Unified Huntington's Disease Rating Scale Motor Research Articles

Editors' note: Motor speech patterns in Huntington disease

In the article “Motor speech patterns in Huntington disease,” Drs. Diehl et al. identified 4 distinct presentations of dysarthria in patients with Huntington disease (HD) based on the evaluation of audio recordings of 48 patients by 6 trained raters. The authors postulated that these distinct presentations may be due to divergent pathologic processes. In response, Drs. Rusz and Tykalova argue that the findings of a patient subgroup characterized by an abnormally fast speaking rate was at odds with prior evidence indicating slow speech rate in HD. They note that patients with a bradykinetic phenotype have previously been shown to have a slower speaking rate than those with a choreatic phenotype, challenging the authors' explanation of fast speaking rate as being related to hypokinetic dysarthria. Besides noting the absence of a control group of healthy patients for comparison, they also contend that the remaining 3 HD dysarthric subgroups may simply reflect overall disease progression. Responding to these comments, the authors cite prior work reporting a higher rate of speech in patients with HD and argue that the studies cited by Drs. Rusz and Tykalova relied on acoustic measures that may only weakly correlate with perceptual ratings of dysarthric speech. They note that the trained raters were asked to rate speech relative to what they considered normal, and that their study identified CAG repeats and Unified HD Rating Scale motor scores as differing significantly across speech subgroups. This exchange highlights potential challenges with reconciling acoustic-based and rater-based phenotyping of speech patterns in neurologic disease. In the article “Motor speech patterns in Huntington disease,” Drs. Diehl et al. identified 4 distinct presentations of dysarthria in patients with Huntington disease (HD) based on the evaluation of audio recordings of 48 patients by 6 trained raters. The authors postulated that these distinct presentations may be due to divergent pathologic processes. In response, Drs. Rusz and Tykalova argue that the findings of a patient subgroup characterized by an abnormally fast speaking rate was at odds with prior evidence indicating slow speech rate in HD. They note that patients with a bradykinetic phenotype have previously been shown to have a slower speaking rate than those with a choreatic phenotype, challenging the authors' explanation of fast speaking rate as being related to hypokinetic dysarthria. Besides noting the absence of a control group of healthy patients for comparison, they also contend that the remaining 3 HD dysarthric subgroups may simply reflect overall disease progression. Responding to these comments, the authors cite prior work reporting a higher rate of speech in patients with HD and argue that the studies cited by Drs. Rusz and Tykalova relied on acoustic measures that may only weakly correlate with perceptual ratings of dysarthric speech. They note that the trained raters were asked to rate speech relative to what they considered normal, and that their study identified CAG repeats and Unified HD Rating Scale motor scores as differing significantly across speech subgroups. This exchange highlights potential challenges with reconciling acoustic-based and rater-based phenotyping of speech patterns in neurologic disease.

Retinal and choroidal morphological changes in Huntington's disease

Purpose: to investigate the choroidal and retinal morphology in Huntington's disease (HD) using optical coherence tomography (OCT) and to analyze how the parameters studied correlate with the clinical data. Material and methods. The study included two groups of subjects, (1) 44 HD patients, averagely aged 37.6 ± 10.2 yrs, and (2) 31 healthy volunteers, averagely aged 37.3 ± 10.8 yrs. The groups had matching age, sex distribution, intraocular pressure and mean refractive error. In the study group, 21 patients had pre-manifest and 23, manifest HD stage. All patients underwent a thorough neurological and ophthalmic examination which included retinal OCT. The foveal choroidal thickness, retinal thickness in 9 areas of the macular zone, retinal ganglion cells complex (GCC) and peripapillary retinal nerve fiber layer thickness (RNFL) were evaluated in 4 quadrants. CAG repeat expansion size (cytosine-adenine-guanine) in the huntingtin gene, the disease duration and Unified HD Rating Scale motor scores (UHDRS) were evaluated for HD patients. Results. The range of the CAG repeat expansion size in the study group was 37–56 repeats (44.3 ± 3.8), the UHDRS motor score was 36.3 ± 29.7, disease duration was 13.7 ± 7.2 years. OCT revealed a significant decrease in the foveal choroidal thickness, GCC complex thickness, average, temporal, inferior and nasal RNFL thickness and total retinal thickness in the external temporal area in HD patients as compared to the controls. In addition, an inverse correlation between the disease duration, UHDRS Motor Score and a number of OCT parameters was found. Conclusion. The results confirm the promising potential of retinal tomographic parameters as a biomarker for early diagnosis and monitoring of the neurodegenerative process progression. The topography of retinal thickness reduction indicates a specific pattern of retinal neurodegeneration in HD.

