Exploring the structural relationship between interviewer and self-rated affective symptoms in Huntington’s disease

This study explores the structural relationship between self-report and interview measures of affect in Huntington’s disease. The findings suggest continued use of both to recognize the multidimensionality within a single common consideration of distress

The role of tau in the pathological process and clinical expression of Huntington's disease.

Huntington's disease is a neurodegenerative disorder caused by an abnormal CAG repeat expansion within exon 1 of the huntingtin gene HTT. While several genetic modifiers, distinct from the Huntington's disease locus itself, have been identified as being linked to the clinical expression and progression of Huntington's disease, the exact molecular mechanisms driving its pathogenic cascade and clinical features, especially the dementia, are not fully understood. Recently the microtubule associated protein tau, MAPT, which is associated with several neurodegenerative disorders, has been implicated in Huntington's disease. We explored this association in more detail at the neuropathological, genetic and clinical level. We first investigated tau pathology by looking for the presence of hyperphosphorylated tau aggregates, co-localization of tau with mutant HTT and its oligomeric intermediates in post-mortem brain samples from patients with Huntington's disease (n = 16) compared to cases with a known tauopathy and healthy controls. Next, we undertook a genotype-phenotype analysis of a large cohort of patients with Huntington's disease (n = 960) with a particular focus on cognitive decline. We report not only on the tau pathology in the Huntington's disease brain but also the association between genetic variation in tau gene and the clinical expression and progression of the disease. We found extensive pathological inclusions containing abnormally phosphorylated tau protein that co-localized in some instances with mutant HTT. We confirmed this related to the disease process rather than age, by showing it is also present in two patients with young-onset Huntington's disease (26 and 40 years old at death). In addition we demonstrate that tau oligomers (suggested to be the most likely neurotoxic tau entity) are present in the Huntington's disease brains. Finally we highlight the clinical significance of this pathology by demonstrating that the MAPT haplotypes affect the rate of cognitive decline in a large cohort of patients with Huntington's disease. Our findings therefore highlight a novel important role of tau in the pathogenic process and clinical expression of Huntington's disease, which in turn opens up new therapeutic avenues for this incurable condition.The authors thank the EHDN REGISTRY Study Group investigators (listed in the Supplementary material) for collecting the data and all participating REGISTRY patients for their time and efforts, the Cambridge Brain Bank for the post-mortem tissue which is supported by a grant to the NIHR Cambridge Biomedical Research Centre and in particular to J. Wilson and Dr D. O’ Donovan. We are grateful to S. Sawcer and M. Ban in the Neurology Unit at the University of Cambridge, for their help with the genotyping, C.H. Williams-Gray at the John van Geest Centre for Brain Repair, University of Cambridge, for her help with the statistical analyses, J. Hardy, J.L. Holton, and T. Revesz at the UCL Institute of Neurology for their helpful discussions as well as K. Strand, F. Javad and A. Posada Bórbon, at the UCL Institute of Neurology, for their support with the experimental work, R. Kayed at the University of Texas Medical Branch, Galveston, for providing the TOMA and T22 antibodies. Finally, P. Tyers, R. Raha-Chowdhury, A. Tolkovsky, B. Ossola and J. Simpson for their support and encouragement throughout this work.This is the final version of the article. It was first available from Oxford University Press viahttp://dx.doi.org/10.1093/brain/awv10

