Cerebrospinal fluid α-synuclein predicts cognitive decline in Parkinson disease progression in the DATATOP cohort.
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SUBMITTER: Stewart T
PROVIDER: S-EPMC3969999 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC7685645 | biostudies-literature
Project description:There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis, differential diagnosis of Parkinsonian disorders, and monitoring disease progression. We and others have demonstrated that a decrease in DJ-1 and/or ?-synuclein in the cerebrospinal fluid (CSF) is a potential index for Parkinson disease diagnosis, but not for PD severity.Using highly sensitive and quantitative Luminex assays, we measured total tau, phosphorylated tau, amyloid beta peptide 1-42 (A?(1-42)), Flt3 ligand, and fractalkine levels in CSF in a large cohort of PD patients at different stages as well as healthy and diseased controls. The utility of these 5 markers was evaluated for disease diagnosis and severity/progression correlation alone, as well as in combination with DJ-1 and ?-synuclein. The major results were further validated in an independent cohort of cross-sectional PD patients as well as in PD cases with CSF samples collected longitudinally.The results demonstrated that combinations of these biomarkers could differentiate PD patients not only from normal controls but also from patients with Alzheimer disease (AD) and multiple system atrophy. Particularly, with CSF Flt3 ligand, PD could be clearly differentiated from multiple system atrophy, a disease that overlaps with PD clinically, with excellent sensitivity (99%) and specificity (95%). In addition, we identified CSF fractalkine/A?(1-42) that positively correlated with PD severity in cross-sectional samples as well as with PD progression in longitudinal samples.We have demonstrated that this panel of 7 CSF proteins could aid in Parkinson disease diagnosis, differential diagnosis, and correlation with disease severity and progression.
| S-EPMC3117674 | biostudies-literature
Project description:BACKGROUND:The genetic architecture of Parkinson's Disease (PD) is complex and not completely understood. Multiple genetic studies to date have identified multiple causal genes and risk loci. Nevertheless, most of the expected genetic heritability remains unexplained. Polygenic risk scores (PRS) may provide greater statistical power and inform about the genetic architecture of multiple phenotypes. The aim of this study was to test the association between PRS and PD risk, age at onset and cerebrospinal fluid (CSF) biomarkers (?-synuclein, A?1-42, t-tau and p-tau). METHODS:The weighted PRS was created using the genome-wide loci from Nalls et al., 2014 PD GWAs meta-analysis. The PRS was tested for association with PD status, age at onset and CSF biomarker levels in 829 cases and 432 controls of European ancestry. RESULTS:The PRS was associated with PD status (p?=?5.83×10-08) and age at onset (p?=?5.70×10-07). The CSF t-tau levels showed a nominal association with the PRS (p?=?0.02). However, CSF ?-synuclein, amyloid beta and phosphorylated tau were not found to be associated with the PRS. CONCLUSION:Our study suggests that there is an overlap in the genetic architecture of PD risk and onset, although the different loci present different weights for those phenotypes. In our dataset we found a marginal association of the PRS with CSF t-tau but not with ?-synuclein CSF levels, suggesting that the genetic architecture for the CSF biomarker levels is different from that of PD risk.
| S-EPMC5688622 | biostudies-literature
Project description:To assess the discriminating power of multiple cerebrospinal fluid (CSF) biomarkers for Parkinson's disease (PD), we measured several proteins playing an important role in the disease pathogenesis. The activities of ?-glucocerebrosidase and other lysosomal enzymes, together with total and oligomeric ?-synuclein, and total and phosphorylated tau, were thus assessed in CSF of 71 PD patients and compared to 45 neurological controls. Activities of ?-glucocerebrosidase, ?-mannosidase, ?-hexosaminidase, and ?-galactosidase were measured with established enzymatic assays, while ?-synuclein and tau biomarkers were evaluated with immunoassays. A subset of PD patients (n?=?44) was also screened for mutations in the ?-glucocerebrosidase-encoding gene (GBA1). In the PD group, ?-glucocerebrosidase activity was reduced (P?<?0.05) and patients at earlier stages showed lower enzymatic activity (P?<?0.05); conversely, ?-hexosaminidase activity was significantly increased (P?<?0.05). Eight PD patients (18%) presented GBA1 sequence variations; 3 of them were heterozygous for the N370S mutation. Levels of total ?-synuclein were significantly reduced (P?<?0.05) in PD, in contrast to increased levels of ?-synuclein oligomers, with a higher oligomeric/total ?-synuclein ratio in PD patients when compared with controls (P?<?0.001). A combination of ?-glucocerebrosidase activity, oligomeric/total ?-synuclein ratio, and age gave the best performance in discriminating PD from neurological controls (sensitivity 82%; specificity 71%, area under the receiver operating characteristic curve?=?0.87). These results demonstrate the possibility of detecting lysosomal dysfunction in CSF and further support the need to combine different biomarkers for improving the diagnostic accuracy of PD.