Assessment Scales for Patients with Advanced Huntington's Disease: Comparison of the UHDRS and UHDRS-FAP.

The standard clinical assessment tool in Huntington's disease is the Unified Huntington's Disease Rating Scale (UHDRS). In patients with advanced Huntington's disease ceiling and floor effects of the UHDRS hamper the detection of changes. Therefore, the UHDRS-For Advanced Patients (UHDRS-FAP) has been designed for patients with late-stage Huntington's disease. This cross-sectional study aims to examine if the UHDRS-FAP can differentiate better between patients with advanced Huntington's disease than the UHDRS. Forty patients, who were institutionalized or received day-care, were assessed with the UHDRS, UHDRS-FAP, and Care Dependency Scale (CDS). The severity of Huntington's disease was defined by the Total Functional Capacity (TFC). Comparisons between consecutive TFC stages were performed for all domains of the UHDRS, UHDRS-FAP, and CDS using Mann-Whitney U tests. The motor scores of the UHDRS-FAP and UHDRS were the only subscales with significantly worse scores in TFC stage 5 compared to stage 4. In TFC stages 4-5, the range of the UHDRS-FAP motor score was broader, the standard error of measurement was lower, and the effect size r was higher than for the UHDRS motor score. The CDS declined significantly across all TFC stages. Our results suggest that the UHDRS-FAP motor score might differentiate better between patients with severe Huntington's disease than the UHDRS motor score. Therefore, the UHDRS-FAP motor score is potentially a better instrument than the UHDRS motor score to improve disease monitoring and, subsequently, care in patients with advanced Huntington's disease in long-term care facilities.

Extrastriatal degeneration correlates with deficits in the motor domain subscales of the UHDRS

IntroductionStriatal degeneration has significant behavioral effects in patients with Huntington's disease (HD). However, there is scant evidence of the possible contribution of extrastriatal regions to the motor alterations assessed within the different domains of the Unified Huntington's Disease Rating Scale (UHDRS). ObjectiveAnalyze if extrastriatal grey matter decrease in patients with HD correlates with motor performance assessed with the UHDRS and its different domains. MethodTwenty-two molecular diagnosed patients with incipient HD, and twenty-two control participants matched for sex and age participated in this study. Voxel-based morphometry (VBM) analyses were done to identify grey matter decrease in the HD patients, and its relationship with the motor deterioration measured with the UHDRS motor scale. To further explore this relationship, a principal component analysis (PCA) was done on the UHDRS domains scores. Then the average of each component was used as a covariate in a VBM analysis. Finally, individual sub-scores from each domain were also tested for correlations with the VBM results. ResultsIn addition to the striatal degeneration, the VBM analysis showed significant negative correlations between the global UHDRS scores and the cerebellum, insula and precuneus atrophy. The UHDRS PCA showed component-related negative correlations suggesting a specific impact of individual degnerations. Further analyses with the individual sub-scores showed more specific corelations, including: chorea, with right caudate and left posterior cingulate gyrus; ocular pursuit, with left precentral gyrus, left superior temporal gyrus, cerebellum culmen and right temporal lobe. Saccadic movements with left postcentral gyrus and left middle occipital gyrus. ConclusionIn the early stages of HD, it is possible to find correlations between behavioral alterations as measured with the UHDRS motor domains, and extrastriatal regions, including specific areas of the cerebellum, and insular, parietal and frontal cortices. These areas could contribute to the HD related impairments along with the classical deficits associated with the striatal degeneration.