Progression of motor subtypes in Huntington’s disease. a 6-year follow-up study

The objective of this study is to investigate the progression of predominantly choreatic and hypokinetic-rigid signs in Huntington's disease (HD) and their relationship with cognitive and general functioning over time. The motor signs in HD can be divided into predominantly choreatic and hypokinetic-rigid subtypes. It has been reported in cross-sectional studies that predominantly choreatic HD patients perform better on functional and cognitive assessments compared to predominantly hypokinetic-rigid HD patients. The course of these motor subtypes and their clinical profiles has not been investigated longitudinally. A total of 4135 subjects who participated in the European HD Network REGISTRY study were included and classified at baseline as either predominantly choreatic (n = 891), hypokinetic-rigid (n = 916), or mixed-motor (n = 2328), based on a previously used method. The maximum follow-up period was 6 years. The mixed-motor group was not included in the analyses. Linear mixed models were constructed to investigate changes in motor subtypes over time and their relationship with cognitive and functional decline. Over the 6-year follow-up period, the predominantly choreatic group showed a significant decrease in chorea, while hypokinetic-rigid symptoms slightly increased in the hypokinetic-rigid group. On the Total Functional Capacity, Stroop test, and Verbal fluency task the rate of change over time was significantly faster in the predominantly choreatic group, while on all other clinical assessments the decline was comparable for both groups. Our results suggest that choreatic symptoms decrease over time, whereas hypokinetic-rigid symptoms slightly increase in a large cohort of HD patients. Moreover, different motor subtypes can be related to different clinical profiles

Repeat Detector: versatile sizing of expanded tandem repeats and identification of interrupted alleles from targeted DNA sequencing

Targeted DNA sequencing approaches will improve how the size of short tandem repeats is measured for diagnostic tests and preclinical studies. The expansion of these sequences causes dozens of disorders, with longer tracts generally leading to a more severe disease. Interrupted alleles are sometimes present within repeats and can alter disease manifestation. Determining repeat size mosaicism and identifying interruptions in targeted sequencing datasets remains a major challenge. This is in part because standard alignment tools are ill-suited for repetitive and unstable sequences. To address this, we have developed Repeat Detector (RD), a deterministic profile weighting algorithm for counting repeats in targeted sequencing data. We tested RD using blood-derived DNA samples from Huntington’s disease and Fuchs endothelial corneal dystrophy patients sequenced using either Illumina MiSeq or Pacific Biosciences single-molecule, real-time sequencing platforms. RD was highly accurate in determining repeat sizes of 609 blood-derived samples from Huntington’s disease individuals and did not require prior knowledge of the flanking sequences. Furthermore, RD can be used to identify alleles with interruptions and provide a measure of repeat instability within an individual. RD is therefore highly versatile and may find applications in the diagnosis of expanded repeat disorders and in the development of novel therapies

Factor Analysis of the Hospital Anxiety and Depression Scale among a Huntington’s Disease Population

ABSTRACT Background Depression and anxiety are common in Huntington’s Disease, a genetic neurodegenerative disorder. Objectives There is a need for measurement tools of mood to be validated within a Huntington’s disease population. The current study aimed to analyze the factor structure of the Hospital Anxiety and Depression Scale in Huntington’s disease. Methods Data from the European Huntington’s Disease Network study REGISTRY 3 was used to undertake a factor analysis of the scale among a sample of 492 Huntington’s disease mutation carriers. The sample was randomly divided into two equal subsamples and an exploratory factor analysis conducted on the first subsample suggested a 2-factor interpretation, using 8 of the items. A confirmatory factor analysis was then performed to test six possible models for goodness-of-fit. Results A bifactor model, with all items loading onto a general distress factor, with two group factors, comprising 4 depression and 4 anxiety items, provided the best fit of the data. The salience of loadings on the bifactor model suggested loadings were high on the general factor (accounting for 64% of the variance) and low on the group factors (21% for anxiety and 15% for depression). Conclusions The findings suggest that 8 items from the scale perform well among the sample. Consistent with recent developments in modeling the Hospital Anxiety and Depression Scale, a bifactor interpretation for an 8-item version outperformed other extant models. Our findings provide support for an 8-item version of the scale to be used as a measure of general distress within Huntington’s disease populations

Irritability in Huntington’s Disease: Factor Analysis of Snaith’s Irritability Scale

