title: Microglial activation in regions related to cognitive function predicts disease onset in Huntington's disease: a multimodal imaging study.
abstract: Huntington's disease (HD) is an inherited neurodegenerative disorder associated with motor, cognitive and psychiatric deficits. This study, using a multimodal imaging approach, aims to assess in vivo the functional and structural integrity of regions and regional networks linked with motor, cognitive and psychiatric function. Predicting disease onset in at risk individuals is problematic and thus we sought to investigate this by computing the 5-year probability of HD onset (p5 HD) and relating it to imaging parameters. Using MRI, (11)C-PK11195 and (11)C-raclopride PET, we have investigated volumes, levels of microglial activation and D2/D3 receptor binding in CAG repeat-matched groups of premanifest and symptomatic HD gene carriers. Findings were correlated with disease-burden and UHDRS scores. Atrophy was detected in sensorimotor striatum (SMST), substantia nigra, orbitofrontal and anterior prefrontal cortex in the premanifest HD. D2/D3 receptor binding was reduced and microglial activation increased in SMST and associative striatum (AST), bed nucleus of the stria terminalis, the amygdala and the hypothalamus. In symptomatic HD cases this extended to involve atrophy in globus pallidus, limbic striatum, the red nuclei, anterior cingulate cortex, and insula. D2/D3 receptor binding was additionally reduced in substantia nigra, globus pallidus, limbic striatum, anterior cingulate cortex and insula, and microglial activation increased in globus pallidus, limbic striatum and anterior prefrontal cortex. In premanifest HD, increased levels of microglial activation in the AST and in the regional network associated with cognitive function correlated with p5 HD onset. These data suggest that pathologically activated microglia in AST and other areas related to cognitive function, maybe better predictors of clinical onset and stresses the importance of early cognitive assessment in HD.
authors.affiliation: Department of Clinical Neurosciences and MRC Clinical Sciences Centre, Faculty of Medicine, Hammersmith Hospital, Imperial College London, London, UK. marios.politis@imperial.ac.uk
authors.forename: Marios
authors.initials: M
authors.lastname: Politis
authors.forename: Nicola
authors.initials: N
authors.lastname: Pavese
authors.forename: Yen F
authors.initials: YF
authors.lastname: Tai
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Kiferle
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Mason
authors.forename: David J
authors.initials: DJ
authors.lastname: Brooks
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
authors.forename: Paola
authors.initials: P
authors.lastname: Piccini
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology*; D001931:Brain Mapping; D003072:Cognition Disorders / Q000209:etiology* / Q000473:pathology*; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000150:complications* / Q000175:diagnosis / Q000235:genetics; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D017628:Microglia / Q000000981:diagnostic imaging / Q000473:pathology*; D008875:Middle Aged; D010100:Oxygen / Q000097:blood; D049268:Positron-Emission Tomography / Q000379:methods; D013223:Statistics as Topic; D018709:Statistics, Nonparametric; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D010100:Oxygen