Performance of the 12-item WHODAS 2.0 in prodromal Huntington disease.
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ABSTRACT:
SUBMITTER: Kim JI
PROVIDER: S-EPMC4613468 | biostudies-other | 2015 Nov
REPOSITORIES: biostudies-other
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Project description:Clinical trials to improve day-to-day function in Huntington disease (HD) require accurate outcome measures. The DSM-5 recommends the World Health Organization Disability Assessment Schedule (WHODAS) 2.0 for use in neuropsychiatric disorders. The DSM-5 also states proxy measures may be useful when cognitive function may be impaired. We tested WHODAS participant and companion ratings for differences in baseline and longitudinal function in three prodromal HD groups and a control group. Participants with prodromal HD were stratified by disease progression (low, medium, and high disease burden) based on their cytosine-adenine-guanine (CAG)-age product (CAP) score. Participant (N=726) and companion (N=630) WHODAS scores were examined for group differences, and for participant versus companion differences using linear mixed effects regression and Akaike's information criterion to test model fit. We also compared WHODAS with the Total Functional Capacity (TFC) scale. At baseline, functioning on the WHODAS was rated worse by participants in the high group and companions compared with controls. For longitudinal changes, companions reported functional decline over time in the medium and high groups. In simultaneous analysis, participant and companion longitudinal trajectories showed divergence in the high group, suggesting reduced validity of self-report. The WHODAS showed greater longitudinal difference than the TFC in the medium group relative to controls, whereas the TFC showed greater longitudinal difference than WHODAS in the high group. Results suggest the WHODAS can identify baseline and longitudinal differences in prodromal HD and may be useful in HD clinical trials. Companions may provide more accurate data as the disease progresses.
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Project description:This study examines perceived stress and its relationship to depressive symptoms, life changes and functional capacity in a large sample of individuals who are positive for the Huntington disease (HD) gene expansion but not yet diagnosed. Participants were classified by estimated proximity to HD diagnosis (far, mid, near) and compared with a non-gene-expanded comparison group. Persons in the mid group had the highest stress scores. A significant interaction between age and time since HD genetic testing was also found. Secondary analyses using data from a different data collection point and including a diagnosed group showed the highest stress scores in the diagnosed group. Possible explanations and implications are discussed.
| S-EPMC3165107 | biostudies-literature
Project description:OBJECTIVE:Assessment of daily functions affected by cognitive loss in prodromal Huntington's disease (HD) is necessary in practice and clinical trials. We evaluated baseline and longitudinal sensitivity of the Everyday Cognition (ECog) scales in prodromal HD and compared self- and companion-ratings. METHOD:Everyday cognition was self-assessed by 850 participants with prodromal HD and 768 companions. We examined internal structure using confirmatory factor analysis (CFA) on baseline data. For longitudinal analysis, we stratified participants into Low, Medium, and High disease progression groups. We examined ECog scores for group differences and participant-and-companion differences using linear mixed effects regression (LMER). Comparison with the Total Functional Capacity (TFC) scale was made. RESULTS:CFA revealed good fit of a 5-factor model having a global factor (total score), and subfactors (subscales) of memory, language, visuospatial perception, and executive function. At study entry, participants and companions in the Medium and High groups reported significantly worsened everyday cognition as well as significant functional decline over time. Losses became more pronounced and participant and companion ratings diverged as individuals progressed. TFC showed significant functional loss over time in the High group but not in the Medium group. CONCLUSIONS:Disease progression is associated with reduced self- and companion-reported everyday cognition in prodromal HD participants who are less than 13 years to estimated motor onset. Our findings suggest companion ratings are more sensitive than participants' for detecting longitudinal change in daily cognitive function. ECog appears more sensitive to specific functional changes in the prodrome of HD than the TFC.
