Pridopidine in early-stage manifest Huntington's disease: a phase 3 trial.

Huntington's disease (HD) is a rare, neurodegenerative disorder for which only symptomatic treatments are available. The PROOF-HD study was a randomized, double-blind, placebo-controlled phase 3 trial evaluating the efficacy and safety of pridopidine, a selective Sigma-1 receptor agonist, in HD. The primary and key secondary endpoints, change in total functional capacity (TFC) and composite Unified Huntington's Disease Rating Scale (cUHDRS) score at week 65, were not met in the overall population.

Imaging of human stem cell-derived dopamine grafts correlates with behavioural recovery and reveals microstructural brain changes.

Cell therapy is a promising therapeutic intervention for Parkinson's disease (PD) and is currently undergoing safety and efficacy testing in clinical trials worldwide. The goals of this project were (1) to determine whether [F]Fluorodopa or [F]Fallypride imaging correlates robustly with functional recovery; and (2) to explore whether diffusion-weighted MR imaging (DWI) could detect graft-induced cytoarchitectural changes in the host brain. hfVM and hESC-derived dopamine precursor cells were transplanted into the 6-OHDA lesioned rat striatum.

Graft ischemia post cell transplantation to the brain: Glucose deprivation as the primary driver of rapid cell death.

Replacing cells lost during the progression of neurodegenerative disorders holds potential as a therapeutic strategy. Unfortunately, the majority of cells die post-transplantation, which creates logistical and biological challenges for cell therapy approaches. The cause of cell death is likely to be multifactorial in nature but has previously been correlated with hypoxia in the graft core.

Huntington's disease phenocopy syndromes revisited: a clinical comparison and next-generation sequencing exploration.

Background: Genetic testing for Huntington's disease (HD) was initially usually positive but more recently the negative rate has increased: patients with negative HD tests are described as having HD phenocopy syndromes (HDPC). This study examines their clinical characteristics and investigates the genetic causes of HDPC.

Methods: Clinical data from neurogenetics clinics and HDPC gene-panel data were analysed.

Protocol for a randomised controlled unblinded feasibility trial of HD-DRUM: a rhythmic movement training application for cognitive and motor symptoms in people with Huntington's disease.

Introduction: Huntington's disease (HD) is an inherited neurodegenerative disease causing progressive cognitive and motor decline, largely due to basal ganglia (BG) atrophy. Rhythmic training offers promise as therapy to counteract BG-regulated deficits. We have developed HD-DRUM, a tablet-based app to enhance movement synchronisation skills and improve cognitive and motor abilities in people with HD.

Language-Independent Acoustic Biomarkers for Quantifying Speech Impairment in Huntington's Disease.

Purpose: Changes in voice and speech are characteristic symptoms of Huntington's disease (HD). Objective methods for quantifying speech impairment that can be used across languages could facilitate assessment of disease progression and intervention strategies. The aim of this study was to analyze acoustic features to identify language-independent features that could be used to quantify speech dysfunction in English-, Spanish-, and Polish-speaking participants with HD.

An Overview of Specialist Services for Huntington's Disease in the United Kingdom.

Background: Huntington's disease (HD) is a rare inherited neurodegenerative disorder characterized by complex evolving needs that change as the condition progresses. There is limited understanding about the organization of HD clinical services and their resourcing in the United Kingdom (UK).

Objective: To understand the organization and resourcing of specialist HD services for people with HD (PwHD) in the UKMethods:This cross-sectional study collected quantitative data via on online survey, and qualitative data via telephone semi-structured interviews.

Single-Cell Transcriptomics Reveals Conserved Regulatory Networks in Human and Mouse Interneuron Development.

Inhibitory GABAergic interneurons originate in the embryonic medial ganglionic eminence (MGE) and control network activity in the neocortex. Dysfunction of these cells is believed to lead to runaway excitation underlying seizure-based neurological disorders such as epilepsy, autism, and schizophrenia. Despite their importance in heath and disease, our knowledge about the development of this diverse neuronal population remains incomplete.

Excessive response to provocation rather than disinhibition mediates irritable behaviour in Huntington's disease.

Background: Irritable and impulsive behaviour are common in Huntington's disease (HD: an autosomal dominant disorder causing degeneration in cortico-striatal networks). However, the cognitive mechanisms underlying these symptoms remain unclear, and previous research has not determined if common mechanisms underpin both symptoms. Here we used established and novel tasks to probe different aspects of irritable and impulsive behaviour to determine the neural mechanisms involved.

Different depression: motivational anhedonia governs antidepressant efficacy in Huntington's disease.

Depression is more common in neurodegenerative diseases such as Huntington's disease than the general population. Antidepressant efficacy is well-established for depression within the general population: a recent meta-analysis showed serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants and mirtazapine outperformed other antidepressants. Despite the severe morbidity, antidepressant choice in Huntington's disease is based on Class IV evidence.

