Eileanoir B Johnson1, Christopher S Parker2, Rachael I Scahill3, Sarah Gregory3, Marina Papoutsi4, Paul Zeun3, Katherine Osborne-Crowley5, Jessica Lowe3, Akshay Nair6, Carlos Estevez-Fraga3, Kate Fayer3, Geraint Rees7, Hui Zhang2, Sarah J Tabrizi8. 1. Huntington's Disease Centre, Department of Neurodegenerative disease, UCL Queen Square Institute of Neurology, University College London, London, UK. Electronic address: eileanoir.johnson@ucl.ac.uk. 2. Centre for Medical Image Computing, Department of Computer Science, UCL, London, UK. 3. Huntington's Disease Centre, Department of Neurodegenerative disease, UCL Queen Square Institute of Neurology, University College London, London, UK. 4. Huntington's Disease Centre, Department of Neurodegenerative disease, UCL Queen Square Institute of Neurology, University College London, London, UK; IXICO Plc, London, , UK. 5. Division of Equity, Diversity and Inclusion, University of New South Wales, Sydney, New South Wales, Australia. 6. Huntington's Disease Centre, Department of Neurodegenerative disease, UCL Queen Square Institute of Neurology, University College London, London, UK; Max Planck University College London Centre for Computational Psychiatry and Ageing Research, UCL Queen Square Institute of Neurology, London, UK. 7. University College London Institute of Cognitive Neuroscience, University College London, London, UK. 8. Huntington's Disease Centre, Department of Neurodegenerative disease, UCL Queen Square Institute of Neurology, University College London, London, UK; Dementia Research Institute at University College London, London, UK.
Abstract
BACKGROUND: Pathological processes in Huntington's disease (HD) begin many years prior to symptom onset. Recently we demonstrated that in a premanifest cohort approximately 24 years from predicted disease onset, despite intact function, there was evidence of subtle neurodegeneration. Here, we use novel imaging techniques to determine whether macro- and micro-structural changes can be detected across the whole-brain in the same cohort. METHODS: 62 premanifest HD (PreHD) and 61 controls from the HD Young Adult Study (HD-YAS) were included. Grey and white matter volume, diffusion weighted imaging (DWI) measures of white matter microstructure, multiparametric maps (MPM) estimating myelin and iron content from magnetization transfer (MT), proton density (PD), longitudinal relaxation (R1) and effective transverse relaxation (R2*), and myelin g-ratio were examined. Group differences between PreHD and controls were assessed; associations between all imaging metrics and disease burden and CSF neurofilament light (NfL) were also performed. Volumetric and MPM results were corrected at a cluster-wise value of familywise error (FWE) 0.05. Diffusion and g-ratio results were corrected via threshold-free cluster enhancement at FWE 0.05. FINDINGS: We showed significantly increased R1 and R2*, suggestive of increased iron, in the putamen, globus pallidum and external capsule of PreHD participants. There was also a significant association between lower cortical R2*, suggestive of reduced myelin or iron, and higher CSF NfL in the frontal lobe and the parieto-occipital cortices. No other results were significant at corrected levels. INTERPRETATION: Increased iron in subcortical structures and the surrounding white matter is a feature of very early PreHD. Furthermore, increases in CSF NfL were linked to microstructural changes in the posterior parietal-occipital cortex, a region previously shown to undergo some of the earliest cortical changes in HD. These findings suggest that disease related process are occurring in both subcortical and cortical regions more than 20 years from predicted disease onset.
BACKGROUND: Pathological processes in Huntington's disease (HD) begin many years prior to symptom onset. Recently we demonstrated that in a premanifest cohort approximately 24 years from predicted disease onset, despite intact function, there was evidence of subtle neurodegeneration. Here, we use novel imaging techniques to determine whether macro- and micro-structural changes can be detected across the whole-brain in the same cohort. METHODS: 62 premanifest HD (PreHD) and 61 controls from the HD Young Adult Study (HD-YAS) were included. Grey and white matter volume, diffusion weighted imaging (DWI) measures of white matter microstructure, multiparametric maps (MPM) estimating myelin and iron content from magnetization transfer (MT), proton density (PD), longitudinal relaxation (R1) and effective transverse relaxation (R2*), and myelin g-ratio were examined. Group differences between PreHD and controls were assessed; associations between all imaging metrics and disease burden and CSF neurofilament light (NfL) were also performed. Volumetric and MPM results were corrected at a cluster-wise value of familywise error (FWE) 0.05. Diffusion and g-ratio results were corrected via threshold-free cluster enhancement at FWE 0.05. FINDINGS: We showed significantly increased R1 and R2*, suggestive of increased iron, in the putamen, globus pallidum and external capsule of PreHD participants. There was also a significant association between lower cortical R2*, suggestive of reduced myelin or iron, and higher CSF NfL in the frontal lobe and the parieto-occipital cortices. No other results were significant at corrected levels. INTERPRETATION: Increased iron in subcortical structures and the surrounding white matter is a feature of very early PreHD. Furthermore, increases in CSF NfL were linked to microstructural changes in the posterior parietal-occipital cortex, a region previously shown to undergo some of the earliest cortical changes in HD. These findings suggest that disease related process are occurring in both subcortical and cortical regions more than 20 years from predicted disease onset.
