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Cortical cell loss is a core feature of Huntington's disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is unclear how genetic topography relates to cortical cell loss. Here, we explore the biological processes and cell types underlying this relationship and validate these using cell-specific post-mortem data. Eighty premanifest participants on average 15 years from disease onset and 71 controls were included. Using volumetric and diffusion MRI we extracted HD-specific whole brain maps where lower grey matter volume and higher grey matter mean diffusivity, relative to controls, were used as proxies of cortical cell loss. These maps were combined with gene expression data from the Allen Human Brain Atlas (AHBA) to investigate the biological processes relating genetic topography and cortical cell loss. Cortical cell loss was positively correlated with the expression of developmental genes (i.e. higher expression correlated with greater atrophy and increased diffusivity) and negatively correlated with the expression of synaptic and metabolic genes that have been implicated in neurodegeneration. These findings were consistent for diffusion MRI and volumetric HD-specific brain maps. As wild-type huntingtin is known to play a role in neurodevelopment, we explored the association between wild-type huntingtin (HTT) expression and developmental gene expression across the AHBA. Co-expression network analyses in 134 human brains free of neurodegenerative disorders were also performed. HTT expression was correlated with the expression of genes involved in neurodevelopment while co-expression network analyses also revealed that HTT expression was associated with developmental biological processes. Expression weighted cell-type enrichment (EWCE) analyses were used to explore which specific cell types were associated with HD cortical cell loss and these associations were validated using cell specific single nucleus RNAseq (snRNAseq) data from post-mortem HD brains. The developmental transcriptomic profile of cortical cell loss in preHD was enriched in astrocytes and endothelial cells, while the neurodegenerative transcriptomic profile was enriched for neuronal and microglial cells. Astrocyte-specific genes differentially expressed in HD post-mortem brains relative to controls using snRNAseq were enriched in the developmental transcriptomic profile, while neuronal and microglial-specific genes were enriched in the neurodegenerative transcriptomic profile. Our findings suggest that cortical cell loss in preHD may arise from dual pathological processes, emerging as a consequence of neurodevelopmental changes, at the beginning of life, followed by neurodegeneration in adulthood, targeting areas with reduced expression of synaptic and metabolic genes. These events result in age-related cell death across multiple brain cell types.
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Doença de Huntington , Humanos , Doença de Huntington/diagnóstico por imagem , Doença de Huntington/genética , Doença de Huntington/metabolismo , Células Endoteliais/metabolismo , Encéfalo/patologia , Substância Cinzenta/patologia , Atrofia/patologia , Imageamento por Ressonância MagnéticaRESUMO
Upregulation of functional network connectivity in the presence of structural degeneration is seen in the premanifest stages of Huntington's disease (preHD) 10-15 years from clinical diagnosis. However, whether widespread network connectivity changes are seen in gene carriers much further from onset has yet to be explored. We characterized functional network connectivity throughout the brain and related it to a measure of disease pathology burden (CSF neurofilament light, NfL) and measures of structural connectivity in asymptomatic gene carriers, on average 24 years from onset. We related these measurements to estimates of cortical and subcortical gene expression. We found no overall differences in functional (or structural) connectivity anywhere in the brain comparing control and preHD participants. However, increased functional connectivity, particularly between posterior cortical areas, correlated with increasing CSF NfL level in preHD participants. Using the Allen Human Brain Atlas and expression-weighted cell-type enrichment analysis, we demonstrated that this functional connectivity upregulation occurred in cortical regions associated with regional expression of genes specific to neuronal cells. This relationship was validated using single-nucleus RNAseq data from post-mortem Huntington's disease and control brains showing enrichment of neuronal-specific genes that are differentially expressed in Huntington's disease. Functional brain networks in asymptomatic preHD gene carriers very far from disease onset show evidence of upregulated connectivity correlating with increased disease burden. These changes occur among brain areas that show regional expression of genes specific to neuronal GABAergic and glutamatergic cells.
