Imaging Characteristics of Choroid Plexuses in Presymptomatic Multiple Sclerosis

Abstract

Background and ObjectivesRecent 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.MethodsThis 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. CP18F-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 had18F-DPA-714 PET, CP SUV differences with MS and HCs were assessed through Crawford-Howell tests. To provide further insight into the interpretation of18F-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.ResultsCompared 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 in18F-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 increased18F-DPA-714 uptake.DiscussionWe 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 InformationAPHP-20210727144630, EudraCT-Number: 2008-004174-40; ClinicalTrials.gov:NCT02305264,NCT01651520, andNCT02319382.

A year in review: brain barriers and brain fluids research in 2022

“…There have been an increasing number of reports using MRI to examine changes in the choroid plexus in different human disease states. That includes increases in human choroid plexus size or volume in multiple sclerosis (including pre-symptomatic) [ 54 – 56 ], Alzheimer’s disease [ 57 ], depression [ 58 ] and obesity [ 59 ]. Such changes may reflect neuroinflammatory events at the choroid plexus as evidenced by positron emission tomography [ 56 , 58 ].…”

“…That includes increases in human choroid plexus size or volume in multiple sclerosis (including pre-symptomatic) [ 54 – 56 ], Alzheimer’s disease [ 57 ], depression [ 58 ] and obesity [ 59 ]. Such changes may reflect neuroinflammatory events at the choroid plexus as evidenced by positron emission tomography [ 56 , 58 ]. MRI has also been used to examine changes in choroid plexus function in patients including perfusion [ 60 ], water movement [ 61 ] and contrast permeability [ 57 ].…”

Choroid plexuses at the interface of peripheral immunity and tissue repair in multiple sclerosis

“…Molecular imaging by PET offers the opportunity to quantify inflammatory infiltrates within ChPs [25 ▪ ,45]. Applying translocator protein (TSPO) tracers that mostly bind to innate immune cells, a neuroinflammatory component has been demonstrated in ChPs of people with temporal lobe epilepsy and MS at different disease stages [25 ▪ ,46 ▪ ,47]. Beyond PET, an increase in pseudo-T2 mapping on MRI, which is a simplification of T2 mapping, was also found in MS ChPs and interpreted as a proxy of inflammation [27 ▪ ].…”

“…Converging studies have further explored the timing of ChP changes during the course of MS. They unraveled that these alterations are one of the earliest signs that can be detected on MRI, being identifiable in presymptomatic MS (where ChP inflammation may precede parenchymal infiltrates) [46 ▪ ], clinically isolated syndrome [61] and pediatric MS [36 ▪▪ ].…”

“…However, ChP enlargement has been detected in several brain disorders and may traduce distinct biological processes depending on the pathological condition or disease stage. As an example, ChP enlargement is more closely associated with inflammatory infiltrates at early stages of MS, such as presymptomatic or relapsing-remitting MS, whereas brain atrophy may increasingly impact at later progressive phases [25 ▪ ,46 ▪ ]. This justifies additional multimodal imaging approaches to disentangle the respective contribution of ChP immune infiltration, perfusion changes, permeability and brain atrophy to ChP dilation.…”