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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.

Project description:Huntington's disease (HD) is a hereditary neurodegenerative condition with no therapeutic intervention known to alter disease progression, but several trials are ongoing and biomarkers of disease progression are needed. Tau is an axonal protein, often altered in neurodegeneration, and recent studies pointed out its role on HD neuropathology. Our goal was to study whether cerebrospinal fluid (CSF) tau is a biomarker of disease progression in HD. After informed consent, healthy controls, pre-symptomatic and symptomatic gene expansion carriers were recruited from two HD clinics. All participants underwent assessment with the Unified HD Rating Scale '99 (UHDRS). CSF was obtained according to a standardized lumbar puncture protocol. CSF tau was quantified using enzyme-linked immunosorbent assay. Comparisons between two groups were tested using ancova. Pearson's correlation coefficients were calculated for disease progression. Significance level was defined as p < 0.05. Seventy-six participants were included in this cross-sectional multicenter international pilot study. Age-adjusted CSF tau was significantly elevated in gene expansion carriers compared with healthy controls (p = 0.002). UHDRS total functional capacity was significantly correlated with CSF tau (r = -0.29, p = 0.004) after adjustment for age, and UHDRS total motor score was significantly correlated with CSF tau after adjustment for age (r = 0.32, p = 0.002). Several UHDRS cognitive tasks were also significantly correlated with CST total tau after age-adjustment. This study confirms that CSF tau concentrations in HD gene mutation carriers are increased compared with healthy controls and reports for the first time that CSF tau concentration is associated with phenotypic variability in HD. These conclusions strengthen the case for CSF tau as a biomarker in HD. In the era of novel targeted approaches to Huntington's disease, reliable biomarkers are needed. We quantified Tau protein, a marker of neuronal death, in cerebrospinal fluid and found it was increased in patients with Huntington's disease and predicted motor, cognitive, and functional disability in patients. It is therefore likely to be a biomarker of disease progression, and possibly of therapeutic response. Read the Editorial Highlight for this article on page 9.

Project description:ObjectiveTo develop and externally validate models to predict probabilities of alpha-synuclein (a-syn) positive or negative status in vivo in a mixture of people with and without Parkinson's disease (PD) using easily accessible clinical predictors.MethodsUni- and multi-variable logistic regression models were developed in a cohort of participants from the Parkinson Progression Marker Initiative (PPMI) study to predict cerebrospinal fluid (CSF) a-syn status as measured by seeding amplification assay (SAA). Models were externally validated in a cohort of participants from the Systemic Synuclein Sampling Study (S4) that had also measured CSF a-syn status using SAA.ResultsThe PPMI model training/testing cohort consisted of 1260 participants, of which 76% had manifest PD with a mean (± standard deviation) disease duration of 1.2 (±1.6) years. Overall, 68.7% of the overall PPMI cohort (and 88.0% with PD of those with manifest PD) had positive CSF a-syn SAA status results. Variables from the full multivariable model to predict CSF a-syn SAA status included age- and sex-specific University of Pennsylvania Smell Identification Test (UPSIT) percentile values, sex, self-reported presence of constipation problems, leucine-rich repeat kinase 2 (LRRK2) genetic status and pathogenic variant, and GBA status. Internal performance of the model on PPMI data to predict CSF a-syn SAA status had an area under the receiver operating characteristic curve (AUROC) of 0.920, and sensitivity/specificity of 0.881/0.845. When this model was applied to the external S4 cohort, which included 71 participants (70.4% with manifest PD for a mean 5.1 (±4.8) years), it performed well, achieving an AUROC of 0.976, and sensitivity/specificity of 0.958/0.870. Models using only UPSIT percentile performed similarly well upon internal and external testing.ConclusionData-driven models using non-invasive clinical features can accurately predict CSF a-syn SAA positive and negative status in cohorts enriched for people living with PD. Scores from the UPSIT were highly significant in predicting a-syn SAA status.

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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