Data Analytics from Enroll-HD, a Global Clinical Research Platform for Huntington's Disease.
ABSTRACT: Background:The study of complex neurodegenerative diseases is moving away from hypothesis-driven biological methods toward large scale multimodal approaches, requiring standardized collaborative efforts. Enroll-HD exemplifies such an integrated clinical research platform, designed and implemented to meet the research and clinical needs of Huntington's disease (HD). The aim of this study was to describe the unique organization of Enroll-HD and report baseline data analyses of its core study. Methods:The Enroll-HD platform incorporates electronic data capture, biosampling, and a longitudinal observational study spanning four continents (ClinicalTrials.gov Identifier: NCT01574053). The primary study population includes HD gene expansion carriers (HDGECs; CAG expansion ?36), subdivided into manifest/premanifest HD. The control population consists of genotype-negative first-degree relatives and family controls not genetically related. The study includes 10 core clinical assessments covering motor, cognitive, and behavioral domains. Results:This data set comprises 1,534 participants (HDGEC = 1,071; controls = 463). Participant retention was high; 42 participants prematurely withdrew from the study. Mean ± standard deviation SD CAG repeat size was 43.5 ± 3.5 for HDGECs and 19.8 ± 3.4 for controls. Motor and behavioral assessments identified numerical differences between controls and HDGECs (manifest > premanifest > controls). Functional and independence assessments were generally similar for the premanifest and control groups with overlap in range of scores obtained. For the majority of cognitive tests, there were large differences between participants with manifest HD and all other groups. Conclusions:These first data from the Enroll-HD clinical research platform demonstrate the maturity and potential of the platform in collecting high-quality, clinically relevant data. Future data sets will be substantially larger as the platform expands longitudinally and regionally.
Project description:Different oculomotor abnormalities have been reported to occur in premanifest Huntington's disease. The aim of this study is to investigate which oculomotor items of the Unified Huntington's Disease Rating Scale (UHDRS) are affected in premanifest individuals compared to healthy controls, and if CAG repeat length and age are correlated with oculomotor abnormalities in premanifest Huntington's disease gene carriers.We compared baseline data of 70 premanifest individuals and 27 controls who participated in the Enroll-HD study at the Leiden University Medical Center, the Netherlands. Premanifest gene carriers were divided in individuals near to disease onset and individuals far from disease onset.Using a logistic regression model, only horizontal ocular pursuit of the six oculomotor items of the UHDRS was significantly more frequently affected in premanifest individuals close to disease onset compared to controls (p = 0.044, OR 13.100). Age was significantly higher in premanifest individuals with affected horizontal ocular pursuit (p = 0.016, OR 1.115) and with affected vertical ocular pursuit (p = 0.030, OR 1.065) compared to premanifest individuals without ocular pursuit deficits.Our results suggest that horizontal ocular pursuit is the only affected oculomotor item of the UHDRS in premanifest individuals and could be used to assess early clinical signs of Huntington's disease. Saccade initiation and saccade velocity do not seem useful for detecting differences between premanifest individuals and controls.
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.
Project description:Evidence from small-scale studies indicates that impairments in postural stability are an early and disabling feature of Huntington's disease (HD) and may be a useful clinical endpoint for disease modifying trials. Larger studies are needed to confirm these preliminary findings and the suitability of postural stability outcomes as clinical endpoints. Static and dynamic postural stability were evaluated in 54 premanifest HD, 36 manifest HD and 45 healthy individuals using the Sensory Organization Test (SOT) and Limits of Stability (LOS) test. Manifest HD displayed significantly lower scores on all SOT conditions and on the SOT composite score and had more falls than healthy and premanifest HD (p?<?0.05). Premanifest and manifest HD demonstrated significantly lower endpoint excursion (p?<?0.001), maximum excursion (p???0.001), and directional control (p???0.004) values than healthy individuals on the LOS test. Deficits in LOS were found to manifest on the left side of premanifest HD. Significant but low associations were observed between UHDRS-TMS, disease burden score, diagnostic confidence level, SOT conditions and SOT composite score. We confirm here that individuals with premanifest and manifest HD display significant impairments in static and dynamic postural stability. Dynamic posturography assessments should be considered as clinical endpoints for future disease modifying trials.
Project description:Huntington's disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.
Project description:Objective:To examine phenotype-genotype discrepancies (PGDs) wherein genotype-concealed and prospective judgments of the motor onset of Huntington disease (HD) occurred among at-risk adults who had nonexpanded (<37) cytosine-adenine-guanine (CAG) trinucleotide DNA repeats. Methods:We examined the prospective clinical assessments of investigators who were kept unaware of individual CAG lengths in the Prospective Huntington At-Risk Observational Study (PHAROS) who enrolled and followed undiagnosed adults at risk for HD who chose not to learn their gene status. Subjects (n = 1001) at 43 Huntington Study Group research sites in the US and Canada were evaluated prospectively and systematically between 1999 and 2009. At each site, an investigator was designated to perform comprehensive clinic assessments and another investigator to rate only the motor examination. Phenoconversion from a "premanifest" status to a confidently "manifest" status was based on investigator judgment (diagnostic confidence level) of the extrapyramidal motor features of HD. Results:There were 20 PGDs that over time had less severe motor scores than the 101 phenoconversions with CAG ?37, but more severe motor scores than nonconversions. Following conversion, subjects with CAG ?37 expansions worsened more motorically and cognitively than PGD subjects in the < 37 group. PGDs were concentrated among three sites and a few investigators, especially raters who only assessed the motor examination. Interpretation:The ability to detect the clinical onset of HD in a timely and reliable fashion remains the key for developing experimental treatments aimed at postponing the clinical onset of HD. Comprehensive clinical evaluation is a more accurate and reliable basis for determining HD clinical onset than sole reliance on judging the extrapyramidal features of HD.
