Structural and functional brain network correlates of depressive symptoms in premanifest Huntington's disease.
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ABSTRACT:
SUBMITTER: McColgan P
PROVIDER: S-EPMC5434856 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundHuntington's disease (HD) is a fatal genetic neurodegenerative disorder with no effective treatment currently available. Progressive basal ganglia and whole-brain atrophy and concurrent cognitive deterioration are prototypical aspects of HD. However, the specific patterns of brain atrophy underlying cognitive impairment of different severity in HD are poorly understood. The aim of this study was to investigate the specific structural brain correlates of major cognitive deficits in HD and to explore its association with neuropsychological indicators.ParticipantsThirty-five symptomatic early-to-mild HD patients and 15 healthy controls (HC) with available T1-MRI imaging were included in this study.MethodsIn this cross-sectional study, HD patients were classified as patients with (HD-Dem) and without (HD-ND) major cognitive impairment in the range of dementia. This classification was based on previously validated PD-CRS cutoff scores for HD. Differences in brain atrophy across groups were studied by means of grey-matter volume voxel-based morphometry (GMV-VBM) and cortical thickness (Cth). Voxelwise and vertexwise general linear models were used to assess the group comparisons, controlling for the effects of age, sex, education, CAG repeat length and severity of motor symptoms. Clusters surviving p < 0.05 and family-wise error (FWE) correction were considered statistically significant. In order to characterize the impact on cognitive performance of the observed brain differences across groups, GMV and Cth values in the set of significant regions were computed and correlated with specific neuropsychological tests.ResultsAll groups had similar sociodemographic profiles, and the HD groups did not significantly differ in terms of CAG repeat length. Compared to HC, both HD groups exhibited significant atrophy in multiple subcortical and parietal brain regions. However, compared to HC and HD-ND groups, HD-Dem patients showed a more prominent pattern of reduced GMV and cortical thinning. Importantly, this thinning was restricted to regions of the parietal-temporal and occipital cortices. Furthermore, these brain alterations were further associated with poorer cognitive performance in tasks assessing frontal-executive and attention domains as well as memory, language and constructional abilities.ConclusionsMajor cognitive impairment in the range of dementia in HD is associated with brain and cognitive alterations exceeding the prototypical frontal-executive deficits commonly recognized in HD. The observed posterior-cortical damage identified by MRI and its association with memory, language, and visuoconstructive dysfunction suggest a strong involvement of extra-striatal atrophy in the onset of severe cognitive dysfunction in HD patients. Critically, major cognitive impairment in this sample was not associated with CAG repeat length, age or education. This finding could support a possible involvement of additional neuropathological mechanisms aggravating cognitive deterioration in HD.
| S-EPMC7519361 | biostudies-literature
Project description:BackgroundThe evaluation of effective disease-modifying therapies for neurodegenerative disorders relies on objective and accurate measures of progression in at-risk individuals. Here we used a computational approach to identify a functional brain network associated with the progression of preclinical Huntington's disease (HD).MethodsTwelve premanifest HD mutation carriers were scanned with [18F]-fluorodeoxyglucose PET to measure cerebral metabolic activity at baseline and again at 1.5, 4, and 7 years. At each time point, the subjects were also scanned with [11C]-raclopride PET and structural MRI to measure concurrent declines in caudate/putamen D2 neuroreceptor binding and tissue volume. The rate of metabolic network progression in this cohort was compared with the corresponding estimate obtained in a separate group of 21 premanifest HD carriers who were scanned twice over a 2-year period.ResultsIn the original premanifest cohort, network analysis disclosed a significant spatial covariance pattern characterized by progressive changes in striato-thalamic and cortical metabolic activity. In these subjects, network activity increased linearly over 7 years and was not influenced by intercurrent phenoconversion. The rate of network progression was nearly identical when measured in the validation sample. Network activity progressed at approximately twice the rate of single region measurements from the same subjects.ConclusionMetabolic network measurements provide a sensitive means of quantitatively evaluating disease progression in premanifest individuals. This approach may be incorporated into clinical trials to assess disease-modifying agents.Trial registrationRegistration is not required for observational studies.FundingNIH (National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering) and CHDI Foundation Inc.
| S-EPMC3754266 | biostudies-literature
Project description:We investigated the viability of psychometrically robust executive function measures as markers for premanifest Huntington's disease (HD).Fifteen premanifest HD subjects and 42 controls were compared on the NIH EXAMINER executive function battery. This battery yields an overall executive composite score, plus working memory, cognitive control, and fluency scores that are measured on psychometrically matched scales. The scores were correlated with two disease markers, disease burden and striatal volumes, in the premanifest HD subjects.The premanifest HD subjects scored significantly lower on the working memory score. The executive composite positively correlated with striatal volumes, and the working memory score negatively correlated with disease burden. The cognitive control and fluency scores did not differ between the groups or correlate significantly with the disease markers.The NIH EXAMINER executive composite and working memory scores are sensitive markers of cognitive dysfunction, striatal volume, and disease burden in premanifest HD.
