Localisation of Key Network Regions Involved in the Conversion to Manifest Huntington’s Disease
Poster No:
133
Submission Type:
Abstract Submission
Authors:
Ellen Younger1, Elizabeth Ellis2, Karen Caeyenberghs1, Juho Joutsa3, Daniel Corp1
Institutions:
1Deakin University, Burwood, Victoria, 2Deakin University, Melbourne, Victoria, 3University of Turku, Turku, Turku
First Author:
Co-Author(s):
Introduction:
Conversion from premanifest to manifest Huntington's disease (HD) is defined by the onset of motor symptoms, such as chorea. However, the key brain areas underlying this disease progression are not well understood. Therefore, this study sought to localise functional brain networks that connect structural brain abnormalities in premanifest and manifest HD, and investigate whether the transition from premanifest to manifest-HD is reflected in the affected networks.
Methods:
A systematic search was conducted to identify studies reporting coordinates of structural brain abnormalities in premanifest- or manifest-HD. Coordinate network mapping (CNM) was used to localise brain networks that were most consistently connected to these coordinates in premanifest and manifest-HD disease stages. The premanifest-HD network was then subtracted from the manifest-HD network to identify key network areas that were unique to the manifest-HD disease stage. To assess whether these areas unique to the manifest-HD network may be causally implicated in chorea, we compared these areas to a previously defined causal network of hemichorea (Ellis et al., 2024). Next, an independent dataset (Klöppel et al., 2015) of rs-fMRI scans from HD patients (n = 72 premanifest-HD, n = 38 manifest-HD) and healthy controls (n= 95) was used to assess if the areas unique to the manifest-HD network also show functional connectivity abnormality in manifest-HD patients compared to premanifest-HD and healthy controls. Finally, we assessed whether functional connectivity from the areas unique to manifest-HD changed during clinical conversion in a longitudinal sample of HD patients (n = 15).
Results:
Coordinates of structural brain abnormality were reported in nine studies of premanifest-HD and 14 studies of manifest-HD. CNM analyses of these coordinates identified brain networks connected to over 90% of studies' findings for each disorder group. Importantly, these CNM results identified key brain areas that were commonly connected to abnormalities in manifest-HD but not premanifest-HD. Most prominently, the posterior putamen was found to be unique to the manifest-HD network, which localised to the motor portion of the putamen and showed spatial overlap with a previously defined causal network of hemichorea (Ellis et al., 2024; Figure 1). These areas unique to the manifest-HD network had significantly lower (p-FDR < 0.001) functional connectivity in manifest-HD patients compared to both premanifest-HD patients and healthy controls. Finally, the longitudinal analysis results demonstrated that connectivity from the areas unique to the manifest-HD network significantly decreased (p-FDR < 0.001) from before to after clinical conversion.
Conclusions:
These findings define brain networks connected to locations of atrophy in premanifest and manifest-HD, and identify key network regions that are unique to the manifest-HD disease stage. The areas unique to manifest-HD may be implicated in the onset of chorea in HD, as these areas align with a causal network of hemichorea, and showed functional abnormality in only manifest-HD in a cross-sectional sample and alterations after motor symptom onset in a longitudinal sample. These findings lend insight to the neuropathological underpinnings of clinical conversion to manifest-HD.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
Connectivity (eg. functional, effective, structural)
fMRI Connectivity and Network Modeling 2
Motor Behavior:
Motor Behavior Other
Keywords:
Movement Disorder
Other - Huntington's disease; Chorea; network mapping; functional connectivity
1|2Indicates the priority used for review
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Were any human subjects research approved by the relevant Institutional Review Board or ethics panel? NOTE: Any human subjects studies without IRB approval will be automatically rejected.
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Provide references using APA citation style.
Klöppel, S. (2015). Compensation in preclinical Huntington's disease: evidence from the track-on HD study. EBioMedicine, 2(10), 1420-1429.