| S-EPMC4282452 | biostudies-literature
Project description:α-Synuclein aggregates, a key hallmark of the pathogenesis of Parkinson's disease, can be amplified by using their seeding activity, and the evaluation of the seeding activity of cerebrospinal fluid (CSF) is reportedly useful for diagnosis. However, conventional shaking-based assays are time-consuming procedures, and the clinical significance of the diversity of seeding activity among patients remains to be clarified. Previously, we reported a high-throughput ultrasonication-induced amyloid fibrillation assay. Here, we adapted this assay to amplify and detect α-synuclein aggregates from CSF, and investigated the correlation between seeding activity and clinical indicators. We confirmed that this assay could detect α-synuclein aggregates prepared in vitro and also aggregates released from cultured cells. The seeding activity of CSF correlated with the levels of α-synuclein oligomers measured by an enzyme-linked immunosorbent assay. Moreover, the seeding activity of CSF from patients with Parkinson's disease was higher than that of control patients. Notably, the lag time of patients with Parkinson's disease was significantly correlated with the MIBG heart-to-mediastinum ratio. These findings showed that our ultrasonication-based assay can rapidly amplify misfolded α-synuclein and can evaluate the seeding activity of CSF.
| S-EPMC6461702 | biostudies-literature
Project description:In addition to amyloid-? (A?) and tau, ?-synuclein, best known for its role in Parkinson's disease (PD), has been suggested to be involved in cognition and pathogenesis of Alzheimer's disease (AD). We investigate the potential of ?-synuclein in cerebrospinal fluid (CSF) as a biomarker of cognitive decline in AD, and its prodromal phase, mild cognitive impairment (MCI). Using an established, sensitive Luminex assay, we measured ?-synuclein levels in the CSF of a cohort of close to 400 healthy control, MCI, and AD subjects obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and factored in APOE genotype in data analysis. CSF ?-synuclein levels were significantly higher in the MCI (p = 0.005) and AD (p < 0.001) groups, compared to controls. However, receiver operating characteristic (ROC) curve analysis suggests that CSF ?-synuclein level on its own only offered modest sensitivity (65%) and specificity (74%) as a diagnostic marker of AD, with an area under the curve (AUC) value of 0.719 for AD versus controls. The effect of APOE genotype, if any, was quite subtle. However, there was a significant correlation between ?-synuclein and cognition (p = 0.001), with increased ?-synuclein levels associated with decreased Mini-Mental State Exam scores. Our results support a role for ?-synuclein even in MCI, the early phase of AD, in addition to being a potential contributor in MCI and AD diagnosis or monitoring of disease progression.
| S-EPMC3740054 | biostudies-literature
Project description:Total CSF ?-synuclein (t-?-syn), phosphorylated ?-syn (pS129-?-syn) and ?-syn oligomers (o-?-syn) have been studied as candidate biomarkers for synucleinopathies, with suboptimal specificity and sensitivity in the differentiation from healthy controls. Studies of ?-syn species in patients with other underlying pathologies are lacking. The aim of this study was to investigate possible alterations in CSF ?-syn species in a cohort of patients with diverse underlying pathologies. A total of 135 patients were included, comprising Parkinson's disease (PD; n = 13), multiple system atrophy (MSA; n = 9), progressive supranuclear palsy (PSP; n = 13), corticobasal degeneration (CBD; n = 9), Alzheimer's disease (AD; n = 51), frontotemporal degeneration (FTD; n = 26) and vascular dementia patients (VD; n = 14). PD patients exhibited higher pS129-?-syn/?-syn ratios compared to FTD (p = 0.045), after exclusion of samples with CSF blood contamination. When comparing movement disorders (i.e., MSA vs. PD vs. PSP vs. CBD), MSA patients had lower ?-syn levels compared to CBD (p = 0.024). Patients with a synucleinopathy (PD and MSA) exhibited lower t-?-syn levels (p = 0.002; cut-off value: ?865 pg/mL; sensitivity: 95%, specificity: 69%) and higher pS129-/t-?-syn ratios (p = 0.020; cut-off value: ?0.122; sensitivity: 71%, specificity: 77%) compared to patients with tauopathies (PSP and CBD). There are no significant ?-syn species alterations in non-synucleinopathies.
