@article{b9ee012547a84107aa0c427c48c907eb,
title = "Early white matter pathology in the fornix of the limbic system in Huntington disease",
abstract = "Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The typical motor symptoms have been associated with basal ganglia pathology. However, psychiatric and cognitive symptoms often precede the motor component and may be due to changes in the limbic system. Recent work has indicated pathology in the hypothalamus in HD but other parts of the limbic system have not been extensively studied. Emerging evidence suggests that changes in HD also include white matter pathology. Here we investigated if the main white matter tract of the limbic system, the fornix, is affected in HD. We demonstrate that the fornix is 34\% smaller already in prodromal HD and 41\% smaller in manifest HD compared to controls using volumetric analyses of MRI of the IMAGE-HD study. In post-mortem fornix tissue from HD cases, we confirm the smaller fornix volume in HD which is accompanied by signs of myelin breakdown and reduced levels of the transcription factor myelin regulating factor but detect no loss of oligodendrocytes. Further analyses using RNA-sequencing demonstrate downregulation of oligodendrocyte identity markers in the fornix of HD cases. Analysis of differentially expressed genes based on transcription-factor/target-gene interactions also revealed enrichment for binding sites of SUZ12 and EZH2, components of the Polycomb Repressive Complex 2, as well as RE1 Regulation Transcription Factor. Taken together, our data show that there is early white matter pathology of the fornix in the limbic system in HD likely due to a combination of reduction in oligodendrocyte genes and myelin break down.",
keywords = "Fornix, Huntingtin, MRI, Oligodendrocyte, RNA sequencing",
author = "Sanaz Gabery and Kwa, \{Jing Eugene\} and Cheong, \{Rachel Y.\} and Barbara Baldo and \{Ferrari Bardile\}, Costanza and Brendan Tan and Catriona McLean and Nellie Georgiou-Karistianis and Poudel, \{Govinda R.\} and Glenda Halliday and Pouladi, \{Mahmoud A.\} and {\AA}sa Peters{\'e}n",
note = "Funding Information: Tissues were received from the New South Wales Brain Tissue Resource Centre at the University of Sydney and the Sydney Brain Bank at Neuroscience Research Australia which are supported by The University of New South Wales, Neuroscience Research Australia and Schizophrenia Research Institute. Tissues were also received from the Victorian Brank Bank at the Florey Institute of Neuroscience and Mental Health which is supported by the Florey Institute, Parkinson?s Victoria, MND Victoria, FightMND, Yugibar Foundation and Ian and Maria Cootes. Research reported in this publication was supported by the National Institute On Alcohol Abuse And Alcoholism of the National Institutes of Health under Award Number R28AA012725. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Laboratory aspects of the research was supported by research grants to AP from the Swedish Research Council (grant number 2018/02559), the ALF system at Region Sk?ne as well as the Knut and Alice Wallenberg Foundation (\# 2019.0467) and to SG from NeuroSweden (F2018-0032). SG is a Swedish Brain Foundation Post-doctoral Fellow (\#PS2018-0002). MAP was supported by grants from the Agency for Science, Technology and Research, the National University of Singapore, the Michael Smith Foundation for Health Research, and the National Multiple Sclerosis Society (USA). GH is a NHMRC Senior Leadership Fellow (\#1176607). We would like to thank Ulla Samuelsson, Ulrika Sparrhult-Bj?rk, Bj?rn Anzelius, Anneli Josefsson and Lina Gefors for excellent technical assistance as well as Tobias Mejstad for statistical assistance. Funding Information: Open access funding provided by Lund University. This study was funded by research grants to AP from the Swedish Research Council (Grant number 2018/02559), the ALF system at Region Sk{\aa}ne as well as the Knut and Alice Wallenberg Foundation (\# 2019.0467), to SG from NeuroSweden (F2018-0032), and to MAP from the Agency for Science, Technology and Research, and the National University of Singapore. SG is a Swedish Brain Foundation Post-doctoral Fellow (\#PS2018-0002). CFB is supported by a fellowship from the Hereditary Disease Foundation. GH is a NHMRC Senior Leadership Fellow (\#1176607). Funding Information: Tissues were received from the New South Wales Brain Tissue Resource Centre at the University of Sydney and the Sydney Brain Bank at Neuroscience Research Australia which are supported by The University of New South Wales, Neuroscience Research Australia and Schizophrenia Research Institute. Tissues were also received from the Victorian Brank Bank at the Florey Institute of Neuroscience and Mental Health which is supported by the Florey Institute, Parkinson{\textquoteright}s Victoria, MND Victoria, FightMND, Yugibar Foundation and Ian and Maria Cootes. Research reported in this publication was supported by the National Institute On Alcohol Abuse And Alcoholism of the National Institutes of Health under Award Number R28AA012725. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Laboratory aspects of the research was supported by research grants to AP from the Swedish Research Council (grant number 2018/02559), the ALF system at Region Sk{\aa}ne as well as the Knut and Alice Wallenberg Foundation (\# 2019.0467) and to SG from NeuroSweden (F2018-0032). SG is a Swedish Brain Foundation Post-doctoral Fellow (\#PS2018-0002). MAP was supported by grants from the Agency for Science, Technology and Research, the National University of Singapore, the Michael Smith Foundation for Health Research, and the National Multiple Sclerosis Society (USA). GH is a NHMRC Senior Leadership Fellow (\#1176607). We would like to thank Ulla Samuelsson, Ulrika Sparrhult-Bj{\"o}rk, Bj{\"o}rn Anzelius, Anneli Josefsson and Lina Gefors for excellent technical assistance as well as Tobias Mejstad for statistical assistance. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = nov,
doi = "10.1007/s00401-021-02362-8",
language = "English",
volume = "142",
pages = "791--806",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer",
number = "5",
}