Specific patterns of brain alterations underlie distinct clinical profiles in Huntington's disease

Abstract

Huntington's disease (HD) is a genetic neurodegenerative disease which involves a triad of motor, cognitive and psychiatric disturbances. However, there is great variability in the prominence of each type of symptom across individuals. The neurobiological basis of such variability remains poorly understood but would be crucial for better tailored treatments. Multivariate multimodal neuroimaging approaches have been successful in disentangling these profiles in other disorders. Thus we applied for the first time such approach to HD. We studied the relationship between HD symptom domains and multimodal measures sensitive to grey and white matter structural alterations. Forty-three HD gene carriers (23 manifest and 20 premanifest individuals) were scanned and underwent behavioural assessments evaluating motor, cognitive and psychiatric domains. We conducted a multimodal analysis integrating different structural neuroimaging modalities measuring grey matter volume, cortical thickness and white matter diffusion indices – fractional anisotropy and radial diffusivity. All neuroimaging measures were entered into a linked independent component analysis in order to obtain multimodal components reflecting common inter-subject variation across imaging modalities. The relationship between multimodal neuroimaging independent components and behavioural measures was analysed using multiple linear regression. We found that cognitive and motor symptoms shared a common neurobiological basis, whereas the psychiatric domain presented a differentiated neural signature. Behavioural measures of different symptom domains correlated with different neuroimaging components, both the brain regions involved and the neuroimaging modalities most prominently associated with each type of symptom showing differences. More severe cognitive and motor signs together were associated with a multimodal component consisting in a pattern of reduced grey matter, cortical thickness and white matter integrity in cognitive and motor related networks. In contrast, depressive symptoms were associated with a component mainly characterised by reduced cortical thickness pattern in limbic and paralimbic regions. In conclusion, using a multivariate multimodal approach we were able to disentangle the neurobiological substrates of two distinct symptom profiles in HD: one characterised by cognitive and motor features dissociated from a psychiatric profile. These results open a new view on a disease classically considered as a uniform entity and initiates a new avenue for further research considering these qualitative individual differences.

Structural brain correlates of dementia in Huntington’s disease

“…Regarding the impact of cortical changes over functional capacity, the most significant associations were found between TFC and the motor cortex, the superior parietal, and the cuneus( Rosas et al, 2008 ). Similarly, other studies highlighted the involvement of multiple areas related to executive functions and sensorimotor and visuospatial processing in cognitive performance in HD( Garcia-Gorro et al, 2019 ). Interestingly, more recent data also point to hippocampal-dependent memory deficits in HD that cannot be solely explained as a function of degeneration in the basal ganglia( Carmichael et al, 2019 , Harris et al, 2019 ).…”

Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington's Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31

“…Microstructural changes, as evidenced by DTI metrics FA and MD, often occur before brain atrophy and are sensitive to alterations at the cellular and molecular levels indicating brain connectivity changes that occur as fibers reorganize and/or degenerate [17,18]. DTI studies of pre-symptomatic HDGCs and/or symptomatic HD patients demonstrated increased MD compared with healthy controls in multiple brain regions, including caudate, putamen, thalamus, hippocampus, and corpus callosum [17,18,53,[103][104][105]. In this study, each of these brain areas also showed elevated MD values in late-symptomatic R6/2 mice.…”

“…LM11A-31 reduced MD to WT magnitude in the globus pallidus, the primary target of medial spiny neurons [ 106 ], and corpus callosum indicating it may prevent loss of neuronal integrity and/or axonal degeneration in these regions as it has been shown to prevent dendritic/axonal injury and p75 NTR can positively regulate myelination [ 8 , 11 , 107 – 109 ]. Concerning FA, diffusivity is reliably increased in the striatum and globus pallidum and reduced in the corpus callosum of premanifest HDGCs and manifest HD patients [ 17 , 18 , 53 , 55 , 103 , 104 , 110 , 111 ]. In this study, R6/2 mice showed FA changes in the same directions as in HD patients in the striatum, hippocampus, and corpus callosum; LM11A-31 normalized these values in the former two areas, with the greatest effect size in the striatum.…”

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

“…Heterogeneity is one of the hallmarks of HD, both in its clinical manifestations and rates of progression. Specific phenotypes are linked to patterns of brain alterations, 82,83 gender, 84 and genetic factors 85‐87 . Variability, which results in the need to recruit large numbers of patients and for prolonged periods of follow‐up, is at the forefront of obstacles to be lifted for future trials 8,88 .…”