Neuroinflammatory component of gray matter pathology in multiple sclerosis.
OBJECTIVE
In multiple sclerosis (MS), using simultaneous magnetic resonance-positron emission tomography (MR-PET) imaging with11C-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 underwent11C-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 high11C-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, increased11C-PBR28 binding in cortex, deep GM, and NAWM correlated with neurological disability and impaired cognitive performance; cortical thinning correlated with increased thalamic TSPO levels.


CONCLUSIONS
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.
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
Elena
E
Herranz
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
Costanza
C
Giannì
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
Céline
C
Louapre
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
Constantina A
CA
Treaba
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA.
Sindhuja T
ST
Govindarajan
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA.
Russell
R
Ouellette
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
Marco L
ML
Loggia
Harvard Medical School, Boston, MA.|Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA.
Jacob A
JA
Sloane
Harvard Medical School, Boston, MA.|Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA.
Nancy
N
Madigan
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
David
D
Izquierdo-Garcia
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA.
Noreen
N
Ward
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA.|Institute of Biomedical Engineering, Polytechnique Montréal, Montréal, QC, Canada.
Gabriel
G
Mangeat
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
Tobias
T
Granberg
Harvard Medical School, Boston, MA.|Department of Neurology, Massachusetts General Hospital, Boston, MA.
Eric C
EC
Klawiter
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
Ciprian
C
Catana
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
Jacob M
JM
Hooker
Harvard Medical School, Boston, MA.|Department of Anesthesiology, Massachusetts General Hospital, Boston, MA.
Norman
N
Taylor
UMass Multiple Sclerosis Medical Center, Worcester, MA.
Carolina
C
Ionete
Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA.|University of San Diego, San Diego, California.
Revere P
RP
Kinkel
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
Caterina
C
Mainero
D000328:Adult; D005260:Female; D066128:Gray Matter / Q000000981:diagnostic imaging* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000000981:diagnostic imaging* / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D020528:Multiple Sclerosis, Chronic Progressive / Q000000981:diagnostic imaging* / Q000378:metabolism; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000000981:diagnostic imaging* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D011743:Pyrimidines; D018079:Receptors, GABA / Q000378:metabolism*; D066127:White Matter / Q000000981:diagnostic imaging* / Q000378:metabolism
C526315:(methyl-(11)C)N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine; D011743:Pyrimidines; D018079:Receptors, GABA; C499229:TSPO protein, human
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