Kelly Sarah C, Nelson Peter T, Counts Scott E
From the Department of Translational Neuroscience, Michigan State University, Grand Rapids, Michigan.
Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky.
J Neuropathol Exp Neurol. 2021 Mar 22;80(4):325-335. doi: 10.1093/jnen/nlab017.
Locus coeruleus (LC) neurodegeneration is associated with cognitive deterioration during the transition from normal cognition to mild cognitive impairment (MCI) and Alzheimer disease (AD). However, the extent to which LC degenerative processes differentiate cognitively normal, "resilient" subjects bearing a high AD pathological burden from those with MCI or AD remains unclear. We approached this problem by quantifying the number of LC neurons and the percentage of LC neurons bearing AT8 tau pathology, TDP-43 pathology, or a marker for DNA/RNA oxidative damage, in well-characterized subjects diagnosed as normal cognition-low AD pathology (NC-LP), NC-high AD pathology (NC-HP), MCI, or mild/moderate AD. In addition, the severity of pontine arteriolosclerosis in each subject was compared across the groups. There was a trend for a step-wise ∼20% loss of LC neuron number between the NC-LP, NC-HP and MCI subjects despite a successive, significant ∼80%-100% increase in tau pathology between these groups. In contrast, increasing pontine arteriolosclerosis severity scores and LC oxidative stress burden significantly separated the NC-LP/HP and MCI/AD groups via comparative, correlation, and regression analysis. Pontine perfusion, as well as LC neuronal metabolic and redox function, may impact noradrenergic LC modulation of cognition during the preclinical and prodromal stages of AD.
蓝斑（LC）神经变性与从正常认知向轻度认知障碍（MCI）和阿尔茨海默病（AD）转变过程中的认知衰退有关。然而，LC退行性变过程在区分认知正常、携带高AD病理负担的“有韧性”受试者与MCI或AD受试者方面的程度仍不清楚。我们通过量化确诊为正常认知-低AD病理（NC-LP）、正常认知-高AD病理（NC-HP）、MCI或轻度/中度AD的特征明确的受试者中LC神经元的数量以及携带AT8 tau病理、TDP-43病理或DNA/RNA氧化损伤标志物的LC神经元的百分比来解决这个问题。此外，还比较了各组中每个受试者脑桥小动脉硬化的严重程度。尽管这些组之间tau病理连续显著增加约80%-100%，但在NC-LP、NC-HP和MCI受试者之间，LC神经元数量有逐步减少约20%的趋势。相比之下，通过比较、相关性和回归分析，增加的脑桥小动脉硬化严重程度评分和LC氧化应激负担显著区分了NC-LP/HP和MCI/AD组。在AD的临床前和前驱阶段，脑桥灌注以及LC神经元的代谢和氧化还原功能可能会影响去甲肾上腺素能LC对认知的调节。
