腎功能障礙對老年人之腦部皮質厚度與 認知功能變化之研究

Abstract

前言: 在老化社會中，失智症已造成嚴重的全球疾病負擔。使用腦部影像去分析大腦結構、例如計算腦部皮質厚度是否變薄，可作為認知功能退化前早期偵測的指標。另一方面，慢性腎臟病逐漸被認為也是造成失智症的危險因子之一，且同時也會造成腦部結構的變化，例如白質病變或者整體大腦萎縮。但過去較少研究討論到慢性腎臟病是否會造成腦部皮質厚度的變化，以及它們對尚未失智的老年人認知功能的長期影響。本論文涵蓋兩部分，首先是橫斷面地探討腎功能與腦部皮質厚度的關係，接著會研究腎功能失調與大腦皮質變薄兩者對於認知功能長期的影響。 第一部分: 腎功能失調與大腦皮質厚度的關聯 背景: 慢性腎病變者容易看到一些腦部結構性變化，例如腦部小血管疾病的表現或腦部整體萎縮。然而，過往較少文獻探討腎功能與大腦皮質厚度此一重要失智症影像指標的關聯性。本研究旨在研究正常認知功能老年人中、腎功能不良對於大腦皮質厚度的影響。 方法: 此一橫斷性研究納入了259位社區居住、認知功能無明顯失常之≥65歲之老年人，他們都接受了腦部核磁共振影像，並且經由FreeSurfer軟體來計算大腦整體以及不同皮質分區的皮質厚度，若某受試者該區塊皮質厚度介於整個族群的最低三分之一的話，則被定義為有皮質變薄。若經抽血計算出的腎絲球過濾率<60毫升/分鐘/1.73平方公尺、或尿液試紙顯示有1+以上的蛋白尿的話，則定義為有腎功能失調。 結果: 有腎功能失調的受試者(43位, 16.7%)其大腦整體皮質厚度明顯較無腎功能失調者較為薄(2.17±0.11 mm vs. 2.26±0.11 mm, P< 0.001)。在校正了年紀、性別、血管危險因子、APOE ε4帶因狀況、以及腦部白質病變和小洞性梗塞之後的多變項線性回歸模型中，腎功能失調與整體皮質厚度呈現負相關( = −0.04, 95%信賴區間 −0.08至 −0.01)，也與其他額葉、頂葉、顳葉、枕葉及島葉呈負相關。在分層分析中，此現象在女性、APOE ε4非帶因者、以及認知功能分數較低者更為明顯。若將皮質變薄作為依變項的話，則腎功能失調會顯著增加島葉皮質變薄的危險(勝算比2.74, 95% 信賴區間1.31至5.74)。 結論: 由低腎絲球過濾率及蛋白尿所代表之腎功能失調，可能是大腦皮質變薄的獨立危險因子。在老年族群應嚴格監控腎功能以防止神經退化。 第二部分: 腎功能失調及大腦皮質變薄對認知功能變化的影響 背景: 大腦皮質變薄可作為預測老年族群認知功能衰退的影像指標，然而，慢性腎病變對於此相關性之間是否扮演有重要的角色、且對不同領域的認知面向是否有不同的影響尚不得而知。此外，腎功能失調與血管病變比較有關，而皮質變薄則可能與阿茲海默症的神經退化有關，兩者是否對於認知功能退化有加乘效應也尚未有研究。本研究旨在探討腎功能失調及大腦皮質變薄，對尚未失智的老人長期認知功能變化的影響。 方法: 此一長期追蹤研究納入了397位社區居住之≥65歲且有接受腦部核磁共振影像之老年人，在基線收案及之後每兩年都會接受一次完整認知功能檢驗，本研究納入了四年內的三次認知測驗，包括整體認知功能、專注力、執行功能、邏輯記憶、以及語言流暢度。在基線時的實驗室檢查數據中，若腎絲球過濾率<60毫升/分鐘/1.73平方公尺、或尿液試紙顯示有1+以上的蛋白尿的話，則定義為有腎功能失調。若任一次認知功能檢驗或實驗室檢查數據有遺失者，則會將其排除。受試者在基線也接受了腦部核磁共振影像，經FreeSurfer軟體計算出皮質厚度後，將整個族群的最低三分之一定義為皮質變薄，計算的皮質區塊包括整體、各皮質分葉，以及阿茲海默症區塊。為了處理重複測量之認知分數，統計使用廣義線性混合模型。 結果: 此研究最終納入244位受試者，並發現受試者基線的腎功能失調本身明顯與專注力退步有關(β=−0.29)，與邏輯記憶減退有關的皮質變薄區塊包括整體皮質(β= −0.30)、阿茲海默症區塊(β= −0.36)、顳葉 (β= −0.31)、枕葉(β= −0.27)以及島葉(β= −0.28)，而額葉變薄則與專注力(β= −0.26)以及執行功能(β =−0.26)的退步有關。腎功能失調會改變記憶功與整體皮質、額葉、邊緣系統變薄與記憶功能變化之間的關係(Pinteraction< 0.05)，也就是腎功能失調者其皮質越薄反而記憶功能越好。若將腎功能失調與皮質變薄加乘考慮的話，則同時有腎功能失調且皮質變薄者，比上腎功能正常且皮質沒有變薄者，其專注力退步有明顯的趨勢效應(β= −0.51, Ptrend= 0.008)。 結論: 腎功能失調與皮質變薄對於認知功能退化有加乘效應，表示可能血管病變及阿茲海默相關的神經退化在老化過程的認知衰退中都扮演了重要角色。在腎功能不良者，皮質厚度與記憶功能可能存在反向關係。在老年族群中，有效監控甚至遏止腎功能變差可能可防止神經退化。

