In vivo imaging of synaptic SV2A protein density in healthy and striatal-lesioned rats with [11C]UCB-J PET.

The number of functionally active synapses provides a measure of neural integrity, with reductions observed in neurodegenerative disorders. [11C]UCB-J binds to synaptic vesicle 2A (SV2A) transmembrane protein located in secretory vesicles. We aimed to assess [11C]UCB-J PET as an in vivo biomarker of regional cerebral synaptic SV2A density in rat lesion models of neurodegeneration. Healthy anesthetized rats had [11C]UCB-J PET and arterial blood sampling. We compared different models describing [11C]UCB-J brain uptake kinetics to determine its regional distribution. Blocking studies were performed with levetiracetam (LEV), an antiepileptic SV2A antagonist. Tracer binding was measured in rodent unilateral acute lesion models of Parkinsonism and Huntington's disease, induced with 6-hydroxydopamine (6-OHDA) and quinolinic acid (QA), respectively. [3H]UCB-J autoradiography was performed in postmortem tissue. Rat brain showed high and fast [11C]UCB-J uptake and washout with up to 80% blockade by LEV. [11C]UCB-J PET showed a 6.2% decrease in ipsilateral striatal SV2A binding after 6-OHDA and 39.3% and 55.1% decreases after moderate and high dose QA confirmed by autoradiography. In conclusion, [11C]UCB-J PET provides a good in vivo marker of synaptic SV2A density which can potentially be followed longitudinally along with synaptic responses to putative neuroprotective agents in models of neurodegeneration.

Psychiatric morbidity and poor follow-up underlie suboptimal functional and survival outcomes in Huntington's disease.

BACKGROUND: Huntington's disease (HD), an inherited, often late-onset, neurodegenerative disorder, is considered to be a rare, orphan disease. Research into its genetic correlates and services for those affected are inadequate in most low-middle income countries, including India. The apparent 'incurability' often deters symptomatic and rehabilitative care, resulting in poor quality of life and sub-optimal outcomes. There are no studies assessing disease burden and outcomes from India. METHODS: We attempted to evaluate individuals diagnosed to have HD at our tertiary-care center between 2013 and 2016 for clinical symptoms, functionality, mortality, follow up status through a structured interview, clinical data from medical records and UHDRS-TFC scoring. RESULTS: Of the 144 patients, 25% were untraceable, and another 17 (11.8%) had already died. Mean age at death and duration of illness at the time of death, were 53 years and 7 years respectively, perhaps due to suicides and other comorbidities at an early age. The patients who could be contacted (n = 81) were assessed for morbidity and total functional capacity (TFC). Mean CAG repeat length and TFC score were 44.2 and 7.5 respectively. Most individuals (66%) were in TFC stage I and II and could perhaps benefit from several interventions. The TFC score correlated inversely with duration of illness (p < 0.0001). The majority were being taken care of at home, irrespective of the physical and mental disability. There was a high prevalence of psychiatric morbidity (91%) including suicidal tendency (22%). Three of the 17 who died had committed suicide, and several other families reported suicidal history in other family members. Only about half the patients (57%) maintained a regular clinical follow-up. CONCLUSIONS: This study demonstrates the poor follow-up rates, significant suicidality and other psychiatric symptoms, sub-optimal survival durations and functional outcomes highlighting the need for holistic care for the majority who appear to be amenable to interventions.

The effects of cognitive behavioral and mindfulness-based therapies on psychological distress in patients with multiple sclerosis, Parkinson's disease and Huntington's disease: Two meta-analyses.