Background: Elevated levels of irritability are reported to occur in a number of neurological conditions, including Huntington's disease (HD), a genetic neurodegenerative disorder. Snaith's Irritability Scale (SIS) is used within HD research, but no psychometric evaluation of this instrument has previously been undertaken. Therefore, the current study aimed to analyze the factor structure of this scale among an HD population. Methods: Exploratory and confirmatory factor analysis were used to examine the structural properties of SIS using responses from 1,264 HD gene expansion carriers, across 15 European countries, who were engaged in the REGISTRY 3 study. Results: An exploratory factor analysis of a subsample of the data suggested a two-factor interpretation of the data comprising “temper” and “self-harm.” Eight possible models were tested for goodness of fit using confirmatory factor analysis. Two bifactor models, testing general and group factors in the structure of the scale, provided an equivocal “good” fit to the data. The first comprised a general irritability factor and two group factors (as originally proposed using SIS): outward irritability and inward irritability. The second comprised a general irritability factor and two group factors (as proposed by the exploratory factor analysis): temper and self-harm. The findings from both models suggested that the loadings of items were higher on the general factor. Conclusions: Bifactor models are proposed to best consider the structure of the SIS, with findings suggesting that an overall score should be used to measure irritability within HD populations

Exploring the structural relationship between interviewer and self-rated affective symptoms in Huntington’s disease

The current study explores the structural relationship between self-report and interview measures of affect in Huntington’s disease. The findings suggest continued use of both to recognize the multidimensionality within a single common consideration of distress

Disease stage, but not sex, predicts depression and psychological distress in Huntington’s disease : A European population study

Objective Depression and anxiety significantly affect morbidity in Huntington’s disease. Mice models of Huntington’s disease have identified sex differences in mood-like behaviours that vary across disease lifespan, but this interaction has not previously been explored in humans with Huntington’s disease. However, among certain medical populations, evidence of sex differences in mood across various disease stages has been found, reflecting trends among the general population that women tend to experience anxiety and depression 1.5 to 2 times more than men. The current study examined whether disease stage and sex, either separately or as an interaction term, predicted anxiety and depression in Huntington’s disease. Methods A cross-sectional study of REGISTRY data involving 453 Huntington’s disease participants from 12 European countries was undertaken using the Hospital Anxiety and Depression Scale. A series of multiple regression analyses were undertaken to discover to what extent disease stage and sex predicted anxiety, depression, and general distress after controlling for a number of known predictors of mood difficulties. Results Disease stage, but not sex, was found to predict depressive symptoms and general distress. Neither disease stage nor sex predicted anxiety. Furthermore, an interaction term computed for disease stage and sex did not contribute to the models tested. Conclusion In terms of considering risks to developing depression and anxiety in the Huntington’s disease population, practitioners may need to pay special attention to disease stage progression (but not sex differences) to enable early detection and treatment of depression (but not anxiety)

β-Defensin Genomic Copy Number Does Not Influence the Age of Onset in Huntington's Disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of a CAG triplet repeat tract in the huntingtin gene. While the length of this CAG expansion is the major determinant of the age of onset (AO), other genetic factors have also been shown to play a modulatory role. Recent evidence suggests that neuroinflammation is a pivotal factor in the pathogenesis of HD, and that targeting this process may have important therapeutic ramifications. The human β-defensin 2 (hBD2) - encoded by DEFB4 - is an antimicrobial peptide that exhibits inducible expression in astrocytes during inflammation and is an important regulator of innate and adaptive immune response. Therefore, DEFB4 may contribute to the neuroinflammatory processes observed in HD

Association between toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells 2 (TREM2) genetic variants and clinical progression of Huntington's disease

Background: Although Huntington's disease (HD) is caused by a single dominant gene, it is clear that there are genetic modifiers that may influence the age of onset and disease progression. Objectives: We sought to investigate whether new inflammation-related genetic variants may contribute to the onset and progression of HD. Methods: We first used postmortem brain material from patients at different stages of HD to look at the protein expression of toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells 2 (TREM2). We then genotyped the TREM2 R47H gene variant and 3 TLR4 single nucleotide polymorphisms in a large cohort of HD patients from the European Huntington's Disease Network REGISTRY. Results: We found an increase in the number of cells expressing TREM2 and TLR4 in postmortem brain samples from patients dying with HD. We also found that the TREM2 R47H gene variant was associated with changes in cognitive decline in the large cohort of HD patients, whereas 2 of 3 TLR4 single nucleotide polymorphisms assessed were associated with changes in motor progression in this same group. Conclusions: These findings identify TREM2 and TLR4 as potential genetic modifiers for HD and suggest that inflammation influences disease progression in this condition. © 2019 International Parkinson and Movement Disorder Society