Optical coherence tomography findings in Huntington's disease: a potential biomarker of disease progression.

Previous reports of ocular abnormalities in Huntington's disease (HD) have detailed eye movement disorders. The objective of this case-control study was to investigate optic nerve and macular morphology in HD using optical coherence tomography (OCT). A total of 26 HD patients and 29 controls underwent a thorough ophthalmic examination including spectral domain OCT scans of the macula and peripapillary retinal nerve fibre layer (RNFL). Genetic testing results, disease duration, HD disease burden scores and Unified HD Rating Scale motor scores were acquired for HD patients. Temporal RNFL thickness was significantly reduced in the HD group (62.3 vs. 69.8 μm, p = 0.005), and there was a significant negative correlation between temporal RNFL thickness and disease duration (R (2) = -0.51, p = 0.04). Average peripapillary RNFL thickness was not significantly different between the HD and control groups. There was a significant negative correlation between macular volume and disease duration (R (2) = -0.71, p = 0.002), and motor scores (R (2) = -0.56, p = 0.01). Colour vision was significantly poorer in the HD group. Temporal RNFL is preferentially thinned in HD patients, possibly implicating mitochondrial dysfunction as the temporal RNFL is reduced in the patients with some mitochondrial disorders, including Leber's hereditary optic neuropathy. The correlation between the decrease in macular volume and temporal RNFL, and increasing disease severity suggests that OCT may be a useful biomarker for disease progression in HD. Larger, longitudinal studies are required.

Domains and correlates of clinical balance impairment associated with Huntington's disease

This study sought to (a) determine the domains of clinical balance impairments associated with Huntington's disease (HD), and (b) evaluate associations between balance test scores and other disease-related impairments. Eighteen subjects with genetically definite HD and 17 age-matched control subjects were evaluated on the Mini-BESTest for their clinical balance impairments as well as the Unified HD Rating Scale (UHDRS) motor and total functional capacity scales, Activity-Specific Balance Confidence (ABC) Scale-short form, Montreal Cognitive Assessment (MoCA), and Symbol Digit Modalities Test (SDMT). Results showed that subjects with HD exhibited significantly lower total Mini-BESTest scores than subjects without HD (mean (95% CI)=76 (64–87)% with HD, 98 (96–99)% without HD; p=0.0011). Mini-BESTest item scores were significantly lower for subjects with HD on one-leg stance, postural responses, standing with eyes closed on foam, and dual-task timed up-and-go. Mini-BESTest scores significantly correlated with UHDRS motor (r2=0.68; p=0.00003) and total functional capacity (r2=0.75; p=0.000006) scores as well as with scores on the ABC short form (r2=0.45; p=0.0024), SDMT (r2=0.42; p=0.0036), and MoCA (r2=0.23; p=0.046) assessments. This study, therefore, demonstrates that balance impairments associated with HD span domains of anticipatory postural adjustments, postural responses, stance in challenging sensory conditions, and gait. Although preliminary, clinical balance impairment appears to be an efficient proxy evaluation of multiple HD-related factors due to associations with functional capacity, other motor impairments, balance confidence, and cognitive abilities.

Relationship of Mediterranean Diet and Caloric Intake to Phenoconversion in Huntington Disease

