Dataset Information

A Longitudinal Study of Total and Phosphorylated ?-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer's Disease and Mild Cognitive Impairment.

ABSTRACT: Alzheimer's disease (AD) features a dynamic sequence of amyloid deposition, neurodegeneration, and cognitive impairment. A significant fraction of AD brains also displays Lewy body pathology, suggesting that addition of classically Parkinson's disease-related proteins to the AD biomarker panel may be of value. To determine whether addition of cerebrospinal fluid (CSF) total ?-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-?1-42 (A?42), tau, and phosphorylated tau (p-tau181)] improves its performance, we examined CSF samples collected longitudinally up to 7 years as part of the Alzheimer's Disease Neuroimaging Initiative. From 87 AD, 177 mild cognitive impairment (MCI), and 104 age-matched healthy controls, 792 baseline and longitudinal CSF samples were tested for total ?-synuclein, pS129, A?42, tau, and p-tau181. pS129, but not total ?-synuclein, was weakly associated with diagnosis at baseline when t-tau/A?42 was included in the statistical model (?=?0.0026, p?=?0.041, 95% CI [(0.0001)-(0.005)]). CSF ?-synuclein predicted Alzheimer's Disease Assessment Scale-Cognitive (?=?-0.59, p?=?0.0015, 95% CI [(-0.96)-(-0.23)]), memory (?=?0.4, p?=?0.00025, 95% CI [(0.16)-(0.59)]), and executive (0.62,<0.0001, 95% CI [(0.31)-(0.93)]) function composite scores, and progression from MCI to AD (?=?0.019, p?=?0.0011, 95% CI [(0.002)-(0.20)]). pS129 was associated with executive function (?=?-2.55, p?=?0.0085, 95% CI [(-4.45)-(-0.66)]). Lower values in the mismatch between ?-synuclein and p-tau181 predicted faster cognitive decline (?=?0.64, p?=?0.0012, 95% CI [(0.48)-(0.84)]). Longitudinal biomarker changes did not differ between groups, and may not reflect AD progression. The ?-synuclein-p-tau181-Mismatch could better predict longitudinal cognitive changes than classical AD markers alone, and its pathological correlates should be investigated further.

SUBMITTER: Wang H

PROVIDER: S-EPMC5828159 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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A Longitudinal Study of Total and Phosphorylated α-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer's Disease and Mild Cognitive Impairment.

Wang Hua H Stewart Tessandra T Toledo Jon B JB Ginghina Carmen C Tang Lu L Atik Anzari A Aro Patrick P Shaw Leslie M LM Trojanowski John Q JQ Galasko Douglas R DR Edland Steven S Jensen Poul H PH Shi Min M Zhang Jing J

Journal of Alzheimer's disease : JAD 20180101 4

Alzheimer's disease (AD) features a dynamic sequence of amyloid deposition, neurodegeneration, and cognitive impairment. A significant fraction of AD brains also displays Lewy body pathology, suggesting that addition of classically Parkinson's disease-related proteins to the AD biomarker panel may be of value. To determine whether addition of cerebrospinal fluid (CSF) total α-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-β1-42 (Aβ42), tau, and phosphory ...[more]

