Neuroinflammatory component of gray matter pathology in multiple sclerosis

• Published in: Annals of neurology Vol. 80; no. 5; pp. 776 - 790
• Main Authors: Herranz, Elena, Giannì, Costanza, Louapre, Céline, Treaba, Constantina A., Govindarajan, Sindhuja T., Ouellette, Russell, Loggia, Marco L., Sloane, Jacob A., Madigan, Nancy, Izquierdo-Garcia, David, Ward, Noreen, Mangeat, Gabriel, Granberg, Tobias, Klawiter, Eric C., Catana, Ciprian, Hooker, Jacob M., Taylor, Norman, Ionete, Carolina, Kinkel, Revere P., Mainero, Caterina
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.11.2016; Wiley Subscription Services, Inc
• Subjects: Adult; Binding; Brain; Cognitive ability; Cortex; Female; Gray Matter - diagnostic imaging; Gray Matter - metabolism; Humans; Image segmentation; In vivo methods and tests; Inflammation; Inflammation - diagnostic imaging; Inflammation - metabolism; Lesions; Macrophages; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Male; Medical imaging; Microglia; Middle Aged; Multimodal Imaging; Multiple sclerosis; Multiple Sclerosis, Chronic Progressive - diagnostic imaging; Multiple Sclerosis, Chronic Progressive - metabolism; Multiple Sclerosis, Relapsing-Remitting - diagnostic imaging; Multiple Sclerosis, Relapsing-Remitting - metabolism; Neurodegeneration; Neuroimaging; Neurological complications; Pathology; Patients; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Pyrimidines; Receptors, GABA - metabolism; Sensitivity analysis; Substantia alba; Substantia grisea; Thalamus; Tomography; White Matter - diagnostic imaging; White Matter - metabolism
• ISSN: 0364-5134; 1531-8249; 1531-8249
• DOI: 10.1002/ana.24791

Objective In multiple sclerosis (MS), using simultaneous magnetic resonance–positron emission tomography (MR‐PET) imaging with 11C‐PBR28, we quantified expression of the 18kDa translocator protein (TSPO), a marker of activated microglia/macrophages, in cortex, cortical lesions, deep gray matter (GM), white matter (WM) lesions, and normal‐appearing WM (NAWM) to investigate the in vivo pathological and clinical relevance of neuroinflammation. Methods Fifteen secondary‐progressive MS (SPMS) patients, 12 relapsing–remitting MS (RRMS) patients, and 14 matched healthy controls underwent 11C‐PBR28 MR‐PET. MS subjects underwent 7T T2*‐weighted imaging for cortical lesion segmentation, and neurological and cognitive evaluation. 11C‐PBR28 binding was measured using normalized 60‐ to 90‐minute standardized uptake values and volume of distribution ratios. Results Relative to controls, MS subjects exhibited abnormally high 11C‐PBR28 binding across the brain, the greatest increases being in cortex and cortical lesions, thalamus, hippocampus, and NAWM. MS WM lesions showed relatively modest TSPO increases. With the exception of cortical lesions, where TSPO expression was similar, 11C‐PBR28 uptake across the brain was greater in SPMS than in RRMS. In MS, increased 11C‐PBR28 binding in cortex, deep GM, and NAWM correlated with neurological disability and impaired cognitive performance; cortical thinning correlated with increased thalamic TSPO levels. Interpretation In MS, neuroinflammation is present in the cortex, cortical lesions, deep GM, and NAWM, is closely linked to poor clinical outcome, and is at least partly linked to neurodegeneration. Distinct inflammatory‐mediated factors may underlie accumulation of cortical and WM lesions. Quantification of TSPO levels in MS could prove to be a sensitive tool for evaluating in vivo the inflammatory component of GM pathology, particularly in cortical lesions. Ann Neurol 2016;80:776–790