OBJECTIVE: Psychological distress has a high impact on quality of life in patients with multiple sclerosis (MS), Parkinson's disease (PD), and Huntington's disease (HD). Studies have shown that cognitive behavioral therapy (CBT) and mindfulness-based therapies (MBTs) are successful in reducing psychological distress in patients with anxiety, depressive, and chronic somatic disorders. We aimed to investigate the effectiveness of these therapies in MS, PD, and HD patients. METHODS: We performed a comprehensive literature search in PubMed, PsycINFO, Embase and the Cochrane Central Register of Controlled Trials up to March 2018. Randomized controlled trials (RCTs) investigating a CBT or MBT and reporting psychological outcome measures were included. Two separate meta-analyses were performed; one on studies comparing psychological therapy with a treatment as usual or waitlist condition and one on studies with active treatment control conditions. RESULTS: The first meta-analysis (N = 12 studies, 8 in MS and 4 in PD populations) showed a significant effect size of g = 0.51 in reducing psychological distress. The second meta-analysis (N = 7 studies, in MS populations) showed a mean effect size of g = 0.36. No RCTs were found in HD populations. The overall quality of the included studies was low and considerable heterogeneity was found. No evidence was found for publication bias. CONCLUSION: CBT and MBTs have a small to moderate effect on reducing psychological distress in patients with PD and MS. However, more research with better methodological quality and larger study samples is warranted, especially in HD patient populations.

Understandings of psychological difficulties in people with the Huntington's disease gene and their expectations of psychological therapy.

OBJECTIVES: This study sought to investigate how people who had tested positive for the Huntington's disease (HD) gene mutation understood and experienced psychological distress and their expectations of psychological therapy. DESIGN: A qualitative methodology was adopted involving semi-structured interviews and interpretative phenomenological analysis (IPA). METHOD: A total of nine participants (five women and four men) who had opted to engage in psychological therapy were recruited and interviewed prior to the start of this particular psychological therapeutic intervention. Interviews were transcribed verbatim and analysed using IPA whereby themes were analysed within and across transcripts and classified into superordinate themes. RESULTS: Three superordinate themes were developed: Attributing psychological distress to HD: 'you're blaming everything on that now'; Changes in attributions of distress over time: 'in the past you'd just get on with it'; and Approaching therapy with an open mind, commitment, and hope: 'a light at the end of the tunnel'. CONCLUSION: Understandings of psychological distress in HD included biological and psychological explanations, with both often being accepted simultaneously by the same individual but with biomedical accounts generally dominating. Individual experience seemed to reflect a dynamic process whereby people's understanding and experience of their distress changed over time. Psychological therapy was accepted as a positive alternative to medication, providing people with HD with hope that their psychological well-being could be enhanced. PRACTITIONER POINTS: People with the Huntington's disease gene mutation have largely biomedical understandings of their psychological distress. This largely biomedical understanding does not, however, preclude them for being interested in the potential gains resulting from psychological therapy. The mechanisms of psychological therapy should be explained in detail before therapy and explored along with current attributions of distress.

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice.

Pridopidine is currently under clinical development for Huntington disease (HD), with on-going studies to better characterize its therapeutic benefit and mode of action. Pridopidine was administered either prior to the appearance of disease phenotypes or in advanced stages of disease in the YAC128 mouse model of HD. In the early treatment cohort, animals received 0, 10, or 30 mg/kg pridopidine for a period of 10.5 months. In the late treatment cohort, animals were treated for 8 weeks with 0 mg/kg or an escalating dose of pridopidine (10 to 30 mg/kg over 3 weeks). Early treatment improved motor coordination and reduced anxiety- and depressive-like phenotypes in YAC128 mice, but it did not rescue striatal and corpus callosum atrophy. Late treatment, conversely, only improved depressive-like symptoms. RNA-seq analysis revealed that early pridopidine treatment reversed striatal transcriptional deficits, upregulating disease-specific genes that are known to be downregulated during HD, a finding that is experimentally confirmed herein. This suggests that pridopidine exerts beneficial effects at the transcriptional level. Taken together, our findings support continued clinical development of pridopidine for HD, particularly in the early stages of disease, and provide valuable insight into the potential therapeutic mode of action of pridopidine.

Ameliorating effect of Celastrus paniculatus standardized extract and its fractions on 3-nitropropionic acid induced neuronal damage in rats: possible antioxidant mechanism.