PMID: 29376878

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Project description:ObjectiveTo compare the effects of a 4-week high-saturated fat/high-glycemic index (HIGH) diet with a low-saturated fat/low-glycemic index (LOW) diet on insulin and lipid metabolism, cerebrospinal fluid (CSF) markers of Alzheimer disease, and cognition for healthy adults and adults with amnestic mild cognitive impairment (aMCI).DesignRandomized controlled trial.SettingVeterans Affairs Medical Center clinical research unit.ParticipantsForty-nine older adults (20 healthy adults with a mean [SD] age of 69.3 [7.4] years and 29 adults with aMCI with a mean [SD] age of 67.6 [6.8] years).InterventionParticipants received the HIGH diet (fat, 45% [saturated fat, > 25%]; carbohydrates, 35%-40% [glycemic index, > 70]; and protein, 15%-20%) or the LOW diet (fat, 25%; [saturated fat, < 7%]; carbohydrates, 55%-60% [glycemic index, < 55]; and protein, 15%-20%) for 4 weeks. Cognitive tests, an oral glucose tolerance test, and lumbar puncture were conducted at baseline and during the fourth week of the diet.Main outcome measuresThe CSF concentrations of β-amyloid (Aβ42 and Aβ40), tau protein, insulin, F2-isoprostanes, and apolipoprotein E, plasma lipids and insulin, and measures of cognition.ResultsFor the aMCI group, the LOW diet increased CSF Aβ42 concentrations, contrary to the pathologic pattern of lowered CSF Aβ42 typically observed in Alzheimer disease. The LOW diet had the opposite effect for healthy adults, ie, decreasing CSF Aβ42, whereas the HIGH diet increased CSF Aβ42. The CSF apolipoprotein E concentration was increased by the LOW diet and decreased by the HIGH diet for both groups. For the aMCI group, the CSF insulin concentration increased with the LOW diet, but the HIGH diet lowered the CSF insulin concentration for healthy adults. The HIGH diet increased and the LOW diet decreased plasma lipids, insulin, and CSF F2-isoprostane concentrations. Delayed visual memory improved for both groups after completion of 4 weeks of the LOW diet.ConclusionOur results suggest that diet may be a powerful environmental factor that modulates Alzheimer disease risk through its effects on central nervous system concentrations of Aβ42, lipoproteins, oxidative stress, and insulin.

Project description:BackgroundVisinin-like protein-1 (VILIP-1) and chitinase-3-like protein 1 (CHI3L1 or YKL-40) in cerebrospinal fluid (CSF) are newly discovered markers indicating neuronal damage and microglial activation, respectively. Phosphorylated tau (p-tau) reflects the neuropathology of Alzheimer's disease (AD) and is useful as diagnostic markers for AD. However, it is unknown whether these biomarkers have similar or complementary information in AD.MethodsWe stratified 121 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database into cognitively normal (CN), stable mild cognitive impairment (sMCI), progressive MCI (pMCI), and dementia due to AD. Analysis of covariance (ANOVA) and chi-square analyses, Spearman correlation, and logistic regression models were performed to test the demographic, associations between biomarkers, and diagnostic accuracies, respectively. Linear mixed-effects models were used to evaluate the effects of CSF amyloid-? (A?) on above biomarkers within diagnostic groups, the combination of diagnostic group and A? status as predictor, and CSF biomarkers as predictors of AD features, including cognition measured by Mini-Mental State Examination (MMSE) and brain structure and white matter hyperintensity (WMH) measured by magnetic resonance imaging (MRI).ResultsP-tau, VILIP-1, and YKL-40 were all predictors of AD diagnosis, but combinations of biomarkers did not improve the diagnostic accuracy (AUC 0.924 for p-tau, VILIP-1, and YKL-40) compared to p-tau (AUC 0.922). P-tau and VILIP-1 were highly correlated (r?=?0.639, p?<?0.001) and strongly associated with A? pathology across clinical stages of AD, while YKL-40 was correlated with A? pathology in CN and AD groups. VILIP-1 was associated with acceleration of cognitive decline, hippocampal atrophy, and expansion of ventricles in longitudinal analyses. YKL-40 was associated with hippocampal atrophy at baseline and follow-up, while p-tau was only associated with worsening WMH at baseline.ConclusionsCSF levels of p-tau, VILIP-1, and YKL-40 may have utility for discriminating between cognitively normal subjects and patients with AD. Increased levels of both VILIP-1 and YKL-40 may be associated with disease degeneration. These CSF biomarkers should be considered for future assessment in the characterization of the natural history of AD.

Dataset Information

A Longitudinal Study of Total and Phosphorylated ?-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer's Disease and Mild Cognitive Impairment.

Publications

A Longitudinal Study of Total and Phosphorylated α-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer's Disease and Mild Cognitive Impairment.

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