Longitudinal atrophy characterization of cortical and subcortical gray matter in Huntington’s disease patients

Abstract

Huntington's disease (HD) is an inherited neurodegenerative disease with clinical manifestations that involve motor, cognitive and psychiatric deficits. Cross-sectional magnetic resonance imaging (MRI) studies have described the main cortical and subcortical macrostructural atrophy of HD. However, longitudinal studies characterizing progressive atrophy are lacking. This study aimed to describe the cortical and subcortical gray matter atrophy using complementary volumetric and surface-based MRI analyses in a cohort of seventeen early HD patients in a cross-sectional and longitudinal analysis and to correlate the longitudinal volumetric atrophy with the functional decline using several clinical measures. A group of seventeen healthy individuals was included as controls. After obtaining structural MRIs, volumetric analyses were performed in 36 cortical and 7 subcortical regions of interest per hemisphere and surface-based analyses were performed in the whole cortex, caudate, putamen and thalamus. Cross-sectional cortical surface-based and volumetric analyses showed significant decreases in frontoparietal and temporo-occipital cortices, while subcortical volumetric analysis showed significant decreases in all subcortical structures except the hippocampus. The longitudinal surface-based analysis showed widespread cortical thinning with volumetric decreases in the superior frontal lobe, while a subcortical volumetric decrease occurred in the caudate, putamen and thalamus with shape deformation on the anterior, medial and dorsal side. Functional capacity and 1828 | RAMIREZ-GARCIA Et Al. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section.

Dynamics of Cortical Degeneration Over a Decade in Huntington’s Disease

“…By early manifest disease, cortical atrophy appears to have occurred (4), but the ongoing process of gray matter (GM) degeneration in HD has not been studied. There is evidence of increasing white matter disorganization during this period (10-13), but there have been conflicting findings regarding the cortex, with regional cortical change only described between two time points over short intervals and via restrictive analysis techniques (6,(14)(15)(16)(17)(18)(19) such as regression models. Because HD is a slowly progressive disease, these studies ultimately fail to capture the nature or extent of cortical change.…”

Isoform-Specific Reduction of the Basic Helix-Loop-Helix Transcription Factor TCF4 Levels in Huntington’s Disease

“…In healthy adults, cognitive functions such as learning and memory rely on neuronal plasticity and neurogenesis in the hippocampus and cerebral cortex ( McClelland et al, 1995 ; Chambers et al, 2004 ; Aimone et al, 2009 ; Gonçalves et al, 2016 ; Mansvelder et al, 2019 ). While atrophy and neurodegeneration in striatum and cerebral cortex is a neuropathological hallmark of HD, the hippocampus remains relatively unaffected in HD patients ( Ramirez‐Garcia et al, 2020 ), although misregulated transcriptional pathway of synaptic vesicles has been observed ( Neueder and Bates, 2014 ). On the other hand, reduced hippocampal adult neurogenesis in subgranular zone (SGZ) of the dentate gyrus (DG) has been reported in R6/2, R6/1, and YAC128 HD mouse models ( Lazic et al, 2004 ; Gil et al, 2005 ; Simpson et al, 2011 ) and Q175FDN knock-in HD mice show deficits in hippocampal synaptic plasticity ( Quirion and Parsons, 2019 ).…”

Brain, cognitive, and physical disability correlates of decreased quality of life in patients with Huntington’s disease

“…Several limitations must be recognized. First, Although our sample size was relatively small, it is similar to that of previous studies assessing GM atrophy [ 1 , 55 , 56 ], or QoL [ 3 , 12 ] in HD patients or QoL in caregivers of HD patients [ 9 , 57 ]. Second, even though we assessed several key variables previously associated to QoL in HD patients (demographic variables, cognitive measurements, and physical disability outcomes) [ 27 , 32 , 33 ], as well as GM volumes, other relevant variables such as behavioral and psychiatric symptoms such as depression, suicidal ideation, anxiety, irritability, anger/aggression, apathy, perseveration and others [ 58 ] were not considered in the current study.…”

“…Huntington’s disease (HD) is an autosomal-dominant, progressive, degenerative disease characterized by multiple cognitive, motor, and behavioral difficulties [ 1 ], associated with multiple brain structural alterations. In particular, HD patients have shown early and selective atrophy in the caudate nucleus and putamen [ 2 ].…”

“…In particular, HD patients have shown early and selective atrophy in the caudate nucleus and putamen [ 2 ]. As the disease progresses, some studies have shown overall cortical thinning with larger changes in the frontal lobe, caudate, putamen and thalamus [ 1 ]. The neurocognitive and behavioral changes impact the quality of life (QoL) of patients and caregivers [ 3 ].…”