在无淀粉样蛋白的老年人群中，年龄、血管疾病和阿尔茨海默病病理。
Age, vascular disease, and Alzheimer's disease pathologies in amyloid negative elderly adults.
机构信息
Institute of Biomedical Engineering, Shenzhen Bay Laboratory, No.5 Kelian Road, Shenzhen, 518132, China.
Helen Wills Neuroscience Institute, University of California, Berkeley, CA, 94720, USA.
出版信息
Alzheimers Res Ther. 2021 Oct 15;13(1):174. doi: 10.1186/s13195-021-00913-5.
BACKGROUND
We recently reported that CSF phosphorylated tau (p-Tau) relative to Aβ (CSF p-Tau/Aβ ratio) was less noisy and increased associations with Alzheimer's disease (AD) biomarkers compared to CSF p-Tau alone. While elevations of CSF p-Tau/Aβ can occur in amyloid-β (Aβ) negative (Aβ-) individuals, the factors associated with these elevations and their role in neurodegeneration and cognitive decline are unknown. We aim to explore factors associated with elevated tau in CSF, and how these elevated tau are related to neurodegeneration and cognitive decline in the absence of Aβ positivity.
METHODS
We examined relationships between CSF p-Tau/Aβ, and CSF Aβ/Aβ, Aβ PET, and white matter hyperintensities (WMH) as well as vascular risk factors in 149 cognitively unimpaired and 52 impaired individuals who were presumably not on the Alzheimer's disease (AD) pathway due to negative Aβ status on both CSF and PET. Subgroups had F-fluorodeoxyglucose (FDG) PET and adjusted hippocampal volume (aHCV), and longitudinal measures of CSF, aHCV, FDG PET, and cognition data, so we examined CSF p-Tau/Aβ associations with these measures as well.
RESULTS
Elevated CSF p-Tau/Aβ was associated with older age, male sex, greater WMH, and hypertension as well as a pattern of hippocampal atrophy and temporoparietal hypometabolism characteristic of AD. Lower CSF Aβ/Aβ, higher WMH, and hypertension but not age, sex, Aβ PET, APOE-ε4 status, body mass index, smoking, and hyperlipidemia at baseline predicted CSF p-Tau/Aβ increases over approximately 5 years of follow-up. The relationship between CSF p-Tau/Aβ and subsequent cognitive decline was partially or fully explained by neurodegenerative measurements.
CONCLUSIONS
These data provide surprising clues as to the etiology and significance of tau pathology in the absence of Aβ. It seems likely that, in addition to age, both cerebrovascular disease and subthreshold levels of Aβ are related to this tau accumulation. Crucially, this phenotype of CSF tau elevation in amyloid-negative individuals share features with AD such as a pattern of metabolic decline and regional brain atrophy.
背景
我们最近报道称，与单独的 CSF 磷酸化 tau（p-Tau）相比，CSF 磷酸化 tau 与 Aβ（CSF p-Tau/Aβ 比值）的比值（CSF p-Tau/Aβ ratio）噪音更小，与阿尔茨海默病（AD）生物标志物的关联更强。虽然 CSF p-Tau/Aβ 在淀粉样蛋白-β（Aβ）阴性（Aβ-）个体中也会升高，但与这些升高相关的因素及其在神经退行性变和认知能力下降中的作用尚不清楚。我们旨在探讨与 CSF 中 tau 升高相关的因素，以及在没有 Aβ 阳性的情况下，这些升高的 tau 与神经退行性变和认知能力下降的关系。
方法
我们在 149 名认知正常和 52 名认知障碍个体中检查了 CSF p-Tau/Aβ 与 CSF Aβ/Aβ、Aβ PET 和脑白质高信号（WMH）以及血管危险因素之间的关系，这些个体由于 CSF 和 PET 上的 Aβ 均为阴性，因此推测未处于阿尔茨海默病（AD）通路中。亚组进行了 F-氟脱氧葡萄糖（FDG）PET 和调整后的海马体积（aHCV）以及 CSF、aHCV、FDG PET 和认知数据的纵向测量，因此我们还检查了 CSF p-Tau/Aβ 与这些测量值的相关性。
结果
升高的 CSF p-Tau/Aβ 与年龄较大、男性、更大的 WMH 和高血压以及 AD 特征性的海马萎缩和颞顶叶代谢减退模式有关。较低的 CSF Aβ/Aβ、更高的 WMH 和高血压，但不是年龄、性别、Aβ PET、APOE-ε4 状态、体重指数、吸烟和高脂血症，预测 CSF p-Tau/Aβ 在大约 5 年的随访期间增加。CSF p-Tau/Aβ 与随后认知能力下降之间的关系部分或完全由神经退行性变测量解释。
结论
这些数据为 Aβ 阴性时 tau 病理学的病因和意义提供了令人惊讶的线索。除了年龄之外，脑血管疾病和亚阈值水平的 Aβ 似乎都与这种 tau 积累有关，这似乎很有可能。至关重要的是，在 Aβ 阴性个体中，CSF tau 升高的这种表型与 AD 具有相似的特征，例如代谢下降和区域脑萎缩的模式。
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