背景:尸检工作表明,广泛投射的去甲肾上腺素能桥脑蓝斑(LC)是最早积累高磷酸化tau的区域之一,神经病理学阿尔茨海默病(AD)标志。这种早期tau沉积伴随着LC投射密度的降低和去甲肾上腺素的神经保护作用的降低。可能损害LC皮质目标的神经元完整性。先前的研究表明,较低的磁共振成像(MRI)衍生的LC完整性可能是认知健康的皮质组织变性的信号,老年人。然而,这些观察结果是否由潜在的AD病理学驱动尚不清楚.为此,我们研究了皮质β-淀粉样蛋白和tau病理对体内LC完整性之间关联的潜在效应修饰,通过LCMRI信号强度量化,皮质神经变性,以皮质厚度为索引。
方法:总共165名老年人(74.24±9.72岁,~60%女性,10%的认知障碍)接受了全脑和专用LC3T-MRI,匹兹堡化合物B(PiB,β-淀粉样蛋白)和Flortaucipir(FTP,tau)正电子发射断层扫描。具有自举标准误差的线性回归分析(n=2000)评估了双侧皮质厚度与i)LCMRI信号强度之间的关联,ii)与皮质FTP或PiB相互作用的LCMRI信号强度(即,ECFTP,ITFTP,整个样品和低β-淀粉样蛋白亚样品中的新皮质PiB)。
结果:在整个样本中,我们发现了一个直接的效应,其中较低的LCMRI信号强度与下中外侧颞皮质厚度相关。通过FTP或PiB对潜在效应修饰的评估显示,较低的LCMRI信号强度与较低的皮质厚度有关,特别是在升高的个体中(EC,IT)FTP或(新皮质)PiB。后一结果从亚阈值PiB值开始存在。在低PiB个体中,在ECFTP升高的情况下,较低的LCMRI信号强度与较低的EC皮质厚度相关.
结论:我们的研究结果表明,老年个体中LC相关的皮质神经变性模式对应于代表Braak早期阶段的区域,并且可能反映了LC投影密度降低和皮质AD病理出现的组合。这提供了一种新的理解,即LC相关的皮质神经变性可能是AD相关病理的下游后果的信号。而不是完全是衰老的结果。
Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer\'s disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine\'s neuroprotective effects, potentially compromising the neuronal integrity of LC\'s cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness.
A total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample.
Across the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP.
Our findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.