Role of attentional resources on gait performance in Huntington's disease

Patients with Huntington's disease (HD) suffer from cognitive deficits with impaired executive functions, including limited attentional resources. We sought to use a dual‐task paradigm to evaluate attentional demands and the ability of patients with HD to concentrate on two tasks simultaneously. We analyzed the interference effects of cognitive and motor tasks on walking in HD and the contribution of clinical symptoms to gait disturbances. Patients and controls were asked to perform either a motor task (carrying a tray with four glasses), a cognitive task (counting backwards), or no task at all while walking at their preferred speed. Kinematic spatial parameters, temporal parameters, and angular parameters related to gait were recorded in 15 patients and 15 controls by means of a videomotion analysis system. Gait instability was assessed using the stride‐to‐stride variability of the various gait parameters. For patients with HD, performing a concurrent cognitive task resulted in a lower gait speed (compared with free walking), with decreased cadence and stride length. However, this effect was not observed in controls. Performing a motor task did not change any kinematic gait parameters in either HD or control subjects. We found correlations between gait speed in the dual cognitive/walking task on one hand and the motor UHDRS score, cognitive status and executive function on the other. Patients with HD had greater difficulty walking while performing a concurrent cognitive task; the drain on attentional resources deteriorated walking performance. © 2007 Movement Disorder Society     

Spectrum of gait impairments in presymptomatic and symptomatic Huntington's disease

The purpose of this study was to quantify gait impairments in presymptomatic and symptomatic Huntington's disease (HD) subjects, and examine sensitivity of gait measures. Our sample (n = 65) included presymptomatic mutation carriers (PMC) (n = 15), symptomatic HD subjects (SHD) (n = 30) and healthy controls (n = 20). Participants were requested to walk at their preferred speed on a computerized walkway that recorded spatiotemporal variables. We administered the Unified HD Rating Scale (UHDRS) for PMC and SHD. PMC demonstrated decreased gait velocity (P < 0.01), stride length (P < 0.008), and increased time in double support (P < 0.001); and demonstrated higher variability in stride length (P < 0.01) and step time (P < 0.004) compared with controls. These impairments worsened with increasing disease severity for SHD. Gait impairments were correlated with predicted years to onset in PMC (velocity = ?0.65; cadence = ?0.70, step time = 0.71) and demonstrated high sensitivity and specificity in distinguishing between controls and mutation carriers. In contrast, UHDRS scores did not reveal impairments in gait and balance. Gait bradykinesia and dynamic balance impairments begin in the presymptomatic stage of HD and continue to worsen in the symptomatic stages. Gait measures are sensitive in differentiating between mutation positive and negative individuals even when impairments were not detected by clinical neurological examination. © 2008 Movement Disorder Society     

Reliability of spatiotemporal gait outcome measures in Huntington's disease.

Gait impairments are very important in Huntington's disease (HD), because loss of independence in gait is an important predictor of nursing home placement. Given this importance, it is imperative to test reliable and sensitive outcome measures that can be tested easily in various clinical environments. Here, we examined the test-retest reliability of gait outcome measures using the GAITRite instrumented carpet. We tested 12 subjects with HD and 12 age-matched controls in two separate sessions. At each session, subjects walked across the GAITRite carpet at a comfortable speed. We used the intraclass correlation coefficient (ICC) and coefficient of variation (CoV) to measure test-retest reliability. Reliability was very high for all outcome measures (velocity, cycle time, stride length, cadence, and base of support), as seen by high ICC scores (0.86 to 0.95) and low CoV scores (0.042-0.102). In addition, the performance across the two subject groups was very different, indicating that the GAITRite is sensitive enough to distinguish between populations. Given that the GAITRite is a relatively inexpensive and portable piece of equipment, it can be used in a wide variety of clinical settings and clinical trials. Our data on high test-retest reliability and sensitivity extends the utility of the GAITRite to the HD population.     

Falls and freezing of gait in Parkinson's disease: a review of two interconnected, episodic phenomena.

Falls and freezing of gait are two "episodic" phenomena that are common in Parkinson's disease. Both symptoms are often incapacitating for affected patients, as the associated physical and psychosocial consequences have a great impact on the patients' quality of life, and survival is diminished. Furthermore, the resultant loss of independence and the treatment costs of injuries add substantially to the health care expenditures associated with Parkinson's disease. In this clinically oriented review, we summarise recent insights into falls and freezing of gait and highlight their similarities, differences, and links. Topics covered include the clinical presentation, recent ideas about the underlying pathophysiology, and the possibilities for treatment. A review of the literature and the current state-of-the-art suggests that clinicians should not feel deterred by the complex nature of falls and freezing of gait; a careful clinical approach may lead to an individually tailored treatment, which can offer at least partial relief for many affected patients.     

