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Background Huntington’s disease (HD) is a rare neurodegenerative disease that causes progressive cognitive, physical, and psychiatric symptoms. Computerised cognitive training (CCT) is a novel intervention that aims to improve and maintain cognitive functions through repeated practice. The effects of CCT have yet to be established in HD. This randomised pilot trial examined the feasibility of a large scale trial to assess efficacy of multidomain CCT in pre-manifest and early-stage HD. Methods 28 participants were randomised to either at-home CCT (2 × 60 min sessions per week for 12 weeks; n  = 13) or lifestyle education through monthly newsletters (n  = 15). Participants completed cognitive tasks and questionnaires at baseline and follow up, either in person ( n  = 18) or via video teleconferencing ( n  = 10). Results All participants were retained at follow up, and adherence to CCT ranged from 96 to 100%, with 11/13 participants completing all sessions. Preliminary analyses showed evidence of a large effect of CCT on task switching and response inhibition, compared to lifestyle education. There was no evidence of specific benefit to other cognitive domains (processing speed, basic and divided attention, working memory), or psychosocial functions (subjective cognition, mood, health-related quality of life). Discussion Whilst retention and adherence rates were high, recruitment rates were low, suggesting that a large scale trial may be feasible with some modifications to increase recruitment rates, such as by reducing time burden associated with the study, and using a multi-site trial design. Potential effects on cognitive functioning warrant further investigation. Clinical trial registration : The trial was prospectively registered on the Australian New Zealand Clinical Trials Registry (ACTRN12622000908730).

Background Cognitive impairment is a core feature of Huntington’s disease (HD), yet no disease-modifying or symptomatic interventions have demonstrated efficacy in addressing these deficits. Non-pharmacological interventions, particularly cognitive training (CT), are promising options for maintaining neural plasticity, enhancing cognition, and improving emotional well-being. Methods This 24-week, single-center, randomized, single-blind study evaluated the safety and efficacy of two cognitive rehabilitation strategies in early-to-middle-stage HD patients. Participants were randomized into a computerized cognitive training (CT; n  = 13) intervention or a music therapy (MT; n  = 16) intervention. A standard of care (SoC; n  = 15) group with no active intervention was also involved. Weekly 45-min sessions were conducted. Baseline and endpoint assessments included measures of global cognition, functional, motor, and neuropsychiatric assessments, along with structural and functional neuroimaging. Results Both CT and MT groups demonstrated significant improvements in primary and secondary cognitive endpoints, including global cognition an composite measures of disease severity. Regression analysis identified longitudinal cognitive score changes as independent predictors of the rate of atrophy in the caudate, putamen, and inferior frontal gyrus. Functional connectivity analysis showed distinct intervention-related effects: CT group exhibited increased connectivity between the central executive and sensorymotor networks, while MT group reduced aberrant connectivity between the central executive and the default-mode network. Conclusion This is the first randomized-controlled trial to evaluate two cognitive rehabilitation strategies in HD using multimodal neuroimaging. Both interventions were effective in improving cognition and modulating structural and functional brain changes in regions critical to HD. Trial Registration ClinicalTrials.gov (ID: NCT05769972).