CONTEXT: Celastrus paniculatus Wild. (Celasteraceae) (CP) is a well-known Ayurvedic 'Medhya Rasayana' (nervine tonic), used extensively as a neuro-protective and memory enhancer, and in different central nervous system disorders. OBJECTIVE: To evaluate the effect of CP against 3-nitropropionic acid (3-NP) induced Huntington's disease (HD) like symptoms in Wistar male rats. MATERIALS AND METHODS: The ethanol extract of CP seeds (CPEE), prepared by maceration, was standardized on the basis of linoleic acid content (6.42%) using thin layer chromatography densitometric analysis. Protective effect of CPEE (100 and 200 mg/kg) and its various fractions, viz., petroleum ether (40 mg/kg), ethyl acetate (2.5 mg/kg), n-butanol (7 mg/kg) and aqueous (18 mg/kg), administered orally for 20 days, against 3-NP (10 mg/kg, i.p. for 14 days) was assessed by their effect on body weight, locomotor activity, grip strength, gait pattern and cognitive dysfunction and biochemical parameters for oxidative damage in the striatum and cortex regions of the brain. RESULTS: CPEE (100 and 200 mg/kg) treated animals exhibited a significant (p < 0.05) improvement in behavioural and oxidative stress parameters in comparison to only 3-NP treated animals. Amongst various tested fractions of CPEE, aqueous fraction (AF) at 18 mg/kg exhibited maximum reversal of 3-NP induced behavioural and biochemical alterations, and was therefore also tested at 9 and 36 mg/kg. CPEE (100 mg/kg) and AF (36 mg/kg) exhibited maximum and significant (p < 0.05) attenuation of 3-NP induced alterations in comparison to 3-NP treated rats. CONCLUSIONS: CPEE has a protective action against 3-NP induced HD like symptoms due to its strong antioxidant effect.

Development of the Music Therapy Assessment Tool for Advanced Huntington's Disease: A Pilot Validation Study.

BACKGROUND: Case studies of people with Huntington's disease (HD) report that music therapy provides a range of benefits that may improve quality of life; however, no robust music therapy assessment tools exist for this population. OBJECTIVE: Develop and conduct preliminary psychometric testing of a music therapy assessment tool for patients with advanced HD. METHODS: First, we established content and face validity of the Music Therapy Assessment Tool for Advanced HD (MATA-HD) through focus groups and field testing. Second, we examined psychometric properties of the resulting MATA-HD in terms of its construct validity, internal consistency, and inter-rater and intra-rater reliability over 10 group music therapy sessions with 19 patients. RESULTS: The resulting MATA-HD included a total of 15 items across six subscales (Arousal/Attention, Physical Presentation, Communication, Musical, Cognition, and Psychological/Behavioral). We found good construct validity (r ≥ 0.7) for Mood, Communication Level, Communication Effectiveness, Choice, Social Behavior, Arousal, and Attention items. Cronbach's α of 0.825 indicated good internal consistency across 11 items with a common focus of engagement in therapy. The inter-rater reliability (IRR) Intra-Class Coefficient (ICC) scores averaged 0.65, and a mean intra-rater ICC reliability of 0.68 was obtained. Further training and retesting provided a mean of IRR ICC of 0.7. CONCLUSION: Preliminary data indicate that the MATA-HD is a promising tool for measuring patient responses to music therapy interventions across psychological, physical, social, and communication domains of functioning in patients with advanced 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.

Supporting physical activity engagement in people with Huntington's disease (ENGAGE-HD): study protocol for a randomized controlled feasibility trial.