Project description:Motor signs are functionally disabling features of Huntington disease. Characteristic motor signs define disease manifestation. Their severity and onset are assessed by the Total Motor Score of the Unified Huntington's Disease Rating Scale, a categorical scale limited by interrater variability and insensitivity in premanifest subjects. More objective, reliable, and precise measures are needed which permit clinical trials in premanifest populations. We hypothesized that motor deficits can be objectively quantified by force-transducer-based tapping and correlate with disease burden and brain atrophy.A total of 123 controls, 120 premanifest, and 123 early symptomatic gene carriers performed a speeded and a metronome tapping task in the multicenter study TRACK-HD. Total Motor Score, CAG repeat length, and MRIs were obtained. The premanifest group was subdivided into A and B, based on the proximity to estimated disease onset, the manifest group into stages 1 and 2, according to their Total Functional Capacity scores. Analyses were performed centrally and blinded.Tapping variability distinguished between all groups and subgroups in both tasks and correlated with 1) disease burden, 2) clinical motor phenotype, 3) gray and white matter atrophy, and 4) cortical thinning. Speeded tapping was more sensitive to the detection of early changes.Tapping deficits are evident throughout manifest and premanifest stages. Deficits are more pronounced in later stages and correlate with clinical scores as well as regional brain atrophy, which implies a link between structure and function. The ability to track motor phenotype progression with force-transducer-based tapping measures will be tested prospectively in the TRACK-HD study.
Project description:Patients with Huntington's disease (HD), an autosomal-dominant neurodegenerative disease, show substantial variability in age-of-onset, symptom severity and course of illness, warranting the need for biomarkers to anticipate and monitor these features. The HD gene encodes the disease protein huntingtin (Htt), a potentially useful biomarker for this disease. In the current study, we determined whether total Htt protein (normal plus mutant; "tHtt") could be reliably measured in human saliva, a body fluid that is much more accessible compared to cerebral spinal fluid or even blood, and whether salivary levels of tHtt were clinically meaningful. We collected 146 saliva samples from manifest HD patients, early-premanifest individuals, late-premanifest patients, gene-negative family members and normal controls. We found that tHtt protein could be reliably and stably detected in human saliva and that tHtt levels were significantly increased in saliva from HD individuals compared to normal controls. Salivary tHtt showed no gender effects, nor were levels correlated with total protein levels in saliva. Salivary tHtt was significantly positively correlated with age, but not age-of-onset or CAG-repeat length. Importantly, salivary tHtt was significantly correlated with several clinical measures, indicating relevance to disease symptom onset and/or severity. Measurements of salivary tHtt offer significant promise as a relevant, non-invasive disease biomarker for HD, and its use could be implemented into clinical applications.
Project description:Huntington disease (HD) is a fatal progressive neurodegenerative disorder for which only symptomatic treatment is available. A better understanding of the pathology, and identification of biomarkers will facilitate the development of disease-modifying treatments. HD is potentially a good model of a neurodegenerative disease for development of biomarkers because it is an autosomal-dominant disease with complete penetrance, caused by a single gene mutation, in which the neurodegenerative process can be assessed many years before onset of signs and symptoms of manifest disease. Previous MRI studies have detected abnormalities in gray and white matter starting in premanifest stages. However, the understanding of how these abnormalities are related, both in time and space, is still incomplete. In this study, we combined deep gray matter shape diffeomorphometry and white matter DTI analysis in order to provide a better mapping of pathology in the deep gray matter and subcortical white matter in premanifest HD. We used 296 MRI scans from the PREDICT-HD database. Atrophy in the deep gray matter, thalamus, hippocampus, and nucleus accumbens was analyzed by surface based morphometry, and while white matter abnormalities were analyzed in (i) regions of interest surrounding these structures, using (ii) tractography-based analysis, and using (iii) whole brain atlas-based analysis. We detected atrophy in the deep gray matter, particularly in putamen, from early premanifest stages. The atrophy was greater both in extent and effect size in cases with longer exposure to the effects of the CAG expansion mutation (as assessed by greater CAP-scores), and preceded detectible abnormalities in the white matter. Near the predicted onset of manifest HD, the MD increase was widespread, with highest indices in the deep and posterior white matter. This type of in-vivo macroscopic mapping of HD brain abnormalities can potentially indicate when and where therapeutics could be targeted to delay the onset or slow the disease progression.
Project description:Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder characterized by motor disturbances, psychiatric disturbances, and cognitive impairment. Visual cognitive deficits and atrophy of the posterior cerebral cortex are additionally present in early disease stages. This study aimed to assess the extent of structural and functional brain alterations of the visual cortex in HD gene carriers using different neuroimaging modalities. Structural and functional magnetic resonance imaging data were acquired from 18 healthy controls, 21 premanifest, and 20 manifest HD gene carriers. Voxel-based morphometry (VBM) analysis and cortical thickness measurements were performed to assess structural changes in the visual cortex. Brain function was measured by assessing neuronal connectivity changes in response to visual stimulation and at rest in visual resting-state networks. Multiple linear regression analyses were performed to examine the relationship between visual cognitive function and structural imaging measures. Compared to controls, pronounced atrophy and decreased neuronal function at rest were present in associative visual cortices in manifest HD. The primary visual cortex did not show group differences in cortical thickness and in vascular activity after visual stimulation. Thinning of the associative visual cortex was related to worse visual perceptual function. Premanifest HD gene carriers did not show any differences in brain structure or function compared to controls. This study improves the knowledge on posterior brain changes in HD, as our findings suggest that the primary visual cortex remains preserved, both structurally and functionally, while atrophy of associative visual cortices is present in early HD and linked to clinical visual deficits.