Systematic review of drug therapy for chorea in NXK2-1-related disorders: Efficacy and safety evidence from case studies and series.

BACKGROUND: The NKX2-1-related disorders (NKX2-1-RD) is a rare disorder characterized by choreiform movements along with respiratory and endocrine abnormalities. The European Reference Network of Rare Neurological Disorders funded by the European Commission conducted a systematic review to assess drug treatment of chorea in NKX2-1-RD, aiming to provide clinical recommendations for its management. METHODS: A systematic pairwise review using various databases, including MEDLINE, Embase, Cochrane, CINAHL, and PsycInfo, was conducted. The review included patients diagnosed with chorea and NKX2-1-RD genetic diagnosis, drug therapy as intervention, no comparator, and outcomes of chorea improvement and adverse events. The methodological quality of the studies was assessed, and the study protocol was registered in PROSPERO. RESULTS: Of the 1417 studies examined, 28 studies met the selection criteria, consisting of 68 patients. The studies reported 22 different treatments for chorea, including carbidopa/levodopa, tetrabenazine, clonazepam, methylphenidate, carbamazepine, topiramate, trihexyphenidyl, haloperidol, propranolol, risperidone, and valproate. No clinical improvements were observed with carbidopa/levodopa, tetrabenazine, or clonazepam, and various adverse effects were reported. However, most patients treated with methylphenidate experienced improvements in chorea and reported only a few negative effects. The quality of evidence was determined to be low. CONCLUSIONS: The management of chorea in individuals with NKX2-1-RD presents significant heterogeneity and lack of clarity. While the available evidence suggests that methylphenidate may be effective in improving chorea symptoms, the findings should be interpreted with caution due to the limitations of the studies reviewed. Nonetheless, more rigorous and comprehensive studies are necessary to provide sufficient evidence for clinical recommendations.

Cell therapy in Huntington's disease: Taking stock of past studies to move the field forward.

Huntington's disease (HD) is a rare inherited neurodegenerative disease that manifests mostly in adulthood with progressive cognitive, behavioral, and motor dysfunction. Neuronal loss occurs predominantly in the striatum but also extends to other brain regions, notably the cortex. Most patients die around 20 years after motor onset, although there is variability in the rate of progression and some phenotypic heterogeneity. The most advanced experimental therapies currently are huntingtin-lowering strategies, some of which are in stage 3 clinical trials. However, even if these approaches are successful, it is unlikely that they will be applicable to all patients or will completely halt continued loss of neural cells in all cases. On the other hand, cellular therapies have the potential to restore atrophied tissues and may therefore provide an important complementary therapeutic avenue. Pilot studies of fetal cell grafts in the 2000s reported the most dramatic clinical improvements yet achieved for this disease, but subsequent studies have so far failed to identify methodology to reliably reproduce these results. Moving forward, a major challenge will be to generate suitable donor cells from (nonfetal) cell sources, but in parallel there are a host of procedural and trial design issues that will be important for improving reliability of transplants and so urgently need attention. Here, we consider findings that have emerged from clinical transplant studies in HD to date, in particular new findings emerging from the recent multicenter intracerebral transplant HD study, and consider how these data may be used to inform future cell therapy trials.

Annonaceae Consumption Worsens Disease Severity and Cognitive Deficits in Degenerative Parkinsonism.

BACKGROUND: High consumption of Annona muricata fruit has been previously identified as a risk factor for atypical parkinsonism in the French Caribbean islands. OBJECTIVE: We tested whether consumption of Annonaceae products could worsen the clinical phenotype of patients with any form of degenerative parkinsonism. METHODS: We analyzed neurological data from 180 Caribbean parkinsonian patients and specifically looked for dose effects of lifelong, cumulative Annonaceae consumption on cognitive performance. Using unsupervised clustering, we identified one cluster with mild/moderate symptoms (N = 102) and one with severe symptoms including cognitive impairment (N = 78). RESULTS: We showed that even low cumulative consumption of fruits/juices (>0.2 fruit-years) or any consumption of herbal tea from Annonaceae worsen disease severity and cognitive deficits in degenerative parkinsonism including Parkinson's disease (OR fruits-juices: 3.76 [95% CI: 1.13-15.18]; OR herbal tea: 2.91 [95% CI: 1.34-6.56]). CONCLUSION: We suggest that more restrictive public health preventive recommendations should be made regarding the consumption of Annonaceae products. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

An MDS Evidence-Based Review on Treatments for Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments. OBJECTIVES: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers. METHODS: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention. RESULTS: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments. CONCLUSIONS: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society.

A case-study of language-specific executive disorder.