BACKGROUND: Huntington's disease (HD) is a complex, single-gene inherited neurodegenerative condition resulting in symptoms that occur across a wide range of neurological domains, including cognitive, behavioral and motor. The benefits of regular physical activity for people with HD are widely recognized. However, a number of factors can prohibit sustained exercise and activity. The purpose of this trial is to explore the feasibility, acceptability and effectiveness of a physical activity intervention program targeted for people with early- to mid-stage HD. METHODS/DESIGN: The proposed trial is a single blind, multisite, exploratory, randomized controlled feasibility trial of a physical activity intervention. A total of 62 participants with genetically confirmed HD will be recruited. Each participant will be involved in the trial for 26 weeks. Participants will be randomized immediately following the baseline assessment into either a physical activity intervention or a social contact control intervention. The physical activity intervention is framed around self-determination theory placed within a broader behaviour change wheel framework. An HD-specific workbook and individual goal setting will be utilized over six 1:1 sessions, with interim telephone calls. All participants will be reassessed at 16 weeks following the baseline assessment, and then again at a final follow-up assessment 26 weeks later. At the end of the study, all participants will be offered a brief version of the alternative intervention, with one home visit and one follow-up telephone call. DISCUSSION: Engaging and supporting people with HD in a regular physical activity program raises a number of challenges. The physical activity intervention and the comparator social interaction intervention have been developed following consultation with people with HD and their families. Each are individually tailored and determined on individual needs and goals. The results from this trial will provide guidance for the development of definitive trials. TRIAL REGISTRATION: The trial was registered with ISRCTN ( http://www.isrctn.com/ISRCTN65378754) on 13 March 2014.

Curcumin nanoparticles attenuate neurochemical and neurobehavioral deficits in experimental model of Huntington's disease.

Till date, an exact causative pathway responsible for neurodegeneration in Huntington's disease (HD) remains elusive; however, mitochondrial dysfunction appears to play an important role in HD pathogenesis. Therefore, strategies to attenuate mitochondrial impairments could provide a potential therapeutic intervention. In the present study, we used curcumin encapsulated solid lipid nanoparticles (C-SLNs) to ameliorate 3-nitropropionic acid (3-NP)-induced HD in rats. Results of MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay and succinate dehydrogenase (SDH) staining of striatum revealed a marked decrease in Complex II activity. However, C-SLN-treated animals showed significant increase in the activity of mitochondrial complexes and cytochrome levels. C-SLNs also restored the glutathione levels and superoxide dismutase activity. Moreover, significant reduction in mitochondrial swelling, lipid peroxidation, protein carbonyls and reactive oxygen species was observed in rats treated with C-SLNs. Quantitative PCR and Western blot results revealed the activation of nuclear factor-erythroid 2 antioxidant pathway after C-SLNs administration in 3-NP-treated animals. In addition, C-SLN-treated rats showed significant improvement in neuromotor coordination when compared with 3-NP-treated rats. Thus, the results of this study suggest that C-SLNs administration might be a promising therapeutic intervention to ameliorate mitochondrial dysfunctions in HD.

Neuroprotective effect of lutein against 3-nitropropionic acid-induced Huntington's disease-like symptoms: possible behavioral, biochemical, and cellular alterations.

3-Nitropropionic acid (3-NP) induces cellular energy deficit and oxidative stress-related neurotoxicity via an irreversible inhibition of mitochondrial complex II enzyme, succinate dehydrogenase. Huntington's disease (HD) is a neurological disorder characterized by cognitive and motor dysfunctions. Lutein is a well-known antioxidant used in the management of oxidative stress related diseases. Clinical trials have supported the beneficial effect of lutein in Alzheimer's disease. The present study was designed to explore possible neuroprotective effects of lutein on 3-NP-induced mitochondrial dysfunction and oxidative stress. Systemic administration of 3-NP (25 mg/kg intraperitoneally [i.p.] for 4 consecutive days) caused loss of body weight and neurobehavioral deficits by hind-limb impairment (Narrow Beam test), motor coordination (locomotor activity) and memory dysfunction (Morris water maze and Elevated Plus maze performance). Biochemical analysis revealed significant increase in lipid peroxidation, nitrite concentration, reduced gutathione levels, and acetyl cholinesterase levels and depleted catalase activities in rat brain. The activities of mitochondrial complexes (I, II, IV, and MTT assay) were found to be significantly lowered in brain mitochondria. Daily lutein (50 or 100 mg/kg orally [p.o.]) administration for 14 days significantly improved body weight, neurobehavioral alterations and attenuated oxidative stress and improved mitochondrial enzymes complex activities of rat brain. Histopathological examination further affirmed the neuroprotective effect of lutein on 3-NP induced pathological lesions. The present study indicates that lutein is a promising candidate for the management of HD and related conditions.