| S-EPMC4029327 | biostudies-literature
Project description:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that progressively affects motor, cognitive, and emotional functions. Structural MRI studies have demonstrated brain atrophy beginning many years prior to clinical onset ("premanifest" period), but the order and pattern of brain structural changes have not been fully characterized. In this study, we investigated brain regional volumes and diffusion tensor imaging (DTI) measurements in premanifest HD, and we aim to determine (1) the extent of MRI changes in a large number of structures across the brain by atlas-based analysis, and (2) the initiation points of structural MRI changes in these brain regions. We adopted a novel multivariate linear regression model to detect the inflection points at which the MRI changes begin (namely, "change-points"), with respect to the CAG-age product (CAP, an indicator of extent of exposure to the effects of CAG repeat expansion). We used approximately 300 T1-weighted and DTI data from premanifest HD and control subjects in the PREDICT-HD study, with atlas-based whole brain segmentation and change-point analysis. The results indicated a distinct topology of structural MRI changes: the change-points of the volumetric measurements suggested a central-to-peripheral pattern of atrophy from the striatum to the deep white matter; and the change points of DTI measurements indicated the earliest changes in mean diffusivity in the deep white matter and posterior white matter. While interpretation needs to be cautious given the cross-sectional nature of the data, these findings suggest a spatial and temporal pattern of spread of structural changes within the HD brain. Hum Brain Mapp 38:5035-5050, 2017. © 2017 Wiley Periodicals, Inc.
| S-EPMC5766002 | biostudies-literature
Project description:Huntington's disease (HD) produces progressive and ultimately widespread impairment of brain function. Neostriatal atrophy alone cannot account for whole-brain losses seen postmortem, and the mutant huntingtin protein and its neuropathologic sequelae are evident throughout the brain. Whole-brain atrophy quantification encompasses the totality of mutant huntingtin's effects on brain volume and may be useful in tracking progression in trials. We studied whole-brain atrophy in HD using a 2-year follow-up design, with three annual MRI scans. We recruited 20 control subjects, 21 premanifest mutation carriers, and 40 patients with early HD and used the brain boundary shift integral to study rate and acceleration of atrophy. Among subjects with an acceptable quality 2-year scan pair, age- and gender-standardized mean brain atrophy rate was greater (P < 0.001) in the patients with HD (n = 21; 0.88%/yr; 95% confidence interval: 0.62-1.13%/yr) than that in controls (n = 13; 0.16%/yr; 0.00-0.32%/yr). In the 12 patients with early HD in whom acceleration could be directly assessed there was evidence (P= 0.048) of acceleration year-on-year (mean acceleration = 0.69% yr(-2); 95% confidence interval: 0.01% yr(-2) to 1.37% yr(-2)), although this was not formally significantly different from that in controls (n = 7, P = 0.055). Statistically significantly increased atrophy rates and acceleration were not seen overall in the premanifest group, who were on average 18 years from predicted disease onset. We conclude that the study of whole-brain atrophy has the potential to inform our understanding of the neurobiology of HD and warrants further study as one means of assessing the outcomes of future clinical trials.
| S-EPMC9136537 | biostudies-literature
Project description:Structural and functional changes attributable to the neurodegenerative process in Huntington's disease (HD) may be evident in HTT CAG repeat expansion carriers before the clinical manifestations of HD. It remains unclear, though, how far from motor onset a consistent signature of the neurodegenerative process in HD can be detected. Twelve far from onset preHD and 22 age-matched healthy control participants underwent volumetric structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and resting-state functional MRI (11 preHD, 22 controls) as well as electrophysiological measurements (12 preHD, 13 controls). There were no significant differences in white matter macro- and microstructure between far from onset preHD participants and controls. Functional connectivity in a basal ganglia-thalamic and motor networks, all measures of the motor efferent and sensory afferent pathways as well as sensory-motor integration were also similar in far from onset preHD and controls. With the methods used in far from onset preHD sensory-motor neural macro- or micro-structure and brain function were similar to healthy controls. This suggests that any observable structural and functional change in preHD nearer to onset, or in manifest HD, at least using comparable techniques such as in this study, most likely reflects an ongoing neurodegenerative process.
| S-EPMC5339687 | biostudies-literature
Project description:Huntington's disease (HD) involves preferential and progressive degeneration of striatum and other subcortical regions as well as regional cortical atrophy. It is caused by a CAG repeat expansion in the Huntingtin gene, and the longer the expansion the earlier the age of onset. Atrophy begins prior to manifest clinical signs and symptoms, and brain atrophy in premanifest expansion carriers can be studied. We employed a diffeomorphometric pipeline to contrast subcortical structures' morphological properties in a control group with three disease groups representing different phases of premanifest HD (far, intermediate, and near to onset) as defined by the length of the CAG expansion and the participant's age (CAG-Age-Product). A total of 1,428 magnetic resonance image scans from 694 participants from the PREDICT-HD cohort were used. We found significant region-specific atrophies in all subcortical structures studied, with the estimated abnormality onset time varying from structure to structure. Heterogeneous shape abnormalities of caudate nuclei were present in premanifest HD participants estimated furthest from onset and putaminal shape abnormalities were present in participants intermediate to onset. Thalamic, hippocampal, and amygdalar shape abnormalities were present in participants nearest to onset. We assessed whether the estimated progression of subcortical pathology in premanifest HD tracked specific pathways. This is plausible for changes in basal ganglia circuits but probably not for changes in hippocampus and amygdala. The regional shape analyses conducted in this study provide useful insights into the effects of HD pathology in subcortical structures.