Authors: J M G van Bergen; J Hua; P G Unschuld; I A L Lim; C K Jones; R L Margolis; C A Ross; P C M van Zijl; X Li Journal: AJNR Am J Neuroradiol Date: 2015-12-17 Impact factor: 3.825
Authors: Eve M Dumas; Maarten J Versluis; Simon J A van den Bogaard; Matthias J P van Osch; Ellen P Hart; Willeke M C van Roon-Mom; Mark A van Buchem; Andrew G Webb; Jeroen van der Grond; Raymund A C Roos Journal: Neuroimage Date: 2012-03-28 Impact factor: 6.556
Authors: Kevin Michael Biglan; Ira Shoulson; Karl Kieburtz; David Oakes; Elise Kayson; M Aileen Shinaman; Hongwei Zhao; Megan Romer; Anne Young; Steven Hersch; Jack Penney; Karen Marder; Jane Paulsen; Kimberly Quaid; Eric Siemers; Caroline Tanner; William Mallonee; Greg Suter; Richard Dubinsky; Carolyn Gray; Martha Nance; Scott Bundlie; Dawn Radtke; Sandra Kostyk; Corrine Baic; James Caress; Francis Walker; Victoria Hunt; Christine O'Neill; Sylvain Chouinard; Stewart Factor; Timothy Greenamyre; Cathy Wood-Siverio; Jody Corey-Bloom; David Song; Guerry Peavy; Carol Moskowitz; Melissa Wesson; Ali Samii; Thomas Bird; Hillary Lipe; Karen Blindauer; Frederick Marshall; Carol Zimmerman; Jody Goldstein; Diana Rosas; Peter Novak; John Caviness; Charles Adler; Amy Duffy; Vicki Wheelock; Teresa Tempkin; David Richman; Lauren Seeberger; Roger Albin; Kelvin L Chou; Brad Racette; Joel S Perlmutter; Susan Perlman; Yvette Bordelon; Wayne Martin; Marguerite Wieler; Blair Leavitt; Lynn Raymond; Joji Decolongon; Lorne Clarke; Joseph Jankovic; Christine Hunter; Robert A Hauser; Juan Sanchez-Ramos; Sarah Furtado; Oksana Suchowersky; Mary Lou Klimek; Mark Guttman; Rustom Sethna; Andrew Feigin; Marie Cox; Barbara Shannon; Alan Percy; Leon Dure; Madaline Harrison; William Johnson; Donald Higgins; Eric Molho; Constance Nickerson; Sharon Evans; Douglas Hobson; Carlos Singer; Nestor Galvez-Jimenez; Kathleen Shannon; Cynthia Comella; Christopher Ross; Marie H Saint-Hilaire; Claudia Testa; Adam Rosenblatt; Penelope Hogarth; William Weiner; Peter Como; Rajeev Kumar; Candace Cotto; Julie Stout; Alicia Brocht; Arthur Watts; Shirley Eberly; Christine Weaver; Tatiana Foroud; James Gusella; Marcy MacDonald; Richard Myers; Stanley Fahn; Clifford Shults Journal: JAMA Neurol Date: 2016-01 Impact factor: 18.302
Authors: Nikolaus Weiskopf; John Suckling; Guy Williams; Marta M Correia; Becky Inkster; Roger Tait; Cinly Ooi; Edward T Bullmore; Antoine Lutti Journal: Front Neurosci Date: 2013-06-10 Impact factor: 4.677
Authors: Chiara Casella; Maxime Chamberland; Pedro L Laguna; Greg D Parker; Anne E Rosser; Elizabeth Coulthard; Hugh Rickards; Samuel C Berry; Derek K Jones; Claudia Metzler-Baddeley Journal: Hum Brain Mapp Date: 2022-04-09 Impact factor: 5.399
Authors: Anna C Pfalzer; Yan Yan; Hakmook Kang; Melissa Totten; James Silverman; Aaron B Bowman; Keith Erikson; Daniel O Claassen Journal: Sci Rep Date: 2022-06-20 Impact factor: 4.996