Predictive Modeling of Huntington's Disease Unfolds Thalamic and Caudate Atrophy Dissociation.

BACKGROUND: Atrophy in the striatum is a hallmark of Huntington's disease (HD), including the period before clinical motor diagnosis (before-CMD), but it extends to other subcortical structures. The study of the covariation of these structures could improve the detection of disease-related longitudinal progression before-CMD, provide mechanistic insights of the disease, and potentially be used to obtain accurate prospective estimates of atrophy before-CMD and early after-CMD. METHODS: We analyzed data from 337 before-CMD individuals, 236 healthy control subjects, and 95 early after-CMD individuals from three studies, and we used nine subcortical regions volumes in two analyses. First, we discriminated before-CMD from healthy control trajectories by integrating volume changes from these regions. Second, we estimated prospective atrophy before-CMD and early after-CMD by considering the influence of a region's present volume over the future volume of another one. RESULTS: Before-CMD progression was robustly detected across studies. Indeed, detection of before-CMD progression improved when multiple structures were integrated, as opposed to analyzing the striatum alone, likely because of the reduced partial correlation between caudate and thalamic volume change before-CMD. Our multivariate atrophy prediction model found a thalamus-caudate association that is consistent with this pattern, which yields an improved caudate atrophy prediction in early after-CMD. CONCLUSIONS: This study is the first attempt to validate before-CMD multivariate subcortical change detection across studies and to do multivariate prospective atrophy prediction in HD. These models achieve improved performance by detecting a dissociation between caudate and thalamic atrophy trajectories, and they provide a possible mechanistic understanding of the dynamics of HD. © 2022 International Parkinson and Movement Disorder Society.

Differentiation of Reversible Hemichorea Due to Vitamin B12 Deficiency From Huntington Disease Via FDG PET.

ABSTRACT: Vitamin B12 deficiency may present with diverse symptoms, complicating the differential diagnosis. Extrapyramidal movement disorders, for instance, are a rare manifestation of vitamin B12 deficiency. MRI of the brain frequently remains without conclusive findings. However, 18 F-FDG PET/CT may reveal characteristic changes in the metabolism of the basal ganglia and thus contribute to an accurate diagnosis. We demonstrate the case of a woman with left-sided hemichoreatic movements due to vitamin B12 deficiency showing a contralateral putaminal hypermetabolism, which normalized after vitamin B12 supplementation, ruling out other deviating causes, particularly Huntington disease.

An Australian Neuro-Palliative perspective on Huntington's disease: a case report.

BACKGROUND: Huntington's Disease (HD) is an incurable, progressive neuro-degenerative disease. For patients with HD access to palliative care services is limited, with dedicated Neuro-Palliative Care Services rare in Australia. We discuss the experiences of and benefits to a patient with late-stage HD admitted to our Neuro-Palliative Care service. CASE PRESENTATION: We present the case of a patient with a 16-year history of HD from time of initial genetic testing to admission to our Neuro-Palliative Care service with late-stage disease. CONCLUSIONS: Given the prolonged, fluctuating and heterogenous HD trajectory, measures need to be implemented to improve earlier access to multi-specialty integrative palliative care services. Given the good outcomes of our case, we strongly advocate for the role of specialised Neuro-Palliative Care services to bridge the gap between clinical need and accessibility.

Morphometric in vivo evidence of thalamic atrophy correlated with cognitive and motor dysfunction in Huntington's disease: The IMAGE-HD study.

In Huntington's disease (HD), neurodegeneration causes progressive atrophy to the striatum, cortical areas, and white matter tracts - components of corticostriatal circuitry. Such processes may affect the thalamus, a key circuit node. We investigated whether differences in dorsal thalamic morphology were detectable in HD, and whether thalamic atrophy was associated with neurocognitive, neuropsychiatric and motor dysfunction. Magnetic resonance imaging scans and clinical outcome measures were obtained from 34 presymptomatic HD (pre-HD), 29 early symptomatic HD (symp-HD), and 26 healthy control individuals who participated in the IMAGE-HD study. Manual region of interest (ROI) segmentation was conducted to measure dorsal thalamic volume, and thalamic ROI underwent shape analysis using the spherical harmonic point distribution method. The symp-HD group had significant thalamic volumetric reduction and global shape deflation, indicative of atrophy, compared to pre-HD and control groups. Thalamic atrophy significantly predicted neurocognitive and motor dysfunction within the symp-HD group only. Thalamic morphology differentiates symp-HD from pre-HD and healthy individuals. Thalamic changes may be one of the structural bases (endomorphotypes), of the endophenotypic neurocognitive and motor manifestations of disease. Future research should continue to investigate the thalamus as a potential in vivo biomarker of disease progression in HD.

