Late-stage Huntington's Disease Research Articles

Feasibility and Safety of an Aquatherapy Program in Mid- to Late-Stage Huntington Disease

Background: The progressive motor dysfunction and cognitive impairment associated with mid- to late-stage Huntington Disease (HD) renders few exercise programs amenable for use in this population. Exercise may slow the symptomatic progression of HD, therefore appropriate programs should be available to those with advanced disease. The pool, with a low risk of falling, boasts an appropriate environment to support choreic limbs. The purpose of this qualitative questionnaire-based study was to assess the feasibility and safety of aquatherapy in mid- to late-stage HD, and program perception by participants/caregivers. Methods: Six participants with manifest HD completed a six-week aquatherapy program comprised of twiceweekly sessions. Participant-tailored aquatherapy sessions involved a warm-up, exercise-set, and a cool-down. Study notes regarding injury and compliance were recorded to track measures of safety and feasibility. Participants (and caregivers where available) gave an interview following the program. Conversations were audio recorded and fully transcribed. Interviews were analyzed to extract themes. Results: Generally, participants reported the aquatherapy to be enjoyable, feasible, and safe, as well described improved mood, sleep, and quality of life. Anecdotal evidence suggests that many participants experienced improved physical conditioning. Conclusions: Twice-weekly aquatherapy is feasible in mid- to late-stage HD, and was perceived to be safe and enjoyable.

A07 Critical consideration of the criteria for the motor diagnosis of huntington disease

Background Huntington disease (HD) is a fatal inherited disorder with typical onset in adulthood. In research studies of HD, it is necessary to characterise the progression of participants in order to validly interpret results. Aims A distinction is often made between gene-positive individuals who are displaying hallmark motor signs (manifest HD) and gene-positive individuals who are not (pre-manifest HD). The conventional threshold for this distinction is the highest rating on the Diagnostic Criterion Level (DCL) scale of the Unified Huntington Disease Rating Scale (UHDRS), which constitutes the motor examiner9s confidence level of ≥99% for an unequivocal movement disorder (DCL=4). Methods A study was undertaken to investigate the empirical support for the use of the DCL for manifest HD classification, and alternatives including cutoffs based on the Total Motor Score (TMS) of the UHDRS. Because a gold standard classification does not exist, extreme case/control differences and extreme of the control distribution were used as a guide to selecting cutoffs. Results The results show that the conventional DCL criteria is too stringent in the sense that (1) cutoffs based on the TMS and the lower DCL confidence level of 90%–99% (DCL=3) both provide a very strong distinction between cases and controls, and (2) the conventional criterion tends to be assigned well after the accelerated deterioration trajectory characteristic of late-stage HD has already commenced. Conclusion The results suggest that alternate criteria, especially the intersection of DCL ≥3 and TMS cutoffs, might be considered in HD research.

Striatal atrophy and dendritic alterations in a knock-in mouse model of Huntington's disease

Huntington's disease (HD) is a progressive neurodegenerative disease characterized by progressive atrophy of the striatum, cerebral cortex, and white matter tracks. Major pathological hallmarks of HD include neuronal loss, primarily in the striatum, and dendritic anomalies in surviving striatal neurons. Although many mouse models of HD have been generated, their success at reproducing all pathological features of the disease is not fully known. Previously, we demonstrated extensive striatal neuronal loss and striatal atrophy at 20-26 months of age in a knock-in (KI) mouse model of HD. To further investigate this model, which carries a human exon 1 with ∼119 CAG repeats inserted into the mouse gene (initially 140 repeats), we have examined whether these mice exhibit the atrophy and neuronal anomalies characteristic of HD. Stereological analyses revealed no changes in the striatal volume of male and female homozygote mice at 4 months, however striatal atrophy was already present at 12 months in both sexes. Analysis of cortical and corpus callosum volume in male homozygotes revealed a loss in corpus callosum volume by 20-26 months. At this later age, the surviving striatal neurons displayed extensive loss of spines in distal branch orders that affected both immature and mature spines. Mirroring late stage HD striatal neuronal morphology, the striatal neurons at this late age also showed reduced dendritic complexity, as revealed by Sholl analysis. Tyrosine hydroxylase immunoreactivity was also decreased in the striatum of 20-26 month old KI mice, suggesting an alteration in striatal inputs. These data further indicate that CAG140 homozygote KI mice exhibit HD-like pathological features and are a useful model to test the effects of early and/or sustained administration of novel neuroprotective treatments.

