From the Department of Medicine (A.P.M., C.M.C., S.C.J., S.A., B.B.B.), Wisconsin Alzheimer's Disease Research Center, and Neuroscience and Public Policy Program (A.P.M.), University of Wisconsin; Geriatric Research Education and Clinical Center (C.M.C., S.C.J., S.A.), William S. Middleton Memorial Veteran's Hospital; Wisconsin Alzheimer's Institute (S.C.J.), Madison; Department of Neurology (S.E.S.), Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO; Department of Psychiatry and Neurochemistry (K.B., H.Z.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg; Clinical Neurochemistry Laboratory (K.B., H.Z.), Sahlgrenska University Hospital, Mölndal, Sweden; Institute of Neurology (H.Z.), University College London, Queen Square; and UK Dementia Research Institute (H.Z.), London.
Neurology. 2018 Jul 31;91(5):e436-e443. doi: 10.1212/WNL.0000000000005901. Epub 2018 Jun 29.
To test the hypothesis that cognitively unimpaired individuals with Alzheimer disease (AD) neuropathology differ from individuals with AD dementia on biomarkers of neurodegeneration, synaptic dysfunction, and glial activation.
In a cross-sectional study, adult participants >70 years old (n = 79, age 77.1 ± 5.3 years) underwent comprehensive cognitive evaluation and CSF collection, which was assayed for markers of amyloid, phosphorylated tau (p-tau), neurodegeneration (neurofilament light protein [NFL] and total tau), synaptic dysfunction (neurogranin), and glial activation (chitinase-3-like protein 1 [YKL-40]). Participants were divided into 3 groups based on diagnosis and p-tau/β-amyloid (Aβ): those with low p-tau/Aβ and unimpaired cognition were classified as controls (n = 25); those with high p-tau/Aβ diagnosed with AD-dementia or AD-mild cognitive impairment were classified as AD-Dementia (n = 40); and those with high p-tau/Aβ but unimpaired cognition were classified as mismatches (n = 14). A similar, secondary analysis was performed with no age exclusion criteria (n = 411).
In both the primary and secondary analyses, biomarker levels between groups were compared with the use of analysis of covariance while controlling for age and demographic variables. Despite p-tau/Aβ and Aβ/Aβ levels comparable to those of the AD-Dementia group, mismatches had significantly lower levels of NFL and total tau. While not significantly lower than the AD-Dementia group on YKL-40 and neurogranin, mismatches were also not significantly different from controls.
These results provide evidence that, in the absence of significant neurodegenerative processes, individuals who harbor AD neuropathology may remain cognitively unimpaired. This finding provides insight into the biological processes phenotypic of dementia and supports monitoring multiple biomarkers in individuals positive for AD neuropathology.
检验假设，即阿尔茨海默病（AD）神经病理学认知正常的个体与 AD 痴呆患者在神经退行性变、突触功能障碍和神经胶质激活的生物标志物上存在差异。
在一项横断面研究中，纳入年龄＞70 岁的成年参与者（n=79，年龄 77.1±5.3 岁），进行全面认知评估和 CSF 采集，对淀粉样蛋白、磷酸化 tau（p-tau）、神经退行性变（神经丝轻链蛋白[NFL]和总 tau）、突触功能障碍（神经颗粒素）和神经胶质激活（几丁质酶 3 样蛋白 1[YKL-40]）标志物进行检测。根据诊断和 p-tau/β-淀粉样蛋白（Aβ）将参与者分为 3 组：低 p-tau/Aβ 且认知正常的参与者被归类为对照组（n=25）；高 p-tau/Aβ 诊断为 AD 痴呆或 AD 轻度认知障碍的患者被归类为 AD-痴呆组（n=40）；高 p-tau/Aβ 但认知正常的患者被归类为不匹配组（n=14）。同时进行了类似的、无年龄排除标准的二次分析（n=411）。
在主要和次要分析中，使用协方差分析比较了各组间的生物标志物水平，同时控制年龄和人口统计学变量。尽管不匹配组的 p-tau/Aβ 和 Aβ/Aβ 水平与 AD-痴呆组相当，但 NFL 和总 tau 水平明显更低。虽然 YKL-40 和神经颗粒素水平与 AD-痴呆组无显著差异，但不匹配组与对照组也无显著差异。
这些结果提供了证据表明，在没有明显神经退行性过程的情况下，携带 AD 神经病理学的个体可能仍然认知正常。这一发现深入了解了痴呆的生物学过程，并支持对 AD 神经病理学阳性个体进行多种生物标志物的监测。