Adherence to Mediterranean-type diet (MeDi) may delay onset of Alzheimer and Parkinson diseases. Whether adherence to MeDi affects time to phenoconversion in Huntington disease (HD), a highly penetrant, single-gene disorder, is unknown. To determine if MeDi modifies the time to clinical onset of HD (phenoconversion) in premanifest carriers participating in Prospective Huntington at Risk Observational Study (PHAROS), and to examine the effects of body mass index and caloric intake on time to phenoconversion. A prospective cohort study of 41 Huntington study group sites in the United States and Canada involving 1001 participants enrolled in PHAROS between July 1999 and January 2004 who were followed up every 9 months until 2010. A total of 211 participants aged 26 to 57 years had an expanded CAG repeat length (≥ 37). A semiquantitative food frequency questionnaire was administered 33 months after baseline. We calculated daily gram intake for dairy, meat, fruit, vegetables, legumes, cereals, fish, monounsaturated and saturated fatty acids, and alcohol and constructed MeDi scores (0-9); higher scores indicate higher adherence. Demographics, medical history, body mass index, and Unified Huntington's Disease Rating Scale (UHDRS) score were collected. Cox proportional hazards regression models to determine the association of MeDi and phenoconversion. RESULTS Age, sex, caloric intake, education status, and UHDRS motor scores did not differ among MeDi tertiles (0-3, 4-5, and 6-9). The highest body mass index was associated with the lowest adherence to MeDi. Thirty-one participants phenoconverted. In a model adjusted for age, CAG repeat length, and caloric intake, MeDi was not associated with phenoconversion (P for trend = 0.14 for tertile of MeDi, and P = .22 for continuous MeDi). When individual components of MeDi were analyzed, higher dairy consumption (hazard ratio, 2.36; 95% CI, 1.0-5.57; P = .05) and higher caloric intake (P = .04) were associated with risk of phenoconversion. MeDi was not associated with phenoconversion; however, higher consumption of dairy products had a 2-fold increased risk and may be a surrogate for lower urate levels (associated with faster progression in manifest HD). Studies of diet and energy expenditure in premanifest HD may provide data for interventions to modify specific components of diet that may delay the onset of HD.

Unawareness of motor phenoconversion in Huntington disease

To determine whether Huntington disease (HD) mutation carriers have motor symptoms (complaints) when definite motor onset (motor phenoconversion) is diagnosed and document differences between the groups with and without unawareness of motor signs. We analyzed data from 550 HD mutation carriers participating in the multicenter PREDICT-HD Study followed through the HD prodrome. Data analysis included demographics, the Unified Huntington's Disease Rating Scale (UHDRS) and the Participant HD History of symptoms, self-report of progression, and cognitive, behavioral, and imaging measures. Unawareness was identified when no motor symptoms were self-reported but when definite motor HD was diagnosed. Of 38 (6.91%) with onset of motor HD, almost half (18/38 = 47.36%) had no motor symptoms despite signs of disease on the UHDRS motor rating and consistent with unawareness. A group with motor symptoms and signs was similar on a range of measures to the unaware group. Those with unawareness of HD signs reported less depression. Patients with symptoms had more striatal atrophy on imaging measures. Only half of the patients with newly diagnosed motor HD had motor symptoms. Unaware patients were less likely to be depressed. Self-report of symptoms may be inaccurate in HD at the earliest stage.

Huntington's Disease: Effect of Memantine on FDG-PET Brain Metabolism?

In this open-label pilot study, the authors evaluated the effect of memantine on the distribution of brain glucose metabolism in four Huntington's disease (HD) patients as determined by serial 18-fluoro-deoxyglucose [F(18)]FDG-PET scans over a period of 3-4 months (90-129 days, with one patient choosing to continue treatment over the 18-month follow-up period). The treatment regimen was well tolerated. No significant differences on neuropsychological parameters before and after treatment were detected; but the patient who continued treatment did not deteriorate at 18 months' reevaluation, whereas the three patients who had stopped treatment after 3 to 4 months had minor progression in all cognitive domains on re-evaluation 12 months after the end of treatment.

F09 Progression of motor symptoms prior to diagnosis in HD-gene carriers

BackgroundIdentifying sensitive, specific, and reliable indicators of disease progression in Huntington's disease (HD) is key to selecting the appropriate population for clinical trials that assess novel treatments that may slow...