Mutant Huntingtin Causes Metabolic Imbalance by Disruption of Hypothalamic Neurocircuits

In Huntington's disease (HD), the mutant huntingtin protein is ubiquitously expressed. The disease was considered to be limited to the basal ganglia, but recent studies have suggested a more widespread pathology involving hypothalamic dysfunction. Here we tested the hypothesis that expression of mutant huntingtin in the hypothalamus causes metabolic abnormalities. First, we showed that bacterial artificial chromosome-mediated transgenic HD (BACHD) mice developed impaired glucose metabolism and pronounced insulin and leptin resistance. Selective hypothalamic expression of a short fragment of mutant huntingtin using adeno-associated viral vectors was sufficient to recapitulate these metabolic disturbances. Finally, selective hypothalamic inactivation of the mutant gene prevented the development of the metabolic phenotype in BACHD mice. Our findings establish a causal link between mutant huntingtin expression in the hypothalamus and metabolic dysfunction, and indicate that metabolic parameters are powerful readouts to assess therapies aimed at correcting dysfunction in HD by silencing huntingtin expression in the brain.

Dysregulated brain creatine kinase is associated with hearing impairment in mouse models of Huntington disease

Huntington disease (HD) is a degenerative disorder caused by expanded CAG repeats in exon 1 of the huntingtin gene (HTT). Patients with late-stage HD are known to have abnormal auditory processing, but the peripheral auditory functions of HD patients have yet to be thoroughly assessed. In this study, 19 HD patients (aged 40-59 years) were assessed for hearing impairment using pure-tone audiometry and assessment of auditory brainstem responses (ABRs). PTA thresholds were markedly elevated in HD patients. Consistent with this, elevated ABR thresholds were also detected in two mouse models of HD. Hearing loss thus appears to be an authentic symptom of HD. Immunohistochemical analyses demonstrated the presence of mutant huntingtin that formed intranuclear inclusions in the organ of Corti of HD mice, which might interfere with normal auditory function. Quantitative RT-PCR and Western blot analyses further revealed reduced expression of brain creatine kinase (CKB), a major enzyme responsible for ATP regeneration via the phosphocreatine-creatine kinase (PCr-CK) system, in the cochlea of HD mice. Treatment with creatine supplements ameliorated the hearing impairment of HD mice, suggesting that the impaired PCr-CK system in the cochlea of HD mice may contribute to their hearing impairment. These data also suggest that creatine may be useful for treating the hearing abnormalities of patients with HD.

J08 The oral health and dental treatment of adults with Huntington's disease

BackgroundThe Royal Hospital for Neuro-Disability (RHN) is the largest provider of care for people with advanced-stage HD in the UK. A dental department within the hospital provides oral health care...

F06 Late-stage huntington's disease (HD): a cohort from the European HD network

BackgroundFew data is available regarding most advanced stages of HD.AimsTo describe clinical manifestations, medication use and caregivers’ burden in late-stage HD (LS-HD).Patients and methodsLS-HD patients were extracted from the database...

IN51-WE-02 Management of late-stage Huntington's disease

IN51-WE-02 Management of late-stage Huntington's disease

Wheel running and environmental enrichment differentially modify exon‐specific BDNF expression in the hippocampus of wild‐type and pre‐motor symptomatic male and female Huntington's disease mice

Brain-derived neurotrophic factor (BDNF) is an essential neurotrophin and regulation of its expression is complex due to multiple 5' untranslated exons which are separately spliced to a common coding exon to form unique mRNA transcripts. Disruption of BDNF gene expression is a key to the development of symptoms in Huntington's disease (HD), a fatal neurodegenerative condition. Abnormal epigenetic modifications are associated with reduced gene expression in late-stage HD but such regulation of BDNF gene expression has yet to be investigated. We hypothesized that BDNF gene expression is altered in the HD hippocampus of pre-motor symptomatic R6/1 transgenic HD mice, correlating with a change in the DNA methylation profile. The effects of wheel-running and environmental enrichment on wild-type mice, in association with a proposed environment-mediated correction of BDNF gene expression deficits in HD mice, were also investigated. Using real-time PCR, levels of total BDNF mRNA were found to be reduced in the hippocampus of both male and female HD mice. Wheel-running significantly increased total BDNF gene expression in all groups of mice except male HD mice. In contrast, environmental enrichment significantly increased expression only in male wild-type animals. Further quantification of BDNF exon-specific transcripts revealed sex-specific changes in relation to the effect of the HD mutation and differential effects on gene expression by wheel-running and environmental enrichment. The HD-associated reduction of BDNF gene expression was not due to increased methylation of the gene sequence. Furthermore, environment-induced changes in BDNF gene expression in the wild-type hippocampus were independent of the extent of DNA methylation. Overall, the results of this study provide new insight into the role of BDNF in HD pathogenesis in addition to the mechanisms regulating normal BDNF gene expression.

