背景:胆碱能神经递质系统对认知功能至关重要,基底前脑(BF)特别容易受到阿尔茨海默病(AD)病理的影响。然而,胆碱能通路中的白质高信号(WMH)与无淀粉样蛋白病理的BF萎缩之间的相互作用仍知之甚少.
方法:我们招募了接受神经心理学测试的患者,磁共振成像,2015年至2022年,在教学大学医院因认知障碍而进行的18F-氟贝塔班正电子发射断层扫描。其中,我们选择了淀粉样蛋白扫描阴性的患者,并排除了可能伴有BF萎缩的帕金森病痴呆患者.胆碱能通路的WMH负荷通过胆碱能通路高信号量表(CHIPS)评分量化,由于CHIPS评分不符合正态分布,将其分为三等组.使用FreeSurfer对体积T1加权MRI进行BF分割,然后对颅内总体积进行归一化。进行多变量回归分析以研究BF体积与CHIPS评分之间的关联。
结果:共纳入187例患者。CHIPS评分中位数为12[IQR5.0;24.0]。最高CHIPS三元组的BF体积(平均值±SD,3.51±0.49,CHIPSt3)比低CHIPS三元组组(3.75±0.53,CHIPSt2;3.83±0.53,CHIPSt1;P=0.02)显着降低。在单变量回归分析中,与BF体积显着相关的因素是CHIPSt3组,年龄,女性,教育,糖尿病,吸烟,既往中风史,脑室周围WMH,和脑微出血。在多元回归分析中,CHIPSt3组(标准化β[βstd]=-0.25,P=0.01),女性(βstd=0.20,P=0.04),和糖尿病(βstd=-0.22,P<0.01)与BF体积显着相关。敏感性分析显示CHIPS评分与归一化BF体积呈负相关,无论WMH严重程度如何。
结论:我们确定了胆碱能途径的战略性WMH负荷与BF萎缩之间的显著相关性,与淀粉样蛋白阳性和WMH严重程度无关。这些结果表明了通过死亡现象引起的胆碱能神经元损失的机制,并提供了一个理论基础,即战略性WMH评估可能有助于确定可能从乙酰胆碱酯酶抑制剂治疗中受益的目标群体。
BACKGROUND: The cholinergic neurotransmitter system is crucial to cognitive function, with the basal forebrain (BF) being particularly susceptible to Alzheimer\'s disease (AD) pathology. However, the interaction of white matter hyperintensities (WMH) in cholinergic pathways and BF atrophy without amyloid pathology remains poorly understood.
METHODS: We enrolled patients who underwent neuropsychological tests, magnetic resonance imaging, and 18F-florbetaben positron emission tomography due to cognitive impairment at the teaching university hospital from 2015 to 2022. Among these, we selected patients with negative amyloid scans and additionally excluded those with Parkinson\'s dementia that may be accompanied by BF atrophy. The WMH burden of cholinergic pathways was quantified by the Cholinergic Pathways Hyperintensities Scale (CHIPS) score, and categorized into tertile groups because the CHIPS score did not meet normal distribution. Segmentation of the BF on volumetric T1-weighted MRI was performed using FreeSurfer, then was normalized for total intracranial volume. Multivariable regression analysis was performed to investigate the association between BF volumes and CHIPS scores.
RESULTS: A total of 187 patients were enrolled. The median CHIPS score was 12 [IQR 5.0; 24.0]. The BF volume of the highest CHIPS tertile group (mean ± SD, 3.51 ± 0.49, CHIPSt3) was significantly decreased than those of the lower CHIPS tertile groups (3.75 ± 0.53, CHIPSt2; 3.83 ± 0.53, CHIPSt1; P = 0.02). In the univariable regression analysis, factors showing significant associations with the BF volume were the CHIPSt3 group, age, female, education, diabetes mellitus, smoking, previous stroke history, periventricular WMH, and cerebral microbleeds. In multivariable regression analysis, the CHIPSt3 group (standardized beta [βstd] = -0.25, P = 0.01), female (βstd = 0.20, P = 0.04), and diabetes mellitus (βstd = -0.22, P < 0.01) showed a significant association with the BF volume. Sensitivity analyses showed a negative correlation between CHIPS score and normalized BF volume, regardless of WMH severity.
CONCLUSIONS: We identified a significant correlation between strategic WMH burden in the cholinergic pathway and BF atrophy independently of amyloid positivity and WMH severity. These results suggest a mechanism of cholinergic neuronal loss through the dying-back phenomenon and provide a rationale that strategic WMH assessment may help identify target groups that may benefit from acetylcholinesterase inhibitor treatment.