Poster 19: Validation of the Modified Motor Score (mMS): A Subscale of the Unified Huntington's Disease Rating Scale (UHDRS) Motor Score

Background The UHDRS assesses various aspects of clinical function and capacity in Huntington's disease (HD). Items in the UHDRS motor section are heterogeneous, relate to various aspects of HD motor symptoms, and can be categorized as eye, involuntary, or voluntary movements. Items relating to voluntary movements appear to correlate strongly with the extent of disability, whereas the correlation between chorea and disability is less pronounced. These findings are supported by a preliminary analysis of baseline data from a phase 2 study of pridopidine (ACR16) in patients with HD (ACR16C007). Methods Motor scales from the UHDRS motor section were analyzed according to their metric properties and correlation with measures of functional disability, assessed by total functional capacity (TFC) and functional assessment (FA) scales. The following motor scales were analyzed, using data from the CARE-HD study dataset: UHDRS motor section items (TMS); TMS excluding eye movements; modified motor scale (mMS: TMS excluding eye movements, chorea, and dystonia), which assessed voluntary movements; chorea; and eye movements. Results The mMS subscale correlated strongly with TMS (ρ = 0.89; p Conclusions The mMS subscale appears to be a valid modification of the UHDRS motor score and has functional relevance, as demonstrated by strong correlations with functional assessments. This subscale of the UHDRS motor sections may offer a simple method of assessing response to treatment in patients with HD.

Poster 27: Characterizing Psychomotor Declines in Prodromal Huntington Disease with the Trail Making Test

Objective Individuals who have the Huntington disease (HD) gene-expansion but do not yet meet clinical criteria for HD (prHD) demonstrate detectable psychomotor declines long before diagnosis. The aim of this study is to assess performance on the Trail Making Test (TMT), a well known neuropsychological measure of psychomotor speed and aspects of attention and executive functioning in prHD. A secondary aim is to determine which aspects of preclinical motor decline affect TMT performance. Method A total of 984 prHD participants and non-gene expanded controls from the PREDICT-HD study were assessed with the TMT and the motor rating scale within the Unified Huntington's Disease Rating Scale (UHDRS). The TMT consists of 2 parts: TMT-A, a measure of psychomotor speed and attention, and TMT-B, which adds a cognitive set-shifting component. Index scores were seconds to complete TMT-A and TMT-B, as well as the difference between the two parts. The UHDRS motor scale was analyzed using the 5 motor factors (i.e., oculomotor, dystonia, rigidity, bradykinesia, and chorea) identified by Marder et al. (2000). PrHD participants were grouped based on estimated proximity to diagnosis (NEAR, 15 years) according to CAG repeat length and age, using Langbehn et al.'s (2004) formula. Results Linear modeling and post-hoc comparisons revealed differences between all prognostic groups, with the NEAR group performing worst on all three TMT measures (p Conclusion PrHD participants ≤15 years to diagnosis are different from controls on all TMT measures, which indicates that TMT might be a sensitive outcome measure in preventative clinical trials. Bradykinesia was most consistently associated with poorer performance, suggesting that slowed performance, rather than oculomotor changes or chorea, are most related to TMT performance.

Electrophysiological deterioration over time in patients with Huntington's disease

In recent studies aimed at assessing the effects of original therapeutic strategies applied to patients with Huntington's disease (HD), we observed informative changes in electrophysiological results that recovered normal values in coherence with clinical improvement. However, longitudinal studies were lacking for determining whether electrophysiological test results evolve in parallel with clinical markers of the natural course of the disease and could consequently provide objective quantifiable markers of disease progression. For this purpose, electrophysiological testing was performed annually in a cohort of 20 patients with HD over a 2-year period (three examinations). The study included the recording of sympathetic skin responses and blink reflexes (BRs) to supraorbital nerve stimulation, long latency reflexes (LLRs) and somatosensory evoked potentials (SEPs) to median nerve stimulation, and cortical silent periods (CSPs) to transcranial magnetic stimulation. Clinical evaluation was based on the Total Functional Capacity scale (TFC) and the Motor part of the Unified Huntington's Disease Rating Scale (UHDRS). A significant deterioration with time was found for BR latency, LLR presence, various SEP parameters (parietal N20 peak amplitude and frontal N30 presence) and CSP duration. Attenuation of the N20 peak and CSP shortening correlated with functional decline, as assessed by the TFC score, whereas delayed BR and LLR abolition correlated with UHDRS Motor score deterioration. This study shows that several electrophysiological parameters are closely associated with dysfunction of various neural circuits in HD and could be useful markers of disease progression.