Fronto-striatal circuitry in children at risk for Huntington's disease

A Critical Review of White Matter Changes in Huntington’s Disease

“…Furthermore, they suggest that these WM changes happen very early in the disease course. 6,12,17,19,53 Importantly, deficits in brain growth and WM changes are already found in children at risk for HD, 18,54 further pointing to a neurodevelopmental effect of mHTT.…”

“…changes are present very early in the disease course, even in children at risk for HD, 18 and in premanifest individuals who are more than 15 years away from symptom onset. 4,17,19 Notably, WM is composed of axons as well as nonneuronal glia cells, such as myelin-producing oligodendrocytes, and it is unclear whether axons, myelin, or both are predominantly responsible for the WM loss.…”

“…This technique characterizes the 3-dimensional diffusion of water as a function of spatial location, and it is based on the differential diffusion of water molecules depending on tissue type and architecture. 62 For example, the molecular diffusion rate (mean diffusivity), the directional preference of diffusion (fractional anisotropy [FA]), the diffusion rate along the main axis of diffusion (axial diffusivity Reduced WM volume Decreased number of axons attributed to Wallerian degeneration [50][51][52][53][54] Decrease in axon myelination 6,5 Reduced axial diffusivity Axonal degeneration 2 Inflammation, nonuniform axonal oedema, beads, varicosities parallel to the axon segments, microglia/macrophage activation 100 Increased radial diffusivity Demyelination 2,9,18,60,69,70 Less coherent alignment of fibers, more crossing fibers from other bundles, lower density or less myelination of the fibers, or a combination of any or all these factors 101 Reductions in the neurite density index Decrease in axonal density 76 Reduced MRI signal because of demyelination 102 Reductions in MPF Demyelination 59 Changes in cells and water content attributed to inflammation 79,83 Shortened T2…”

“…Specifically, the authors hypothesized that this increase may reflect an impairment in myelin integrity because of a dysfunction in the trophic support mechanisms usually carried out by normal HTT . This in turn is suggested to affect myelin integrity by hindering the production and maintenance of large lipid membranes 18 . In addition, Di Paola and colleagues 64 suggested that demyelination is present in the premanifest HD brain, whereas both myelin breakdown and axonal damage are present in manifest HD.…”

“…Although some work suggests that WM damage in HD is secondary to the loss of GM volume in the form of Wallerian degeneration, 11 there is evidence suggesting that WM aberrations are a feature of HD that occurs independent of neuronal cell loss. 1 , 5 , 8 , 12 , 13 , 14 , 15 , 16 , 17 Accordingly, WM changes are present very early in the disease course, even in children at risk for HD, 18 and in premanifest individuals who are more than 15 years away from symptom onset. 4 , 17 , 19 Notably, WM is composed of axons as well as nonneuronal glia cells, such as myelin‐producing oligodendrocytes, and it is unclear whether axons, myelin, or both are predominantly responsible for the WM loss.…”