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

Abstract

Highlights Limbic and caudal motor cortico-striatal tracts appear to be selectively vulnerable to degeneration in the early premanifest Huntington’s disease (preHD), approximately 11 years from predicted onset. Similarly of cortico-thalamic connections, pre-motor and primary motor-thalamic connections appear selectively vulnerable to early degeneration. However these connections appear preserved in a preHD cohort 25 years from predicted onset. This highlights vulnerable subregions of the striatum and thalamus that may be important targets for future therapies that seek to prevent early neurodegeneration in preHD.

Protocol for a randomised controlled feasibility trial of HD-DRUM, a rhythmic movement training application for cognitive and motor symptoms in people with Huntington’s disease

“…Ultra-strong gradients allow the acquisition of diffusion-weighted data with high diffusion-weighting b-values, with good signal to noise ratio for the estimation of intracellular diffusion properties 32 . Multi- shell high angular resolution diffusion imaging (msHARDI) 33 data (max b-value = 6,000 s/mm 2 ) will be acquired to estimate microstructural white and grey matter properties of axon and soma density 34 35 . Myelin properties will be estimated with quantitative magnetization transfer (qMT) imaging 36 and multicomponent driven equilibrium single pulse observation of T and T (mcDESPOT) 37 .…”

“…Huntington’s disease (HD) is a genetic neurodegenerative disease that leads to the progressive loss of cognitive and motor abilities, largely due to basal ganglia (BG) atrophy. Striatal atrophy 1 and microstructural alterations in white matter (WM) connections 2 with associated cognitive control dysfunctions 3–5 occur many years before the clinical onset of motor symptoms and will eventually negatively impact a person’s ability to live independently 6 .…”

HD-DRUM, a Tablet-Based Drumming Training App Intervention for People With Huntington Disease: App Development Study (Preprint)

“…Huntington's disease (HD) is an inherited progressive neurodegenerative disease where cell loss in basal ganglia networks of the brain that manifests as cognitive decline, loss of motor control, and mood disturbances. Striatal atrophy [1] and white matter degeneration [2] are observed many years prior to the onset of movement symptoms. These early brain changes are accompanied with impairments in psychomotor speed and executive functions [3,4] including problems in decisionmaking, multi-tasking, and motor sequence learning, all of which may hamper a person's everyday functional abilities such as working capacity [5].…”

Differential tractography as a dynamic imaging biomarker: A methodological pilot study for Huntington’s disease

“…Both PREDICT-HD and TRACK-HD confirmed previous reports supporting the value of imaging markers, especially of striatal and whole-brain atrophy during the premanifest stage ( Biglan et al, 2009 , Tabrizi et al, 2009 ). A recent study ( Zeun et al, 2022 ) that applied fixel-based analysis in a large sample of premanifest individuals suggests that white matter structures such as the cortico-basal ganglia display signs of degeneration or “vulnerability” at around 11–25 years after diagnosis, with preserved integrity as early as 25 years before diagnosis has been established. In addition, the aforementioned study observed that the sensory and motor components of the thalamus and the limbic and motor striatum have demonstrated to be at risk in this population, suggesting that clear observable white matter changes at the voxel level can be demonstrated years after diagnosis and not during the premanifest phase.…”

“…CSF volume acting as an artifact) ( Berlot et al, 2014 , Jeurissen et al, 2013 , Metzler-Baddeley et al, 2012 ), while still only demonstrating a difference in HD patients at a group level when compared to a control population. Recent studies have applied beyond-DTI methods such as fixel-based analyses using constraint spherical deconvolution (CSD) in early HD ( Adanyeguh et al, 2021 , Oh et al, 2021 ) and in premanifest HD ( Zeun et al, 2022 ) to identify neurodegeneration in HD. However, although the fixel-based approach provides a high angular resolution advantage ( Tournier et al, 2004 ), several technical considerations need to be taken to avoid a critical flaw in tractography clinical studies ( Parker et al, 2013 ).…”