Timing of selective basal ganglia white matter loss in Huntington’s disease

Abstract

Objectives: To investigate the timeframe prior to symptom onset when cortico-basal ganglia white matter (WM) loss begins in premanifest Huntington's disease (preHD), and which striatal and thalamic sub-region WM tracts are most vulnerable. Methods: We performed fixel-based analysis, which allows resolution of crossing WM fibres at the voxel level, on diffusion tractography derived WM tracts of striatal and thalamic sub-regions in two independent cohorts; TrackON-HD, which included 72 preHD (approx. 11 years before disease onset) and 85 controls imaged at three time points over two years; and the HD young adult study (HD-YAS), which included 54 preHD (approx. 25 years before disease onset) and 53 controls, imaged at one time point. Group differences in fibre density and cross section (FDC) were investigated. Results: We found no significant group differences in cortico-basal ganglia sub-region FDC in preHD gene carriers 25 years before onset. In gene carriers 11 years before onset, there were reductions in striatal (limbic and caudal motor) and thalamic (premotor, motor and sensory) FDC at baseline, with no significant change over 2 years. Caudal motor-striatal, pre-motor-thalamic, and primary motor-thalamic FDC at baseline, showed significant correlations with the Unified Huntington's disease rating scale (UHDRS) total motor score (TMS). Limbic cortico-striatal FDC and apathy were also significantly correlated. Conclusions: Our findings suggest that the initiation of disease modifying therapies 25 years before onset could protect these important brain networks from undergoing neurodegeneration and highlight selectively vulnerable sub-regions of the striatum and thalamus that may be important targets for future therapies.

Neurofilament light-associated connectivity in young-adult Huntington’s disease is related to neuronal genes

“…As there were no differences in WM organisation in our previous analyses 19,20 Our findings are consistent with our earlier work focusing exclusively on fronto-striatal connectivity 11 . In that earlier work, fronto-striatal connectivity related to cognitive flexibility (posterior regions were not interrogated as part of these analyses) differed in preHD participants, while connections from the striatum to both frontal and posterior cortical regions showed higher connectivity with evidence of compensatory activity to support maintained performance (in review).…”

“…As there were no differences in white matter organization in our previous analyses 19 , 20 and a limited number of white matter connections showing significant negative correlation with CSF NfL (only for the 514 atlas) in this study, this suggests that large-scale functional changes precede those of microstructure in Huntington’s disease gene carriers furthest from disease onset. It is important to note that as a marker of axonal degeneration, CSF NfL increases indicate some degree of underlying molecular change.…”

“…As such, marked axonal loss may lead to upregulated functional network connections unaffected by structural change or the recruitment of extra-network functional connections in those around 10-15 years from disease onset 1,[16][17][18] . We have previously shown that there are no detectable changes in structural network connectivity in a young-adult preHD cohort (HD-YAS) on average 24 years from disease onset 19,20 , but there was evidence of functional network change 11 . This is consistent with considerable evidence of neuronal network hyperexcitability driven by glutamatergic excitotoxicity and/or reduced inhibitory GABAergic activity in the earliest stages of neurodegeneration [21][22][23][24][25] .…”