| S-EPMC7830324 | biostudies-literature
Project description:ObjectiveCognitive decline associated with Parkinson disease (PD) is common and highly disabling. Biomarkers that help identify patients at risk for cognitive decline would be useful additions to the clinical management of the disease.MethodsA total of 45 patients with PD were enrolled in this prospective cohort study and had at least 1 yearly longitudinal follow-up evaluation. CSF was collected at baseline and cognition was assessed at baseline and follow-up visits using the Mattis Dementia Rating Scale (DRS-2). CSF was tested for amyloid β 1-42 (Aβ(1-42)), p-tau(181p), and total tau levels using the Luminex xMAP platform. Mixed linear models were used to test for associations between baseline CSF biomarker levels and change in cognition over time.ResultsLower baseline CSF Aβ(1-42) was associated with more rapid cognitive decline. Subjects with CSF Aβ(1-42) levels ≤192 pg/mL declined an average of 5.85 (95% confidence interval 2.11-9.58, p = 0.002) points per year more rapidly on the DRS-2 than subjects above that cutoff, after adjustment for age, disease duration, and baseline cognitive status. CSF total tau and p-tau(181p) levels were not significantly associated with cognitive decline.ConclusionsReduced CSF Aβ(1-42) was an independent predictor of cognitive decline in patients with PD. This observation is consistent with previous research showing that Alzheimer disease pathology contributes to cognitive impairment in PD. This biomarker may provide clinically useful prognostic information, particularly if combined with other risk factors for cognitive impairment in PD.
| S-EPMC2942062 | biostudies-literature
Project description:IntroductionElevated cortisol levels have been reported in Alzheimer's disease (AD) and may accelerate the development of brain pathology and cognitive decline. Dehydroepiandrosterone sulfate (DHEAS) has anti-glucocorticoid effects and it may be involved in the AD pathophysiology.ObjectivesTo investigate associations of cerebrospinal fluid (CSF) cortisol and DHEAS levels with (1) cognitive performance at baseline; (2) CSF biomarkers of amyloid pathology (as assessed by CSF Aβ levels), neuronal injury (as assessed by CSF tau), and tau hyperphosphorylation (as assessed by CSF p-tau); (3) regional brain volumes; and (4) clinical disease progression.Materials and methodsIndividuals between 49 and 88 years (n = 145) with mild cognitive impairment or dementia or with normal cognition were included. Clinical scores, AD biomarkers, brain MRI volumetry along with CSF cortisol and DHEAS were obtained at baseline. Cognitive and functional performance was re-assessed at 18 and 36 months from baseline. We also assessed the following covariates: apolipoprotein E (APOE) genotype, BMI, and education. We used linear regression and mixed models to address associations of interest.ResultsHigher CSF cortisol was associated with poorer global cognitive performance and higher disease severity at baseline. Cortisol and cortisol/DHEAS ratio were positively associated with tau and p-tau CSF levels, and negatively associated with the amygdala and insula volumes at baseline. Higher CSF cortisol predicted more pronounced cognitive decline and clinical disease progression over 36 months. Higher CSF DHEAS predicted more pronounced disease progression over 36 months.ConclusionIncreased cortisol in the CNS is associated with tau pathology and neurodegeneration, and with decreased insula and amygdala volume. Both CSF cortisol and DHEAS levels predict faster clinical disease progression. These results have implications for the identification of patients at risk of rapid decline as well as for the development of interventions targeting both neurodegeneration and clinical manifestations of AD.
| S-EPMC9301040 | biostudies-literature
Project description:BackgroundThe objective of this study was to investigate the discriminating value of a range of CSF α-synuclein species for dementia with Lewy bodies compared with Alzheimer's disease, PD, and cognitively normal controls.MethodsWe applied our recently published enzyme-linked immunosorbent assays to measure the CSF levels of total α-synuclein, oligomeric α-synuclein, and phosphorylated α-synuclein in dementia with Lewy bodies (n = 42), Alzheimer's disease (n = 39), PD (n = 46), and controls (n = 78). General linear models corrected for age and sex were performed to assess differences in α-synuclein levels between groups. We used backward-elimination logistic regression analysis to investigate the combined discriminating value of the different CSF α-synuclein species and Alzheimer's disease biomarkers.ResultsCSF levels of total α-synuclein were lower in dementia with Lewy bodies and PD compared with Alzheimer's disease as well as controls (P < 0.001). In contrast, CSF levels of oligomeric α-synuclein were higher in dementia with Lewy bodies and PD compared with Alzheimer's disease (P < 0.05) and controls (P < 0.001). No group differences were found for phosphorylated α-synuclein. In dementia with Lewy bodies and PD, CSF total α-synuclein levels positively correlated with tau and phosphorylated tau (both r > 0.40, P < 0.01), but not with amyloid-β1-42 . The optimal combination to differentiate dementia with Lewy bodies from controls consisted of amyloid-β1-42 , tau, total α-synuclein, oligomeric α-synuclein, age, and sex (AUC, 0.90). To differentiate dementia with Lewy bodies from Alzheimer's disease, the combination of tau and oligomeric α-synuclein resulted in an AUC of 0.83. CSF α-synuclein species do not contribute to the differentiation of dementia with Lewy bodies from PD.ConclusionsCSF α-synuclein species could be useful as part of a biomarker panel for dementia with Lewy bodies. Evaluating both oligomeric α-synuclein and total α-synuclein in CSF helps in the diagnosis of dementia with Lewy bodies. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
| S-EPMC6519232 | biostudies-literature