Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania, Philadelphia, PA, USA.
Department of Neurology, Department of Epidemiology, Institute for Memory Impairments and Neurological Disorders, University of California at Irvine, Irvine, CA, USA.
Acta Neuropathol. 2018 Sep;136(3):377-388. doi: 10.1007/s00401-018-1872-5. Epub 2018 Jun 18.
The diagnosis of Alzheimer's disease (AD) in the oldest-old is complicated by the increasing prevalence of age-related neurofibrillary tangles, plaques and non-AD pathologies such as cerebrovascular disease (CVD), hippocampal sclerosis (HS), aging-related tau astrogliopathy (ARTAG), as well as TDP-43 and Lewy pathology. The contribution of these non-AD pathologies to dementia and cognitive resilience is unclear. We assessed the level of AD neuropathologic change (ADNPC) and non-AD pathology in 185 participants enrolled in The 90+ Study with available cognitive assessments and brain tissue. Logistic regression models-adjusting for age, sex and education-determined the association between each pathology and dementia or between subgroups. 53% had dementia, primarily AD or mixed AD; 23% had cognitive impairment without dementia (CIND); 23% were not impaired. Both AD and non-AD pathology was prevalent. 100% had tangles, 81% had plaques, and both tangles and plaques associated with dementia. ARTAG distributed across limbic (70%), brainstem (39%) and cortical regions (24%). 49% had possible CVD and 26% had definite CVD, while HS was noted in 15%. Cortical ARTAG, CVD and HS were each associated with dementia, but limbic and brainstem ARTAGs were not. TDP-43 and Lewy pathologies were found in 36 and 17% and both associated with dementia. No pathology distinguished CIND and the not impaired. By NIA-AA criteria and dementia status, the cohort was subdivided into four groups: those with minimal ADNPC included the not dementia (ND) and Not AD dementia groups; and those with significant ADNPC included the Resilient without dementia and AD dementia groups. Compared to the ND group, the Not AD dementia group had more HS, cortical ARTAG, TDP-43, and Lewy pathology. Compared to the AD dementia group, the Resilient group had less CVD, no HS and less cortical ARTAG, TDP-43 and Lewy pathology. Our findings imply that reductions in non-AD pathologies including CVD contribute to cognitive resilience in the oldest-old.
阿尔茨海默病（AD）在最年长人群中的诊断因与年龄相关的神经原纤维缠结、斑块和非 AD 病理学（如脑血管病[CVD]、海马硬化[HS]、与年龄相关的 Tau 星形胶质病[ARTAG]以及 TDP-43 和 Lewy 病理学）的患病率增加而变得复杂。这些非 AD 病理学对痴呆和认知储备的贡献尚不清楚。我们评估了 185 名参加 90+研究的参与者的 AD 神经病理学变化（ADNPC）和非 AD 病理学水平，这些参与者具有可用的认知评估和脑组织。逻辑回归模型调整了年龄、性别和教育，以确定每种病理学与痴呆或亚组之间的关联。53%的人患有痴呆症，主要是 AD 或混合 AD；23%的人患有认知障碍但无痴呆症（CIND）；23%的人没有受损。AD 和非 AD 病理学都很普遍。100%的人有缠结，81%的人有斑块，缠结和斑块都与痴呆有关。ARTAG 分布在边缘系统（70%）、脑干（39%）和皮质区域（24%）。49%的人可能有 CVD，26%的人有明确的 CVD，而 15%的人有 HS。皮质 ARTAG、CVD 和 HS 均与痴呆有关，但边缘和脑干 ARTAG 则没有。TDP-43 和 Lewy 病理学分别在 36%和 17%的人中发现，两者均与痴呆有关。没有病理学可以区分 CIND 和未受损者。根据 NIA-AA 标准和痴呆状态，该队列分为四组：ADNPC 最少的组包括未痴呆（ND）和非 AD 痴呆组；ADNPC 显著的组包括无痴呆的有弹性组和 AD 痴呆组。与 ND 组相比，非 AD 痴呆组有更多的 HS、皮质 ARTAG、TDP-43 和 Lewy 病理学。与 AD 痴呆组相比，有弹性组的 CVD 较少，没有 HS，皮质 ARTAG、TDP-43 和 Lewy 病理学也较少。我们的研究结果表明，包括 CVD 在内的非 AD 病理学的减少有助于最年长人群的认知储备。