Huntington's disease and the law.

Huntington's disease (HD) is a relentlessly progressive and fatal neurological condition that is inherited. It has serious and disabling physical and mental components. As such, it impacts upon those who have HD, those with the potential to inherit it, and those who care for those with HD in a wide variety of ways. These can have many legal ramifications including in relation to evolving impairments of capacity which can have an outcome in terms of involuntary status as mental health patients, testamentary capacity and the need for guardianship and administration. It can have effects upon fitness for parenting, obligations for spousal maintenance, and the quantum of compensation from a tortious incident to which a person is entitled. It has repercussions for criminal liability and culpability. This article reviews case law from a number of countries in relation to such matters, noting the broader radiation to others of the effects of HD, and reflecting on the need for legal and medical professionals to be aware of the legal consequences of HD for them to be able to discharge their responsibilities holistically, sensitively and informedly.

Personal factors associated with reported benefits of Huntington disease family history or genetic testing.

AIMS: A family history of Huntington disease (HD) or receiving results of HD predictive genetic testing can influence individual well-being, family relationships, and social interactions in positive and negative ways. The aim of this study was to examine benefits reported by people with an HD family history or those who have undergone predictive HD testing, as well as the personal variables associated with perceived benefits. METHODS: Seventy-four of 433 people completing the International Response of a Sample Population to HD risk (I-RESPOND-HD) survey reported benefits. Knowledge and understanding was perceived as the most common benefit from participants in both groups. The next most frequent perceived benefits from a family history were connecting with others and achieving life meaning and insights. The next most common perceived benefits from genetic testing were life planning and social support. The least common perceived benefit for both groups was renewed hope and optimism. Older age and spirituality were significantly associated with benefits in both groups. CONCLUSIONS: Perceptions of benefit may not be as likely until later years in people with prodromal HD. A developed sense of spirituality is identified as a personal resource associated with the perception of benefit from genetic testing for HD. Associations among spirituality, perceived benefits, and other indicators of personal and family well-being may be useful in genetic counseling and health care of people with prodromal HD.

Ripples from a stone skipping across the lake: a narrative approach to the meaning of Huntington's disease.

Huntington's disease (HD) is a progressive neurogenetic disorder that has a 50% inheritance rate. The ability to have 100% confirmation of the illness became a reality with the discovery of the gene in 1993. The effect of confirmatory testing and the issues faced by the individual and the family facing diagnosis have not been addressed. The purpose of this research study was to explore the meaning of being diagnosed with HD using narrative inquiry. Ten participants, during the first year of diagnosis, were asked to tell their story of what it meant to be diagnosed with HD. A holistic-content approach was used for data analysis. An integrated narrative, "The Story of HD: Ripples From a Stone Skipping Across the Lake," was created from the stories. The stories were analyzed for plot, predicaments, protagonist, and antagonist. The predicaments of "discovering the existence of HD," "confirming the diagnosis of HD," "revealing the diagnosis to others," and "experiencing the reverberations of HD" served as the main chapters that formed the structure of the stories. Each predicament contains a set of themes that function as subheadings for the chapters. In the final chapter or epilogue, participants were asked to reflect on the meaning of being diagnosed with HD. The psychological impact of receiving a positive genetic diagnosis has implications for patients and their extended families. Nurses should develop their understanding of the role of genetics in healthcare today. Clinical evaluations of the effectiveness of treatments and assessment for changes in mood, behavior, and motor function are an essential part of nursing care. Advocacy and supportive roles must be incorporated into the patient visit. Patient education material on home safety, nutrition, medication management, and general health practices should be provided during the outpatient visits. Through the development of a more comprehensive role, the nurse can assist patients and families in finding the personal meaning of being diagnosed.