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Project description:Depression is associated with more severe cognitive deficits in many neurological disorders, though the investigation of this relationship in Huntington disease (HD) has been limited. This study examined the relationship between depressive symptom severity and measures of executive functioning, learning/memory, and attention in prodromal HD.Participants (814 prodromal HD, 230 gene-negative) completed a neuropsychological test battery and the Beck Depression Inventory-II (BDI-II). Based on the BDI-II, there were 637 participants with minimal depression, 89 with mild depression, 61 with moderate depression, and 27 with severe depression in the prodromal HD group.ANCOVA (controlling for age, sex, and education) revealed that performance on SDMT, Trails B, Hopkins Verbal Learning Test--Revised (HVLT-R) Immediate Recall, and Stroop interference was significantly different between the BDI-II severity groups, with the moderate and severe groups performing worse than the minimal and mild groups. There were no significant differences between the BDI-II severity groups for Trails A or HVLT-R Delayed Recall. Linear regression revealed that both gene status and depression severity were significant predictors of performance on all cognitive tests examined, with contributions of BDI-II and gene status comparable for Trails A, SDMT, and Stroop interference. Gene status had a higher contribution for HVLT-R Immediate and Delayed Recall and Trails B.Our results suggest that depressive symptom severity is related to poorer cognitive performance in individuals with prodromal HD. Though there are currently no approved therapies for cognitive impairment in HD, our findings suggest that depression may be a treatable contributor to cognitive impairment in this population.
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Project description:Antidepressant usage in prodromal Huntington Disease (HD) remains uncharacterized, despite its relevance in designing experiments, studying outcomes of HD, and evaluating the efficacy of therapeutic interventions. We searched baseline medication logs of 787 prodromal HD and 215 healthy comparison (HC) participants for antidepressant use. Descriptive and mixed-effects logistic regression modeling characterized usage across participants. At baseline, approximately one in five prodromal HD participants took antidepressants. Of those, the vast majority took serotonergic antidepressants (selective serotonin reuptake inhibitor (SSRI) or serotonin/norepinephrine reuptake inhibitor (SNRI)). Significantly more prodromal HD participants used serotonergic antidepressants than their HC counterparts. Because of the prevalence of these medications, further analyses focused on this group alone. Mixed-effects logistic regression modeling revealed significant relationships of both closer proximity to diagnosis and female sex with greater likelihood to be prescribed a serotonergic antidepressant. More prodromal HD participants took antidepressants in general and specifically the subclass of serotonergic antidepressants than their at-risk counterparts, particularly when they were closer to predicted time of conversion to manifest HD. These propensities must be considered in studies of prodromal HD participants.
| S-EPMC3763706 | biostudies-literature
Project description:Cognitive changes in the prodromal phase of Huntington disease (prHD) are found in multiple domains, yet their neural bases are not well understood. One component process that supports cognition is inhibitory control. In the present fMRI study, we examined brain circuits involved in response inhibition in 65 prHD participants and 36 gene-negative (NEG) controls using the stop signal task (SST). PrHD participants were subdivided into three groups (LOW, MEDIUM, HIGH) based on their CAG-Age Product (CAP) score, an index of genetic exposure and a proxy for expected time to diagnosis. Poorer response inhibition (stop signal duration) correlated with CAP scores. When response inhibition was successful, activation of the classic frontal inhibitory-network was normal in prHD, yet stepwise reductions in activation with proximity to diagnosis were found in the posterior ventral attention network (inferior parietal and temporal cortices). Failures in response inhibition in prHD were related to changes in inhibition centers (supplementary motor area (SMA)/anterior cingulate and inferior frontal cortex/insula) and ventral attention networks, where activation decreased with proximity to diagnosis. The LOW group showed evidence of early compensatory activation (hyperactivation) of right-hemisphere inhibition and attention reorienting centers, despite an absence of cortical atrophy or deficits on tests of executive functioning. Moreover, greater activation for failed than successful inhibitions in an ipsilateral motor-control network was found in the control group, whereas such differences were markedly attenuated in all prHD groups. The results were not related to changes in cortical volume and thickness, which did not differ among the groups. However, greater hypoactivation of classic right-hemisphere inhibition centers [inferior frontal gyrus (IFG)/insula, SMA/anterior cingulate cortex (ACC)] during inhibition failures correlated with greater globus pallidus atrophy. These results are the first to demonstrate that response inhibition in prHD is associated with altered functioning in brain networks that govern inhibition, attention, and motor control.