The Role of Hypothalamic Pathology for Non-Motor Features of Huntington's Disease.

Huntington's disease (HD) is a fatal genetic neurodegenerative disorder. It has mainly been considered a movement disorder with cognitive symptoms and these features have been associated with pathology of the striatum and cerebral cortex. Importantly, individuals with the mutant huntingtin gene suffer from a spectrum of non-motor features often decades before the motor disorder manifests. These symptoms and signs include a range of psychiatric symptoms, sleep problems and metabolic changes with weight loss particularly in later stages. A higher body mass index at diagnosis is associated with slower disease progression. The common psychiatric symptom of apathy progresses with the disease. The fact that non-motor features are present early in the disease and that they show an association to disease progression suggest that unravelling the underlying neurobiological mechanisms may uncover novel targets for early disease intervention and better symptomatic treatment. The hypothalamus and the limbic system are important brain regions that regulate emotion, social cognition, sleep and metabolism. A number of studies using neuroimaging, postmortem human tissue and genetic manipulation in animal models of the disease has collectively shown that the hypothalamus and the limbic system are affected in HD. These findings include the loss of neuropeptide-expressing neurons such as orexin (hypocretin), oxytocin, vasopressin, somatostatin and VIP, and increased levels of SIRT1 in distinct nuclei of the hypothalamus. This review provides a summary of the results obtained so far and highlights the potential importance of these changes for the understanding of non-motor features in HD.

Suicidality in Huntington's Disease: A Qualitative Study on Coping Styles and Support Strategies.

BACKGROUND: Huntington's disease (HD) mutation carriers are at increased risk of suicidal ideation, suicide attempts, and completed suicide. However, research is lacking on coping strategies and treatment options that can be offered to suicidal HD mutation carriers. OBJECTIVE: This study explores how individuals with pre-motor or motor symptomatic HD cope with suicidality, how their partners support them, and their ideas and wishes regarding how relatives and healthcare professionals can help them in coping with suicidality. METHODS: This qualitative study included 11 HD mutation carriers who experienced suicidal ideation or attempted suicide and 3 of their partners. They participated in a focus group discussion or an individual in-depth interview. Two independent researchers fragmented the transcribed interviews, coded these fragments, grouped them under themes, and structured the data. RESULTS: HD study participants used four main strategies to cope with suicidality, including talking about suicidality, employing self-management activities, using medication, and discussing end-of-life wishes. Partners, relatives, and healthcare professionals can support suicidal HD mutation carriers in each of those four strategies. CONCLUSIONS: Despite the absence of a turnkey solution for suicidality in HD, healthcare professionals can play an important role in supporting suicidal HD mutation carriers by providing an opportunity to talk about suicidality, providing psychoeducation on self-management, prescribing medication, and discussing end-of-life wishes. Future HD-specific intervention studies could investigate the effect of combining these treatment strategies into one holistic approach.

Subjective sleep problems in Huntington's disease: A pilot investigation of the relationship to brain structure, neurocognitive, and neuropsychiatric function.

Subjective reports of sleep disturbance are a common feature of Huntington's disease (HD); however, there is limited research investigating the relationship between sleep problems with changes in brain and behaviour. This study aimed to investigate whether subjective reports of sleep problems in HD are associated with brain volume, neurocognitive decline, and neuropsychiatric symptoms. This retrospective pilot study used brain volume, neurocognitive and neuropsychiatric data from premanifest (pre-HD) and symptomatic HD (symp-HD). Subjective sleep problem was measured using the sleep item of the Beck's Depression Inventory-II (BDI-II). Pre-HD individuals reporting sleep problems had significantly poorer neuropsychiatric outcomes compared to those not reporting sleep problems. In the symp-HD group, those with sleep problems had significantly accelerated thalamic degeneration and poorer neuropsychiatric outcomes compared to those without sleep problems. There was no relationship between subjective sleep problems and neurocognitive measures. These findings suggest an association between subjective sleep disturbance, neuropathology, and development of neuropsychiatric symptoms in HD. Further studies using quantitative EEG-based monitoring of sleep in HD and changes in the brain and behaviour will be necessary to establish the causal nature of this relationship.

