Altered iron and myelin in premanifest Huntington's Disease more than 20 years before clinical onset: Evidence from the cross-sectional HD Young Adult Study

Abstract

Background Pathological processes in Huntington's disease (HD) begin many years prior to symptom onset. Recently we demonstrated that in a premanifest cohort approximately 24 years from predicted disease onset, despite intact function, there was evidence of subtle neurodegeneration. Here, we use novel imaging techniques to determine whether macro- and micro-structural changes can be detected across the whole-brain in the same cohort. Methods 62 premanifest HD (PreHD) and 61 controls from the HD Young Adult Study (HD-YAS) were included. Grey and white matter volume, diffusion weighted imaging (DWI) measures of white matter microstructure, multiparametric maps (MPM) estimating myelin and iron content from magnetization transfer (MT), proton density (PD), longitudinal relaxation (R1) and effective transverse relaxation (R2*), and myelin g-ratio were examined. Group differences between PreHD and controls were assessed; associations between all imaging metrics and disease burden and CSF neurofilament light (NfL) were also performed. Volumetric and MPM results were corrected at a cluster-wise value of familywise error (FWE) 0.05. Diffusion and g-ratio results were corrected via threshold-free cluster enhancement at FWE 0.05. Findings We showed significantly increased R1 and R2*, suggestive of increased iron, in the putamen, globus pallidum and external capsule of PreHD participants. There was also a significant association between lower cortical R2*, suggestive of reduced myelin or iron, and higher CSF NfL in the frontal lobe and the parieto-occipital cortices. No other results were significant at corrected levels. Interpretation Increased iron in subcortical structures and the surrounding white matter is a feature of very early PreHD. Furthermore, increases in CSF NfL were linked to microstructural changes in the posterior parietal-occipital cortex, a region previously shown to undergo some of the earliest cortical changes in HD. These findings suggest that disease related process are occurring in both subcortical and cortical regions more than 20 years from predicted disease onset.

Mutation-related apparent myelin, not axon density, drives white matter differences in premanifest Huntington’s disease: Evidence from in vivo ultra-strong gradient MRI

“…Alternatively, such a result might reflect axonal swelling 113 . Consistent with this suggestion, previous evidence demonstrated higher iron levels in the left CST of premanifest patients 91,114 , interpreted as indicating an homeostatic increase in oligodendrocytes to repair myelin damage. In turn, myelin damage leads to axon swelling 115 .…”

“…Additionally, this explanation agrees with findings from neuropathology showing increased density of oligodendrocytes in the brain of premanifest patients 23 ; furthermore, mHTT directly alters the proliferation property of cultured oligodendrocyte precursor cells (OPCs), with the degree of cell proliferation of OPCs increasing with pathological severity and increasing CAG repeat length 25 . Finally, recent evidence from the cross-sectional HD Young Adult Study demonstrated increased R1 and R2* values, suggestive of either increased iron or increased myelin, in the putamen, globus pallidum and external capsule of HD patients more than 20 years away from clinical onset 91 .…”

“…Accordingly, there is increasing evidence that neurodevelopment is affected in HD 99,102 and that such developmental elements of HD are independent of ongoing neurodegeneration 91 .…”

“…These changes may reflect early neuronal dysfunction 98 or a CAG-driven neurodevelopmental component to the pathogenesis of HD, as a precursor to the more global neurodegeneration process 25,99–101 . Accordingly, there is increasing evidence that neurodevelopment is affected in HD 99,102 and that such developmental elements of HD are independent of ongoing neurodegeneration 91 . Nevertheless, as the present study was not designed to detect HD-associated developmental changes, future studies following young premanifest subjects longitudinally should address the possibility of toxic myelin levels because of pathological CAG repeats size.…”

“…To date, only one other study has used extensive microstructural measures in premanifest HD 91 . Nevertheless, such measurements are essential for understanding the trajectory of myelin alterations across the disease course, which is expected to vary as disease processes change 91,121 . Notably, though much of our understanding of HD pathology will increasingly rely on advanced neuroimaging techniques, it is important to remember and address the shortcomings of these approaches.…”