Dataset Information

Imaging Characteristics of Choroid Plexuses in Presymptomatic Multiple Sclerosis: A Retrospective Study.

ABSTRACT:

Background and objectives

Recent imaging studies have suggested a possible involvement of the choroid plexus (CP) in multiple sclerosis (MS). Here, we investigated whether CP changes are already detectable at the earliest stage of MS, preceding symptom onset.

Methods

This study is a retrospective analysis of 27 patients with presymptomatic MS, 97 patients with clinically definite MS (CDMS), and 53 healthy controls (HCs) who underwent a cross-sectional 3T-MRI acquisition; of which, 22 MS, 19 HCs, and 1 presymptomatic MS (evaluated 8 months before conversion to CDMS) also underwent translocator protein (TSPO) ¹⁸F-DPA-714 PET and were included in the analysis. CPs were manually segmented on 3D T1-weighted images for volumetric analysis. CP ¹⁸F-DPA-714 uptake, reflecting inflammation, was calculated as the average standardized uptake value (SUV). Multivariable regressions adjusted for age, sex, and ventricular and brain volume were fitted to test CP volume differences between presymptomatic patients and MS or HCs. For the presymptomatic case who also had ¹⁸F-DPA-714 PET, CP SUV differences with MS and HCs were assessed through Crawford-Howell tests. To provide further insight into the interpretation of ¹⁸F-DPA-714-PET uptake at the CP level, a postmortem analysis of CPs in MS vs HCs was performed to characterize the cellular localization of TSPO expression.

Results

Compared with HCs, patients with presymptomatic MS had 32% larger CPs (β = 0.38, p = 0.001), which were not dissimilar to MS CPs (p = 0.69). Moreover, in the baseline scan of the presymptomatic case who later on developed MS, TSPO PET showed 33% greater CP inflammation vs HCs (p = 0.04), although no differences in ¹⁸F-DPA-714 uptake were found in parenchymal regions vs controls. CP postmortem analysis identified a population of CD163⁺ mononuclear phagocytes expressing TSPO in MS, possibly contributing to the increased ¹⁸F-DPA-714 uptake.

Discussion

We identified an imaging signature in CPs at the presymptomatic MS stage using MRI; in addition, we found an increased CP inflammation with PET in a single presymptomatic patient. These findings suggest a role of CP imaging as an early biomarker and argue for the involvement of the blood-CSF barrier dysfunction in disease development.

Trial registration information

APHP-20210727144630, EudraCT-Number: 2008-004174-40; ClinicalTrials.gov: NCT02305264, NCT01651520, and NCT02319382.

SUBMITTER: Ricigliano VAG

PROVIDER: S-EPMC9562043 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

Imaging Characteristics of Choroid Plexuses in Presymptomatic Multiple Sclerosis: A Retrospective Study.

Ricigliano Vito A G VAG Louapre Céline C Poirion Emilie E Colombi Annalisa A Yazdan Panah Arya A Lazzarotto Andrea A Morena Emanuele E Martin Elodie E Bottlaender Michel M Bodini Benedetta B Seilhean Danielle D Stankoff Bruno B

Neurology(R) neuroimmunology & neuroinflammation 20221013 6

<h4>Background and objectives</h4>Recent imaging studies have suggested a possible involvement of the choroid plexus (CP) in multiple sclerosis (MS). Here, we investigated whether CP changes are already detectable at the earliest stage of MS, preceding symptom onset.<h4>Methods</h4>This study is a retrospective analysis of 27 patients with presymptomatic MS, 97 patients with clinically definite MS (CDMS), and 53 healthy controls (HCs) who underwent a cross-sectional 3T-MRI acquisition; of which, ...[more]