Therapeutic strategies for circadian rhythm and sleep disturbances in Huntington disease.

Aside from the well-known motor, cognitive and psychiatric signs and symptoms, Huntington disease (HD) is also frequently complicated by circadian rhythm and sleep disturbances. Despite the observation that these disturbances often precede motor onset and have a high prevalence, no studies are available in HD patients which assess potential treatments. In this review, we will briefly outline the nature of circadian rhythm and sleep disturbances in HD and subsequently focus on potential treatments based on findings in other neurodegenerative diseases with similarities to HD, such as Parkinson and Alzheimer disease. The most promising treatment options to date for circadian rhythm and sleep disruption in HD include melatonin (agonists) and bright light therapy, although further corroboration in clinical trials is warranted.

Caring for stoma patients with arthritis and mental incapacities.

Mental incapacities in the form of dementia, Parkinson's disease, Huntington's disease, and the physical incapacities of arthritis are difficult hurdles for an older patient who has to undergo stoma surgery, irrespective of the stoma being temporary or permanent. The loss of intellectual and physical function can cause significant deterioration in the patient's ability to carry out day-to-day activities and can also manifest itself in changes in social behaviour. Caring for these patients in the community will require the nurse to adjust the patient's care accordingly, and provide a holistic and more individualised care package that includes the support of the carer or spouse. This article discusses the ways in which community nurses can help the older stoma patient and carer.

Oral treatment with herbal formula B307 alleviates cardiac failure in aging R6/2 mice with Huntington's disease via suppressing oxidative stress, inflammation, and apoptosis.

Cardiac failure is often observed in aging patients with Huntington's disease (HD). However, conventional pharmacological treatments for cardiac failure in HD patients have rarely been studied. Chinese herbal medicines, especially combined herbal formulas, have been widely used to treat cardiac dysfunctions over the centuries. Thus, we assess whether oral treatment with herbal formula B307 can alleviate cardiac failure in transgenic mice with HD. After oral B307 or vehicle treatment for 2 weeks, cardiac function and cardiomyocytes in 12-week-old male R6/2 HD mice and their wild-type littermate controls (WT) were examined and then compared via echocardiography, immunohistochemistry, and Western blotting. We found that cardiac performance in aging R6/2 HD mice had significantly deteriorated in comparison with their WT (P<0.01). Cardiac expressions of superoxide dismutase 2 (SOD2) and B-cell lymphoma 2 (Bcl-2) in aging R6/2 HD mice were significantly lower than their WT (P<0.01), but cardiac expressions of tumor necrosis factor alpha (TNF-α), neurotrophin-3 (3-NT), 4-hydroxynonenal (4-HNE), Bcl-2-associated X protein (Bax), calpain, caspase 12, caspase 9, and caspase 3 of aging R6/2 HD mice were significantly higher than their WT (P<0.05). Furthermore, we found that cardiac performance in aging R6/2 HD mice had significantly improved under oral B307 treatment (P<0.05). Cardiac expressions of SOD2 and Bcl-2 of aging R6/2 HD mice were significantly higher under oral B307 treatment (P<0.01), but cardiac expressions of TNF-α, 3-NT, 4-HNE, Bax, calpain, caspase 12, caspase 9, and caspase 3 of aging R6/2 HD mice were significantly reduced under oral B307 treatment (P<0.05). Oral B307 treatment may briefly alleviate cardiac failure in aging HD R6/2 mice via suppressing cardiac oxidative stress, inflammation, and apoptosis. We suggested that the herbal formula B307 may be further developed as a potential health supplement for ameliorating cardiac failure associated with aging.