Seizures in juvenile Huntington's disease: Frequency and characterization in a multicenter cohort

Little is known about the epilepsy that often occurs in the juvenile form of Huntington's disease (HD), but is absent from the adult‐onset form. The primary aim of this study was to characterize the seizures in juvenile HD (JHD) subjects with regard to frequency, semiology, defining EEG characteristics, and response to antiepileptic agents. A multicenter, retrospective cohort was identified by database query and/or chart review. Data on age of HD onset, primary HD manifestations, number of CAG repeats, the presence or absence of seizures, seizure type(s), antiepileptic drugs used, subjects' response to antiepileptic drugs (AEDs), and EEG results were assembled, where available. Ninety subjects with genetically confirmed JHD were included. Seizures were present in 38% of subjects and were more likely to occur with younger ages of HD onset. Generalized tonic‐clonic seizures were the most common seizure type, followed by tonic, myoclonic, and staring spells. Multiple seizure types commonly occurred within the same individual. Data on EEG findings and AED usage are presented. Seizure risk in JHD increases with younger age of HD onset. Our ability to draw firm conclusions about defining EEG characteristics and response to AEDs was limited by the retrospective nature of the study. Future prospective studies are required. © 2012 Movement Disorder Society     

Role of hypokinesia and bradykinesia in gait disturbances in Huntington's disease

Objective To evaluate specific patterns of locomotion in Huntington's disease (HD) and notably the respective roles of hypokinesia (i. e. a decrease in the amplitude of movement) and bradykinesia (i. e. difficulty in executing a movement, slowness) in gait disturbance. Methods Kinematic, spatial (stride length, speed), temporal (cadence, speed, and stride time) and angular gait parameters (joint ankle range) were recorded in 15 early–stage HD patients by means of a video motion analysis system and then compared with 15 controls and 15 Parkinson's disease (PD) patients. Hypokinesia was studied in terms of both spatial (decrease in stride length) and angular gait parameters (decrease in joint ankle range), whereas hyperkinesia was characterized by an increase in joint ankle range. Bradykinesia (defined by a decrease in gait velocity) was also assessed in terms of temporal parameters (cadence, stride time). We studied the influence of clinical symptoms (motor dysfunction, chorea, overall disability and cognitive impairment) and the CAG repeat number on gait abnormalities. Results we observed a clear decrease in gait speed, a decrease in cadence and an increase in stride time (i. e. bradykinesia) for HD, with significant intra–individual variability. Cadence remained normal in PD. In HD, there was no evidence for a clear decrease in stride length, although the latter is a characteristic feature of hypokinetic gait (such as that observed in PD). Angle analysis revealed the coexistence of hyperkinesia and hypokinesia in HD, which thus participate in gait abnormalities. Gait speed in HD was correlated to the motor part of the UHDRS. Conclusion Gait in HD is mainly characterized by a timing disorder: bradykinesia was present, with severe intra–individual variability in temporal gait parameters.     

Reduced Purkinje cell density in Huntington's disease

We studied, in a "blind" and quantitative fashion, the density of cerebellar Purkinje cells in 17 adult cases of Huntington's disease (HD), 17 patients with other movement disorders, 17 with schizophrenia, and 23 normal controls. There was a highly significant reduction in Purkinje cell density in HD compared with any of the other three groups. A much smaller difference in neuronal density between patients with other movement disorders and normal controls was barely significant. Eight of the 17 HD patients and only 1 of the other 57 subjects had Purkinje cell density less than 50% of the mean for the normal controls. The low density of Purkinje cells in HD could not be attributed to aging, seizures, or cause of death, nor was it merely a part of a generalized brain atrophy. The loss of large Purkinje cells suggests that the neuronal loss in HD may not be restricted to small and medium-size neurons.     

Psychopathology in Huntington's disease patients

A retrospective study of 30 Huntington's disease families (110 patients: 75 alive and 35 dead) known to a regional genetic centre, using multiple sources of information, showed the minimum lifetime prevalence of depression to be 39% in the prodrome and the diagnosed disease phase of the illness. The frequency of symptomatic schizophrenia was found to be about 9% and significant personality changes were found in 72% of the sample, some of them leading to gross behavioural anomalies. The findings reinforce the point that depression and schizophrenia, unaccompanied or preceded by organic personality changes and/or very early neural symptoms, are unlikely to lead to the eventual manifestation of the disease.     