Challenges in progressing cell therapies to the clinic for Huntington's disease: A review of the progress made with pluripotent stem cell derived medium spiny neurons.

Huntington's disease (HD) is a hereditary, neurodegenerative disorder characterized by a triad of symptoms: motor, cognitive and psychiatric. HD is caused by a genetic mutation, expansion of the CAG repeat in the huntingtin gene, which results in loss of medium spiny neurons (MSNs) of the striatum. Cell replacement therapy (CRT) has emerged as a possible therapy for HD, aiming to replace those cells lost to the disease process and alleviate its symptoms.

Huntington's disease age at motor onset is modified by the tandem hexamer repeat in TCERG1.

Huntington's disease is caused by an expanded CAG tract in HTT. The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously reported to be associated with Huntington's disease and a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 with a central pure repeat.

Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities.

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 need for a standard for informed consent for collection of human fetal material.

The ISSCR has developed the Informed Consent Standards for Human Fetal Tissue Donation and Research to promote uniformity and transparency in tissue donation and collection. This standard is designed to assist those working with and overseeing the regulation of such tissue and reassure the wider community and public.

Mutation-related magnetization-transfer, not axon density, drives white matter differences in premanifest Huntington disease: Evidence from in vivo ultra-strong gradient MRI.

White matter (WM) alterations have been observed in Huntington disease (HD) but their role in the disease-pathophysiology remains unknown. We assessed WM changes in premanifest HD by exploiting ultra-strong-gradient magnetic resonance imaging (MRI). This allowed to separately quantify magnetization transfer ratio (MTR) and hindered and restricted diffusion-weighted signal fractions, and assess how they drove WM microstructure differences between patients and controls.

Exome sequencing of individuals with Huntington's disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset.

The age at onset of motor symptoms in Huntington's disease (HD) is driven by HTT CAG repeat length but modified by other genes. In this study, we used exome sequencing of 683 patients with HD with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We discovered damaging coding variants in candidate modifier genes identified in previous genome-wide association studies associated with altered HD onset or severity.

Translating cell therapies for neurodegenerative diseases: Huntington's disease as a model disorder.

There has been substantial progress in the development of regenerative medicine strategies for CNS disorders over the last decade, with progression to early clinical studies for some conditions. However, there are multiple challenges along the translational pipeline, many of which are common across diseases and pertinent to multiple donor cell types. These include defining the point at which the preclinical data are sufficiently compelling to permit progression to the first clinical studies; scaling-up, characterization, quality control and validation of the cell product; design, validation and approval of the surgical device; and operative procedures for safe and effective delivery of cell product to the brain.

Do foetal transplant studies continue to be justified in Huntington's disease?

Early CNS transplantation studies used foetal derived cell products to provide a foundation of evidence for functional recovery in preclinical studies and early clinical trials. However, it was soon recognised that the practical limitations of foetal tissue make it unsuitable for widespread clinical use. Considerable effort has since been directed towards producing target cell phenotypes from pluripotent stem cells (PSCs) instead, and there now exist several publications detailing the differentiation and characterisation of PSC-derived products relevant for transplantation in Huntington's disease (HD).

Oxygen-glucose deprivation in neurons: implications for cell transplantation therapies.

Cell replacement therapies hold the potential to restore neuronal networks compromised by neurodegenerative diseases (such as Parkinson's disease or Huntington's disease), or focal tissue damage (via a stroke or spinal cord injury). Despite some promising results achieved to date, transplanted cells typically exhibit poor survival in the central nervous system, thus limiting therapeutic efficacy of the graft. Although cell death post-transplantation is likely to be multifactorial in causality, growing evidence suggests that the lack of vascularisation at the graft site, and the resulting ischemic host environment, may play a fundamental role in the fate of grafted cells.

Multi-compartment analysis of the complex gradient-echo signal quantifies myelin breakdown in premanifest Huntington's disease.

White matter (WM) alterations have been identified as a relevant pathological feature of Huntington's disease (HD). Increasing evidence suggests that WM changes in this disorder are due to alterations in myelin-associated biological processes. Multi-compartmental analysis of the complex gradient-echo MRI signal evolution in WM has been shown to quantify myelin in vivo, therefore pointing to the potential of this technique for the study of WM myelin changes in health and disease.

Timing and Impact of Psychiatric, Cognitive, and Motor Abnormalities in Huntington Disease.

Objective: To assess the prevalence, timing, and functional impact of psychiatric, cognitive, and motor abnormalities in Huntington disease (HD) gene carriers, we analyzed retrospective clinical data from individuals with manifest HD.

Methods: Clinical features of patients with HD were analyzed for 6,316 individuals in an observational study of the European Huntington's Disease Network (REGISTRY) from 161 sites across 17 countries. Data came from clinical history and the patient-completed Clinical Characteristics Questionnaire that assessed 8 symptoms: motor, cognitive, apathy, depression, perseverative/obsessive behavior, irritability, violent/aggressive behavior, and psychosis.