title: Increased central microglial activation associated with peripheral cytokine levels in premanifest Huntington's disease gene carriers.
abstract: Previous studies have shown activation of the immune system and altered immune response in Huntington's disease (HD) gene carriers. Here, we hypothesized that peripheral and central immune responses could be concurrent pathophysiological events and represent a global innate immune response to the toxic effects of mutant huntingtin in HD gene carriers. We sought to investigate our hypothesis using [(11)C]PK11195 PET as a translocator protein (TSPO) marker of central microglial activation, together with assessment of peripheral plasma cytokine levels in a cohort of premanifest HD gene carriers who were more than a decade from predicted symptomatic conversion. Data were also compared to those from a group of healthy controls matched for age and gender. We found significantly increased peripheral plasma IL-1β levels in premanifest HD gene carriers compared to the group of normal controls (P=0.018). Premanifest HD gene carriers had increased TSPO levels in cortical, basal ganglia and thalamic brain regions (P<0.001). Increased microglial activation in somatosensory cortex correlated with higher plasma levels of IL-1β (rs=0.87, P=0.013), IL-6 (rs=0.85, P=0.013), IL-8 (rs=0.68, P=0.045) and TNF-α (rs=0.79; P=0.013). Our findings provide first in vivo evidence for an association between peripheral and central immune responses in premanifest HD gene carriers, and provide further supporting evidence for the role of immune dysfunction in the pathogenesis of HD.
authors: Neurodegeneration Imaging Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors: Marios
authors: M
authors: Politis
authors: Huntington's Disease Research Group, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK.
authors: Nayana
authors: N
authors: Lahiri
authors: Neurodegeneration Imaging Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors: Flavia
authors: F
authors: Niccolini
authors: Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors: Paul
authors: P
authors: Su
authors: Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors: Kit
authors: K
authors: Wu
authors: Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors: Paolo
authors: P
authors: Giannetti
authors: Huntington's Disease Research Group, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK.
authors: Rachael I
authors: RI
authors: Scahill
authors: Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors: Federico E
authors: FE
authors: Turkheimer
authors: Huntington's Disease Research Group, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK.
authors: Sarah J
authors: SJ
authors: Tabrizi
authors: Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK. Electronic address: paola.piccini@imperial.ac.uk.
authors: Paola
authors: P
authors: Piccini
mesh_terms: D000328:Adult; D000577:Amides; D001921:Brain / Q000000981:diagnostic imaging / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000097:blood*; D004660:Encephalitis / Q000000981:diagnostic imaging / Q000276:immunology* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006816:Huntington Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D007249:Inflammation / Q000097:blood / Q000276:immunology*; D018836:Inflammation Mediators / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D007546:Isoquinolines; D008297:Male; D017628:Microglia / Q000000981:diagnostic imaging / Q000276:immunology*; D008875:Middle Aged; D049268:Positron-Emission Tomography; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: C504060:(R)-(11C)1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide; D000577:Amides; D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D007546:Isoquinolines; D014409:Tumor Necrosis Factor-alpha
keywords: Huntington's disease; MRI; Microglia; PET; Peripheral inflammation