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Early white matter pathology in the fornix of the limbic system in Huntington disease

Gabery, Sanaz LU ; Kwa, Jing Eugene ; Cheong, Rachel Y. LU ; Baldo, Barbara LU ; Ferrari Bardile, Costanza ; Tan, Brendan ; McLean, Catriona ; Georgiou-Karistianis, Nellie ; Poudel, Govinda R. and Halliday, Glenda , et al. (2021) In Acta Neuropathologica 142(5). p.791-806
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Fornix, Huntingtin, MRI, Oligodendrocyte, RNA sequencing
in
Acta Neuropathologica
volume
142
issue
5
pages
791 - 806
publisher
Springer
external identifiers
  • scopus:85113427693
  • pmid:34448021
ISSN
0001-6322
DOI
10.1007/s00401-021-02362-8
language
English
LU publication?
yes
id
b10b758f-af5a-4e62-915f-69c7cb3ad76f
date added to LUP
2021-09-09 10:58:23
date last changed
2024-05-19 13:13:19
@article{b10b758f-af5a-4e62-915f-69c7cb3ad76f,
  abstract     = {{<p>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.</p>}},
  author       = {{Gabery, Sanaz and Kwa, Jing Eugene and Cheong, Rachel Y. and Baldo, Barbara and Ferrari Bardile, Costanza and Tan, Brendan and McLean, Catriona and Georgiou-Karistianis, Nellie and Poudel, Govinda R. and Halliday, Glenda and Pouladi, Mahmoud A. and Petersén, Åsa}},
  issn         = {{0001-6322}},
  keywords     = {{Fornix; Huntingtin; MRI; Oligodendrocyte; RNA sequencing}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{791--806}},
  publisher    = {{Springer}},
  series       = {{Acta Neuropathologica}},
  title        = {{Early white matter pathology in the fornix of the limbic system in Huntington disease}},
  url          = {{http://dx.doi.org/10.1007/s00401-021-02362-8}},
  doi          = {{10.1007/s00401-021-02362-8}},
  volume       = {{142}},
  year         = {{2021}},
}