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Quantifications of CSF Apoptotic Bodies Do Not Provide Clinical Value in Multiple Sclerosis.

ABSTRACT: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) that leads to the death of neurons and oligodendrocytes, which cannot be measured in living subjects. Physiological cellular death, otherwise known as apoptosis, progresses through a series of stages which culminates in the discharge of cellular contents into vesicles known as apoptotic bodies (ABs) or apoptosomes. These ABs can be detected in bodily fluids as Annexin-V-positive vesicles of 0.5-4.0 ?m in size. In addition, the origin of these ABs might be detected by staining for cell-specific surface markers. Thus, we investigated whether quantifications of the total and CNS cell-specific ABs in the cerebrospinal fluid (CSF) of patients provided any clinical value in MS. Extracellular vesicles, from CSF of 64 prospectively-acquired subjects, were collected in a blinded fashion using ultra-centrifugation. ABs were detected by flow cytometry using bead-enabled size-gating and Annexin-V-staining. The origin of these ABs was further classified by staining the vesicles for cell-specific surface markers. Upon unblinding, we evaluated the differences between diagnostic categories and correlations with clinical measures. There were no statistically significant differences in the numbers of total or any cell-specific ABs across different disease diagnostic subgroups and no significant correlations with any of the tested clinical measures of CNS tissue destruction, disability, MS activity, and severity (i.e., rates of disability accumulation). Overlap of cell surface markers suggests inability to reliably determine origin of ABs using antibody-based flow cytometry. These negative data suggest that CNS cells in MS either die by non-apoptotic mechanisms or die in frequencies indistinguishable by current assays from apoptosis of other cells, such as immune cells performing immunosurveillance in healthy conditions.

SUBMITTER: Masvekar R

PROVIDER: S-EPMC6901963 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Quantifications of CSF Apoptotic Bodies Do Not Provide Clinical Value in Multiple Sclerosis.

Masvekar Ruturaj R Mizrahi Jordan J Park John J Williamson Peter R PR Bielekova Bibiana B

Frontiers in neurology 20191126

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) that leads to the death of neurons and oligodendrocytes, which cannot be measured in living subjects. Physiological cellular death, otherwise known as apoptosis, progresses through a series of stages which culminates in the discharge of cellular contents into vesicles known as apoptotic bodies (ABs) or apoptosomes. These ABs can be detected in bodily fluids as Annexin-V-positive vesicles of 0.5-4.0 μm in size. ...[more]

PMID: 31849814

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Project description:Neurodegeneration occurs during the early stages of multiple sclerosis. It is an essential, devastating part of the pathophysiology. Tools for measuring the degree of neurodegeneration could improve diagnostics and patient characterization.This study aimed to determine the diagnostic value of biomarkers of degeneration in patients with recent clinical onset of suspected multiple sclerosis, and to evaluate these biomarkers for characterizing disease course.This cross-sectional study included 271 patients with clinical features of suspected multiple sclerosis onset and was the baseline of a prospective study. After diagnostic investigations, the patients were classified into the following disease groups: patients with clinically isolated syndrome (n = 4) or early relapsing remitting multiple sclerosis (early RRMS; n = 93); patients with relapsing remitting multiple sclerosis with disease durations ?2 years (established RRMS; n = 39); patients without multiple sclerosis, but showing symptoms (symptomatic controls; n = 89); and patients diagnosed with other diseases (n = 46). In addition, we included healthy controls (n = 51) and patients with progressive multiple sclerosis (n = 23). We analyzed six biomarkers of neurodegeneration: cerebrospinal fluid neurofilament light chain levels; cerebral spinal fluid glial fibrillary acidic protein; cerebral spinal fluid tau; retinal nerve fiber layer thickness; macula volume; and the brain parenchymal fraction.Except for increased cerebral spinal fluid neurofilament light chain levels, median 670 ng/L (IQR 400-2110), we could not find signs of early degeneration in the early disease group with recent clinical onset. However, the intrathecal immunoglobin G production and cerebral spinal fluid neurofilament light chain levels showed diagnostic value. Moreover, elevated levels of cerebral spinal fluid glial fibrillary acidic protein, thin retinal nerve fiber layers, and low brain parenchymal fractions were associated with progressive disease, but not with the other phenotypes. Thin retinal nerve fiber layers and low brain parenchymal fractions, which indicated neurodegeneration, were associated with longer disease duration.In clinically suspected multiple sclerosis, intrathecal immunoglobin G production and neurofilament light chain levels had diagnostic value. Therefore, these biomarkers could be included in diagnostic work-ups for multiple sclerosis. We found that the thickness of the retinal nerve fiber layer and the brain parenchymal fraction were not different between individuals that were healthy, symptomatic, or newly diagnosed with multiple sclerosis. This finding suggested that neurodegeneration had not reached a significant magnitude in patients with a recent clinical onset of multiple sclerosis.

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Quantifications of CSF Apoptotic Bodies Do Not Provide Clinical Value in Multiple Sclerosis.

Publications

Quantifications of CSF Apoptotic Bodies Do Not Provide Clinical Value in Multiple Sclerosis.

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