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Doença de Huntington , Adulto , Humanos , Doença de Huntington/patologia , Filamentos Intermediários , Imageamento por Ressonância Magnética , Mapeamento Encefálico , Encéfalo/patologiaRESUMO
Converging lines of evidence from several models, and post-mortem human brain tissue studies, support the involvement of the kynurenine pathway (KP) in Huntington's disease (HD) pathogenesis. Quantifying KP metabolites in HD biofluids is desirable, both to study pathobiology and as a potential source of biomarkers to quantify pathway dysfunction and evaluate the biochemical impact of therapeutic interventions targeting its components. In a prospective single-site controlled cohort study with standardised collection of cerebrospinal fluid (CSF), blood, phenotypic and imaging data, we used high-performance liquid-chromatography to measure the levels of KP metabolites-tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid and quinolinic acid-in CSF and plasma of 80 participants (20 healthy controls, 20 premanifest HD and 40 manifest HD). We investigated short-term stability, intergroup differences, associations with clinical and imaging measures and derived sample-size calculation for future studies. Overall, KP metabolites in CSF and plasma were stable over 6 weeks, displayed no significant group differences and were not associated with clinical or imaging measures. We conclude that the studied metabolites are readily and reliably quantifiable in both biofluids in controls and HD gene expansion carriers. However, we found little evidence to support a substantial derangement of the KP in HD, at least to the extent that it is reflected by the levels of the metabolites in patient-derived biofluids.
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Doença de Huntington/sangue , Doença de Huntington/líquido cefalorraquidiano , Cinurenina/sangue , Cinurenina/líquido cefalorraquidiano , Transdução de Sinais , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Cromatografia Líquida de Alta Pressão , Estudos de Coortes , Feminino , Humanos , Doença de Huntington/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos ProspectivosRESUMO
OBJECTIVE: The identification of sensitive biomarkers is essential to validate therapeutics for Huntington disease (HD). We directly compare structural imaging markers across the largest collective imaging HD dataset to identify a set of imaging markers robust to multicenter variation and to derive upper estimates on sample sizes for clinical trials in HD. METHODS: We used 1 postprocessing pipeline to retrospectively analyze T1-weighted magnetic resonance imaging (MRI) scans from 624 participants at 3 time points, from the PREDICT-HD, TRACK-HD, and IMAGE-HD studies. We used mixed effects models to adjust regional brain volumes for covariates, calculate effect sizes, and simulate possible treatment effects in disease-affected anatomical regions. We used our model to estimate the statistical power of possible treatment effects for anatomical regions and clinical markers. RESULTS: We identified a set of common anatomical regions that have similarly large standardized effect sizes (>0.5) between healthy control and premanifest HD (PreHD) groups. These included subcortical, white matter, and cortical regions and nonventricular cerebrospinal fluid (CSF). We also observed a consistent spatial distribution of effect size by region across the whole brain. We found that multicenter studies were necessary to capture treatment effect variance; for a 20% treatment effect, power of >80% was achieved for the caudate (n = 661), pallidum (n = 687), and nonventricular CSF (n = 939), and, crucially, these imaging markers provided greater power than standard clinical markers. INTERPRETATION: Our findings provide the first cross-study validation of structural imaging markers in HD, supporting the use of these measurements as endpoints for both observational studies and clinical trials. ANN NEUROL 2020;87:751-762.
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Doença de Huntington/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Neuroimagem/métodos , Adulto , Ensaios Clínicos como Assunto , Feminino , Humanos , Doença de Huntington/patologia , Doença de Huntington/terapia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Estudos Observacionais como Assunto , Estudos RetrospectivosRESUMO
OBJECTIVES: Cognitive flexibility, which is key for adaptive decision-making, engages prefrontal cortex (PFC)-striatal circuitry and is impaired in both manifest and premanifest Huntington's disease (pre-HD). The aim of this study was to examine cognitive flexibility in a far from onset pre-HD cohort to determine whether an early impairment exists and if so, whether fronto-striatal circuits were associated with this deficit. METHODS: In the present study, we examined performance of 51 pre-HD participants (mean age=29.22 (SD=5.71) years) from the HD Young Adult Study cohort and 53 controls matched for age, sex and IQ, on the Cambridge Neuropsychological Test Automated Battery (CANTAB) Intra-Extra Dimensional Set-Shift (IED) task. This cohort is unique as it is the furthest from disease onset comprehensively studied to date (mean years=23.89 (SD=5.96) years). The IED task measures visual discrimination learning, cognitive flexibility and specifically attentional set-shifting. We used resting-state functional MRI to examine whether the functional connectivity between specific fronto-striatal circuits was dysfunctional in pre-HD, compared with controls, and whether these circuits were associated with performance on the critical extradimensional shift stage. RESULTS: Our results demonstrated that the CANTAB IED task detects a mild early impairment in cognitive flexibility in a pre-HD group far from onset. Attentional set-shifting was significantly related to functional connectivity between the ventrolateral PFC and ventral striatum in healthy controls and to functional connectivity between the dorsolateral PFC and caudate in pre-HD participants. CONCLUSION: We postulate that this incipient impairment of cognitive flexibility may be associated with intrinsically abnormal functional connectivity of fronto-striatal circuitry in pre-HD.
