title: Microglia activation in multiple sclerosis black holes predicts outcome in progressive patients: an in vivo [(11)C](R)-PK11195-PET pilot study.
abstract: The pathophysiological correlates and the contribution to persisting disability of hypointense T1-weighted MRI lesions, black holes (BH), in multiple sclerosis (MS) are still unclear. In order to study the in vivo functional correlates of this MRI finding, we used 11C-PK11195 PET (PK-PET) to investigate changes in microglial activity. Ten relapsing and 9 progressive MS subjects had a PK-PET scan and a MRI scan alongside a full clinical assessment, including the expanded disability status scale (EDSS) for evaluation of disability. We studied the PK binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BPND) in T1 BHs. Out of a total of 1242 BHs identified, 947 were PK enhancing. The PKBPND was correlated with the EDSS (r=0.818; p<0.05) only in the progressive group. In the relapsing patients there was an inverse correlation between PKBPND and BH total lesion volume in whole brain (r=-0.781; p<0.05). When progressive patients were grouped according to the disability outcome at 2years from the PK-PET scan, the total PKBPND in BHs was found to be a significant outcome predictor of disability (p<0.01). Our findings show that relapsing and progressive patients have heterogeneous patterns of PKBPND in T1 BHs and indicate that BHs are not just "holes" representing loss of axons and myelin, but display inflammatory activity in the form of activated microglia. The significant association between PKBPND, neurological impairment and outcome in progressive subjects supports a role for activated microglia in disability progression.
authors: Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. Electronic address: p.giannetti@imperial.ac.uk.
authors: Paolo
authors: P
authors: Giannetti
authors: Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK; Neurodegeneration Imaging Group, Department of Clinical Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK. Electronic address: marios.politis@imperial.ac.uk.
authors: Marios
authors: M
authors: Politis
authors: Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. Electronic address: paul.su08@imperial.ac.uk.
authors: Paul
authors: P
authors: Su
authors: Centre for Neuroimaging, Institute of Psychiatry, King's College London, De Crespigny Park, London SE5 8AF, UK. Electronic address: federico.turkheimer@kcl.ac.uk.
authors: Federico
authors: F
authors: Turkheimer
authors: Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. Electronic address: Omar.Malik@imperial.nhs.uk.
authors: Omar
authors: O
authors: Malik
authors: Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. Electronic address: s.keihaninejad@ucl.ac.uk.
authors: Shiva
authors: S
authors: Keihaninejad
authors: Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. Electronic address: kit.wu@imperial.ac.uk.
authors: Kit
authors: K
authors: Wu
authors: Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. Electronic address: r.reynolds@imperial.ac.uk.
authors: Richard
authors: R
authors: Reynolds
authors: Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. Electronic address: richard.nicholas@imperial.nhs.uk.
authors: Richard
authors: R
authors: Nicholas
authors: Centre for Neuroinflammation and Neurodegeneration, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. Electronic address: paola.piccini@imperial.ac.uk.
authors: Paola
authors: P
authors: Piccini
mesh_terms: D000328:Adult; D000577:Amides / Q000493:pharmacokinetics*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000493:pharmacokinetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000000981:diagnostic imaging* / Q000473:pathology*; D010865:Pilot Projects; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests
chemical_list: C504060:(R)-(11C)1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide; D000577:Amides; D007546:Isoquinolines
keywords: Black holes; Microglia; Multiple sclerosis; Neurodegeneration; PK11195-PET