Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Department of Neurology, University Hospital RWTH Aachen, Aachen, Germany.
Alzheimers Res Ther. 2024 May 31;16(1):119. doi: 10.1186/s13195-024-01485-w.
Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and pharmacological studies reported that left frontoparietal network functional connectivity (LFPN-FC) confers resilience against beta-amyloid (Aβ)-related cognitive decline in preclinical sporadic and autosomal dominant Alzheimer's disease (AD), as well as against LC-related cognitive changes. Given that the LFPN and the LC play important roles in attention, and attention deficits have been observed early in the disease process, we examined whether LFPN-FC and LC structural health attenuate attentional decline in the context of AD pathology.
142 participants from the Harvard Aging Brain Study who underwent resting-state functional MRI, LC structural imaging, PiB(Aβ)-PET, and up to 5 years of cognitive follow-ups were included (mean age = 74.5 ± 9.9 years, 89 women). Cross-sectional robust linear regression associated LC integrity (measured as the average of five continuous voxels with the highest intensities in the structural LC images) or LFPN-FC with Digit Symbol Substitution Test (DSST) performance at baseline. Longitudinal robust mixed effect analyses examined associations between DSST decline and (i) two-way interactions of baseline LC integrity (or LFPN-FC) and PiB or (ii) the three-way interaction of baseline LC integrity, LFPN-FC, and PiB. Baseline age, sex, and years of education were included as covariates.
At baseline, lower LFPN-FC, but not LC integrity, was related to worse DSST performance. Longitudinally, lower baseline LC integrity was associated with a faster DSST decline, especially at PiB > 10.38 CL. Lower baseline LFPN-FC was associated with a steeper decline on the DSST but independent of PiB. At elevated PiB levels (> 46 CL), higher baseline LFPN-FC was associated with an attenuated decline on the DSST, despite the presence of lower LC integrity.
Our findings demonstrate that the LC can provide resilience against Aβ-related attention decline. However, when Aβ accumulates and the LC's resources may be depleted, the functioning of cortical target regions of the LC, such as the LFPN-FC, can provide additional resilience to sustain attentional performance in preclinical AD. These results provide critical insights into the neural correlates contributing to individual variability at risk versus resilience against Aβ-related cognitive decline.
尸检报告表明，蓝斑核（LC）中的神经元密度为认知能力下降提供了神经储备，以预防痴呆。最近的神经影像学和药理学研究报告称，左额顶网络功能连接（LFPN-FC）可以抵抗β-淀粉样蛋白（Aβ）相关的认知能力下降，这种认知能力下降发生在临床前散发性和常染色体显性阿尔茨海默病（AD）以及 LC 相关的认知变化中。鉴于 LFPN 和 LC 在注意力中起着重要作用，并且在疾病过程的早期就观察到了注意力缺陷，我们研究了 LFPN-FC 和 LC 结构健康是否会减轻 AD 病理背景下的注意力下降。
本研究纳入了来自哈佛衰老大脑研究的 142 名参与者，他们接受了静息态功能磁共振成像、LC 结构成像、PiB（Aβ）-PET 以及长达 5 年的认知随访（平均年龄为 74.5±9.9 岁，89 名女性）。使用稳健的线性回归对 LC 完整性（以结构 LC 图像中五个具有最高强度的连续体素的平均值来衡量）或 LFPN-FC 与基线时数字符号替换测试（DSST）表现进行了横断面关联。使用稳健的混合效应分析纵向检查了 DSST 下降与（i）基线 LC 完整性（或 LFPN-FC）和 PiB 的双向交互作用，或（ii）基线 LC 完整性、LFPN-FC 和 PiB 的三向交互作用之间的关联。将基线年龄、性别和受教育年限作为协变量。
在基线时，较低的 LFPN-FC，但不是 LC 完整性，与 DSST 表现较差相关。纵向分析显示，较低的基线 LC 完整性与 DSST 下降速度更快有关，尤其是在 PiB＞10.38 CL 时。较低的基线 LFPN-FC 与 DSST 的下降速度更快相关，但与 PiB 无关。在 PiB 水平升高（＞46 CL）时，较高的基线 LFPN-FC 与 DSST 下降速度减慢有关，尽管 LC 完整性较低。
我们的研究结果表明，LC 可以提供对 Aβ 相关注意力下降的适应能力。然而，当 Aβ 积累且 LC 的资源可能耗尽时，LC 的皮质靶区（如 LFPN-FC）的功能可以提供额外的适应能力，以维持临床前 AD 中的注意力表现。这些结果为个体易感性和对 Aβ 相关认知能力下降的适应能力的神经相关性提供了关键见解。