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Cognição , Corpo Estriado/patologia , Doença de Huntington/patologia , Córtex Pré-Frontal/patologia , Adulto , Estudos de Casos e Controles , Cognição/fisiologia , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/fisiopatologia , Feminino , Humanos , Doença de Huntington/diagnóstico por imagem , Doença de Huntington/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Neuroimagem , Testes Neuropsicológicos , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: The composite Unified Huntington's Disease Rating Scale (cUHDRS) is a multidimensional measure of progression in Huntington's disease (HD) being used as a primary outcome in clinical trials investigating potentially disease-modifying huntingtin-lowering therapies. OBJECTIVE: Evaluating volumetric and structural connectivity correlates of the cUHDRS. METHODS: One hundred and nineteen premanifest and 119 early-HD participants were included. Gray and white matter (WM) volumes were correlated with cUHDRS cross-sectionally and longitudinally using voxel-based morphometry. Correlations between baseline fractional anisotropy (FA); mean, radial, and axial diffusivity; and baseline cUHDRS were examined using tract-based spatial statistics. RESULTS: Worse performance in the cUHDRS over time correlated with longitudinal volume decreases in the occipito-parietal cortex and centrum semiovale, whereas lower baseline scores correlated with decreased volume in the basal ganglia and surrounding WM. Lower cUHDRS scores were also associated with reduced FA and increased diffusivity at baseline. CONCLUSION: The cUHDRS correlates with imaging biomarkers and tracks atrophy progression in HD supporting its biological relevance. © 2021 International Parkinson and Movement Disorder Society.
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Doença de Huntington , Substância Branca , Anisotropia , Atrofia/patologia , Biomarcadores , Progressão da Doença , Humanos , Doença de Huntington/diagnóstico por imagem , Doença de Huntington/patologia , Imageamento por Ressonância Magnética , Substância Branca/diagnóstico por imagem , Substância Branca/patologiaRESUMO
Huntington's disease (HD) is a monogenic disorder with 100% penetrance. With the advent of genetic testing in adults, disease-related, structural brain changes can be investigated from the earliest, premorbid stages of HD. While examining macrostructural change characterises global neuronal damage, investigating microstructural alterations provides information regarding brain organisation and its underlying biological properties. Diffusion MRI can be used to track the progression of microstructural anomalies in HD decades prior to clinical disease onset, providing a greater understanding of neurodegeneration. Multiple approaches, including voxelwise, region of interest and tractography, have been used in HD cohorts, showing a centrifugal pattern of white matter (WM) degeneration starting from deep brain areas, which is consistent with neuropathological studies. The corpus callosum, longer WM tracts and areas that are more densely connected, in particular the sensorimotor network, also tend to be affected early during premanifest stages. Recent evidence supports the routine inclusion of diffusion analyses within clinical trials principally as an additional measure to improve understanding of treatment effects, while the advent of novel techniques such as multitissue compartment models and connectomics can help characterise the underpinnings of progressive functional decline in HD.
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BACKGROUND: Structural brain MRI measures are frequently examined in both healthy and clinical groups, so an understanding of how these measures vary over time is desirable. PURPOSE: To test the stability of structural brain MRI measures over time. POPULATION: In all, 112 healthy volunteers across four sites. STUDY TYPE: Retrospective analysis of prospectively acquired data. FIELD STRENGTH/SEQUENCE: 3 T, magnetization prepared - rapid gradient echo, and single-shell diffusion sequence. ASSESSMENT: Diffusion, cortical thickness, and volume data from the sensorimotor network were assessed for stability over time across 3 years. Two sites used a Siemens MRI scanner, two sites a Philips scanner. STATISTICAL TESTS: The stability of structural measures across timepoints was assessed using intraclass correlation coefficients (ICC) for absolute agreement, cutoff ≥0.80, indicating high reliability. Mixed-factorial analysis of variance (ANOVA) was used to examine between-site and between-scanner type differences in individuals over time. RESULTS: All cortical thickness and gray matter volume measures in the sensorimotor network, plus all diffusivity measures (fractional anisotropy plus mean, axial and radial diffusivities) for primary and premotor cortices, primary somatosensory thalamic connections, and the cortico-spinal tract met ICC. The majority of measures differed significantly between scanners, with a trend for sites using Siemens scanners to produce larger values for connectivity, cortical thickness, and volume measures than sites using Philips scanners. DATA CONCLUSION: Levels of reliability over time for all tested structural MRI measures were generally high, indicating that any differences between measurements over time likely reflect underlying biological differences rather than inherent methodological variability. LEVEL OF EVIDENCE: 4. TECHNICAL EFFICACY STAGE: 1.