Well-Being of Family Caregivers of Persons with Late-Stage Huntington's Disease: Lessons in Stress and Coping

The utility of a stress-process model in predicting health and quality-of-life outcomes for family caregivers of persons with Huntington's disease (HD) was tested. HD is an inherited neurodegenerative disease that poses particular challenges to patients and families. Seventeen family caregivers were interviewed and completed scales measuring stressors, appraisals, protective factors, and outcomes. No direct relationship between stress and caregiver well-being was found; the impact of stressors was mediated by appraisals and protective factors. Bivariate correlation analysis revealed significant positive relationships between satisfaction with emotionally supportive communication and life satisfaction. Significant positive correlations were found between positive appraisals of the benefits of the caregiving experience and life satisfaction and health. Mastery was significantly positively correlated with life satisfaction and negatively correlated with depressive symptoms; similar results were found between spirituality and outcome measures. Caregivers' interpretations appeared to have a more significant impact on well-being than did objective characteristics of the experience.

A Large Number of Protein Expression Changes Occur Early in Life and Precede Phenotype Onset in a Mouse Model for Huntington Disease

Huntington disease (HD) is fatal in humans within 15-20 years of symptomatic disease. Although late stage HD has been studied extensively, protein expression changes that occur at the early stages of disease and during disease progression have not been reported. In this study, we used a large two-dimensional gel/mass spectrometry-based proteomics approach to investigate HD-induced protein expression alterations and their kinetics at very early stages and during the course of disease. The murine HD model R6/2 was investigated at 2, 4, 6, 8, and 12 weeks of age, corresponding to absence of disease and early, intermediate, and late stage HD. Unexpectedly the most HD stage-specific protein changes (71-100%) as well as a drastic alteration (almost 6% of the proteome) in protein expression occurred already as early as 2 weeks of age. Early changes included mainly the up-regulation of proteins involved in glycolysis/gluconeogenesis and the down-regulation of the actin cytoskeleton. This suggests a period of highly variable protein expression that precedes the onset of HD phenotypes. Although an up-regulation of glycolysis/gluconeogenesis-related protein alterations remained dominant during HD progression, late stage alterations at 12 weeks showed an up-regulation of proteins involved in proteasomal function. The early changes in HD coincide with a peak in protein alteration during normal mouse development at 2 weeks of age that may be responsible for these massive changes. Protein and mRNA data sets showed a large overlap on the level of affected pathways but not single proteins/mRNAs. Our observations suggest that HD is characterized by a highly dynamic disease pathology not represented by linear protein concentration alterations over the course of disease.

A large number of protein expression changes occur early in life and precede phenotype onset in different animal models for Huntington's disease

Huntington's disease (HD) is fatal in humans within 15 to 20 years of symptomatic disease. Although late stage HD has been studied extensively, protein expression changes that occur at the early stages of disease and during disease progression have not been reported. In this study, we used a large 2‐D gel/mass spectrometry based proteomics approach to investigate HD‐induced protein expression alterations and their kinetics at very early stages and during the course of disease. Different HD animal models were investigated at absence, early, intermediate and late stage HD. Preliminary results showed that in at least two animal models HD‐stage‐specific protein changes (above 70%) as well as a drastic alteration in protein expression already occurred before symptoms appeared. Early changes included in both cases the dys‐regulation of proteins involved in glycolysis/gluconeogenesis and the actin‐cytoskeleton formation. This suggests a period of highly variable protein expression which precedes the onset of an HD phenotype. More animal models will be investigated to further characterize protein alteration kinetics and their role in HD. Our observations suggest that HD is characterized by a highly dynamic disease pathology not represented by linear protein concentration alterations over the course of disease.