Respiratory muscle training on pulmonary and swallowing function in patients with Huntington's disease: a pilot randomised controlled trial.

OBJECTIVE: To examine the effects of 4-month of respiratory muscle training on pulmonary and swallowing function, exercise capacity and dyspnoea in manifest patients with Huntington's disease. DESIGN: A pilot randomised controlled trial. SETTING: Home based training program. PARTICIPANTS: Eighteen manifest Huntington's disease patients with a positive genetic test and clinically verified disease expression, were randomly assigned to control group (n=9) and training group (n=9). INTERVENTION: Both groups received home-based inspiratory (5 sets of 5 repetitions) and expiratory (5 sets of 5 repetitions) muscle training 6 times a week for 4 months. The control group used a fixed resistance of 9 centimeters of water, and the training group used a progressively increased resistance from 30% to 75% of each patient's maximum respiratory pressure. MAIN MEASURES: Spirometric indices, maximum inspiratory pressure, maximum expiratory pressure, six minutes walk test, dyspnoea, water-swallowing test and swallow quality of life questionnaire were assessed before, at 2 and 4 months after training. RESULTS: The magnitude of increases in maximum inspiratory (d=2.9) and expiratory pressures (d=1.5), forced vital capacity (d=0.8), forced expiratory volume in 1 second (d=0.9) and peak expiratory flow (d=0.8) was substantially greater for the training group in comparison to the control group. Changes in swallowing function, dyspnoea and exercise capacity were small (d ≤ 0.5) for both groups without substantial differences between groups. CONCLUSIONS: A home-based respiratory muscle training program appeared to be beneficial to improve pulmonary function in manifest Huntington's disease patients but provided small effects on swallowing function, dyspnoea and exercise capacity.

Striatal disorders dissociate mechanisms of enhanced and impaired response selection - Evidence from cognitive neurophysiology and computational modelling.

Paradoxically enhanced cognitive processes in neurological disorders provide vital clues to understanding neural function. However, what determines whether the neurological damage is impairing or enhancing is unclear. Here we use the performance of patients with two disorders of the striatum to dissociate mechanisms underlying cognitive enhancement and impairment resulting from damage to the same system. In a two-choice decision task, Huntington's disease patients were faster and less error prone than controls, yet a patient with the rare condition of benign hereditary chorea (BHC) was both slower and more error prone. EEG recordings confirmed significant differences in neural processing between the groups. Analysis of a computational model revealed that the common loss of connectivity between striatal neurons in BHC and Huntington's disease impairs response selection, but the increased sensitivity of NMDA receptors in Huntington's disease potentially enhances response selection. Crucially the model shows that there is a critical threshold for increased sensitivity: below that threshold, impaired response selection results. Our data and model thus predict that specific striatal malfunctions can contribute to either impaired or enhanced selection, and provide clues to solving the paradox of how Huntington's disease can lead to both impaired and enhanced cognitive processes.

Characteristics and occurrence of speech impairment in Huntington's disease: possible influence of antipsychotic medication.

Although motor speech impairment is a common manifestation of Huntington's disease (HD), its description remains limited. The aim of the current study was therefore to estimate the occurrence and characteristics of speech disorder in HD and to explore the influence of antipsychotic medication on speech performance. Speech samples, including reading passage and monologue, were acquired from 40 individuals diagnosed with HD and 40 age- and sex-matched healthy controls. Objective acoustic analyses were used to evaluate key aspects of speech including vowel articulation, intensity, pitch and timing. A predictive model was constructed to detect the occurrence and most prominent patterns of speech dysfunction in HD. We revealed that 93% of HD patients manifest some degree of speech impairment. Decreased number of pauses, slower articulation rate, imprecise vowel articulation and excess intensity variations were found to be the most salient patterns of speech dysfunction in HD. We further demonstrated that antipsychotic medication may induce excessive loudness and pitch variations perceptually resembling excess patterns of word stress, and may also accentuate general problems with speech timing. Additionally, antipsychotics induced a slight improvement of vowel articulation. Specific speech alterations observed in HD patients indicate that speech production may reflect the pathophysiology of the disease as well as treatment effects, and may therefore be considered a valuable marker of functional disability in HD.

