Rethinking functional outcome measures: the development of an upper limb test to assess basal ganglia dysfunction

The basal ganglia is implicated in a wide range of motor, cognitive and behavioural activities required for normal function. This region is predominantly affected in Huntington’s disease (HD), meaning that functional ability progressively worsens. However, functional outcome measures for HD, particularly those for the upper limb, are limited meaning there is an imperative for well-defined, quantitative measures. Here we describe the development and evaluation of the Moneybox test (MBT). This novel, functional upper limb assessment was developed in accordance with translational neuroscience and physiological principles for people with a broad disease manifestation, such as HD. Participants with HD (n=64) and healthy controls (n=21) performed the MBT, which required subjects to transfer tokens into a container in order of size (Baseline Transfer), value (Complex Transfer) with and without reciting the alphabet (Dual Transfer). Disease specific measures of motor, cognition, behaviour and function were collected. HD patients were grouped into disease stage, from which, discriminative and convergent validity was assessed using Analysis of Variance and Pearson’s correlation respectively. Manifest HD participants were slower than pre-manifest and control participants, and achieved significantly lower MBT total scores. Performance in the Complex Transfer and Dual Transfer tasks were significantly different between pre-manifest and stage 1 HD. All MBT performance variables significantly correlated with routinely used measures of motor, cognition, behaviour and function. The MBT provides a valid, sensitive and affordable functional outcome measure. Unlike current assessments, MBT performance significantly distinguished the subtle differences between the earliest disease stages of HD, which are the populations typically targeted in clinical trials

Hypertension, antihypertensive use and the delayed onset of Huntington's Disease

Background: Hypertension is a modifiable cardiovascular risk factor implicated in neurodegeneration and dementia risk. In Huntington's disease, a monogenic neurodegenerative disease, autonomic and vascular abnormalities have been reported. This study's objective was to examine the relationship between hypertension and disease severity and progression in Huntington's disease. Methods: Using longitudinal data from the largest worldwide observational study of Huntington's disease (n = 14,534), we assessed the relationship between hypertension, disease severity, and rate of clinical progression in Huntington's disease mutation carriers. Propensity score matching was used to statistically match normotensive and hypertensive participants for age, sex, body mass index, ethnicity, and CAG length. Results: Huntington's disease patients had a lower prevalence of hypertension compared with age‐matched gene‐negative controls. Huntington's disease patients with hypertension had worse cognitive function, a higher depression score, and more marked motor progression over time compared with Huntington's disease patients without hypertension. However, hypertensive patients taking antihypertensive medication had less motor, cognitive, and functional impairment than Huntington's disease patients with untreated hypertension and a later age of clinical onset compared with untreated hypertensive patients and normotensive individuals with Huntington's disease. Conclusions: We report the novel finding that hypertension and antihypertensive medication use are associated with altered disease severity, progression, and clinical onset in patients with Huntington's disease. These findings have implications for the management of hypertension in Huntington's disease and suggest that prospective studies of the symptomatic or disease‐modifying potential of antihypertensives in neurodegenerative diseases are warranted

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

BackgroundIrritable 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.MethodsWe recruited a cohort of 53 gene positive HD participants and 26 controls from non-affected family members and local volunteers. We used established questionnaire measures of irritability in HD (Snaith Irritability Scale, Problem Behaviours Assessment) and impulsivity [Urgency, Premeditation Perseverance, Sensation-seeking, Positive urgency scale (UPPSP), Barratt Impulsivity Scale], in addition to cognitive tasks of provocation, motor inhibition, delay discounting and decision making under uncertainty. We used generalised linear models to determine differences between cases and controls, and associations with irritability in the HD group.ResultsWe found differences between cases and controls on the negative urgency subscale of the UPPSP, which was associated with irritability in HD. The frustrative non-reward provocation task also showed differences between cases and controls, in addition to predicting irritability in HD. The stop signal reaction time task showed case-control differences but was not associated with irritability in HD. None of the other measures showed group differences or predicted irritability in HD after correcting for confounding variables.DiscussionIrritability in HD is mediated by excessive response to provocation, rather than a failure of motor inhibition

