Huntington disease: natural history, biomarkers and prospects for therapeutics

Huntington disease (HD) can be seen as a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic testing, with estimation of years to predicted onset, enabling the entire range of disease natural history to be studied. Structural neuroimaging biomarkers show that progressive regional brain atrophy begins many years before the emergence of diagnosable signs and symptoms of HD, and continues steadily during the symptomatic or 'manifest' period. The continued development of functional, neurochemical and other biomarkers raises hopes that these biomarkers might be useful for future trials of disease-modifying therapeutics to delay the onset and slow the progression of HD. Such advances could herald a new era of personalized preventive therapeutics. We describe the natural history of HD, including the timing of emergence of motor, cognitive and emotional impairments, and the techniques that are used to assess these features. Building on this information, we review recent progress in the development of biomarkers for HD, and potential future roles of these biomarkers in clinical trials

A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes

BACKGROUND: Huntington disease (HD) is caused by an unstable CAG/CAA repeat expansion encoding a toxic polyglutamine tract. Here, we tested the hypotheses that HD outcomes are impacted by somatic expansion of, and polymorphisms within, the HTT CAG/CAA glutamine-encoding repeat, and DNA repair genes. METHODS: The sequence of the glutamine-encoding repeat and the proportion of somatic CAG expansions in blood DNA from participants inheriting 40 to 50 CAG repeats within the TRACK-HD and Enroll-HD cohorts were determined using high-throughput ultra-deep-sequencing. Candidate gene polymorphisms were genotyped using kompetitive allele-specific PCR (KASP). Genotypic associations were assessed using time-to-event and regression analyses. FINDINGS: Using data from 203 TRACK-HD and 531 Enroll-HD participants, we show that individuals with higher blood DNA somatic CAG repeat expansion scores have worse HD outcomes: a one-unit increase in somatic expansion score was associated with a Cox hazard ratio for motor onset of 3·05 (95% CI = 1·94 to 4·80, p = 1·3 × 10-6). We also show that individual-specific somatic expansion scores are associated with variants in FAN1 (pFDR = 4·8 × 10-6), MLH3 (pFDR = 8·0 × 10-4), MLH1 (pFDR = 0·004) and MSH3 (pFDR = 0·009). We also show that HD outcomes are best predicted by the number of pure CAGs rather than total encoded-glutamines. INTERPRETATION: These data establish pure CAG length, rather than encoded-glutamine, as the key inherited determinant of downstream pathophysiology. These findings have implications for HD diagnostics, and support somatic expansion as a mechanistic link for genetic modifiers of clinical outcomes, a driver of disease, and potential therapeutic target in HD and related repeat expansion disorders. FUNDING: CHDI Foundation

Standardised assessment of personality – a study of validity and reliability in substance abusers

<p>Abstract</p> <p>Background</p> <p>Brief screening instruments for co-morbid personality disorders could potentially have great value in substance abuse treatment settings.</p> <p>Methods</p> <p>We assessed the psychometric properties of the 8-item Standardised Assessment of Personality – Abbreviated Scale (SAPAS) in a sample of 58 methadone maintenance patients.</p> <p>Results</p> <p>Internal consistency was modest, but similar to the original value (alpha = 0.62), and test-retest correlation at four months follow-up was moderately encouraging for a short instrument such as this (n = 31, test retest intraclass correlation = 0.58), and change at the mean level was minimal, but marginally significant (from an average of 3.3 to 3.8, p = 0.06). Analyses of nurse ratings of patients' behaviour at the clinic showed that SAPAS was significantly correlated with nurse ratings of externalizing behaviour (r = 0.42, p = 0.001), and Global Assessment of Functioning (r = -0.36, p = 0.006), but unrelated to intoxication (r = 0.02, NS), or withdrawal (r = 0.20, NS).</p> <p>Conclusion</p> <p>There is evidence that the SAPAS is a modestly valid and relatively reliable brief screening measure of personality disorders in patients with ongoing substance abuse undergoing methadone maintenance. It can be used in situations where limited resources are available, and researchers or others wish to get an impression of the degree of personality pathology in a clinical population, as well as for screening purposes.</p