Executive control is recruited for language processing, particularly in complex linguistic tasks. Although the issue of the existence of an executive control specific to language is still an open issue, there is much evidence that executively-demanding language tasks rely on domain-general rather than language-specific executive resources. Here, we addressed this issue by assessing verbal and non-verbal executive capacities in LG, an aphasic patient after a stroke. First, we showed that LG's performance was spared in all non-verbal tasks regardless of the executive demands. Second, by contrasting conditions of high and low executive demand in verbal tasks, we showed that LG was only impaired in verbal task with high executive demand. The performance dissociation between low and high executive demand conditions in the verbal domain, not observed in the non-verbal domain, shows that verbal executive control partly dissociates from non-verbal executive control. This language-specific executive disorder suggests that some executive processes might be language-specific.

Learning spectro-temporal representations of complex sounds with parameterized neural networks.

Deep learning models have become potential candidates for auditory neuroscience research, thanks to their recent successes in a variety of auditory tasks, yet these models often lack interpretability to fully understand the exact computations that have been performed. Here, we proposed a parametrized neural network layer, which computes specific spectro-temporal modulations based on Gabor filters [learnable spectro-temporal filters (STRFs)] and is fully interpretable. We evaluated this layer on speech activity detection, speaker verification, urban sound classification, and zebra finch call type classification. We found that models based on learnable STRFs are on par for all tasks with state-of-the-art and obtain the best performance for speech activity detection. As this layer remains a Gabor filter, it is fully interpretable. Thus, we used quantitative measures to describe distribution of the learned spectro-temporal modulations. Filters adapted to each task and focused mostly on low temporal and spectral modulations. The analyses show that the filters learned on human speech have similar spectro-temporal parameters as the ones measured directly in the human auditory cortex. Finally, we observed that the tasks organized in a meaningful way: the human vocalization tasks closer to each other and bird vocalizations far away from human vocalizations and urban sounds tasks.

Human Fetal Cell Therapy in Huntington's Disease: A Randomized, Multicenter, Phase II Trial.

BACKGROUND: Huntington's disease is a rare, severe, inherited neurodegenerative disease in which we assessed the safety and efficacy of grafting human fetal ganglionic eminence intrastriatally. METHODS: Patients at the early stage of the disease were enrolled in the Multicentric Intracerebral Grafting in Huntington's Disease trial, a delayed-start phase II randomized study. After a run-in period of 12 months, patients were randomized at month 12 to either the treatment group (transplanted at month 13-month 14) or the control group and secondarily treated 20 months later (month 33-month 34). The primary outcome was total motor score compared between both groups 20 months postrandomization (month 32). Secondary outcomes included clinical, imaging, and electrophysiological findings and a comparison of pregraft and postgraft total motor score slopes during the entire study period (month 0-month 52) regardless of the time of transplant. RESULTS: Of 54 randomized patients, 45 were transplanted; 26 immediately (treatment) and 19 delayed (control). Mean total motor score at month 32 did not differ between groups (treated controls difference in means adjusted for M12: +2.9 [95% confidence interval, -2.8 to 8.6]; P = 0.31). Its rate of decline after transplantation was similar to that before transplantation. A total of 27 severe adverse events were recorded in the randomized patients, 10 of which were related to the transplant procedure. Improvement of procedures during the trial significantly decreased the frequency of surgical events.We found antihuman leucocytes antigen antibodies in 40% of the patients. CONCLUSION: No clinical benefit was found in this trial. This may have been related to graft rejection. Ectopia and high track number negatively influence the graft outcome. Procedural adjustments substantially improved surgical safety. (ClinicalTrials.gov NCT00190450.) © 2020 International Parkinson and Movement Disorder Society.

Rating scales for cognition in Huntington's disease: Critique and recommendations.

Cognitive impairment is one of the main features of Huntington's disease and is present across the disease spectrum. As part of the International Parkinson's Disease and Movement Disorder Society-sponsored project to review all clinical rating scales used in Huntington's disease, a systematic review of the literature was performed to identify cognitive scales used in Huntington's disease and make recommendations for their use. A total of 17 cognitive scales were identified and evaluated. None of the scales met criteria for a "recommended" status. For assessing severity of cognitive dysfunction, the Montreal Cognitive Assessment was "recommended with caveats." The UHDRS Cognitive Assessment, the UHDRS-For Advanced Patients cognitive section, the Alzheimer's Disease Assessment Scale-Cognitive Subscale, the Frontal Assessment Battery, the Mattis Dementia Rating Scale, the Mini-Mental State Examination, and the Repeatable Battery for the Assessment of Neuropsychological Status were "suggested" for evaluating severity of cognitive impairment. The MoCA was "suggested" as a screening tool for cognitive impairment. The major challenge in the assessment of cognition in Huntington's disease is the lack of a formal definition of dementia and/or mild cognitive impairment in this disease. The committee concluded that there is a need to further validate currently available cognitive scales in Huntington's disease, but that it is premature to recommend the development of new scales. Recently developed Huntington's disease-specific scales, such as the Huntington's Disease-Cognitive Assessment Battery, hold promise but require the completion of more comprehensive clinimetric development. © 2017 International Parkinson and Movement Disorder Society.

