title: Selective vulnerability of Rich Club brain regions is an organizational principle of structural connectivity loss in Huntington's disease.
abstract: Huntington's disease can be predicted many years before symptom onset, and thus makes an ideal model for studying the earliest mechanisms of neurodegeneration. Diffuse patterns of structural connectivity loss occur in the basal ganglia and cortex early in the disease. However, the organizational principles that underlie these changes are unclear. By understanding such principles we can gain insight into the link between the cellular pathology caused by mutant huntingtin and its downstream effect at the macroscopic level. The 'rich club' is a pattern of organization established in healthy human brains, where specific hub 'rich club' brain regions are more highly connected to each other than other brain regions. We hypothesized that selective loss of rich club connectivity might represent an organizing principle underlying the distributed pattern of structural connectivity loss seen in Huntington's disease. To test this hypothesis we performed diffusion tractography and graph theoretical analysis in a pseudo-longitudinal study of 50 premanifest and 38 manifest Huntington's disease participants compared with 47 healthy controls. Consistent with our hypothesis we found that structural connectivity loss selectively affected rich club brain regions in premanifest and manifest Huntington's disease participants compared with controls. We found progressive network changes across controls, premanifest Huntington's disease and manifest Huntington's disease characterized by increased network segregation in the premanifest stage and loss of network integration in manifest disease. These regional and whole brain network differences were highly correlated with cognitive and motor deficits suggesting they have pathophysiological relevance. We also observed greater reductions in the connectivity of brain regions that have higher network traffic and lower clustering of neighbouring regions. This provides a potential mechanism that results in a characteristic pattern of structural connectivity loss targeting highly connected brain regions with high network traffic and low clustering of neighbouring regions. Our findings highlight the role of the rich club as a substrate for the structural connectivity loss seen in Huntington's disease and have broader implications for understanding the connection between molecular and systems level pathology in neurodegenerative disease.
authors.affiliation: 1 Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG, UK s.tabrizi@ucl.ac.uk g.rees@ucl.ac.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: McColgan
authors.affiliation: 2 Developmental Imaging and Biophysics Section, UCL Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Kiran K
authors.initials: KK
authors.lastname: Seunarine
authors.affiliation: 3 Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, London, WC1N 3BG, UK 4 Department of Electronic Engineering, NED University of Engineering and Technology, Karachi, Pakistan.
authors.forename: Adeel
authors.initials: A
authors.lastname: Razi
authors.affiliation: 5 Computational, Cognitive and Clinical Neuroimaging Laboratory, Department of Medicine, Imperial College London, W12 0HS, UK.
authors.forename: James H
authors.initials: JH
authors.lastname: Cole
authors.affiliation: 3 Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, London, WC1N 3BG, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gregory
authors.affiliation: 6 APHP Department of Genetics, Groupe Hospitalier Pitié-Salpêtrière, and Institut du Cerveau et de la Moelle, INSERM U1127, CNRS UMR7225, Sorbonne Universités - UPMC Université Paris VI UMR_S1127, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.affiliation: 7 Department of Neurology, Leiden University Medical Centre, 2300RC Leiden, The Netherlands.
authors.forename: Raymund A C
authors.initials: RA
authors.lastname: Roos
authors.affiliation: 8 School of Psychological Sciences, Monash University, VIC, Australia.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Stout
authors.affiliation: 9 Department of Neurology, University of Ulm, Oberer Eselsberg 45-1, D-89081, Ulm, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Landwehrmeyer
authors.affiliation: 1 Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG, UK.
authors.forename: Rachael I
authors.initials: RI
authors.lastname: Scahill
authors.affiliation: 2 Developmental Imaging and Biophysics Section, UCL Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Chris A
authors.initials: CA
authors.lastname: Clark
authors.affiliation: 3 Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, London, WC1N 3BG, UK.
authors.forename: Geraint
authors.initials: G
authors.lastname: Rees
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
mesh_terms: D000328:Adult; D001479:Basal Ganglia / Q000473:pathology; D001921:Brain / Q000473:pathology; D016022:Case-Control Studies; D002421:Caudate Nucleus / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology*; D038524:Diffusion Magnetic Resonance Imaging; D056324:Diffusion Tensor Imaging; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000473:pathology*; D007091:Image Processing, Computer-Assisted; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D017072:Neostriatum / Q000473:pathology*; D009434:Neural Pathways / Q000473:pathology; D011699:Putamen / Q000473:pathology; D013788:Thalamus / Q000473:pathology*
keywords: Huntington’s disease; rich club; tractography