Premorbid combat related ptsd in Huntington's disease - Case report.

Huntington's disease (HD) is a neurodegenerative, autosomal dominant disease that manifests with a triad of symptom clusters including movement disorder, cognitive impairment and psychiatric symptoms. We present a patient with HD who, prior to developing neurological signs and symptoms, had been exposed to war trauma and had developed posttraumatic stress disorder. Fifteen years later he manifested with dysarthria, difficulties with swallowing and involuntary movement. What brought him to psychiatrist was a heteroanamnestically noticed change in personality with irritable mood, impulsivity, aggressive outbursts in behavior and delusional ideation. Therapy was stared with haloperidol, but patient developed severe extrapiramidal side effects. Subsequent treatment with olanzapine, diazepam and omega 3 fatty acids lead to mood stabilization and better impulse control with even some improvement in motoric symptoms. To our knowledge, this is the first case report on combat related PTSD as psychiatric disorder manifested prior to HD. We discuss a possible influence of psychological stress disorder on severity of psychiatric symptoms in the HD. The importance of personalized approach in both psychopharmacological and psychotherapeutical treatment of patients with HD is emphasized. If the influence of environmental stress on the psychiatric phenotype of the disease should be confirmed by clinical trials and further studies, both screening methods and interventions aimed to reduce psychological stress in carriers of Huntington gene could be considered.

Huntington's disease: pathogenesis to animal models.

Huntington's disease (HD) is an inherited genetic disorder, characterized by cognitive dysfunction and abnormal body movements called chorea. George Huntington, an Ohio physician, described the disease precisely in 1872. HD is a dominantly inherited disorder, characterized by progressive neurodegeneration of the striatum but also involves other regions, primarily the cerebral cortex. The mutation responsible for this fatal disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding the huntingtin protein. Various hypotheses have been put forward to explain the pathogenic mechanisms of mutant huntingtin-induced neuronal dysfunction and cell death. None of these hypotheses, however, offers a clear explanation; thus, it remains a topic of research interest. HD is considered to be an important disease, embodying many of the major themes in modern neuroscience, including molecular genetics, selective neuronal vulnerability, excitotoxicity, mitochondrial dysfunction, apoptosis and transcriptional dysregulation. A number of recent reports have concluded that oxidative stress plays a key role in HD pathogenesis. Although there is no specific treatment available to block disease progression, treatments are available to help in controlling the chorea symptoms. As animal models are the best tools to evaluate any therapeutic agent, there are also different animal models available, mimicking a few or a larger number of symptoms. Each model has its own advantages and limitations. The present review deals with the pathophysiology and various cascades contributing to HD pathogenesis and progression as well as drug targets, such as dopaminergic, gamma-amino butyric acid (GABA)ergic, glutamate adenosine receptor, peptidergic pathways, cannabinoid receptor, and adjuvant therapeutic drug targets such as oxidative stress and mitochondrial dysfunction that can be targeted for future experimental study. The present review also focuses on the animal models (behavioral and genetic) used to unravel pathogenetic mechanisms and the identification of novel drug targets.

The processing of emotion in patients with Huntington's disease: variability and differential deficits in disgust.

