title: Increased PK11195-PET binding in normal-appearing white matter in clinically isolated syndrome.
abstract: The most accurate predictor of the subsequent development of multiple sclerosis in clinically isolated syndrome is the presence of lesions at magnetic resonance imaging. We used in vivo positron emission tomography with (11)C-(R)-PK11195, a biomarker of activated microglia, to investigate the normal-appearing white matter and grey matter of subjects with clinically isolated syndrome to explore its role in the development of multiple sclerosis. Eighteen clinically isolated syndrome and eight healthy control subjects were recruited. Baseline assessment included: history, neurological examination, expanded disability status scale, magnetic resonance imaging and PK11195-positron emission tomography scans. All assessments except the PK11195-positron emission tomography scan were repeated over 2 years. SUPERPK methodology was used to measure the binding potential relative to the non-specific volume, BPND. We show a global increase of normal-appearing white matter PK11195 BPND in clinically isolated syndrome subjects compared with healthy controls (P = 0.014). Clinically isolated syndrome subjects with T2 magnetic resonance imaging lesions had higher PK11195 BPND in normal-appearing white matter (P = 0.009) and their normal-appearing white matter PK11195 BPND correlated with the Expanded Disability Status Scale (P = 0.007; r = 0.672). At 2 years those who developed dissemination in space or multiple sclerosis, had higher PK11195 BPND in normal-appearing white matter at baseline (P = 0.007 and P = 0.048, respectively). Central grey matter PK11195 BPND was increased in subjects with clinically isolated syndrome compared to healthy controls but no difference was found in cortical grey matter PK11195 BPND. Microglial activation in clinically isolated syndrome normal-appearing white matter is diffusely increased compared with healthy control subjects and is further increased in those who have magnetic resonance imaging lesions. Furthermore microglial activation in clinically isolated syndrome normal-appearing white matter is also higher in those subjects who developed multiple sclerosis at 2 years. Our finding, if replicated in a larger study, could be of prognostic value and aid early treatment decisions in clinically isolated syndrome.
authors.affiliation: 1 Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK p.giannetti@imperial.ac.uk.
authors.forename: Paolo
authors.initials: P
authors.lastname: Giannetti
authors.affiliation: 1 Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK 2 Neurodegeneration Imaging Group, Department of Clinical Neuroscience, King's College London, De Crespigny Park, London, SE5 8AF, UK.
authors.forename: Marios
authors.initials: M
authors.lastname: Politis
authors.affiliation: 1 Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Su
authors.affiliation: 3 Centre for Neuroimaging, Institute of Psychiatry, King's College London, De Crespigny Park, London, SE5 8AF, UK.
authors.forename: Federico E
authors.initials: FE
authors.lastname: Turkheimer
authors.affiliation: 1 Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
authors.forename: Omar
authors.initials: O
authors.lastname: Malik
authors.affiliation: 1 Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
authors.forename: Shiva
authors.initials: S
authors.lastname: Keihaninejad
authors.affiliation: 1 Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
authors.forename: Kit
authors.initials: K
authors.lastname: Wu
authors.affiliation: 1 Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Waldman
authors.affiliation: 1 Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Reynolds
authors.affiliation: 1 Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Nicholas
authors.affiliation: 1 Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Piccini
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D004185:Disability Evaluation; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000493:pharmacokinetics*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology*; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D066127:White Matter / Q000000981:diagnostic imaging* / Q000187:drug effects*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007546:Isoquinolines; C037850:PK 11195
keywords: PK11195-PET; clinically isolated syndrome; microglia; multiple sclerosis; normal-appearing white matter