Lancaster Thomas M, Murphy Kevin, Chandler Hannah
Cardiff University Brain Research Imaging Centre (CUBRIC), School of Physics and Astronomy, Cardiff University, Maindy Road, Cathays, Cardiff, CF24 4HQ, UK.
Department of Psychology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
Alzheimers Res Ther. 2025 Jul 26;17(1):177. doi: 10.1186/s13195-025-01829-0.
Alterations to brain macrostructure, assessed via T1-weighted magnetic resonance imaging are observed in preclinical models of Alzheimer's disease (AD), reflecting susceptibility, prodromal stages of AD or correlates of early AD pathophysiology. While changes in cingulate and medial temporal lobe structures may be functionally implicated in cognitive decline, little is known about the viability of brain-based biomarkers that support autonomic functions implicated in preclinical AD risk such as the brainstem.
In a series of multiple linear regressions, we assess the volume of the brainstem in two asymptomatic at-AD-risk samples, assessed via the presence of either mild cognitive impairment (MCI, N = 148), or extremely high polygenic risk (N = 13) with matched demographics (mean age = 67 [range 58-76], in both cases). We further determine the strength of the association, compared to 150 other structural MRI features.
We observed brainstem volume reductions (MCI: b = -0.29, P = 0.018; Genetic risk: b = -1.29, P = 0.002) in both samples. The magnitude of each preclinical AD marker (MCI / AD-polygenic risk)- brainstem association was empirically larger (Z > 2.3, P < 0.05, in both cases) than 150 frequently segmented MRI features. We further replicate the negative AD-polygenic risk score- brainstem association in UK Biobank (N = 31968; b = -0.002, P = 0.03), with weaker evidence that the association was larger than all other MRI features (Z = 1.622; P = 0.052).
These observations suggest that AD risk, assessed via the presence of MCI or extremely high AD-polygenic risk score is linked to reduced brainstem volume before most typically observed morphological brain alterations. This conforms with evidence implicating the brainstem as one of the earliest sites of morphological neurodegeneration and provides a plausible biological mechanism linking prodromal autonomic symptoms to AD risk in later life. These observations warrant future investigation into the molecular correlates of AD-linked brainstem dysfunction, assessment as a candidate biomarker, and the exploration of brainstem mediated treatment strategies in AD prevention.
通过T1加权磁共振成像评估发现，阿尔茨海默病（AD）临床前模型中存在脑宏观结构改变，这反映了AD的易感性、前驱阶段或早期AD病理生理学的相关因素。虽然扣带回和内侧颞叶结构的变化可能在功能上与认知衰退有关，但对于支持临床前AD风险中涉及的自主功能（如脑干）的脑生物标志物的可行性知之甚少。
在一系列多元线性回归分析中，我们评估了两个无症状的AD风险样本的脑干体积，这两个样本分别通过轻度认知障碍（MCI，N = 148）或极高的多基因风险（N = 13）以及匹配的人口统计学特征（两个样本的平均年龄均为67岁[范围58 - 76岁]）来确定。我们还将其与其他150个结构MRI特征进行比较，进一步确定这种关联的强度。
我们在两个样本中均观察到脑干体积减小（MCI：b = -0.29，P = 0.018；遗传风险：b = -1.29，P = 0.002）。每个临床前AD标志物（MCI / AD多基因风险）与脑干的关联强度在经验上比150个经常分割的MRI特征更大（两种情况均为Z > 2.3，P < 0.05）。我们在英国生物银行（N = 31968；b = -0.002，P = 0.03）中进一步重复了AD多基因风险评分与脑干的负相关关系，但证据较弱，表明该关联比所有其他MRI特征更大（Z = 1.622；P = 0.052）。
这些观察结果表明，通过MCI的存在或极高的AD多基因风险评分评估的AD风险与脑干体积减小有关，这发生在大多数典型的脑形态学改变之前。这与将脑干视为形态学神经退行性变最早部位之一的证据相符，并提供了一种合理的生物学机制，将前驱自主神经症状与晚年的AD风险联系起来。这些观察结果值得未来对AD相关脑干功能障碍的分子相关性进行研究，评估其作为候选生物标志物，并探索AD预防中脑干介导的治疗策略。
