McColgan, Peter;
Gregory, Sarah;
Zeun, Paul;
Zarkali, Angeliki;
Johnson, Eileanoir B;
Parker, Christopher;
Fayer, Kate;
... Rees, Geraint; + view all
(2022)
Neurofilament light associated connectivity in young-adult Huntington's disease is related to neuronal genes.
Brain
, Article awac227. 10.1093/brain/awac227.
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Abstract
Upregulation of functional network connectivity in the presence of structural degeneration is seen in the premanifest stages of Huntington's disease (preHD) 10-15 years from clinical diagnosis. However, whether widespread network connectivity changes are seen in gene-carriers much further from onset has yet to be explored. We characterised functional network connectivity throughout the brain and related it to a measure of disease pathology burden (CSF Neurofilament Light, NfL) and measures of structural connectivity in asymptomatic gene-carriers, on average 24 years from onset. We related these measurements to estimates of cortical and subcortical gene-expression. We found no overall differences in functional (or structural) connectivity anywhere in the brain comparing control and preHD participants. However, increased functional connectivity, particularly between posterior cortical areas, correlated with increasing CSF NfL level in preHD participants. Using the Allen Human Brain Atlas and expression-weighted cell-type enrichment analysis, we demonstrated that this functional connectivity upregulation occurred in cortical regions associated with regional expression of genes specific to neuronal cells. This relationship was validated using single-nucleus RNAseq data from post-mortem HD and control brains showing enrichment of neuronal-specific genes that are differentially expressed in HD. Functional brain networks in asymptomatic preHD gene-carriers very far from disease onset, show evidence of upregulated connectivity correlating with increased disease burden. These changes occur among brain areas that show regional expression of genes specific to neuronal GABAergic and glutamatergic cells.
| Type: | Article |
|---|---|
| Title: | Neurofilament light associated connectivity in young-adult Huntington's disease is related to neuronal genes |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/brain/awac227 |
| Publisher version: | https://doi.org/10.1093/brain/awac227 |
| Language: | English |
| Additional information: | © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Huntington’s disease, connectivity, gene-expression, neurofilament light |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Computer Science UCL > Provost and Vice Provost Offices > UCL BEAMS |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10151020 |
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