Sexuality and the Late Stage Huntington's Disease Patient

Huntington's Disease (HD) is an irreversible subcortical dementia resulting in uncontrolled movement; loss of intellectual function; impaired memory, thought, speech and perception; and emotional disturbance. This study assessed sexual interests, needs related to sexuality, and intimacy issues in severely impaired, late stage HD patients through use of structured interviews. Results of interviews of a small population of HD patients residing in a long-term care facility are provided; interviews focused on sexuality issues, patients' perceptions of their intimate and sexual relationships, and their interest in discussing sexuality concerns with staff. Almost half of the patient population displayed an interest in discussing sexuality issues. Interview results indicated the need for caregivers to recognize that patients are sexual beings, with sexual needs, fantasies and wishes. HD patients have the potential to develop feelings of attraction, which must be dealt with in a clear, careful, sensitive manner. Suggestions are offered for ways in which caregiving staff could compensate for the sexual losses, including: providing a private room for a married patient to have intimate time with a spouse; offering sexually-oriented videos or reading materials if the individual wants them; providing romance novels and films; considering the possibility of providing a patient with a means to stimulate himself or herself.

Palliative care for people with late-stage huntington's disease

Huntington's disease provides a unique model to examine issues of long-term and palliative care for a younger and more mobile population who remain institutionalized longer than other nursing home residents. A lack of community-based alternatives for young families, and the need for highly complex care planning encourage long term care placement mid-way in the disease process. Despite the need for a body of knowledge specific to environmental enrichment and therapeutic strategies for improving quality of life for people in the later stages of Huntington's disease, there is no published data in the neurological or rehabilitation literature. This article reviews the signs and symptoms and offers a multidisciplinary approach to ameliorate problems frequently encountered in caring for this population.

Early Degenerative Changes in Transgenic Mice Expressing Mutant Huntingtin Involve Dendritic Abnormalities but No Impairment of Mitochondrial Energy Production

Mitochondrial defects, which occur in the brain of late-stage Huntington's disease (HD) patients, have been proposed to underlie the selective neuronal loss in the disease. To shed light on the possible role of mitochondrial energy impairment in the early phases of HD pathophysiology, we carried out Golgi impregnation and quantitative histochemical/biochemical studies in HD full-length cDNA transgenic mice that were symptomatic but had not developed to a stage in which neuronal loss could be documented. Golgi staining showed morphologic abnormalities that included a significant decrease in the number of dendritic spines and a thickening of proximal dendrites in striatal and cortical neurons. In contrast, measurements of mitochondrial electron transport Complexes I–IV did not reveal changes in the striatum and cerebral cortex in these mice. Examination of the neostriatum and cerebral cortex in human presymptomatic and pathological Grade 1 HD cases also showed no change in the activity of mitochondrial Complexes I–IV. These data suggest that dendritic alterations precede irreversible cell loss in HD, and that mitochondrial energy impairment is a consequence, rather than a cause, of early neuropathological changes.

Progression of symptoms in the early and middle stages of Huntington disease.

To delineate the progression of symptoms in the early and middle stages of Huntington disease (HD). A survey of individuals with symptomatic HD completed by a first-degree relative. The National Huntington Disease Research Roster for Patients and Families, Indianapolis, Ind. The survey included 1238 individuals with a minimum of a 6-year history of symptomatic HD. Participating families completed a series of surveys, including the Affected Individual Questionnaire, which consists of 19 physical, emotional, and cognitive signs commonly thought to occur during disease progression. The respondent indicates if each of the symptoms occurred and, if so, at what time during the course of the disease: (1) within 1 year, (2) within 2 to 5 years, (3) within 6 to 10 years, (4) after more than 10 years, (5) has not occurred, or (6) "don't know." The symptoms are categorized into 6 onset periods. Involuntary movements are grouped alone as the earliest reported symptom. The second group is composed entirely of mental and emotional symptoms, including sadness, depression, and difficult to get along with. The third group includes clumsiness, sexual problems, lack of motivation, and suspiciousness/paranoia. As the disease progresses, a variety of motor, emotional/behavioral, and cognitive symptoms are experienced, including unsteadiness, trouble holding onto things, trouble walking, changes in sleeping patterns, delusions and hallucinations, intellectual decline, and memory loss. With the approach of late-stage HD, affected individuals begin to experience speech difficulty and weight loss. In the late stage, patients lose bowel and bladder control. Even though the symptoms of HD are fairly well characterized, their progression, especially in the early and middle stages, remains uncertain. Clarification of the disease progression is vital to improved understanding of the pathogenesis of HD and to the evaluation of therapeutic agents that are designed to slow the progression of disease. The results of this study assist in clarifying HD progression from early involuntary movements and emotional changes to more overt motor symptoms and difficulty with activities of daily living.