Introduction: Dementia increase rapidly in the aging society and results in a huge global disease burden. Structural neuroimaging, such as cerebral cortical thickness (CTh), can serve as a biomarker to detect corresponding brain morphological change developed gradually before clinically detectable cognitive decline. Chronic kidney disease has been proposed as an independent risk factor for cognitive impairment and is also linked to brain structural abnormalities such as white matter lesion or generalized atrophy. However, only few studies explored the relationship between kidney function and CTh, as well as their effects on long-term cognitive change in non-demented elderly population. This dissertation consists of two parts: the first part focus on cross-sectional associations between kidney dysfunction and CTh, and the second part will investigate the impacts of kidney dysfunction and cortical thinning on cognitive change in a prospective cohort study. Part 1. Associations between kidney dysfunction and cortical thickness Background: Chronic kidney disease has been linked to morphological brain change, such as cerebral small vessel disease or brain atrophy. However, less is known about the relationship between kidney functions and cerebral cortical thickness. This study aimed to evaluate the potential impact of kidney dysfunction on cortical thickness in a group of independently living older persons. Methods: This cross-sectional study recruited 259 elderly participants from the annual elderly health checkup program. They received brain magnetic resonance image study, and the global and lobar cerebral cortical thickness (CTh) were calculated by FreeSurfer, a surface-based imaging analysis suite. Cortical thinning was defined as being lowest tertile of the global or lobar CTh. Glomerular filtration rate (GFR) and proteinuria were obtained from blood and urine sample, and kidney dysfunction was defined as either GFR <60 ml/min/1.73m2 or presence (≥ 1+) of proteinuria. Results: Participants with kidney dysfunction (n=43, 16.7%) had significantly thinner global CTh than those without kidney dysfunction (2.17±0.11 mm vs 2.26±0.11 mm, P<0.001). Kidney dysfunction was associated with thinner global ( = −0.04, 95% CI= −0.08 to −0.01) as well as frontal, parietal, temporal, occipital, and insular lobar CTh after adjustment of age, sex, vascular risk factors, APOE ε4 status, and MRI markers of small vessel disease. In the stratified analysis, the associations were more pronounced in women, APOE ε4 non-carriers, and participants with a lower cognitive score. Besides, kidney dysfunction significantly increased the risk of cortical thinning in the insular lobe (adjusted OR= 2.74, 95% CI= 1.31−5.74). Conclusion: Kidney dysfunction, represented by lower GFR or proteinuria, was independently related to cortical thinning. Kidney dysfunction should be closely monitored and managed in elderly population to prevent neurodegeneration. Part 2. Impacts of kidney dysfunction and cortical thinning on cognitive change Background: Cerebral cortical thinning is one important neuroimaging marker to predict cognitive decline in the elderly population. However, whether kidney dysfunction plays a crucial role or modifies the relationship between cortical thickness (CTh) and cognitive decline is unknown. This study aimed to investigate the associations of kidney dysfunction and cortical thinning on cognitive change in a prospective cohort design. Methods: This study recruited 397 elderly participants from elderly health checkup program in a tertiary medical center in Taiwan and all of them received with baseline brain MRI. They also received comprehensive exam at baseline and biannually afterwards (total 3 times). The neurocognitive tests administered at baseline and follow-up included global cognition, attention, executive function, logical memory, and verbal fluency. Laboratory study was collected at baseline, and kidney dysfunction was defined as having either glomerular filtration rate <60 ml/min/1.73m2 or proteinuria (≥ 1+). Those who had any missing cognitive exam or laboratory data were excluded. CTh of global, lobar, and Alzheimer’s disease (AD) signature area were derived from brain MRI at baseline, and cortical thinning was defined as the lowest tertile of cortical thickness. Generalized linear mixed models were applied to evaluate the effects of KD and cortical thinning on cognitive changes. Results: In total, 244 participants were included in the study. KD was associated with the decline in attention function (β= −0.29). Thinning of global (β= −0.30), AD signature area (β= −0.36), temporal (β= −0.31), occipital (β= −0.27) and insular lobes (β= −0.28) predicted poor logical memory over time, while frontal thinning predicted poor attention (β= −0.26) and executive function (β= −0.26). KD modified the relationship between thinning of global, frontal, and limbic, and change of logical memory function (Pinteraction< 0.05). When considering jointly, participants with both KD and cortical thinning had greatest decline in attention function compared with those without KD or cortical thinning (β= −0.51, Ptrend= 0.008). Conclusion: Kidney dysfunction and cortical thinning have joint effect on cognitive decline, especially the attention function. Reverse associations may exist between cortical thinning and memory function in participants with kidney dysfunction. The role of kidney dysfunction in the process of neurodegeneration should be emphasized.