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Substância Cinzenta , Imageamento por Ressonância Magnética , Adulto , Encéfalo/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Humanos , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Biomarkers are often organized into networks, in which the strengths of network connections vary across subjects depending on subject-specific covariates (eg, genetic variants). Variation of network connections, as subject-specific feature variables, has been found to predict disease clinical outcome. In this work, we develop a two-stage method to estimate biomarker networks that account for heterogeneity among subjects and evaluate network's association with disease clinical outcome. In the first stage, we propose a conditional Gaussian graphical model with mean and precision matrix depending on covariates to obtain covariate-dependent networks with connection strengths varying across subjects while assuming homogeneous network structure. In the second stage, we evaluate clinical utility of network measures (connection strengths) estimated from the first stage. The second-stage analysis provides the relative predictive power of between-region network measures on clinical impairment in the context of regional biomarkers and existing disease risk factors. We assess the performance of proposed method by extensive simulation studies and application to a Huntington's disease (HD) study to investigate the effect of HD causal gene on the rate of change in motor symptom through affecting brain subcortical and cortical gray matter atrophy connections. We show that cortical network connections and subcortical volumes, but not subcortical connections are identified to be predictive of clinical motor function deterioration. We validate these findings in an independent HD study. Lastly, highly similar patterns seen in the gray matter connections and a previous white matter connectivity study suggest a shared biological mechanism for HD and support the hypothesis that white matter loss is a direct result of neuronal loss as opposed to the loss of myelin or dysmyelination.
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Doença de Huntington , Substância Branca , Atrofia/patologia , Encéfalo/patologia , Humanos , Doença de Huntington/genética , Imageamento por Ressonância MagnéticaRESUMO
The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure 'lab' using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.
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Gerenciamento de Dados , Sistemas de Gerenciamento de Base de Dados , Demência , Pesquisa Biomédica , Estudos de Coortes , Conjuntos de Dados como Assunto , Humanos , Reino UnidoRESUMO
Huntington's disease is a chronic progressive neurodegenerative condition for which there is no disease-modifying treatment. The known genetic cause of Huntington's disease makes it possible to identify individuals destined to develop the disease and instigate treatments before the onset of symptoms. Multiple trials are already underway that target the cause of HD, yet clinical measures are often insensitive to change over typical clinical trial duration. Robust biomarkers of drug target engagement, disease severity and progression are required to evaluate the efficacy of treatments and concerted efforts are underway to achieve this. Biofluid biomarkers have potential advantages of direct quantification of biological processes at the molecular level, whilst imaging biomarkers can quantify related changes at a structural level in the brain. The most robust biofluid and imaging biomarkers can offer complementary information, providing a more comprehensive evaluation of disease stage and progression to inform clinical trial design and endpoints.
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Encéfalo/diagnóstico por imagem , Proteína Huntingtina/líquido cefalorraquidiano , Doença de Huntington/líquido cefalorraquidiano , Doença de Huntington/diagnóstico por imagem , Mediadores da Inflamação/líquido cefalorraquidiano , Imageamento por Ressonância Magnética/métodos , Animais , Biomarcadores/líquido cefalorraquidiano , Humanos , Proteínas de Neurofilamentos/líquido cefalorraquidianoRESUMO
Multiple targeted therapeutics for Huntington's disease are now in clinical trials, including intrathecally delivered compounds. Previous research suggests that CSF dynamics may be altered in Huntington's disease, which could be of paramount relevance to intrathecal drug delivery to the brain. To test this hypothesis, we conducted a prospective cross-sectional study comparing people with early stage Huntington's disease with age- and gender-matched healthy controls. CSF peak velocity, mean velocity and mean flow at the level of the cerebral aqueduct, and sub-arachnoid space in the upper and lower spine, were quantified using phase contrast MRI. We calculated Spearman's rank correlations, and tested inter-group differences with Wilcoxon rank-sum test. Ten people with early Huntington's disease, and 10 controls were included. None of the quantified measures was associated with potential modifiers of CSF dynamics (demographics, osmolality, and brain volumes), or by known modifiers of Huntington's disease (age and HTTCAG repeat length); and no significant differences were found between the two studied groups. While external validation is required, the attained results are sufficient to conclude tentatively that a clinically relevant alteration of CSF dynamics - that is, one that would justify dose-adjustments of intrathecal drugs - is unlikely to exist in Huntington's disease.