A randomized, double-blind, placebo-controlled trial evaluating cysteamine in Huntington's disease.

BACKGROUND: Cysteamine has been demonstrated as potentially effective in numerous animal models of Huntington's disease. METHODS: Ninety-six patients with early-stage Huntington's disease were randomized to 1200 mg delayed-release cysteamine bitartrate or placebo daily for 18 months. The primary end point was the change from baseline in the UHDRS Total Motor Score. A linear mixed-effects model for repeated measures was used to assess treatment effect, expressed as the least-squares mean difference of cysteamine minus placebo, with negative values indicating less deterioration relative to placebo. RESULTS: At 18 months, the treatment effect was not statistically significant - least-squares mean difference, -1.5 ± 1.71 (P = 0.385) - although this did represent less mean deterioration from baseline for the treated group relative to placebo. Treatment with cysteamine was safe and well tolerated. CONCLUSIONS: Efficacy of cysteamine was not demonstrated in this study population of patients with Huntington's disease. Post hoc analyses indicate the need for definitive future studies. © 2017 International Parkinson and Movement Disorder Society.

Automatic segmentation of the striatum and globus pallidus using MIST: Multimodal Image Segmentation Tool.

Accurate segmentation of the subcortical structures is frequently required in neuroimaging studies. Most existing methods use only a T1-weighted MRI volume to segment all supported structures and usually rely on a database of training data. We propose a new method that can use multiple image modalities simultaneously and a single reference segmentation for initialisation, without the need for a manually labelled training set. The method models intensity profiles in multiple images around the boundaries of the structure after nonlinear registration. It is trained using a set of unlabelled training data, which may be the same images that are to be segmented, and it can automatically infer the location of the physical boundary using user-specified priors. We show that the method produces high-quality segmentations of the striatum, which is clearly visible on T1-weighted scans, and the globus pallidus, which has poor contrast on such scans. The method compares favourably to existing methods, showing greater overlap with manual segmentations and better consistency.

Rating scales for behavioral symptoms in Huntington's disease: Critique and recommendations.

Behavioral symptoms are an important feature of Huntington's disease and contribute to impairment in quality of life. The Movement Disorder Society commissioned the assessment of the clinimetric properties of rating scales in Huntington's disease to make recommendations regarding their use, following previously used standardized criteria. A systematic literature search was conducted to identify the scales used to assess behavioral symptoms in Huntington's disease. For the purpose of this review, 7 behavioral domains were deemed significant in Huntington's disease: irritability, anxiety, depression, apathy, obsessive-compulsive behaviors, psychosis, and suicidal ideation. We included a total of 27 behavioral rating scales, 19 of which were of a single behavioral domain and the remaining 8 scales included multiple behavioral domains. Three rating scales were classified as "recommended" exclusively for screening purposes: the Irritability Scale for irritability, the Beck Depression Inventory-II, and the Hospital Anxiety and Depression Scale for depression. There were no "recommended" scales for other purposes such as diagnosis, severity, or change in time or to treatment. The main challenges identified for assessment of behavioral symptoms in Huntington's disease are the co-occurrence of multiple behavioral symptoms, the particular features of a behavioral symptom in Huntington's disease, and the need to address stage- and disease-specific features, including cognitive impairment and lack of insight. The committee concluded that there is a need to further validate currently available behavioral rating scales in Huntington's disease to address gaps in scale validation for specific behavioral domains and purpose of use. © 2016 International Parkinson and Movement Disorder Society.

Pointing to others: How the target gender influences pointing performance.

Pointing is a communicative gesture that allows individuals to share information about surrounding objects with other humans. Patients with heterotopagnosia are specifically impaired in pointing to other humans' body parts but not in pointing to themselves or to objects. Here, we describe a female patient with heterotopagnosia who was more accurate in pointing to men's body parts than to women's body parts. We replicated this gender effect in healthy participants with faster reaction times for pointing to men's body parts than to women's body parts. We discuss the role of gender stereotypes in explaining why it is more difficult to point to women than to men.

