Characterizing White Matter in Huntington's Disease

Abstract

Background Background: Investigating early white matter (WM) change in Huntington's disease (HD) can improve our understanding of the way in which disease spreads from the striatum. Objectives Objectives: We provide a detailed characterization of pathology-related WM change in HD. We first examined WM microstructure using diffusion-weighted imaging and then investigated both underlying biological properties of WM and products of WM damage including iron, myelin plus neurofilament light, a biofluid marker of axonal degeneration-in parallel with the mutant huntingtin protein. MethodsMethods: We examined WM change in HD gene carriers from the HD-CSFcohort, baseline visit. We used standard-diffusion magnetic resonance imaging to measure metrics including fractional anisotropy, a marker of WM integrity, and diffusivity; a novel diffusion model (neurite orientation dispersion and density imaging) to measure axonal density and organization; T1-weighted and T2-weighted structural magnetic resonance imaging images to derive proxy iron content and myelin-contrast measures; and biofluid concentrations of neurofilament light (in cerebrospinal fluid (CSF) and plasma) and mutant huntingtin protein (in CSF). ResultsResults: HD gene carriers displayed reduced fractional anisotropy and increased diffusivity when compared with controls, both of which were also associated with disease progression, CSF, and mutant huntingtin protein levels. HD gene carriers also displayed proxy measures of reduced myelin contrast and iron in the striatum. Conclusion Conclusion: Collectively, these findings present a more complete characterization of HD-related microstructural brain changes. The correlation between reduced fractional anisotropy, increased axonal orientation, and biofluid markers suggest that axonal breakdown is associated with increased WM degeneration, whereas higher quantitative T2 signal and lower myelin-contrast may indicate a process of demyelination limited to the striatum.The ongoing development of novel therapeutics to treat Huntington's disease (HD) necessitates improved characterization of HD-related brain changes. HD is a progressive neurodegenerative disorder characterized by a motor, cognitive, and neuropsychiatric phenotype and caused by CAG expansions in the huntingtin gene (HTT). Given the certainty of onset in those that inherit the gene combined with genetic testing, we can examine brain changes from the earliest, presymptomatic disease stages.Magnetic resonance imaging (MRI) measures of neuronal atrophy have characterized macrostructural brain changes associated with HD progression. 1,2 Neurodegeneration primarily originates in the striatum, extending to white matter (WM) and finally the cortex. 1,3 However, although a robust marker of disease progression, macrostructural changes provide limited descriptions of pathological mechanisms underlying HD. Investigating early WM microstructural changes in HD can improve our understanding of WM organization

Diffusion imaging in Huntington’s disease: comprehensive review

“…72 Neurite orientation dispersion and density imaging (NODDI) has recently been used in HD cohorts to characterise microstructures more fully. [73][74][75] NODDI uses a three-tissue compartment model whereby each tissue element is independently estimated according to its proposed diffusion properties. The three components are intraneurite, extraneurite and a CSF component.…”

“…74 These widespread decreases in NDI, combined with increased diffusivity, persist in manifest HD gene carriers. 75 Other advanced techniques include quantitative magnetisation transfer, which nominally tracks demyelination, by characterising the macromolecular proton fraction 76 and correlates with increases in diffusivity in HD. 77 Alternatively, the isotropic volume fraction measures extracellular fast-moving water, a potential proxy measure of WM atrophy, which has been shown to be sensitive to disease-related WM change in corticostriatal pathways.…”

“… 74 These widespread decreases in NDI, combined with increased diffusivity, persist in manifest HD gene carriers. 75 …”

Cerebrospinal fluid endo-lysosomal proteins as potential biomarkers for Huntington’s disease

“…Furthermore, administration of gangliosides has been found to reduce apoptosis in HD cell lines and restore normal ganglioside concentration in YAK128 mice, resulting in improved motor function [ 40 , 41 ]. Given that gangliosides are involved in regulating white matter integrity [ 42 ], and that white matter atrophy is associated with HD [ 43 – 45 ], the exploration of CSF GM2A, a protein pivotal for ganglioside catabolism, is warranted and may further explain white matter pathology in HD.…”

Cerebrospinal fluid endo-lysosomal proteins as potential biomarkers for Huntington’s disease

“…Furthermore, administration of gangliosides has been found to reduce apoptosis in HD cell lines and restore normal ganglioside concentration in YAK128 mice, resulting in improved motor function [30,31]. Given that gangliosides are involved in regulating white matter integrity [32], and that white matter atrophy is associated with HD [33][34][35], the exploration of CSF GM2A, a protein pivotal for ganglioside catabolism, is warranted and may further explain white matter pathology in HD.…”