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Líquido Cefalorraquidiano/diagnóstico por imagem , Líquido Cefalorraquidiano/fisiologia , Doença de Huntington/diagnóstico por imagem , Doença de Huntington/fisiopatologia , Imageamento por Ressonância Magnética , Estudos Transversais , Feminino , Humanos , Hidrodinâmica , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos ProspectivosRESUMO
OBJECTIVE: Huntington's disease (HD) is a monogenic, fully penetrant neurodegenerative disorder, providing an ideal model for understanding brain changes occurring in the years prior to disease onset. Diffusion tensor imaging (DTI) studies show widespread white matter disorganization in the early premanifest stages (pre-HD). However, although DTI has proved informative, it provides only limited information about underlying changes in tissue properties. Neurite orientation dispersion and density imaging (NODDI) is a novel magnetic resonance imaging (MRI) technique for characterizing axonal pathology more specifically, providing metrics that separately quantify axonal density and axonal organization. Here, we provide the first in vivo characterization of white matter pathology in pre-HD using NODDI. METHODS: Diffusion-weighted MRI data that support DTI and NODDI were acquired from 38 pre-HD and 45 control participants. Using whole-brain and region-of-interest analyses, NODDI metrics were compared between groups and correlated with clinical scores of disease progression. Whole-brain changes in DTI metrics were also examined. RESULTS: The pre-HD group displayed widespread reductions in axonal density compared with control participants; this correlated with measures of clinical disease progression in the body and genu of the corpus callosum. There was also evidence in the pre-HD group of increased coherence of axonal packing in the white matter surrounding the basal ganglia. INTERPRETATION: Our findings suggest that reduced axonal density is one of the major factors underlying white matter pathology in pre-HD, coupled with altered local organization in areas surrounding the basal ganglia. NODDI metrics show promise in providing more specific information about the biological processes underlying HD and neurodegeneration per se. Ann Neurol 2018;84:497-504.
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Encéfalo/diagnóstico por imagem , Doença de Huntington/diagnóstico por imagem , Doença de Huntington/genética , Sintomas Prodrômicos , Substância Branca/diagnóstico por imagem , Adulto , Idoso , Encéfalo/patologia , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Doença de Huntington/patologia , Masculino , Pessoa de Meia-Idade , Substância Branca/patologiaRESUMO
OBJECTIVE: Huntington's disease (HD) gene carriers can be identified before clinical diagnosis; however, statistical models for predicting when overt motor symptoms will manifest are too imprecise to be useful at the level of the individual. Perfecting this prediction is integral to the search for disease modifying therapies. This study aimed to identify an imaging marker capable of reliably predicting real-life clinical diagnosis in HD. METHOD: A multivariate machine learning approach was applied to resting-state and structural magnetic resonance imaging scans from 19 premanifest HD gene carriers (preHD, 8 of whom developed clinical disease in the 5 years postscanning) and 21 healthy controls. A classification model was developed using cross-group comparisons between preHD and controls, and within the preHD group in relation to "estimated" and "actual" proximity to disease onset. Imaging measures were modeled individually, and combined, and permutation modeling robustly tested classification accuracy. RESULTS: Classification performance for preHDs versus controls was greatest when all measures were combined. The resulting polymarker predicted converters with high accuracy, including those who were not expected to manifest in that time scale based on the currently adopted statistical models. INTERPRETATION: We propose that a holistic multivariate machine learning treatment of brain abnormalities in the premanifest phase can be used to accurately identify those patients within 5 years of developing motor features of HD, with implications for prognostication and preclinical trials. Ann Neurol 2018;83:532-543.