Brain activation pattern related to gait disturbances in Parkinson's disease

Gait disturbances represent a therapeutic challenge in Parkinson's disease (PD). To further investigate their underlying pathophysiological mechanisms, we compared brain activation related to mental imagery of gait between 15 PD patients and 15 age‐matched controls using a block‐design functional MRI experiment. On average, patients showed altered locomotion relatively to controls, as assessed with a standardized gait test that evaluated the severity of PD‐related gait disturbances on a 25‐m path. The experiment was conducted in the subjects as they rehearsed themselves walking on the same path with a gait pattern similar as that during locomotor evaluation. Imagined walking times were measured on a trial‐by‐trial basis as a control of behavioral performance. In both groups, mean imagined walking time was not significantly different from that measured during real gait on the path used for evaluation. The between‐group comparison of the mental gait activation pattern with reference to mental imagery of standing showed hypoactivations within parieto‐occipital regions, along with the left hippocampus, midline/lateral cerebellum, and presumed pedunculopontine nucleus/mesencephalic locomotor area, in patients. More specifically, the activation level of the right posterior parietal cortex located within the impaired gait‐related cognitive network decreased proportionally with the severity of gait disturbances scored on the path used for gait evaluation and mental imagery. These novel findings suggest that the right posterior parietal cortex dysfunction is strongly related to the severity of gait disturbances in PD. This region may represent a target for the development of therapeutic interventions for PD‐related gait disturbances. © 2012 Movement Disorder Society     

Prevalence of Huntington's disease in Southern Sardinia,Italy

BackgroundThe frequency of Huntington's disease (HD) may vary considerably, with higher estimates in non Asian populations. In Italy, two recent studies performed in Ferrara county and Molise provided different prevalence estimates, varying from 4.2 × 10⁵ to 10.8 × 10⁵. Here we present a study performed in the Southern part of Sardinia, a large Italian mediterranean island that is considered a genetic isolate.MethodsThe study area included the two neighbouring counties of South Sardinia and Cagliari with 353,830 and 431,955 inhabitants respectively on December 31st, 2017 (prevalence date). Case-patients were ascertained through multiple sources in Sardinia and Italy.ResultsWe identified 54 individuals with HD, of whom 47 were alive on prevalence date. The resulting prevalence rate was 5.98 × 10⁵ in the overall study area, however with marked variations between South Sardinia and Cagliari (9.6 × 10⁵ vs. 3.0 × 10⁵, p = 0.02). In the two study areas, we found similar CAG repeat length in normal alleles (17.5 ± 2.1 vs. 17.7 ± 2.2, p = 0.5).ConclusionsThe overall prevalence of HD in Sardinia is close to the correspondent estimates in Europeans. Our findings also highlighted the possibility of local microgeographic variations in the epidemiology of HD.     

The incidence and prevalence of Huntington's disease: A systematic review and meta‐analysis

Huntington's disease (HD) is a rare, neurodegenerative disorder characterized by chorea, behavioral manifestations, and dementia. The aim of this study was to estimate the incidence and prevalence of HD through a systematic review of the literature. Medline and Embase databases were searched using terms specific to HD as well as studies of incidence, prevalence, and epidemiology. All studies reporting the incidence and/or prevalence of HD were included. Twenty original research articles were included. Eight studies examined incidence, and 17 studies examined prevalence. Meta‐analysis of data from four incidence studies revealed an incidence of 0.38 per 100,000 per year (95% confidence interval [CI]: 0.16, 0.94). Lower incidence was reported in the Asian studies (n = 2), compared to the studies performed in Europe, North America, and Australia (n = 6). The worldwide service‐based prevalence of HD, based on a meta‐analysis (n = 13 studies), was 2.71 per 100,000 (95% CI: 1.55–4.72). Eleven studies were conducted in Europe, North American, and Australia, with an overall prevalence of 5.70 per 100,000 (95% CI: 4.42–7.35). Three studies were conducted in Asia, with an overall prevalence of 0.40 per 100,000 (95% CI: 0.26–0.61). Metaregression revealed a significantly lower prevalence of HD in Asia, compared to European, North American, and Australian populations. HD is a devastating neurodegenerative disorder with a higher prevalence in Europe, North America, and Australia than in Asia. The difference in prevalence of this genetic disorder can be largely explained by huntingtin gene haplotypes. © 2012 Movement Disorder Society     

Huntington's disease like-2 neuropathology.