PMID: 36229188

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Project description:ImportanceUnrecognized demyelinating events often precede the clinical onset of multiple sclerosis (MS). Identification of these events at the time of occurrence would have implications for early diagnosis and the search of causal factors for the disease.ObjectiveTo assess whether serum neurofilament light chain (sNfL) levels are elevated before the clinical MS onset.Design, setting, and participantsNested case-control study among US military personnel who have serum samples stored in the US Department of Defense Serum Repository. Serum samples were collected from 2000 to 2011; sNfL assays and data analyses were performed from 2018 to 2019. We selected 60 case patients with MS who either had 2 samples collected before onset (mean follow-up, 6.3 years) or 1 sample collected before and 1 after onset (mean follow-up, 1.3 years), among 245 previously identified case patients. For each case, we randomly selected 1 of 2 previously identified control individuals matched by age, sex, race/ethnicity, and dates of sample collection. The sample size was chosen based on the available funding.ExposuresSerum NfL concentrations measured using an ultrasensitive single-molecule array assay (Simoa).Main outcomes and measurementsLog-transformed sNfL concentrations in case patients and control individuals compared using conditional logistic regression and linear mixed models.ResultsMean age at baseline was 27.5 years, and 92 of 120 participants (76.7%) were men. Serum NfL levels were higher in case patients with MS compared with their matched control individuals in samples drawn a median of 6 years (range, 4-10 years) before the clinical onset (median, 16.7 pg/mL; interquartile range [IQR], 12.6-23.1 pg/mL vs 15.2 pg/m; IQR, 10.3-19.9 pg/mL; P = .04). This difference increased with decreasing time to the case clinical onset (estimated coefficient for interaction with time = 0.063; P = .008). A within-person increase in presymptomatic sNfL levels was associated with higher MS risk (rate ratio for ≥5 pg/mL increase, 7.50; 95% CI, 1.72-32.80). The clinical onset was associated with a marked increase in sNfL levels (median, 25.0; IQR, 17.1-41.3 vs 45.1; IQR, 27.0-102.7 pg/mL for presymptomatic and postonset MS samples; P = .009).Conclusions and relevanceThe levels of sNfL were increased 6 years before the clinical MS onset, indicating that MS may have a prodromal phase lasting several years and that neuroaxonal damage occurs already during this phase.

Project description:BackgroundHypoxemia can cause secondary acute brain injury, but the mechanisms behind it are not entirely clear and could involve disturbances in the brain extracellular fluids. We aimed to explore the effects of hypoxemia on the choroid plexus (CPs) and cerebrospinal fluid (CSF) system in rats.MethodsMale Sprague Dawley rats were kept in O2 control in vivo cabinet with either 21% (normoxia) or 8% O2 (hypoxemia) for up to 48 h. In some cases, signaling of selected cytokines was inhibited prior to hypoxemia. CSF and blood samples were collected by Cisterna Magna puncture and through venous catheters, respectively. The percentages of dead cells in the CPs and ependymal layers (EL) after hypoxemia or normoxia was estimated using TUNEL staining. CP's ultrastructure was analyzed by transmission electron microscopy. Protein concentration in the CSF and plasma was measured and the CSF albumin-to-total protein ratios were estimated. Concentrations of hypoxia-related cytokines in the CSF and plasma samples were estimated using the multiplex immunoassay. Data was analyzed by one-way ANOVA followed by either Bonferroni or Tukey's multiple comparison tests, or Student's t-test. Results are presented as mean ± SD; p < 0.05 was considered statistically significant.ResultsDuration of hypoxemia exerted significant effects on the cell viability in the CPs (p < 0.01) and EL (p < 0.01) and caused apoptosis-related changes in the CP. Hypoxemia had significant effects on the protein concentration in the CSF (p < 0.05), but not in plasma (p > 0.05), with a significant increase in the CSF albumin-to-total protein ratio after 6 h hypoxemia (p < 0.05). Thirty-two cytokines were detected in the CSF. Hypoxemia caused a statistically significant reduction in the concentrations of 12 cytokines, while concentrations of erythropoietin (EPO) and vascular endothelial growth factor (VEGF) increased significantly. Exposure to hypoxemia after inhibitions of EPO, VEGF, or tumor necrosis factor alpha (TNFα) signaling resulted in more dead cells (p < 0.01), less dead cells (p < 0.01) and more dead cells (p < 0.01) in the CPs, respectively, when compared to the number of dead cells when these cytokines were not inhibited. The density of macrophages in the CPs decreased significantly during hypoxemia; that effect was cancelled out by TNFα inhibition.ConclusionHypoxemia had detrimental effects on the CPs and CSF system, which was modulated by hypoxia- and inflammation-related cytokines.

Dataset Information

Imaging Characteristics of Choroid Plexuses in Presymptomatic Multiple Sclerosis: A Retrospective Study.

Background and objectives

Methods

Results

Discussion

Trial registration information

Publications

Imaging Characteristics of Choroid Plexuses in Presymptomatic Multiple Sclerosis: A Retrospective Study.

Similar Datasets

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