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Doença de Huntington/diagnóstico por imagem , Doença de Huntington/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos TestesRESUMO
OBJECTIVES: Previous research has demonstrated an association between emotion recognition and apathy in several neurological conditions involving fronto-striatal pathology, including Parkinson's disease and brain injury. In line with these findings, we aimed to determine whether apathetic participants with early Huntington's disease (HD) were more impaired on an emotion recognition task compared to non-apathetic participants and healthy controls. METHODS: We included 43 participants from the TRACK-HD study who reported apathy on the Problem Behaviours Assessment - short version (PBA-S), 67 participants who reported no apathy, and 107 controls matched for age, sex, and level of education. During their baseline TRACK-HD visit, participants completed a battery of cognitive and psychological tests including an emotion recognition task, the Hospital Depression and Anxiety Scale (HADS) and were assessed on the PBA-S. RESULTS: Compared to the non-apathetic group and the control group, the apathetic group were impaired on the recognition of happy facial expressions, after controlling for depression symptomology on the HADS and general disease progression (Unified Huntington's Disease Rating Scale total motor score). This was despite no difference between the apathetic and non-apathetic group on overall cognitive functioning assessed by a cognitive composite score. CONCLUSIONS: Impairment of the recognition of happy expressions may be part of the clinical picture of apathy in HD. While shared reliance on frontostriatal pathways may broadly explain associations between emotion recognition and apathy found across several patient groups, further work is needed to determine what relationships exist between recognition of specific emotions, distinct subtypes of apathy and underlying neuropathology. (JINS, 2019, 25, 453-461).
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Apatia/fisiologia , Emoções/fisiologia , Expressão Facial , Reconhecimento Facial/fisiologia , Doença de Huntington/fisiopatologia , Percepção Social , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
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.
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Mapeamento Encefálico/métodos , Doença de Huntington/patologia , Doença de Huntington/terapia , Adulto , Encéfalo/patologia , Cognição/fisiologia , Estudos de Coortes , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Destreza Motora/fisiologia , Vias Neurais/fisiopatologia , Doenças Neurodegenerativas/patologia , Testes NeuropsicológicosRESUMO
Huntington's disease (HD) is a monogenic neurodegenerative disorder caused by a CAG-repeat expansion in the Huntingtin gene. Presence of this expansion signifies certainty of disease onset, but only partly explains age at which onset occurs. Genome-wide association studies have shown that naturally occurring genetic variability influences HD pathogenesis and disease onset. Investigating the influence of biological traits in the normal population, such as variability in white matter properties, on HD pathogenesis could provide a complementary approach to understanding disease modification. We have previously shown that while white matter diffusivity patterns in the left sensorimotor network were similar in controls and HD gene-carriers, they were more extreme in the HD group. We hypothesized that the influence of natural variation in diffusivity on effects of HD pathogenesis on white matter is not limited to the sensorimotor network but extends to cognitive, limbic, and visual networks. Using tractography, we investigated 32 bilateral pathways within HD-related networks, including motor, cognitive, and limbic, and examined diffusivity metrics using principal components analysis. We identified three independent patterns of diffusivity common to controls and HD gene-carriers that predicted HD status. The first pattern involved almost all tracts, the second was limited to sensorimotor tracts, and the third encompassed cognitive network tracts. Each diffusivity pattern was associated with network specific performance. The consistency in diffusivity patterns across both groups coupled with their association with disease status and task performance indicates that naturally-occurring patterns of diffusivity can become accentuated in the presence of the HD gene mutation to influence clinical brain function.
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Variação Biológica Individual , Mapeamento Encefálico , Imagem de Tensor de Difusão , Doença de Huntington/patologia , Rede Nervosa/diagnóstico por imagem , Substância Branca/patologia , Adulto , Feminino , Genótipo , Humanos , Proteína Huntingtina/genética , Doença de Huntington/diagnóstico por imagem , Doença de Huntington/genética , Masculino , Pessoa de Meia-Idade , Rede Nervosa/fisiologia , Testes Neuropsicológicos , Desempenho Psicomotor , Substância Branca/diagnóstico por imagemRESUMO
Depression is common in premanifest Huntington's disease (preHD) and results in significant morbidity. We sought to examine how variations in structural and functional brain networks relate to depressive symptoms in premanifest HD and healthy controls. Brain networks were constructed using diffusion tractography (70 preHD and 81 controls) and resting state fMRI (92 preHD and 94 controls) data. A sub-network associated with depression was identified in a data-driven fashion and network-based statistics was used to investigate which specific connections correlated with depression scores. A replication analysis was then performed using data from a separate study. Correlations between depressive symptoms with increased functional connectivity and decreased structural connectivity were seen for connections in the default mode network (DMN) and basal ganglia in preHD. This study reveals specific connections in the DMN and basal ganglia that are associated with depressive symptoms in preHD. Hum Brain Mapp 38:2819-2829, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.
