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.

Figure 1. Enlarged CPs in Presymptomatic MS

(A) Unenhanced 3D T1-weighted magnetization-prepared rapid gradient echo (MPRAGE) images showing the segmentation of the left and right CP (outlined in red) in axial (top) and coronal (bottom) planes in a patient with presymptomatic MS. (B) Box plots showing significantly higher CP volume in the whole presymptomatic MS group vs HCs and no difference compared with MS. CP volume was normalized according to TIV. Note that the dot corresponding to the volume of the presymptomatic case further examined in the PET part of this study is colored in red. Box represents the interquartile range and median, whereas whiskers represent minimum and maximum values in data. The p value corresponds to that of the multivariable linear regression model. (C–D) Graphical illustration of the distribution of normalized CP volume in HCs vs the single presymptomatic woman (C) and in MS vs the single presymptomatic woman (D) from the Crawford-Howell test. Note that the presence of a distribution for a single case value is based on the assumptions of the test performed and depends on the statistics of the reference cohort. CP = choroid plexus; HCs = healthy controls; MS = multiple sclerosis; TIV = total intracranial volume.

Figure 2. Higher ¹⁸F-DPA-714 Uptake in the CPs of Presymptomatic MS

(A) Axial ¹⁸F-DPA-714 SUV_60-90 map registered onto the 3D T1-weighted magnetization-prepared rapid gradient echo (MPRAGE) image of the presymptomatic MS case, with the corresponding color bar (left) and magnification on the CP of the right lateral ventricle (right). (B, C) Examples of axial ¹⁸F-DPA-714 SUV_60-90 maps registered onto the 3D T1-weighted MPRAGE images from 2 controls (B) and 2 patients with RRMS (C). (D, E) Graphical illustration of the distribution of CP ¹⁸F-DPA-714 SUV_60-90 in HCs vs the presymptomatic woman (D) and in MS vs the presymptomatic woman (E) from the Crawford-Howell test. The presence of a distribution for a single case value is based on the assumptions of the test performed and depends on the statistics of the reference cohort. CP = choroid plexus; HCs = healthy controls; MS = multiple sclerosis; SUV_60-90 = standardized uptake value between 60 and 90 minutes of acquisition; TIV = total intracranial volume.

Figure 3. TSPO+/CD163+ Macrophages Are Found in MS CPs

(A, B) Excess of CD163⁺ macrophages (mouse monoclonal antibody, Cell Marque®; brown, arrows) in a PPMS case (A) compared with a healthy control (B). (C, F) TSPO (monoclonal rabbit antibody, Abcam®; brown) is highly expressed in epithelial cells (arrows) of choroid plexuses in both MS (C: PPMS and E: SPMS) and controls (D: HCs and F: epilepsy control). CD163⁺ (red) and TSPO⁺ (brown) perivascular macrophages (arrowheads) are found in MS (C, E), but not in controls (D, F). Scale bars = 40 µm (A, B) and 20 µm (C–F). HCs = healthy controls; MS = multiple sclerosis; PPMS = primary progressive MS; SPMS = secondary progressive MS; TSPO = translocator protein.