BACKGROUND: Some studies of emotion recognition in Huntington's disease (HD) have not supported early reports of selective impairment in the recognition of facial expressions of disgust. This inconsistency could imply that loss of disgust is not a feature of all patients with this disease. OBJECTIVES: This study examined whether disproportionate impairment in the recognition of disgust was present in some HD patients and not in others. Second, we examined whether patients unable to recognize facial disgust had parallel impairments in other aspects of the emotion. METHOD: Fourteen HD patients and 14 age-matched healthy controls and education-matched healthy controls were first assessed on facial emotion recognition, with follow-up of individual-level analyses on patients D.W. and M.J. RESULTS: Although the group-level analyses revealed a broad profile of impaired recognition of negative emotions, individual-level analyses revealed a selective impairment of disgust in 47% of HD patients and of fear in 13%. Cross-modal impairments were only present for disgust, and then only in D.W. and M.J., who were unable to recognize disgust faces and had differential deficits on other emotion tasks: auditory recognition of vocal disgust expressions, matching the label "disgust" to a picture of a disgusting scene, and semantic knowledge of disgust elicitors. CONCLUSION: The findings support the view that impairment in the recognition of disgusted facial expressions may reflect processes involving the central aspects of disgust knowledge.

Cortical dysfunction in patients with Huntington's disease during working memory performance.

Previous functional neuroimaging studies on executive function suggested multiple functionally aberrant cortical regions in patients with Huntington's disease (HD). However, little is known about the neural mechanisms of working memory (WM) function in this patient population. The objective of this study was to investigate the functional neuroanatomy of WM in HD patients. We used event-related functional magnetic resonance imaging and a parametric verbal WM task to investigate cerebral function during WM performance in 16 healthy control subjects and 12 mild to moderate stage HD patients. We excluded incorrectly performed trials to control for potential accuracy-related activation confounds. Voxel-based morphometry (VBM) was used to control for confounding cortical and subcortical atrophy. We found that HD patients were slower and less accurate than healthy controls across all WM load levels. In addition, HD patients showed lower activation in the left dorso- and ventrolateral prefrontal cortex, the left inferior parietal cortex, the left putamen, and the right cerebellum at high WM load levels only. VBM revealed gray matter differences in the bilateral caudate nucleus and the thalamus, as well as in inferior parietal and right lateral prefrontal regions. However, volumetric abnormalities in the patient group did not affect the activation differences obtained during WM task performance. These findings demonstrate that WM-related functional abnormalities in HD patients involve distinct WM network nodes associated with cognitive control and subvocal rehearsal. Moreover, aberrant cortical function in HD patients may occur in brain regions, which are relatively well preserved in terms of brain atrophy.

Striatal degeneration impairs language learning: evidence from Huntington's disease.

Although the role of the striatum in language processing is still largely unclear, a number of recent proposals have outlined its specific contribution. Different studies report evidence converging to a picture where the striatum may be involved in those aspects of rule-application requiring non-automatized behaviour. This is the main characteristic of the earliest phases of language acquisition that require the online detection of distant dependencies and the creation of syntactic categories by means of rule learning. Learning of sequences and categorization processes in non-language domains has been known to require striatal recruitment. Thus, we hypothesized that the striatum should play a prominent role in the extraction of rules in learning a language. We studied 13 pre-symptomatic gene-carriers and 22 early stage patients of Huntington's disease (pre-HD), both characterized by a progressive degeneration of the striatum and 21 late stage patients Huntington's disease (18 stage II, two stage III and one stage IV) where cortical degeneration accompanies striatal degeneration. When presented with a simplified artificial language where words and rules could be extracted, early stage Huntington's disease patients (stage I) were impaired in the learning test, demonstrating a greater impairment in rule than word learning compared to the 20 age- and education-matched controls. Huntington's disease patients at later stages were impaired both on word and rule learning. While spared in their overall performance, gene-carriers having learned a set of abstract artificial language rules were then impaired in the transfer of those rules to similar artificial language structures. The correlation analyses among several neuropsychological tests assessing executive function showed that rule learning correlated with tests requiring working memory and attentional control, while word learning correlated with a test involving episodic memory. These learning impairments significantly correlated with the bicaudate ratio. The overall results support striatal involvement in rule extraction from speech and suggest that language acquisition requires several aspects of memory and executive functions for word and rule learning.