| S-EPMC4227536 | biostudies-literature
Project description:Huntington disease (HD) is most widely known for its selective degeneration of striatal neurons but there is also growing evidence for white matter (WM) deterioration. The primary objective of this research was to conduct a large-scale analysis using multisite diffusion-weighted imaging (DWI) tractography data to quantify diffusivity properties along major prefrontal cortex WM tracts in prodromal HD. Fifteen international sites participating in the PREDICT-HD study collected imaging and neuropsychological data on gene-positive HD participants without a clinical diagnosis (i.e., prodromal) and gene-negative control participants. The anatomical prefrontal WM tracts of the corpus callosum (PFCC), anterior thalamic radiations (ATRs), inferior fronto-occipital fasciculi (IFO), and uncinate fasciculi (UNC) were identified using streamline tractography of DWI. Within each of these tracts, tensor scalars for fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity coefficients were calculated. We divided prodromal HD subjects into three CAG-age product (CAP) groups having Low, Medium, or High probabilities of onset indexed by genetic exposure. We observed significant differences in WM properties for each of the four anatomical tracts for the High CAP group in comparison to controls. Additionally, the Medium CAP group presented differences in the ATR and IFO in comparison to controls. Furthermore, WM alterations in the PFCC, ATR, and IFO showed robust associations with neuropsychological measures of executive functioning. These results suggest long-range tracts essential for cross-region information transfer show early vulnerability in HD and may explain cognitive problems often present in the prodromal stage. Hum Brain Mapp 36:3717-3732, 2015. © 2015 Wiley Periodicals, Inc.
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Project description:Analysis of microRNA (miRNA) expression in CSF from prodromal Huntington disease patients.
2020-05-10 | GSE150174 | GEO
Project description:As therapeutics are being developed to target the underlying neuropathology of Huntington disease, interest is increasing in methodologies for conducting clinical trials in the prodromal phase. This study was designed to examine the potential utility of structural MRI measures as outcome measures for such trials.Data are presented from 211 prodromal individuals and 60 controls, scanned both at baseline and at the 2-year follow-up. Prodromal participants were divided into groups based on proximity to estimated onset of diagnosable clinical disease: far (>15 years from estimated onset), mid (9-15 years) and near (<9 years). Volumetric measurements of caudate, putamen, total striatum, globus pallidus, thalamus, total grey and white matter and cerebrospinal fluid were performed.All prodromal groups showed a faster rate of atrophy than controls in striatum, total brain and cerebral white matter (especially in the frontal lobe). Neither prodromal participants nor controls showed any significant longitudinal change in cortex (either total cortical grey or within individual lobes). When normal age-related atrophy (ie, change observed in the control group) was taken into account, there was more statistically significant disease-related atrophy in white matter than in striatum.Measures of volume change in striatum and white-matter volume, particularly in the frontal lobe, may serve as excellent outcome measures for future clinical trials in prodromal Huntington disease. Clinical trials using white matter or striatal volume change as an outcome measure will be most efficient if the sample is restricted to individuals who are within 15 years of estimated onset of diagnosable disease.
| S-EPMC3105627 | biostudies-literature
Project description:This study compares self-paced timing performance (cross-sectionally and longitudinally) between participants with prodromal Huntington's disease (pr-HD) and a comparison group of gene non-expanded participants from affected families (NC).Participants (747 pr-HD: 188 NC) listened to tones presented at 550-ms intervals, matched that pace by tapping response keys and continued the rhythm (self-paced) after the tone had stopped. Standardized cross-sectional and longitudinal linear models examined the relationships between self-paced timing precision and estimated proximity to diagnosis, and other demographic factors.Pr-HD participants showed significantly less timing precision than NC. Comparison of pr-HD and NC participants showed a significant performance difference on two task administration conditions (dominant hand: p < .0001; alternating thumbs: p < .0001). Additionally, estimated proximity to diagnosis was related to timing precision in both conditions, (dominant hand: t = -11.14, df = 920, p < .0001; alternating thumbs: t = -11.32, df = 918, p < .0001). Longitudinal modeling showed that pr-HD participants worsen more quickly at the task than the NC group, and rate of decline increases with estimated proximity to diagnosis in both conditions (dominant hand: t = -2.85, df = 417, p = .0045; alternating thumbs: t = -3.56, df = 445, p = .0004). Effect sizes based on adjusted mean annual change ranged from -0.34 to 0.25 in the longitudinal model.The self-paced timing paradigm has potential for use as a screening tool and outcome measure in pr-HD clinical trials to gauge therapeutically mediated improvement or maintenance of function.
| S-EPMC2900808 | biostudies-literature