默病神經(jīng)病理學的診斷標準的不同，使用ARB類藥物可使患者被診斷為“病理尸解確診的阿爾茨海默病”的可能性下降32-35%。依據(jù)NIH的Khachaturian標準，服ARB類降壓藥的AD 患者與服其它降壓藥患者相比，OR值為0.43（95%CI0.21-0.91），而根據(jù)Braakf分期的評分其OR值是0.52（95%CI0.31-0.85）。

    對服用ARB類藥物與ACEI類藥物的AD患者直接比較發(fā)現(xiàn)，前者淀粉樣蛋白沉積及神經(jīng)炎性斑塊的比例較少，這表明ARB的保護作用具有特異性。對血管相關病理評估顯示，使用ARB類藥物卒中的可能性稍高（P=0.03），其也與梗塞、大動脈出血相關，但經(jīng)過其他因素校正后，其相關性不太顯著。研究人員說，使用ARB類藥物的患者其之所以血管病理的情況較糟糕可能與這些患者本身血管情況就較使用其他類降壓藥物的患者重，而不是由于使用ARB類藥物所致。

    研究者指出，ARB類藥物干擾Aβ沉積的機制仍未完全闡明，但是ARB類藥物治療可能是通過促進膜相關胰島素降解酶介導的機制來降低腦內(nèi)的Aβ蛋白總量。

    這項研究結(jié)果可能對今后ARB類藥物治療對是否能確實改善阿爾茨海默病患者臨床癥狀的研究提供依據(jù)，為阿爾茨海默病治療的研究開辟了新的途徑。

    英文原文：

    Impact of Angiotensin Receptor Blockers on Alzheimer Disease Neuropathology in a Large Brain Autopsy Series.

    Hajjar I, Brown L, Mack WJ, Chui H.

    BACKGROUND Angiotensin II may be involved in amyloid metabolism in the brain. Angiotensin receptor blockers （ARBs） may also prevent cognitive decline. OBJECTIVE To evaluate the impact of treatment with ARBs on the neuropathology of Alzheimer disease （AD） in the National Alzheimer Coordinating Center database, which includes aggregated data and brain autopsies from 29 AD centers throughout the United States. DESIGN Multiple logistic regression was used to compare the pathologic findings in hypertensive subjects taking ARBs with those taking other antihypertensive treatments as well as with hypertensive subjects who did not receive antihypertensive medications. SETTING Neuropathologic data included neuritic plaque and neurofibrillary tangle measures and vascular injury markers. PATIENTS Data were collected from participants who were self-referred or provider-referred and included those with and without cognitive disorders. Our sample included only hypertensive participants and excluded cognitively and neuropathologically normal participants （N = 890; mean age at death, 81 years [range, 39-107 years]; 43% women; 94% white）。 RESULTS Participants with or without AD who were treated with ARBs showed less amyloid deposition markers compared with those treated with other antihypertensive medications （lower Consortium to Establish a Registry of Alzheimer Disease score: odds ratio, 0.47, 95% CI, 0.27-0.81; Alzheimer Disease and Related Disorders Association score: odds ratio, 0.43, 95% CI, 0.21-0.91; Braak and Braak stage: odds ratio, 0.52, 95% CI, 0.31-0.85; neuritic plaques: odds ratio, 0.59, 95% CI, 0.37-0.96）。 They also had less AD-related pathology compared with untreated hypertensive subjects. Participants who received ARBs were more likely to have had a stroke; hence, they had more frequent pathologic evidence of large vessel infarct and hemorrhage. CONCLUSION Treatment with ARBs is associated with less AD-related pathology on autopsy evaluations. The effect of ARBs on cognitive decline in those with dementia or AD needs further investigation.