Huntington's disease gene hunters: an expanding tale

MacDonald ME. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 1993;72:971–983. It is 28 years since the Huntington's Disease (HD) gene and mutation were identified and published in Cell by the Huntington's Disease Collaborative Research Group (HD-CRG; Fig. 1A).1 The genetic defect causing HD had been assigned to chromosome 4 in 1983 in one of the first successful linkage analyses using polymorphic DNA markers in humans,2 but it took another ten years to pinpoint the gene and determine the mutation. The long lag was largely because this research was conducted before the human genome was mapped, and was the culmination of a painstaking process involving repeatedly refining the location of the gene, based on locating markers and cloning transcripts from the genome across six independent laboratories. The nature of the genetic mutation—an expanded CAG repeat sequence—was also instrumental in the resolution of this detective story. Expanded repeats in DNA had already been associated with several diseases that had features in common with HD, such as genetic anticipation, including fragile X syndrome,3 spinal and bulbar muscular atrophy,4 and myotonic dystrophy.5-7 This meant the HD-CRG were actively looking for length mutations that segregated with disease that might indicate the presence of an expanding repeat tract. As we enter a new phase of HD research, with the advent of trials of potential disease-modifying treatments, it seems a good time to reflect on the legacy of the HD-CRG publication

Oxygen producing microscale spheres affect cell survival in conditions of oxygen-glucose deprivation in a cell specific manner: Implications for cell transplantation

This study outlines the synthesis of microscale oxygen producing spheres, which, when used in conjunction with catalase, can raise the dissolved oxygen content of cell culture media for 16-20 hours. In conditions of oxygen and glucose deprivation, designed to mimic the graft environment in vivo, the spheres rescue SH-SY5Y cells and meschymal stem cells, showing that oxygen producing biomaterials may hold potential to improve the survival of cells post-transplantation

Oxygen producing microscale spheres affect cell survival in conditions of oxygen-glucose deprivation in a cell specific manner: implications for cell transplantation

This study outlines the synthesis of microscale oxygen producing spheres, which, when used in conjunction with catalase, can raise the dissolved oxygen content of cell culture media for 16–20 hours. In conditions of oxygen and glucose deprivation, designed to mimic the graft environment in vivo, the spheres rescue SH-SY5Y cells and meschymal stem cells, showing that oxygen producing biomaterials may hold potential to improve the survival of cells post-transplantation

Robust MR-based approaches to quantifying white matter structure and structure/function alterations in Huntington's disease

Background: Huge advances have been made in understanding and addressing confounds in diffusion MRI data to quantify white matter microstructure. However, there has been a lag in applying these advances in clinical research. Some confounds are more pronounced in HD which impedes data quality and interpretability of patient-control differences. This study presents an optimised analysis pipeline and addresses specific confounds in a HD patient cohort. Method: 15 HD gene-positive and 13 matched control participants were scanned on a 3T MRI system with two diffusion MRI sequences. An optimised post processing pipeline included motion, eddy current and EPI correction, rotation of the B matrix, free water elimination ( FWE ) and tractography analysis using an algorithm capable of reconstructing crossing fibres. The corpus callosum was examined using both a region-of-interest and a deterministic tractography approach, using both conventional diffusion tensor imaging ( DTI )-based and spherical deconvolution analyses. Results: Correcting for CSF contamination significantly altered microstructural metrics and the detection of group differences. Reconstructing the corpus callosum using spherical deconvolution produced a more complete reconstruction with greater sensitivity to group differences, compared to DTI-based tractography. Tissue volume fraction ( TVF ) was reduced in HD participants and was more sensitive to disease burden compared to DTI metrics. Conclusion: Addressing confounds in diffusion MR data results in more valid, anatomically faithful white matter tract reconstructions with reduced within-group variance. TVF is recommended as a complementary metric, providing insight into the relationship with clinical symptoms in HD not fully captured by conventional DTI metrics

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. We used tractometry to investigate region-specific alterations across callosal segments with well-characterized early- and late-myelinating axon populations, while brain-wise differences were explored with tract-based cluster analysis (TBCA). Behavioral measures were included to explore disease-associated brain-function relationships. We detected lower MTR in patients' callosal rostrum (tractometry: p = .03; TBCA: p = .03), but higher MTR in their splenium (tractometry: p = .02). Importantly, patients' mutation-size and MTR were positively correlated (all p-values < .01), indicating that MTR alterations may directly result from the mutation. Further, MTR was higher in younger, but lower in older patients relative to controls (p = .003), suggesting that MTR increases are detrimental later in the disease. Finally, patients showed higher restricted diffusion signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) in the cortico-spinal tract (p = .03), which correlated positively with MTR in the posterior callosum (p = .033), potentially reflecting compensatory mechanisms. In summary, this first comprehensive, ultra-strong gradient MRI study in HD provides novel evidence of mutation-driven MTR alterations at the premanifest disease stage which may reflect neurodevelopmental changes in iron, myelin, or a combination of these