Multiple brain networks underpinning word learning from fluent speech revealed by independent component analysis.

Although neuroimaging studies using standard subtraction-based analysis from functional magnetic resonance imaging (fMRI) have suggested that frontal and temporal regions are involved in word learning from fluent speech, the possible contribution of different brain networks during this type of learning is still largely unknown. Indeed, univariate fMRI analyses cannot identify the full extent of distributed networks that are engaged by a complex task such as word learning. Here we used Independent Component Analysis (ICA) to characterize the different brain networks subserving word learning from an artificial language speech stream. Results were replicated in a second cohort of participants with a different linguistic background. Four spatially independent networks were associated with the task in both cohorts: (i) a dorsal Auditory-Premotor network; (ii) a dorsal Sensory-Motor network; (iii) a dorsal Fronto-Parietal network; and (iv) a ventral Fronto-Temporal network. The level of engagement of these networks varied through the learning period with only the dorsal Auditory-Premotor network being engaged across all blocks. In addition, the connectivity strength of this network in the second block of the learning phase correlated with the individual variability in word learning performance. These findings suggest that: (i) word learning relies on segregated connectivity patterns involving dorsal and ventral networks; and (ii) specifically, the dorsal auditory-premotor network connectivity strength is directly correlated with word learning performance.

A cortical-subcortical syntax pathway linking Broca's area and the striatum.

Combinatorial syntax has been shown to be underpinned by cortical key regions such as Broca's area and temporal cortices, and by subcortical structures such as the striatum. The cortical regions are connected via several cortico-to-cortical tracts impacting syntactic processing (e.g., the arcuate) but it remains unclear whether and how the striatum can be integrated into this cortex-centered syntax network. Here, we used a systematic stepwise approach to investigate the existence and syntactic function of an additional deep Broca-striatum pathway. We first asked 15 healthy controls and 12 patients with frontal/striatal lesions to perform three syntax tests. The results obtained were subjected to voxel-based lesion-symptom mapping (VLSM) to provide an anatomo-functional approximation of the pathway. The significant VLSM clusters were then overlapped with the probability maps of four cortico-cortical language tracts generated for 12 healthy participants (arcuate, extreme capsule fiber system, uncinate, aslant), including a probabilistic Broca-striatum tract. Finally, we carried out quantitative analyses of the relationship between the lesion load along the tracts and syntactic processing, by calculating tract-lesion overlap for each patient and analyzing the correlation with syntactic data. Our findings revealed a Broca-striatum tract linking BA45 with the left caudate head and overlapping with VLSM voxel clusters relating to complex syntax. The lesion load values for this tract were correlated with complex syntax scores, whereas no such correlation was observed for the other tracts. These results extend current syntax-network models, by adding a deep "Broca-caudate pathway," and are consistent with functional accounts of frontostriatal circuits.

Reliability and factor structure of the Short Problem Behaviors Assessment for Huntington's disease (PBA-s) in the TRACK-HD and REGISTRY studies.

The authors report the inter-rater reliability and factor structure of the Short Problem Behaviors Assessment (PBA-s), a semistructured interview to measure severity and frequency of behavioral problems in Huntington's disease. Video recordings of 410 PBA-s interviews were rescored by an independent rater, and Cohen's kappa calculated to assess inter-rater reliability. The mean kappa was 0.74 for severity and 0.76 for frequency scores, whereas weighted kappa (allowing scores to differ by 1 point) was 0.94 for severity and 0.92 for frequency scores. The results of factor analysis were consistent with previous studies using other measures. The authors conclude that the PBA-s is a reliable measure.

Modifiable factors associated with Huntington's disease progression in presymptomatic participants.

OBJECTIVE: Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms. Our aim here was to identify factors that can be modified to slow disease progression even before the first symptoms appear. METHODS: We included 2636 presymptomatic individuals (comparison with family controls) drawn from the prospective observational cohort Enroll-HD, with more than 35 CAG repeats and at least two assessments of disease progression measured with the composite Huntington's disease rating Scale (cUHDRS). The association between sociodemographic factors, health behaviors, health history, and cUHDRS trajectory was assessed with a mixed-effects random forest using partial dependence plots and Shapley additive explanation method. RESULTS: Participants were followed by an average of 3.4 (SD = 1.97) years. We confirmed the negative impact of age and a high number of CAG repeats. We found that a high level of education, a body mass index (BMI) <23 kg/m2 before the age of 40 and >23 kg/m2 thereafter, alcohol consumption of <15 units per week, current coffee consumption and no smoking were linked to slow disease progression, as did no previous exposure to antidepressants or anxiolytic, no psychiatric history or comorbidities, and being female. Other comorbidities or marital status showed no major association with HD evolution. INTERPRETATION: Reducing modifiable risk factors for HD is one way to support the presymptomatic population. A high level of education, low-to-moderate alcohol consumption, no smoking, and BMI control are likely to slow disease progression in this population.

