Stage Eddie, Svaldi Diana, Sokolow Sophie, Risacher Shannon L, Marosi Krisztina, Rotter Jerome I, Saykin Andrew J, Apostolova Liana G
Indiana Alzheimer Disease Center Indianapolis IN USA.
Department of Neurology IU School of Medicine Indianapolis IN USA.
Alzheimers Dement (N Y). 2021 Dec 31;7(1):e12168. doi: 10.1002/trc2.12168. eCollection 2021.
Analyses of off-label use of acetylcholinesterase inhibitors (AChEIs) in mild cognitive impairment (MCI) has produced mixed results. Post hoc analyses of observational cohorts, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), have reported deleterious effects in AChEI-treated subjects (AChEI+). Here, we used neuroimaging biomarkers to determine whether AChEI+ subjects had a greater rate of neurodegeneration than untreated (AChEI-) subjects while accounting for baseline differences.
We selected 121 ADNI MCI AChEI+ subjects and 151 AChEI- subjects with a magnetic resonance imaging (MRI) scan; 82 AChEI+ and 110 AChEI- also had a fluorodeoxyglucose (FDG) scan. A subset (83 AChEI+ and 98 AChEI-) had cerebrospinal fluid (CSF) or amyloid positron emission tomography (PET) assessment for amyloid positivity. Linear regression models were used to compare the effect of treatment on changes in Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes scores. We used standard regression in SPM (for baseline) and the SPM toolbox sandwich estimator, SwE (for longitudinal) for comparisons of AChEI+ and AChEI- FDG PET and MRI data.
At baseline, the AChEI+ group had significantly reduced cortical gray matter density (GMD) and more hypometabolism than AChEI- subjects. The greater rate of atrophy and hypometabolic changes over time in AChEI+ compared to AChEI- subjects did not survive correction for baseline differences. AChEI+ participants were more likely to be amyloid-positive and have lower GMD and FDG standardized uptake value ratio than AChEI- at baseline. AChEI+ subjects showed greater atrophy over time, which remained significant after controlling for amyloid status.
Our data suggest that the observed differences in rates of cognitive decline, atrophy, and hypometabolism are likely the result of significant baseline differences between the groups. Furthermore, the data indicate no treatment effect of AChEI (positive of negative), rather that physicians prescribe AChEI to subjects who present with more severe clinical impairment. This alone may account for the negative effect seen previously in the ADNI population of AChEI use among MCI subjects.
对乙酰胆碱酯酶抑制剂（AChEIs）在轻度认知障碍（MCI）中的非标签使用分析结果不一。对观察性队列的事后分析，如阿尔茨海默病神经影像学倡议（ADNI），报告了接受AChEI治疗的受试者（AChEI+）存在有害影响。在此，我们使用神经影像学生物标志物来确定AChEI+受试者的神经退行性变率是否高于未治疗的（AChEI-）受试者，同时考虑基线差异。
我们选取了121名接受AChEI治疗的ADNI MCI受试者和151名未接受AChEI治疗的受试者进行磁共振成像（MRI）扫描；82名AChEI+受试者和110名AChEI-受试者还进行了氟脱氧葡萄糖（FDG）扫描。一个子集（83名AChEI+受试者和98名AChEI-受试者）进行了脑脊液（CSF）或淀粉样蛋白正电子发射断层扫描（PET）评估以确定淀粉样蛋白阳性情况。使用线性回归模型比较治疗对简易精神状态检查和临床痴呆评定量表总分变化的影响。我们在统计参数映射（SPM）中使用标准回归（用于基线），并使用SPM工具箱夹心估计器SwE（用于纵向）来比较AChEI+和AChEI-受试者的FDG PET和MRI数据。
在基线时，AChEI+组的皮质灰质密度（GMD）显著降低，且代谢减退程度高于AChEI-受试者。与AChEI-受试者相比，AChEI+受试者随时间推移更大的萎缩率和代谢减退变化在对基线差异进行校正后不再显著。AChEI+参与者在基线时比AChEI-参与者更有可能淀粉样蛋白呈阳性，且GMD和FDG标准化摄取值比率更低。AChEI+受试者随时间显示出更大的萎缩，在控制淀粉样蛋白状态后仍具有显著性。
我们的数据表明，观察到的认知衰退、萎缩和代谢减退率差异可能是两组之间显著基线差异的结果。此外，数据表明AChEI没有治疗效果（无论是阳性还是阴性），而是医生将AChEI开给临床损伤更严重的受试者。仅此一点可能就解释了先前在ADNI人群中观察到的MCI受试者使用AChEI的负面影响。