Huntington's disease like-2 (HDL-2) neurodegeneration is a recently described autosomal dominant disorder with features similar to Huntington's disease (HD). Only one case report has described neuropathology from an affected patient. We describe the clinical presentation and illustrate the pathology in two additional molecularly confirmed patients, compare these with the previously published case, and contrast them with HD. We examined two patients with HDL-2. Their charts were reviewed, their brains were examined using standard neuropathology techniques, including immunoperoxidase stains, and their diagnoses were confirmed with a PCR-based assay for repeat length. The first patient presented with obsessive suspiciousness, while the second had depression and decreased visual acuity. Both patients developed increased tone and cogwheel rigidity, but neither developed choreoathetosis. Extensive degeneration affected the caudate nucleus and putamen, especially dorsally and laterally. In addition, the first patient showed lateral temporal, lateral frontal, and orbitofrontal cortical atrophy, while the second patient displayed marked degeneration in the occipital and parietal cortices. Neither patient showed significant changes in the cerebellum or brainstem. Both cases had ubiquitin-immunoreactive neuronal intranuclear inclusions (NII). The patients with of HDL-2 reviewed here were remarkable for significant frontal inhibition with parkinsonism, a lack of choreiform movements, and African ancestry. Pathologically, HDL-2 is similar to HD in its effect on the neostriatum but may differ, at least in some cases, in its degree of focal cortical involvement, including the occipital lobe.     

Late-onset Huntington's disease: Diagnostic and prognostic considerations

ObjectiveTo address diagnostic and prognostic issues in patients with late-onset Huntington's disease (HD).MethodsWe analyzed a cohort of 41 late-onset (≥60 years) HD patients and compared them to 39 late-onset patients referred for HD testing that were negative for the HD-expansion and to 290 usual-onset (20–59 years) HD patients. Disease severity was assessed by the Total Functional Capacity Scale.ResultsLate-onset HD comprised 11.5% of our HD cohort. In total, 70.7% of late-onset HD patients had positive family history compared to 15.4% of late-onset expansion-negative patients (p < 0.001). Clinical features at onset or presentation could not usefully distinguish between late-onset expansion-positive and negative patients, excepting hemichorea, which was absent from the HD group (p = 0.024). Chorea was the first clinical feature in 53.7% and a presenting feature in 90.2% of late-onset HD. The mutation hit rate for late-onset patients was 51.3%, lower than in usual-onset patients (p = 0.04). Frequencies of chorea, cognitive impairment and psychiatric manifestations at onset or presentation were not significantly different between late-onset and usual-onset HD patients. Gait unsteadiness however was more common at presentation in late-onset HD (p = 0.007). Late-onset HD patients reached a severe stage of illness on average 2.8 years earlier than usual-onset HD patients (p = 0.046).ConclusionsA positive family history suggestive of HD, although absent in a third of patients, remains a helpful clue in diagnosing late-onset HD. Prognosis of late-onset HD in terms of Total Functional Capacity appears no better and shows a trend of being somewhat less favorable compared to usual-onset HD.     

Diffusion tensor imaging in presymptomatic and early Huntington's disease: Selective white matter pathology and its relationship to clinical measures.

Atrophy of cortical and subcortical gray matter is apparent in Huntington's disease (HD) before symptoms manifest. We hypothesized that the white matter (WM) connecting cortical and subcortical regions must also be affected early and that select clinical symptoms were related to systems degeneration. We used diffusion tensor magnetic resonance imaging (DTI) to examine the regional nature of WM abnormalities in early HD, including the preclinical period, and to determine whether regional changes correlated with clinical features. We studied individuals in early stages (HD), presymptomatic individuals known to carry the genetic mutation that causes HD (Pre-HD), and matched healthy controls. DTI indices of tissue integrity were obtained from several regions of interest, including the corpus callosum (CC), internal capsule (IC), and basal ganglia, were compared across groups by t tests, and were correlated to cognitive and clinical measures. WM alterations were found throughout the CC, in the anterior and posterior limbs of the IC, and in frontal subcortical WM in HD subjects, supporting the selective involvement of the pyramidal tracts in HD; a similar distribution of changes was seen in Pre-HD subjects, supporting presymptomatic alterations. There was a significant relationship between select DTI measures and cognitive performance. Alterations in diffusion indices were also seen in the striatum that were independent of atrophy. Our findings support that WM alterations occur very early in HD. The distribution of the changes suggests that these changes contribute to the disruption of pyramidal and extrapyramidal circuits and also support a role of compromised cortical circuitry in early cognitive and subtle motor impairment during the preclinical stages of HD.     