Insights from European Reference Network for rare neurological disorders study surveys on diagnosis, treatment, and management of NKX2-1-related disorders.

BACKGROUND: NKX2-1-related disorder (NKX2-1-RD) is a rare disease characterized by a triad of primary hypothyroidism, neonatal respiratory distress, and neurological features, including chorea. OBJECTIVE: This study aimed to identify discrepancies in the management of NKX2-1-RD among European Union (EU) specialists. METHODS: The ERN-RND Chorea & Huntington disease group designed a survey to conduct a cross-sectional multicenter study on the management of NKX2-1-RD. Descriptive analysis was performed, and total responses are presented for each item. RESULTS: The study involved 23 experts from 13 EU countries with experience in evaluating hyperkinetic patients with NKX2-1-RD: 11 were adult specialists, and 12 were pediatric specialists. NKX2-1-RD diagnosis was made at different ages, with the most common initial symptoms being hypotonia and/or motor developmental delay (reported by 11 experts) and chorea (reported by 8 experts). Chorea involved various body parts and showed improvement as reported by 9 experts, stabilization by 12 experts, and worsening by 2 experts with age. The pharmacological treatment of chorea varied widely among the experts. Misdiagnosis was reported by 14 experts. NKX2-1 pathogenic variants or deletions were confirmed in >75 % of patients (reported by 12 experts). Pulmonary and endocrinology evaluations were requested by 7 and 12 experts, respectively. The management of psychiatric comorbidities also varied among the different experts. CONCLUSIONS: This study highlights the need for a clinical practice guideline for the management of NKX2-1-RD to ensure that patients across the EU receive consistent and appropriate care. Such a guideline would benefit both doctors and healthcare practitioners.

Cognitive reserve involves decision making and is associated with left parietal and hippocampal hypertrophy in neurodegeneration.

Cognitive reserve is the ability to actively cope with brain deterioration and delay cognitive decline in neurodegenerative diseases. It operates by optimizing performance through differential recruitment of brain networks or alternative cognitive strategies. We investigated cognitive reserve using Huntington's disease (HD) as a genetic model of neurodegeneration to compare premanifest HD, manifest HD, and controls. Contrary to manifest HD, premanifest HD behave as controls despite neurodegeneration. By decomposing the cognitive processes underlying decision making, drift diffusion models revealed a response profile that differs progressively from controls to premanifest and manifest HD. Here, we show that cognitive reserve in premanifest HD is supported by an increased rate of evidence accumulation compensating for the abnormal increase in the amount of evidence needed to make a decision. This higher rate is associated with left superior parietal and hippocampal hypertrophy, and exhibits a bell shape over the course of disease progression, characteristic of compensation.

Graph methods to infer spatial disturbances: Application to Huntington's Disease's speech.

OBJECTIVE: Huntington's Disease (HD) is an inherited neurodegenerative disease caused by the mutation of the Htt gene, impacting all aspects of living and functioning. Among cognitive disabilities, spatial capacities are impaired, but their monitoring remains scarce as limited by lengthy experts' assessments. Language offers an alternative medium to evaluate patients' performance in HD. Yet, its capacities to assess HD's spatial abilities are unknown. Here, we aimed to bring proof-of-concept that HD's spatial deficits can be assessed through speech. METHODS: We developed the Spatial Description Model to graphically represent spatial relations described during the Cookie Theft Picture (CTP) task. We increased the sensitivity of our model by using only sentences with spatial terms, unlike previous studies in Alzheimer's disease. 78 carriers of the mutant Htt, including 56 manifest and 22 premanifest individuals, as well as 25 healthy controls were included from the BIOHD & (NCT01412125) & Repair-HD (NCT03119246) cohorts. The convergence and divergence of the model were validated using the SelfCog battery. RESULTS: Our Spatial Description Model was the only one among the four assessed approaches, revealing that individuals with manifest HD expressed fewer spatial relations and engaged in less spatial exploration compared to healthy controls. Their graphs correlated with both visuospatial and language SelfCog performances, but not with motor, executive nor memory functions. CONCLUSIONS: We provide the proof-of-concept using our Spatial Description Model that language can grasp HD patient's spatial disturbances. By adding spatial capabilities to the panel of functions tested by the language, it paves the way for eventual remote clinical application.