Chapter 18 Neural transplantation for the treatment of Huntington's disease

Neural transplantation is applicable in the treatment of Huntington's disease (HD). At this time, there is only preliminary evidence of safety, tolerability, and efficacy of fetal striatal transplantation for the treatment of HD. The safety profile may differ adversely from similar transplant programs for the treatment of Parkinson's disease, because of the atrophy associated with HD that may predispose patients to the development of subdural hematomas after surgically induced cerebrospinal fluid (CSF) loss. Although graft survival has been demonstrated at autopsy, there is significant gliosis associated with late-stage HD, which may make transplantation in late-stage patients less favorable. Human fetal striatal grafts in both rodent models and patients with HD are capable of receiving appropriate neuritic in growth from the host brain. It remains unproven if striatal grafts in patients with HD are similarly capable of extending projections over the distances necessary to reach appropriate target areas, as seen in animal allograft transplant models of HD. There is currently no agreement on the optimal way to dissect human fetal tissue for transplantation purposes.

Dysfunction of brain kynurenic acid metabolism in Huntington's disease: focus on kynurenine aminotransferases

The levels of the neuroprotective excitatory amino acid receptor antagonist kynurenic acid (KYNA) have been previously shown to be reduced in several regions of the brain of Huntington's disease (HD) patients. Thus, KYNA has been speculatively linked to the pathogenesis of HD. We have examined KYNA levels and the activity of its two biosynthetic enzymes (kynurenine aminotransferases (KAT) I and II) in 12 regions of brains from late-stage HD patients and control donors ( n = 17 each). KYNA levels were measured in the original tissue homogenate. Using [ 3H]kynurenine as the substrate, enzyme activities were determined in dialyzed tissue homogenates. KYNA levels in the caudate nucleus decreased from 733 ± 95 in controls to 401 ± 62 fmol/mg tissue in HD ( p < 0.01). The activity of both enzymes was highest in cortical areas (e.g. control frontal cortex: KAT I: 148 ± 18 fmol/mg tissue/h; KAT II: 25 ± 2 fmol/mg tissue/h). The activities of both KAT I and KAT II, when expressed per mg original weight, showed significant decreases (48–55%) in the HD putamen ( p < 0.01). Trends toward lower enzyme activities and KYNA concentrations were detected in other brain areas as well. Kinetic analyses, performed in putamen and cerebellum, showed an approximately 3-fold increase in K m values for both KAT I and KAT II in the putamen only. V max values remained unchanged in the HD brain. These findings indicate a selective impairment in KYNA biosynthesis in the neostriatum of HD patients, possibly due to the loss of (an) endogenous KAT activators). Future studies should examine whether the demonstrated dysfunction in the production of the endogenous neuroprotecive agent KYNA is causally related to the neurodegenerative process in HD.

Heterogeneous dopamine receptor changes in early and late Huntington's disease

Quantitative receptor autoradiography was used to study dopamine (DA) receptors in dorsal striatum and its projection regions in brains from individuals dying with Huntington's disease (HD) and controls. Heterogeneous loss of both D 1 and D 2 receptors was present in the striatum of early and late stage HD brains. The degree of receptor loss was greater for the D 1 receptor than for the D 2 receptor in early stage HD. The pattern of receptor loss did not correspond to heterogeneities identified with acetylcholinesterase staining. Progressive loss of D 1 receptors in the internal globus pallidus and substantia nigra pars reticulata and D 2 receptors in the external globus pallidus corresponded to advancing pathologic grade.

Late Stage Huntington's Disease: Effect of Treating Specific Disabilities

Huntington's disease is an hereditary degenerative condition resulting, eventually, in physical and mental, behavioural and emotional disability. Four severely affected patients were included in a multiple-baseline, single-case experimental design study to test the hypothesis that occupational therapy for specific activities would Improve function in those activities. There was no evidence of improvement resulting from specific treatment of activities over the 8-month observation period. However, only one patient deteriorated and, therefore it is possible that the occupational therapy input had a generalised effect In preventing the deterioration of activities, it is concluded that, in the severe form of Huntington's disease, intensive therapy for specific activities does not result in Improvement and that a more general programme may be more productive.