| S-EPMC6420821 | biostudies-literature
Project description:Huntington's disease (HD) is characterized by clinical motor impairment (e.g., involuntary movements, poor coordination, parkinsonism), cognitive deficits, and psychiatric symptoms. An inhered expansion of the CAG triplet in the huntingtin gene causing a pathogenic gain-of-function of the mutant huntingtin (mHTT) protein has been identified. In this review, we focus on known biomarkers (e.g., mHTT, neurofilament light chains) and on new biofluid biomarkers that can be quantified in plasma or peripheral blood mononuclear cells from mHTT carriers. Circulating biomarkers may fill current unmet needs in HD management: better stratification of patients amenable to etiologic treatment; the initiation of preventive treatment in premanifest HD; and the identification of peripheral pathogenic central nervous system cascades.
| S-EPMC10094222 | biostudies-literature
Project description:Huntington's disease (HD) is a progressive neurodegenerative disorder that can be diagnosed with certainty decades before symptom onset. Studies using structural MRI have identified grey matter (GM) loss predominantly in the striatum, but also involving various cortical areas. So far, voxel-based morphometric studies have examined each brain region in isolation and are thus unable to assess the changes in the interrelation of brain regions. Here, we examined the structural covariance in GM volumes in pre-specified motor, working memory, cognitive flexibility, and social-affective networks in 99 patients with manifest HD (mHD), 106 presymptomatic gene mutation carriers (pre-HD), and 108 healthy controls (HC). After correction for global differences in brain volume, we found that increased GM volume in one region was associated with increased GM volume in another. When statistically comparing the groups, no differences between HC and pre-HD were observed, but increased positive correlations were evident for mHD, relative to pre-HD and HC. These findings could be explained by a HD-related neuronal loss heterogeneously affecting the examined network at the pre-HD stage, which starts to dominate structural covariance globally at the manifest stage. Follow-up analyses identified structural connections between frontoparietal motor regions to be linearly modified by disease burden score (DBS). Moderator effects of disease load burden became significant at a DBS level typically associated with the onset of unequivocal HD motor signs. Together with existing findings from functional connectivity analyses, our data indicates a critical role of these frontoparietal regions for the onset of HD motor signs.
| S-EPMC6867397 | biostudies-literature
Project description:The initial stages of neurodegeneration are commonly marked by normal levels of cognitive and motor performance despite the presence of structural brain pathology. Compensation is widely assumed to account for this preserved behaviour, but despite the apparent simplicity of such a concept, it has proven incredibly difficult to demonstrate such a phenomenon and distinguish it from disease-related pathology. Recently, we developed a model of compensation whereby brain activation, behaviour and pathology, components key to understanding compensation, have specific longitudinal trajectories over three phases of progression. Here, we empirically validate our explicit mathematical model by testing for the presence of compensation over time in neurodegeneration. Huntington's disease is an ideal model for examining longitudinal compensation in neurodegeneration as it is both monogenic and fully penetrant, so disease progression and potential compensation can be monitored many years prior to diagnosis. We defined our conditions for compensation as non-linear longitudinal trajectories of brain activity and performance in the presence of linear neuronal degeneration and applied our model of compensation to a large longitudinal cohort of premanifest and early-stage Huntington's disease patients from the multisite Track-On HD study. Focusing on cognitive and motor networks, we integrated progressive volume loss, task and resting state functional MRI and cognitive and motor behaviour across three sequential phases of neurodegenerative disease progression, adjusted for genetic disease load. Multivariate linear mixed models were fitted and trajectories for each variable tested. Our conceptualization of compensation was partially realized across certain motor and cognitive networks at differing levels. We found several significant network trends that were more complex than that hypothesized in our model. These trends suggest changes to our theoretical model where the network effects are delayed relative to performance effects. There was evidence of compensation primarily in the prefrontal component of the cognitive network, with increased effective connectivity between the left and right dorsolateral prefrontal cortex. Having developed an operational model for the explicit testing of longitudinal compensation in neurodegeneration, it appears that general patterns of our framework are consistent with the empirical data. With the proposed modifications, our operational model of compensation can be used to test for both cross-sectional and longitudinal compensation in neurodegenerative disease with similar patterns to Huntington's disease.
| S-EPMC6022638 | biostudies-literature