Behavioral therapy reverses circadian deficits in a transgenic mouse model of Huntington's disease.

Progressive disruption of circadian rhythmicity associated with disturbance of the sleep-wake cycle is one of the most insidious symptoms of Huntington's disease (HD) and represents a critical management issue for both patients and their care takers. The R6/2 mouse model of HD shows a progressive disruption of the circadian rhythmicity at both behavioral and molecular levels, although the intrinsic cellular machinery that drives circadian rhythmicity in individual cells appears to be fundamentally intact. Circadian rhythms are controlled by a master clock located in the suprachiasmatic nuclei (SCN) and can be synchronized by light and non-photic factors such as exercise. Here, we aimed to test whether or not stimulating the SCN directly could prevent the loss of circadian rhythmicity in R6/2 mice. We used combinations of bright light therapy and voluntary exercise as our treatment regimes. We found that all treatments had some beneficial effects, as measured by delayed disintegration of the rest-activity rhythm and improved behavioral synchronization to the light-dark cycle. The best effects were observed in mice treated with a combination of bright light therapy and restricted periods of voluntary exercise. Neither the cause nor the consequence of deteriorating sleep-wake activity in HD patients is known. Nevertheless, our findings can be translated immediately to human patients with little cost or risk, since both light therapy and restricted exercise regimes are non-pharmacological interventions that are relatively easy to schedule. Improved circadian rhythmicity is likely to have beneficial knock-on effects on mood and general health in HD patients. Until effective treatments are found for HD, strategies that reduce deleterious effects of disordered physiology should be part of HD patient treatment programs.

Surface electromyograph activity of submental muscles during swallowing and expiratory muscle training tasks in Huntington's disease patients.

INTRODUCTION: Huntington's disease (HD) patients have difficulty in swallowing, leading to aspiration pneumonia, which is a major cause of death. It seems possible that submental muscles that are crucial for preventing an escape of a bolus into the airway, are affected by HD, but no previous studies have investigated this. OBJECTIVE: To assess surface electromyograph (sEMG) activity of submental muscles during swallowing and expiratory muscle training (EMT) tasks in HD patients in comparison to healthy volunteers. METHODS: sEMG activities of submental muscles during saliva, water swallowing, EMT tasks performed at 25% and 75% of maximum expiratory pressure were recorded and normalised by the sEMG activity during an effortful swallow in 17 early to mid stage HD patients and 17 healthy volunteers. RESULTS: sEMG activity was greater (p<0.05) during EMT tasks than saliva and water swallowing, but was not significantly different between groups for saliva, water swallowing and EMT at 25%. HD patients had lower sEMG activity for EMT at 75% (p<0.05). CONCLUSION: Decreases in submental muscle activity were not evident in HD patients except during EMT at 75%. This suggests that relative submental muscle weakness is observed only during a high intensity task in early to mid stage HD patients.

Suprachiasmatic nucleus neuropeptide expression in patients with Huntington's Disease.

STUDY OBJECTIVE: To study whether sleep and circadian rhythm disturbances in patients with Huntington's disease (HD) arise from dysfunction of the body's master clock, the hypothalamic suprachiasmatic nucleus. DESIGN: Postmortem cohort study. PATIENTS: Eight patients with HD and eight control subjects matched for sex, age, clock time and month of death, postmortem delay, and fixation time of paraffin-embedded hypothalamic tissue. MEASUREMENTS AND RESULTS: Using postmortem paraffin-embedded tissue, we assessed the functional integrity of the suprachiasmatic nucleus in patients with HD and control subjects by determining the expression of two major regulatory neuropeptides, vasoactive intestinal polypeptide and arginine vasopressin. Additionally, we studied melatonin 1 and 2 receptor expression. Compared with control subjects, the suprachiasmatic nucleus contained 85% fewer neurons immunoreactive for vasoactive intestinal polypeptide and 33% fewer neurons for arginine vasopressin in patients with HD (P = 0.002 and P = 0.027). The total amount of vasoactive intestinal polypeptide and arginine vasopressin messenger RNA was unchanged. No change was observed in the number of melatonin 1 or 2 receptor immunoreactive neurons. CONCLUSIONS: These findings indicate posttranscriptional neuropeptide changes in the suprachiasmatic nucleus of patients with HD, and suggest that sleep and circadian rhythm disorders in these patients may at least partly arise from suprachiasmatic nucleus dysfunction.