Plasma melatonin is reduced in Huntington's disease

This study was undertaken to determine whether the production of melatonin, a hormone regulating sleep in relation to the light/dark cycle, is altered in Huntington's disease. We analyzed the circadian rhythm of melatonin in a 24‐hour study of cohorts of control, premanifest, and stage II/III Huntington's disease subjects. The mean and acrophase melatonin concentrations were significantly reduced in stage II/III Huntington's disease subjects compared with controls. We also observed a nonsignificant trend toward reduced mean and acrophase melatonin in premanifest Huntington's disease subjects. Onset of melatonin rise was significantly more temporally spread in both premanifest and stage II/III Huntington's disease subjects compared with controls. A nonsignificant trend also was seen for reduced pulsatile secretion of melatonin. Melatonin concentrations are reduced in Huntington's disease. Altered melatonin patterns may provide an explanation for disrupted sleep and circadian behavior in Huntington's disease, and represent a biomarker for disease state. Melatonin therapy may help the sleep disorders seen in Huntington's disease. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Factors contributing to institutionalization in patients with Huntington's disease

The objective of this study was to determine which factors are predictive of institutionalization in Huntington's disease. Seven hundred and ninety‐nine subjects with 4313 examinations from the Baltimore Huntington's Disease Center were included in the data set; 88 of these patients with an average follow‐up time of 9.2 years went from living at home to being institutionalized while being observed in our clinic. We examined demographic, genetic, and clinical variables for a relationship with institutionalization using linear regressions, a Cox proportional hazards model, and χ² or t tests in certain cases. In our linear models, scores on the Quantified Neurologic Examination (R² = 0.203, P < .001), Huntington's disease Activities of Daily Living Scale (R² = 0.259, P < .001), and Motor Impairment Score (R² = 0.173, P < .001) were found to have the strongest correlation with time until institutionalization. In addition, CAG repeat length (R² = 0.248, P < .001) was significantly associated with disease duration at institutionalization, when controlling for age at onset. In the Cox proportional hazards model, scores on the Activities of Daily Living Scale, Mini–Mental State Examination, Quantified Neurologic Examination, and Motor Impairment Score all significantly predicted placement in long‐term care. Finally, institutionalized patients were shown to have a higher CAG number and a lower level of educational attainment than patients who avoided institutionalization for at least 15 years after disease onset. Neurologic findings, functional capacity, cognitive impairment, and CAG repeat length are all likely determinants of institutionalization. In contrast with other dementing conditions like Parkinson's and Alzheimer's, psychiatric symptoms were not shown to predict institutionalization in Huntington's disease. This may illustrate the especially debilitating nature of the movement disorder of Huntington's disease in comparison with the other dementias. © 2011 Movement Disorder Society     

Inhibitory control during smooth pursuit in Parkinson's disease and Huntington's disease

The basal ganglia are involved in the preferential selection and suppression of competing responses. Parkinson's disease and Huntington's disease are 2 prototypical basal ganglia disorders that feature impaired inhibitory control, a function of poor conflict resolution. Previous saccadic studies showed that individuals with Parkinson's disease experience difficulty suppressing unwanted ocular motor responses, whereas evidence for a similar difficulty in Huntington's disease is more equivocal. Relative to saccades, few research studies have examined inhibitory control processes in the context of an ongoing smooth pursuit task. In this study, we examined the ability of 16 patients with Parkinson's disease and 12 patients with Huntington's disease to suppress automatic responses to irrelevant distracters that transiently appeared during the tracking of a moving visual stimulus. Compared with an equivalent number of age‐matched controls, patients with Parkinson's disease generated proportionately more saccades to distracter stimuli. This was particularly evident for distracters appearing far away from the target. Conversely, whereas individuals with early‐stage Huntington's disease and healthy controls made a comparable number of errors toward distracter stimuli, those in a more advanced clinical stage demonstrated significantly poorer inhibitory control. The current findings in parkinsonian patients replicate those previously reported in the saccadic and manual response literature, demonstrating difficulty inhibiting a competing motor response. However, in Huntington's disease we demonstrate for the first time that inhibitory control declines in more advanced‐disease stages. This suggests that ocular motility may provide a sensitive marker of clinical disease progression in Huntington's disease. © 2011 Movement Disorder Society     

The current clinical management of Huntington's disease

Huntington's disease is a neurodegenerative condition, characterized by movement disorders, cognitive decline, and psychiatric disturbance. We review the pharmacological management of the various movement disorders associated with the disease, the cognitive decline and the commonly encountered behavioral disturbances. We discuss the nonclassical features of the disease, important in the management of these patients. Nonpharmacological support including genetic counseling and therapy and the importance of palliative care are also addressed. Finally, experimental approaches that may soon impact upon clinical practice are discussed. © 2008 Movement Disorder Society