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Cerebrospinal fluid ?-synuclein predicts neurodegeneration and clinical progression in non-demented elders.

ABSTRACT: BACKGROUND:Accumulating reports have suggested that ?-synuclein is involved in the pathogenesis of Alzheimer's disease (AD). As the cerebrospinal fluid (CSF) ?-synuclein has been suggested as a potential biomarker of AD, this study was set out to test whether CSF ?-synuclein is associated with other AD biomarkers and could predict neurodegeneration and clinical progression in non-demented elders. METHODS:The associations between CSF ?-synuclein and other AD biomarkers were investigated at baseline in non-demented Chinese elders. The predictive values of CSF ?-synuclein for longitudinal neuroimaging change and the conversion risk of non-demented elders were assessed using linear mixed effects models and multivariate Cox proportional hazard models, respectively, in the Alzheimer's disease Neuroimaging Initiative (ADNI) database. RESULTS:The CSF ?-synuclein levels correlated with AD-specific biomarkers, CSF total tau and phosphorylated tau levels, in 651 Chinese Han participants (training set). These positive correlations were replicated in the ADNI database (validation set). Using a longitudinal cohort from ADNI, the CSF ?-synuclein concentrations were found to increase with disease severity. The CSF ?-synuclein had high diagnostic accuracy for AD based on the "ATN" (amyloid, tau, neurodegeneration) system (A?+?T+ versus A?-?T?-?control) (area under the receiver operating characteristic curve, 0.84). Moreover, CSF ?-synuclein predicted longitudinal hippocampus atrophy and conversion from MCI to AD dementia. CONCLUSIONS:CSF ?-synuclein is associated with CSF tau levels and could predict neurodegeneration and clinical progression in non-demented elders. This finding indicates that CSF ?-synuclein is a potentially useful early biomarker for AD.

SUBMITTER: Li JQ

PROVIDER: S-EPMC7685645 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Cerebrospinal fluid α-synuclein predicts neurodegeneration and clinical progression in non-demented elders.

Li Jie-Qiong JQ Bi Yan-Lin YL Shen Xue-Ning XN Wang Hui-Fu HF Xu Wei W Tan Chen-Chen CC Dong Qiang Q Wang Yan-Jiang YJ Tan Lan L Yu Jin-Tai JT

Translational neurodegeneration 20201123 1

<h4>Background</h4>Accumulating reports have suggested that α-synuclein is involved in the pathogenesis of Alzheimer's disease (AD). As the cerebrospinal fluid (CSF) α-synuclein has been suggested as a potential biomarker of AD, this study was set out to test whether CSF α-synuclein is associated with other AD biomarkers and could predict neurodegeneration and clinical progression in non-demented elders.<h4>Methods</h4>The associations between CSF α-synuclein and other AD biomarkers were investi ...[more]

PMID: 33228804

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Project description:BackgroundThere are many pathological changes in the brains of Alzheimer's disease (AD) patients. For many years, the mainstream view on the pathogenesis of AD believes that β-amyloid (Aβ) usually acts independently in addition to triggering functions. However, the evidence now accumulating indicates another case that these pathological types have synergies. The objective of this study was to investigate whether effects of Aβ pathology on cognition were mediated by AD pathologies, including tau-related pathology (p-tau), neurodegeneration (t-tau, MRI measurements), axonal injury (NFL), synaptic dysfunction (neurogranin), and neuroinflammation (sTREM2, YKL-40).MethodsThree hundred seventy normal controls (CN) and 623 MCI patients from the ADNI (Alzheimer's Disease Neuroimaging Initiative) database were recruited in this research. Linear mixed-effects models were used to evaluate the associations of baseline Aβ with cognitive decline and biomarkers of several pathophysiological pathways. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects of AD pathologies on cognition.ResultsTau-related pathology, neurodegeneration, neuroinflammation are correlated with the concentration of Aβ, even in CN participants. The results show that age, gender, and APOE ε4 carrier status have a moderating influence on some of these relationships. There is a stronger association of Aβ with biomarkers and cognitive changes in the elderly and females. In CN group, Aβ pathology is directly related to poor cognition and has no mediating effect (p < 0.05). In mild cognitive impairment, tau-related pathology (26.15% of total effect) and neurodegeneration (14.8% to 47.0% of total effect) mediate the impact of Aβ on cognition.ConclusionsIn conclusion, early Aβ accumulation has an independent effect on cognitive decline in CN and a tau, neurodegeneration-dependent effect in the subsequent cognitive decline in MCI patients.

Dataset Information

Cerebrospinal fluid ?-synuclein predicts neurodegeneration and clinical progression in non-demented elders.

Publications

Cerebrospinal fluid α-synuclein predicts neurodegeneration and clinical progression in non-demented elders.

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