Survey of UK speech and language therapists' assessment and treatment practices for people with progressive dysarthria.

BACKGROUND: Dysarthria knowledge is predominantly impairment-based. As a result, speech and language therapists (SLTs) have traditionally adopted impairment-focused management practices. However, guidance for best practice suggests that SLTs should consider the client holistically, including the impact of dysarthria beyond the impairment. AIMS: To investigate the current assessment and treatment practices used by UK SLTs with clients with progressive dysarthria and to identify whether these satisfy the needs of SLTs in their everyday practice. To investigate the extent to which they consider oromotor abilities, intelligibility, functional communication, participation and interaction to be important regarding assessment and treatment decisions. To explore whether management decisions are affected by level of clinical experience or settings in which SLTs work. METHODS & PROCEDURES: An online survey of UK SLTs working with adults with progressive dysarthria. OUTCOMES & RESULTS: A total of 119 SLTs completed the survey. Respondents considered that targeting the levels of impairment, activity and participation are important in the management of clients with progressive dysarthria, as recommended by clinical guidelines and recent research. However a particularly high proportion of respondents reported the use of impairment-based assessments. Respondents reported lacking the necessary tools to target interaction in assessment and intervention. The intervention that respondents use with clients varies according to the progressive disorder and dysarthria severity. There is evidence for a trend that less experienced SLTs and those working predominantly in hospital-based settings focus on the impairment, whereas more SLTs with more experience and those based in predominantly community-based settings look beyond the impairment. CONCLUSIONS & IMPLICATIONS: The values held by SLTs match guideline recommendations for best practice, however the clinical reality is that the assessment of progressive dysarthria remains predominantly impairment-focused. New tools need to be developed and integrated into practice to target interaction in assessment and intervention, to reduce the gap between best practice recommendations and clinical reality. Ongoing research into the effectiveness of SLT intervention with clients with progressive dysarthria is required to guide clinical management decisions.

Deficits in selective attention in symptomatic Huntington disease: assessment using an attentional blink paradigm.

BACKGROUND: Impaired selective attention in Huntington disease (HD) may manifest as difficulty in identifying a single target embedded among a series of distractors in rapid serial visual presentation tasks. METHOD: We used an attentional blink (AB) paradigm to examine whether attentional control is impaired in symptomatic HD. Fourteen HD patients and 13 age-matched healthy controls performed a rapid serial visual presentation task in which 2 targets (T1 and T2) and numerous distractors were presented in rapid succession. We assessed the accuracy of T1 identification and the AB (impaired T2 detection after the correct identification of T1). RESULTS: Among the HD patients, identification of T1 was significantly impaired and AB was significantly larger but not longer. The HD patients also made significantly more random errors. CONCLUSIONS: Frontostriatal or frontoparietal dysfunction is likely to compromise attentional control in HD, such that well-masked and rapidly presented target stimuli are difficult to detect and identify, especially as the difficulty level increases. Although we previously reported no AB deficits in presymptomatic HD, with manifest disease we found that the progressive frontoparietal cortical changes compromise attentional control mechanisms.

Pharmacologic approaches to the treatment of Huntington's disease.

Huntington's disease (HD) is an inherited, progressive neurodegenerative disorder characterized by chorea, cognitive impairment, and behavioral disturbances. Despite advances in diagnosis and improved understanding of HD, treatment remains difficult due to challenging symptoms and a paucity of approved therapeutic interventions. Nonpharmacologic and pharmacologic strategies have been evaluated; regarding the latter, over 80 agents of various classes have been investigated in clinical trials or examined in case reports. Symptomatic treatment, however, is generally confined to antidopaminergic agents for motor dysfunction and antidepressants for mood disorders, while treatment for cognitive dysfunction remains vacant. Several different mechanisms to modify symptoms and disease progression have been targeted in clinical trials. This article reviews some of the more common pharmacologic treatments used for HD, discusses data regarding suboptimal agents that have been tested, and surveys treatments under investigation.