Dataset Information

Quantifying Beta-Galactosylceramide Kinetics in Cerebrospinal Fluid of Healthy Subjects Using Deuterium Labeling.

ABSTRACT: Therapeutics promoting myelin synthesis may enhance recovery in demyelinating diseases, such as multiple sclerosis. However, no suitable method exists to quantify myelination. The turnover of galactosylceramide (myelin component) is indicative of myelination in mice, but its turnover has not been determined in humans. Here, six healthy subjects consumed 120 mL 70% D2 O daily for 70 days to label galactosylceramide. We then used mass spectrometry and compartmental modeling to quantify the turnover rate of galactosylceramide in cerebrospinal fluid. Maximum deuterium enrichment of body water ranged from 1.5-3.9%, whereas that of galactosylceramide was much lower: 0.05-0.14%. This suggests a slow turnover rate, which was confirmed by the model-estimated galactosylceramide turnover rate of 0.00168 day-1 , which corresponds to a half-life of 413 days. Additional studies in patients with multiple sclerosis are needed to investigate whether galactosylceramide turnover could be used as an outcome measure in clinical trials with remyelination therapies.

SUBMITTER: Kanhai K

PROVIDER: S-EPMC5351000 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Quantifying Beta-Galactosylceramide Kinetics in Cerebrospinal Fluid of Healthy Subjects Using Deuterium Labeling.

Kanhai Kms K Goulooze S C SC Stevens J J Hay J L JL Dent G G Verma A A Hankemeier T T de Boer T T Meijering H H Chavez J C JC Cohen A F AF Groeneveld G J GJ

Clinical and translational science 20161015 6

Therapeutics promoting myelin synthesis may enhance recovery in demyelinating diseases, such as multiple sclerosis. However, no suitable method exists to quantify myelination. The turnover of galactosylceramide (myelin component) is indicative of myelination in mice, but its turnover has not been determined in humans. Here, six healthy subjects consumed 120 mL 70% D<sub>2</sub> O daily for 70 days to label galactosylceramide. We then used mass spectrometry and compartmental modeling to quantify ...[more]

PMID: 27743499

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Project description:In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-β1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-β1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-β amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-β1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-β1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-β1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-β1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.

Dataset Information

Quantifying Beta-Galactosylceramide Kinetics in Cerebrospinal Fluid of Healthy Subjects Using Deuterium Labeling.

Publications

Quantifying Beta-Galactosylceramide Kinetics in Cerebrospinal Fluid of Healthy Subjects Using Deuterium Labeling.

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