TRACK-HD is a multinational prospective observational study of Huntington's disease (HD) that examines clinical and biological findings of disease progression in individuals with premanifest HD (preHD) and early-stage HD. We aimed to describe phenotypic changes in these participants over 36 months and identify baseline predictors of progression. Individuals without HD but carrying the mutant huntingtin gene (classed as preHD-A if ≥10·8 years and preHD-B if <10·8 years from predicted onset), participants with early HD (classed as HD1 if they had a total functional capacity score of 11–13 and HD2 if they had a score of 7–10), and healthy control individuals were assessed at four study sites in the Netherlands, the UK, France, and Canada. We measured 36-month change for 3T MRI, clinical, cognitive, quantitative motor, and neuropsychiatric assessments and examined their prognostic value. We also assessed the relation between disease progression and the combined effect of CAG repeat length and age. All participants were analysed according to their baseline subgroups. Longitudinal results were analysed using a combination of repeated-measure weighted least squares models and, when examining risk of new diagnosis, survival analysis. At baseline, 366 participants were enrolled between Jan 17, and Aug 26, 2008, and of these 298 completed 36-month follow-up: 97 controls, 58 participants with preHD-A, 46 with preHD-B, 66 with HD1, and 31 with HD2. In the preHD-B group, several quantitative motor and cognitive tasks showed significantly increased rates of decline at 36 months, compared with controls, whereas few had at 24 months. Of the cognitive measures, the symbol digit modality test was especially sensitive (adjusted mean loss 4·11 points [95% CI 1·49–6·73] greater than controls; p=0·003). Among psychiatric indicators, apathy ratings specifically showed significant increases (0·34 points [95% CI 0·02–0·66] greater than controls; p=0·038). There was little evidence of reliable change in non-imaging measures in the preHD-A group, with the exception of the speeded tapping inter-tap interval (0·01 s [95% CI 0·01–0·02] longer than controls; p=0·0001). Several baseline imaging, quantitative motor, and cognitive measures had prognostic value, independent of age and CAG repeat length, for predicting subsequent clinical diagnosis in preHD. Of these, grey-matter volume and inter-tap interval were particularly sensitive (p=0·013 and 0·002, respectively). Longitudinal change in these two measures was also greater in participants with preHD who received a diagnosis of HD during the study compared with those who did not, after controlling for CAG repeat length and age-related risk (p=0·006 and 0·0003, respectively). In early HD, imaging, quantitative motor, and cognitive measures were predictive of decline in total functional capacity and tracked longitudinal change; also, neuropsychiatric changes consistent with frontostriatal pathological abnormalities were associated with this loss of functional capacity (problem behaviours assessment composite behaviour score p<0·0001). Age and CAG repeat length explained variance in longitudinal change of multimodal measures, with the effect more prominent in preHD. We have shown changes in several outcome measures in individuals with preHD over 36 months. These findings further our understanding of HD progression and have implications for clinical trial design. CHDI Foundation.

Previous trials have shown that pridopidine might reduce motor impairment in patients with Huntington's disease. The aim of this study was to ascertain whether higher doses of pridopidine than previously tested reduce motor symptoms in a dose-dependent manner while maintaining acceptable safety and tolerability. PRIDE-HD was a randomised, placebo-controlled, phase 2, dose-ranging study in adults (aged ≥21 years) with Huntington's disease at outpatient clinics in 53 sites across 12 countries (Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, the Netherlands, the UK, and the USA). Eligible patients had clinical onset after age 18 years, 36 or more cytosine-adenine-guanine repeats in the huntingtin gene, motor symptoms (Unified Huntington's Disease Rating Scale total motor score [UHDRS-TMS] ≥25 points), and reduced independence (UHDRS independence score ≤90%). Patients were randomly assigned (1:1:1:1:1) with centralised interactive-response technology to receive one of four doses of pridopidine (45, 67·5, 90, or 112·5 mg) or placebo orally twice a day for 52 weeks. Randomisation was stratified within centres by neuroleptic drug use. The primary efficacy endpoint was change in the UHDRS-TMS from baseline to 26 weeks, which was assessed in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment (full analysis set). Participants and investigators were masked to treatment assignment. This trial is registered with EudraCT (2013-001888-23) and ClinicalTrials.gov (NCT02006472). Between Feb 13, 2014, and July 5, 2016, 408 patients were enrolled and randomly assigned to receive placebo (n=82) or pridopidine 45 mg (n=81), 67·5 mg (n=82), 90 mg (n=81), or 112·5 mg (n=82) twice daily for 26 weeks. The full analysis set included 397 patients (81 in the placebo group, 75 in the 45 mg group, 79 in the 67·5 mg group, 81 in the 90 mg group, and 81 in the 112·5 mg group). Pridopidine did not significantly change the UHDRS-TMS at 26 weeks compared with placebo at any dose. The most frequent adverse events across all groups were diarrhoea, vomiting, nasopharyngitis, falls, headache, insomnia, and anxiety. The most common treatment-related adverse events were insomnia, diarrhoea, nausea, and dizziness. Serious adverse events occurred in the pridopidine groups only and were most frequently falls (n=5), suicide attempt (n=4), suicidal ideation (n=3), head injury (n=3), and aspiration pneumonia (n=3). No new safety or tolerability concerns emerged in this study. One death in the pridopidine 112·5 mg group due to aspiration pneumonia was considered to be possibly related to the study drug. Pridopidine did not improve the UHDRS-TMS at week 26 compared with placebo and, thus, the results of secondary or tertiary analyses in previous trials were not replicated. A potentially strong placebo effect needs to be ruled out in future studies. Teva Pharmaceutical Industries.

Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by a CAG tract expansion in the huntingtin gene (HTT). HD is characterized by involuntary movements, cognitive decline, and behavioral changes. Pathologically, patients with HD show selective striatal neuronal vulnerability at the early disease stage, although the mutant protein is ubiquitously expressed. Activation of the immune system and glial cell-mediated neuroinflammatory responses are early pathological features and have been found in all neurodegenerative diseases (NDDs), including HD. However, the role of inflammation in HD, as well as its therapeutic significance, has been less extensively studied compared to other NDDs. This review highlights the significantly elevated levels of inflammatory proteins and cellular markers observed in various HD animal models and HD patient tissues, emphasizing the critical roles of microglia, astrocytes, and oligodendrocytes in mediating neuroinflammation in HD. Moreover, it expands on recent discoveries related to the peripheral immune system’s involvement in HD. Although current immunomodulatory treatments and inflammatory biomarkers for adjunctive diagnosis in HD are limited, targeting inflammation in combination with other therapies, along with comprehensive personalized treatment approaches, shows promising therapeutic potential.

Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself.In this Review, Tabrizi et al. discuss new insights into the molecular pathogenesis of Huntington disease and outline potential therapeutic strategies, which could include the modulation of DNA repair processes.

Huntington's disease is the most frequent autosomal dominant neurodegenerative disorder; however, no disease-modifying interventions are available for patients with this disease. The molecular pathogenesis of Huntington's disease is complex, with toxicity that arises from full-length expanded huntingtin and N-terminal fragments of huntingtin, which are both prone to misfolding due to proteolysis; aberrant intron-1 splicing of the HTT gene; and somatic expansion of the CAG repeat in the HTT gene. Potential interventions for Huntington's disease include therapies targeting huntingtin DNA and RNA, clearance of huntingtin protein, DNA repair pathways, and other treatment strategies targeting inflammation and cell replacement. The early termination of trials of the antisense oligonucleotide tominersen suggest that it is time to reflect on lessons learned, where the field stands now, and the challenges and opportunities for the future.

