title: Regional expression of the MAPT gene is associated with loss of hubs in brain networks and cognitive impairment in Parkinson disease and progressive supranuclear palsy.
abstract: Abnormalities of tau protein are central to the pathogenesis of progressive supranuclear palsy, whereas haplotype variation of the tau gene MAPT influences the risk of Parkinson disease and Parkinson's disease dementia. We assessed whether regional MAPT expression might be associated with selective vulnerability of global brain networks to neurodegenerative pathology. Using task-free functional magnetic resonance imaging in progressive supranuclear palsy, Parkinson disease, and healthy subjects (n = 128), we examined functional brain networks and measured the connection strength between 471 gray matter regions. We obtained MAPT and SNCA microarray expression data in healthy subjects from the Allen brain atlas. Regional connectivity varied according to the normal expression of MAPT. The regional expression of MAPT correlated with the proportionate loss of regional connectivity in Parkinson's disease. Executive cognition was impaired in proportion to the loss of hub connectivity. These effects were not seen with SNCA, suggesting that alpha-synuclein pathology is not mediated through global network properties. The results establish a link between regional MAPT expression and selective vulnerability of functional brain networks to neurodegeneration.
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK; Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK. Electronic address: tr332@medschl.cam.ac.uk.
authors.forename: Timothy
authors.initials: T
authors.lastname: Rittman
authors.affiliation: Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK; Department of Psychiatry, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK; Churchill College, University of Cambridge, Cambridge, UK.
authors.forename: Mikail
authors.initials: M
authors.lastname: Rubinov
authors.affiliation: Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK; Department of Psychiatry, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK.
authors.forename: Petra E
authors.initials: PE
authors.lastname: Vértes
authors.affiliation: Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK; Department of Psychiatry, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK.
authors.forename: Ameera X
authors.initials: AX
authors.lastname: Patel
authors.affiliation: Department of Biostatistics, Institute of Psychiatry Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Cedric E
authors.initials: CE
authors.lastname: Ginestet
authors.affiliation: Wessex Neurological Centre, University Hospital Southampton, Southampton, UK.
authors.forename: Boyd C P
authors.initials: BCP
authors.lastname: Ghosh
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK; Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK; John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK; John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Spillantini
authors.affiliation: Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK; Department of Psychiatry, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Bullmore
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Herchel Smith Building for Brain and Mind Sciences, Cambridge, UK; Department of Psychology, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK; Medical Research Council Cognition and Brain Sciences Unit, Cambridge, UK.
authors.forename: James B
authors.initials: JB
authors.lastname: Rowe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000473:pathology*; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000473:pathology*; D010300:Parkinson Disease / Q000473:pathology* / Q000523:psychology*; D013494:Supranuclear Palsy, Progressive / Q000473:pathology* / Q000523:psychology*; D016875:tau Proteins / Q000235:genetics*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins
keywords: Brain imaging; Functional connectivity; Gene expression; Parkinson's disease; Progressive supranuclear palsy; Tau