Is Cerebrospinal Fluid Responsible for Innate Immune Cell Activation and Neurotoxicity in Multiple Sclerosis?

Abstract Overactivation of microglia is associated with most neurodegenerative diseases. In this study we examined whether PET-measurable innate immune cell activation predicts multiple sclerosis disease progression. Activation of microglia/macrophages was measured using the 18-kDa translocator protein (TSPO)-binding radioligand 11C-PK11195 and PET imaging in 69 patients with multiple sclerosis and 18 age- and sex-matched healthy controls. Radioligand binding was evaluated as the distribution volume ratio from dynamic PET images. Conventional MRI and disability measurements using the Expanded Disability Status Scale were performed for patients at baseline and 4.1 ± 1.9 (mean ± standard deviation) years later. Fifty-one (74%) of the patients were free of relapses during the follow-up period. Patients had increased activation of innate immune cells in the normal-appearing white matter and in the thalamus compared to the healthy control group (P = 0.033 and P = 0.003, respectively, Wilcoxon). Forward-type stepwise logistic regression was used to assess the best variables predicting disease progression. Baseline innate immune cell activation in the normal-appearing white matter was a significant predictor of later progression when the entire multiple sclerosis cohort was assessed [odds ratio (OR) = 4.26; P = 0.048]. In the patient subgroup free of relapses there was an association between macrophage/microglia activation in the perilesional normal-appearing white matter and disease progression (OR = 4.57; P = 0.013). None of the conventional MRI parameters measured at baseline associated with later progression. Our results strongly suggest that innate immune cell activation contributes to the diffuse neural damage leading to multiple sclerosis disease progression independent of relapses.

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Individual Mapping of Innate Immune Cell Activation Is a Candidate Marker of Patient-Specific Trajectories of Worsening Disability in Multiple Sclerosis

Journal of Nuclear Medicine ◽

10.2967/jnumed.119.231340 ◽

2020 ◽

Vol 61 (7) ◽

pp. 1043-1049 ◽

Cited By ~ 2

Author(s):

Benedetta Bodini ◽

Emilie Poirion ◽

Matteo Tonietto ◽

Charline Benoit ◽

Raffaele Palladino ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cell Activation ◽

Immune Cell ◽

Innate Immune ◽

Innate Immune Cell ◽

Patient Specific ◽

Candidate Marker ◽

Immune Cell Activation

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Structural and Clinical Correlates of a Periventricular Gradient of Neuroinflammation in Multiple Sclerosis

Neurology ◽

10.1212/wnl.0000000000011700 ◽

2021 ◽

pp. 10.1212/WNL.0000000000011700

Author(s):

Emilie Poirion ◽

Matteo Tonietto ◽

François-Xavier Lejeune ◽

Vito A.G. Ricigliano ◽

Marine Boudot de la Motte ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cell Activation ◽

Immune Cell ◽

Innate Immune ◽

Innate Immune Cell ◽

Magnetization Transfer Ratio ◽

Immune Cell Activation ◽

Microstructural Damage ◽

Ventricular Surface

Objectives:To explore in-vivo innate immune cell activation as a function of the distance from ventricular CSF in patients with Multiple Sclerosis (MS) using [18F]-DPA714 PET, and to investigate its relationship with periventricular microstructural damage, evaluated by magnetization transfer ratio (MTR), and with trajectories of disability worsening.Methods:Thirty-seven MS patients and nineteen healthy controls underwent MRI and [18F]-DPA714 TSPO dynamic PET, from which individual maps of voxels characterized by innate immune cell activation (DPA+) were generated. White matter (WM) was divided in 3mm-thick concentric rings radiating from the ventricular surface toward the cortex, and the percentage of DPA+ voxels and mean MTR were extracted from each ring. Two-year trajectories of disability worsening were collected to identify patients with and without recent disability worsening.Results:The percentage of DPA+ voxels was higher in patients compared to controls in the periventricular WM (p=6.10e-6), and declined with increasing distance from ventricular surface, with a steeper gradient in patients compared to controls (p=0.001). This gradient was found both in periventricular lesions and normal-appearing WM. In the total WM, it correlated with a gradient of microstructural tissue damage measured by MTR (rs=-0.65, p=1.0e-3). When compared to clinically stable patients, patients with disability worsening were characterized by a higher percentage of DPA+ voxels in the periventricular normal-appearing WM (p=0.025).Conclusions:Our results demonstrate that in MS the innate immune cell activation predominates in periventricular regions and associates with microstructural damage and disability worsening. This could result from the diffusion of pro-inflammatory CSF-derived factors into surrounding tissues.

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