Diffusion imaging in Huntington’s disease: comprehensive review

Abstract

Huntington’s disease (HD) is a monogenic disorder with 100% penetrance. With the advent of genetic testing in adults, disease-related, structural brain changes can be investigated from the earliest, premorbid stages of HD. While examining macrostructural change characterises global neuronal damage, investigating microstructural alterations provides information regarding brain organisation and its underlying biological properties. Diffusion MRI can be used to track the progression of microstructural anomalies in HD decades prior to clinical disease onset, providing a greater understanding of neurodegeneration. Multiple approaches, including voxelwise, region of interest and tractography, have been used in HD cohorts, showing a centrifugal pattern of white matter (WM) degeneration starting from deep brain areas, which is consistent with neuropathological studies. The corpus callosum, longer WM tracts and areas that are more densely connected, in particular the sensorimotor network, also tend to be affected early during premanifest stages. Recent evidence supports the routine inclusion of diffusion analyses within clinical trials principally as an additional measure to improve understanding of treatment effects, while the advent of novel techniques such as multitissue compartment models and connectomics can help characterise the underpinnings of progressive functional decline in HD.

A novel rhesus macaque model of Huntington’s disease recapitulates key neuropathological changes along with progressive motor and cognitive decline

“…Interestingly, the caudate and several widespread cortical regions also exhibited reduced FA as well, a phenomenon less reported in human HD cases, and which could potentially indicate atrophy affecting dendritic processes in these regions. In contrast, areas of the putamen and globus pallidus exhibited significantly increased FA in HTT85Q-treated animals, which has also been described in both premanifest and symptomatic HD patients [41][42][43][44] and speculated to result from the of loss of radially-dispersed fibers projecting from striatal medium spiny neurons 44 . We hypothesize that increased FA in the putamen and globus pallidus may have also resulted secondarily from an increase in gliotic processes, affecting water diffusion in these areas of degeneration, and histological studies are planned when brain tissue from these animals becomes available.…”

“…Due to the long scanning times achievable with anesthetized NHPs, high-resolution DTI enabled a more detailed analyses of white matter tracts, in addition to cortical and sub-cortical gray matter brain structures than has been previously achieved. The reduction in white matter FA, a biomarker associated with myelin breakdown and axonal swelling, seen in HTT85Q macaques closely mirrors changes seen in human HD patient white matter tracts, including the prefrontal WM tracts, corona radiata, internal and external capsules, and the corpus callosum 43 . Interestingly, the caudate and several widespread cortical regions also exhibited reduced FA as well, a phenomenon less reported in human HD cases, and which could potentially indicate atrophy affecting dendritic processes in these regions.…”

“…More recently, a pattern of increased FA in the putamen and globus pallidus has been described in premanifest/early symptomatic HD patients; and a pattern of decreased FA in gray matter in areas including the ventromedial frontal cortex, insula cortex, and the cerebellum has been described in advanced HD patients 11,[41][42][43][44] . To explore whether similar changes in FA are evident in gray matter (GM) regions in our HD macaques, we conducted voxel-wise comparisons between the baseline (pre-surgical) FA maps and subsequent timepoints for each group separately using a GM mask.…”

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

“…The common implementation of fixel-based analysis is a whole-brain analysis which then requires correction for a very large number of comparisons at a cost of reduced power to detect subtle changes. Since a large literature in preHD already exists to suggest the earliest structural changes occur in the striatum and associated white matter ( Estevez-Fraga et al, 2021 ), we sought to specifically look at cortico-striatal white matter tracts only whilst still leveraging the advantages of fixel-based analysis in terms of diffusion signal processing. Seed-based diffusion tractography was used to delineate tracts of interest for subsequent fixel-based analysis.…”

Altered M2 Cortex - Superior Colliculus visual perception circuit in Huntington’s Disease

“…In HD patients, the most affected structural and functional striatal connexions arise from cortical premotor areas, analogous to the secondary motor (M2) cortex in rodents. Notably, these affectations appear many years before the onset of motor symptoms in HD carriers (Estevez-Fraga et al, 2021; Johnson et al, 2021; Shaffer et al, 2017; Unschuld et al, 2012) and are profoundly impaired in animal models (Creus-Muncunill et al, 2019; Fernández-García et al, 2020; Hintiryan et al, 2016). However, it is unclear whether dysregulated information flow from the M2 cortex in HD affects only cortico-striatal functions or could have an additional impact in the remaining long-distance output nuclei.…”