Striatal connectivity in pre‐manifest Huntington’s disease is differentially affected by disease burden

Abstract

Background and purpose: Different amounts of cumulative exposure to the toxic mutant form of the huntingtin protein might underlie the distinctive pattern of striatal connectivity in pre-manifest Huntington's disease (pre-HD). The aim of this study was to investigate disease-burden-dependent corticalstriatal and subcortical-striatal loops at different pre-HD stages. Methods: A total of 16 participants with pre-HD and 25 controls underwent magnetic resonance imaging to investigate striatal structural and functional connectivity (FC). Individuals with pre-HD were stratified into far-from-onset and close-to-onset disease groups according to the disease-burden score. Cortical-striatal and subcortical-striatal FC was investigated through seed-region of interest (ROI) and ROI-to-ROI approaches, respectively. The integrity of white-matter pathways originating from striatal seeds was investigated through probabilistic tractography. Results: In far-from-onset pre-HD, the left caudate nucleus showed cortical increased FC in brain regions overlapping with the default mode network and increased coupling connectivity with the bilateral thalamus. By contrast, close-to-onset individuals showed increased fractional anisotropy (and mean diffusivity) in the right caudate nucleus and widespread striatal atrophy. Finally, we reported an association between cortical-caudate FC and caudate structural connectivity, although this did not survive multiple comparison correction. Conclusions: Functional reorganization of the caudate nucleus might underlie plasticity compensatory mechanisms that recede as individuals with pre-HD approach clinical symptom onset and neurodegeneration.

Neuroimaging Biomarkers for Huntington’s Disease

“…No significant differences were found between the close-toonset subgroup and healthy controls. There was also no difference between the total premanifest group and controls with regard to functional connectivity of the right caudate nucleus, bilateral putamen, and bilateral nucleus accumbens [105]. These differences in activity and locations sometimes differ from each other, partly due to differences in task designs.…”

“…Other studies showed that diffusion imaging could be used as a method to differentiate the subgroup close-to-onset premanifest HDEGC from far-from-onset HDEGC. They showed an increased MD in close-toonset-HD, compared to far-from-onset and healthy controls [104,105].…”

Decreased Functional Connectivities of Low-Degree Level Rich Club Organization and Caudate in Post-stroke Cognitive Impairment Based on Resting-State fMRI and Radiomics Features

“…However, due to the severe brain damage, the clinical symptoms of cognitive impairment still appeared. The functional reorganization of CAU_L might underlie compensatory plasticity mechanisms ( Pini et al, 2020 ; Zhang et al, 2021 ). However, CAU_R efficiency decreased in iPSCI.…”

Cell therapy in Huntington's disease: Taking stock of past studies to move the field forward

“…90 When this study commenced, no cognitive assessments were universally accepted except the UHDRS cognitive score, which also lacks sensitivity, and TFC was discounted consider- 94 Likewise future trials should capitalize on volumetric MRI and connectivity measures. 95,96 Additional trial design measures might include enrichment strategies to recruit patients predicted to have faster rates of progression based on neuroimaging analyses, genetic polymorphisms, clinical profiles, or retest effects 85,[97][98][99][100] to increase the likelihood of demonstrating treatment efficacy with small cohorts over shorter durations.…”

“…New tracers, such as ligands to phosphodiesterase‐10A, an enzyme expression by striatal MSN whose reduction is one of the earliest biochemical changes in HD 93 may prove to be a reliable indicator of disease progression 94 . Likewise future trials should capitalize on volumetric MRI and connectivity measures 95,96 …”