Huntington's disease is a rare, neurodegenerative disease caused by an expanded CAG repeat mutation in the huntingtin gene. Compared with adult-onset Huntington's disease, juvenile Huntington's disease (onset ≤20 years) is even rarer and has not been studied extensively. We aimed to further characterise juvenile Huntington's disease by examining the effect of CAG repeat size on disease presentation, progression, and survival. We did a retrospective analysis of patients with juvenile Huntington's disease aged 20 years or younger, according to the length of their CAG repeat and who had disabling psychiatric symptoms (with motor symptoms) or motor symptoms alone, and of patients with adult-onset Huntington's disease manifesting aged 30–60 years with 40 or more CAG repeats, from the REGISTRY and ENROLL-HD platforms and from two institutional databases (Lega Italiana Ricerca Huntington Foundation and the Instituto Neurociencias de Buenos Aires and the Sanatorio de la Trinidad Mitre). Patients with psychiatric but no motor symptoms were excluded. We compared symptoms at onset and longitudinally in patients with juvenile Huntington's disease with highly expanded (HE subgroup) or low expansion (LE subgroup) mutations, grouped by hierarchical clustering analysis. We also compared disease progression (longitudinal change in Unified Huntington's Disease Rating Scale–Total Motor Score) and survival of patients with juvenile and adult-onset Huntington's disease. We extracted medical records from 580 patients entered into the studies or databases between June 23, 2004, and March 31, 2018, of whom 36 patients met our definition of juvenile Huntington's disease and 197 for adult-onset Huntington's disease. According to caregiver reports, gait disturbance was more often a first presenting symptom in the HE subgroup (eight [80%] of 10 patients) than in the LE subgroup (seven [27%] of 26 patients; p=0·0071), whereas loss of hand dexterity was more common in the LE subgroup (11 [42%] of 26 patients) than in the HE subgroup (0 [0%] of 10 patients; p=0·0160). Compared with the LE subgroup, development delay (0 [0%] in the LE subgroup vs nine [90%] in the HE subgroup; p<0·0001), severe gait impairment (nine [35%] in the LE subgroup vs nine [90%] in the HE subgroup; p=0·0072), and seizures (three [11%] in the LE subgroup vs eight [80%] in the HE subgroup; p<0·0001) prevailed over time in the HE subgroup. Disease progression was more rapid in juvenile Huntington's disease (n=14) than in adult-onset Huntington's disease (n=52; generalised estimating equation model, p=0·0003). Of 121 deceased patients, median survival was shorter in the juvenile Huntington's disease (n=17) cohort than in adult-onset Huntington's disease (n=104) cohort (hazard ratio 2·18 [95% CI 1·08–4·40]; p=0·002). Patients with HE juvenile Huntington's disease differ clinically from patients with LE juvenile Huntington's disease or adult-onset Huntington's disease, suggesting reclassification of this particularly aggressive form of Huntington's disease might be required. Lega Italiana Ricerca Huntington Foundation and IRCCS Ospedale Casa Sollievo della Sofferenza.

The current research paradigm for Huntington's disease is based on participants with overt clinical phenotypes and does not address its pathophysiology nor the biomarker changes that can precede by decades the functional decline. We have generated a new research framework to standardise clinical research and enable interventional studies earlier in the disease course. The Huntington's Disease Integrated Staging System (HD-ISS) comprises a biological research definition and evidence-based staging centred on biological, clinical, and functional assessments. We used a formal consensus method that involved representatives from academia, industry, and non-profit organisations. The HD-ISS characterises individuals for research purposes from birth, starting at Stage 0 (ie, individuals with the Huntington's disease genetic mutation without any detectable pathological change) by using a genetic definition of Huntington's disease. Huntington's disease progression is then marked by measurable indicators of underlying pathophysiology (Stage 1), a detectable clinical phenotype (Stage 2), and then decline in function (Stage 3). Individuals can be precisely classified into stages based on thresholds of stage-specific landmark assessments. We also demonstrated the internal validity of this system. The adoption of the HD-ISS could facilitate the design of clinical trials targeting populations before clinical motor diagnosis and enable data standardisation across ongoing and future studies.

The pathogenic mechanisms of these diseases must be well understood for the treatment of neurological disorders such as Huntington's disease. Huntington's Disease (HD), a dominant and neurodegenerative disease, is characterized by the CAG re-expansion that occurs in the gene encoding the polyglutamine-expanded mutant Huntingtin (mHTT) protein. Genome editing approaches include zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeats/Caspase 9 (CRISPR/Cas9) systems. CRISPR/Cas9 technology allows effective gene editing in different cell types and organisms. Through these systems are created isogenic control of human origin induced pluripotent stem cells (iPSCs). In human and mouse models, HD-iPSC lines can be continuously corrected using these systems. HD-iPSCs can be corrected through the CRISPR/Cas9 system and the cut-and-paste mechanism using isogenic control iPSCs. This mechanism is a piggyBac transposon-based selection system that can effectively switch between vectors and chromosomes. In studies conducted, it has been determined that in neural cells derived from HD-iPSC, there are isogenic controls as corrected lines recovered from phenotypic abnormalities and gene expression changes. It has been determined that trinucleotide repeat disorders occurring in HD can be cured by single-guide RNA (sgRNA) and normal exogenous DNA restoration, known as the single guideline RNA specific to Cas9. The purpose of this review in addition to give general information about HD, a neurodegenerative disorder is to explained the role of CRISPR/Cas9 system with iPSCs in HD treatment.