Assuntos
Mapeamento Encefálico , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Transtorno Depressivo/patologia , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Apatia , Estudos de Coortes , Transtorno Depressivo/etiologia , Feminino , Humanos , Doença de Huntington/complicações , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/patologia , Oxigênio/sangue , Escalas de Graduação PsiquiátricaRESUMO
OBJECTIVES: The purpose of this study was to inform the design of randomized clinical trials in early-stage manifest Huntington's disease through analysis of longitudinal data from TRACK-Huntington's Disease (TRACK-HD), a multicenter observational study. METHODS: We compute sample sizes required for trials with candidate clinical, functional, and imaging outcomes, whose aims are to reduce rates of change. The calculations use a 2-stage approach: first using linear mixed models to estimate mean rates of change and components of variability from TRACK-HD data and second using these to predict sample sizes for a range of trial designs. RESULTS: For each outcome, the primary drivers of the required sample size were the anticipated treatment effect and the duration of treatment. Extending durations from 1 to 2 years yielded large sample size reductions. Including interim visits and incorporating stratified randomization on predictors of outcome together with covariate adjustment gave more modest, but nontrivial, benefits. Caudate atrophy, expressed as a percentage of its baseline, was the outcome that gave smallest required sample sizes. DISCUSSION: Here we consider potential required sample sizes for clinical trials estimated from naturalistic observation of longitudinal change. Choice among outcome measures for a trial must additionally consider their relevance to patients and the expected effect of the treatment under study. For all outcomes considered, our results provide compelling arguments for 2-year trials, and we also demonstrate the benefits of incorporating stratified randomization coupled with covariate adjustment, particularly for trials with caudate atrophy as the primary outcome. The benefits of enrichment are more debatable, with statistical benefits offset by potential recruitment difficulties and reduced generalizability. © 2017 International Parkinson and Movement Disorder Society.
Assuntos
Núcleo Caudado/diagnóstico por imagem , Doença de Huntington/terapia , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Projetos de Pesquisa/estatística & dados numéricos , Adulto , Atrofia/patologia , Feminino , Humanos , Doença de Huntington/diagnóstico por imagem , Doença de Huntington/fisiopatologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Adulto JovemRESUMO
While the HTT CAG-repeat expansion mutation causing Huntington's disease (HD) is highly correlated with the rate of pathogenesis leading to disease onset, considerable variance in age-at-onset remains unexplained. Therefore, other factors must influence the pathogenic process. We asked whether these factors were related to natural biological variation in the sensory-motor system. In 243 participants (96 premanifest and 35 manifest HD; 112 controls), sensory-motor structural MRI, tractography, resting-state fMRI, electrophysiology (including SEP amplitudes), motor score ratings, and grip force as sensory-motor performance were measured. Following individual modality analyses, we used principal component analysis (PCA) to identify patterns associated with sensory-motor performance, and manifest versus premanifest HD discrimination. We did not detect longitudinal differences over 12 months. PCA showed a pattern of loss of caudate, grey and white matter volume, cortical thickness in premotor and sensory cortex, and disturbed diffusivity in sensory-motor white matter tracts that was connected to CAG repeat length. Two further major principal components appeared in controls and HD individuals indicating that they represent natural biological variation unconnected to the HD mutation. One of these components did not influence HD while the other non-CAG-driven component of axial versus radial diffusivity contrast in white matter tracts were associated with sensory-motor performance and manifest HD. The first component reflects the expected CAG expansion effects on HD pathogenesis. One non-CAG-driven component reveals an independent influence on pathogenesis of biological variation in white matter tracts and merits further investigation to delineate the underlying mechanism and the potential it offers for disease modification. Hum Brain Mapp 37:4615-4628, 2016. © 2016 Wiley Periodicals, Inc.