Survival End Points for Huntington Disease Trials Prior to a Motor Diagnosis

IMPORTANCE: Predictive genetic testing in Huntington disease (HD) enables therapeutic trials in HTT gene expansion mutation carriers prior to a motor diagnosis. Progression-free survival (PFS) is the composite of a motor diagnosis or a progression event, whichever comes first. OBJECTIVE: To determine if PFS provides feasible sample sizes for trials with mutation carriers who have not yet received a motor diagnosis. DESIGN, SETTING AND PARTICIPANTS: This study uses data from the 2-phase, longitudinal cohort studies called Track and from a longitudinal cohort study called the Cooperative Huntington Observational Research Trial (COHORT). Track had 167 prediagnosis mutation carriers and 156 noncarriers, whereas COHORT had 366 prediagnosis mutation carriers and noncarriers. Track studies were conducted at 4 sites in 4 countries (Canada, France, England, and the Netherlands) from which data were collected from January 17, 2008, through November 17, 2014. The COHORT was conducted at 38 sites in 3 countries (Australia, Canada, and the United States) from which data were collected from February 14, 2006, through December 31, 2009. Results from the Track data were externally validated with data from the COHORT. The required sample size was estimated for a 2-arm prediagnosis clinical trial. Data analysis took place from May 1, 2016, to June 10, 2017. MAIN OUTCOMES AND MEASURES: The primary end point is PFS. Huntington disease progression events are defined for the Unified Huntington's Disease Rating Scale total motor score, total functional capacity, symbol digit modalities test, and Stroop word test. RESULTS: Of Track’s 167 prediagnosis mutation carriers, 93 (55.6%) were women, and the mean (SD) age was 40.06 (8.92) years; of the 156 noncarriers, 87 (55.7%) were women, and the mean (SD) age was 45.58 (10.30) years. Of the 366 COHORT participants, 229 (62.5%) were women and the mean (SD) age was 42.21 (12.48) years. The PFS curves of the Track mutation carriers showed good external validity with the COHORT mutation carriers after adjusting for initial progression. For required sample size, PFS with a motor diagnosis or total motor score progression required about 4 times fewer participants than a motor diagnosis alone. Including additional cognitive progression events further reduced the number. For example, a 3-year trial with 10% attrition and a treatment effect of 50% requires a total of 661 with motor diagnosis as the survival end point but only 177 with a total motor score PFS. CONCLUSIONS AND RELEVANCE: Reasonably sized prediagnosis Huntington disease trials can be planned with PFS, and there is evidence of generalizability of this approach

Characterization of a Large Group of Individuals with Huntington Disease and Their Relatives Enrolled in the COHORT Study

Careful characterization of the phenotype and genotype of Huntington disease (HD) can foster better understanding of the condition.We conducted a cohort study in the United States, Canada, and Australia of members of families affected by HD. We collected demographic and clinical data, conducted the Unified Huntington's Disease Rating Scale and Mini-Mental State Examination, and determined Huntingtin trinucleotide CAG repeat length. We report primarily on cross-sectional baseline data from this recently completed prospective, longitudinal, observational study.As of December 31, 2009, 2,318 individuals enrolled; of these, 1,985 (85.6%) were classified into six analysis groups. Three groups had expanded CAG alleles (36 repeats or more): individuals with clinically diagnosed HD [n = 930], and clinically unaffected first-degree relatives who had previously pursued [n = 248] or not pursued [n = 112] predictive DNA testing. Three groups lacked expanded alleles: first-degree relatives who had previously pursued [n = 41] or not pursued [n = 224] genetic testing, and spouses and caregivers [n = 430]. Baseline mean performance differed across groups in all motor, behavioral, cognitive, and functional measures (p<0.001). Clinically unaffected individuals with expanded alleles weighed less (76.0 vs. 79.6 kg; p = 0.01) and had lower cognitive scores (28.5 vs. 29.1 on the Mini Mental State Examination; p = 0.008) than individuals without expanded alleles. The frequency of "high normal" repeat lengths (27 to 35) was 2.5% and repeat lengths associated with reduced penetrance (36 to 39) was 2.7%.Baseline analysis of COHORT study participants revealed differences that emerge prior to clinical diagnosis. Longitudinal investigation of this cohort will further characterize the natural history of HD and genetic and biological modifiers.Clinicaltrials.gov NCT00313495

Design optimization for clinical trials in early-stage manifest Huntington's disease.

The purpose of this study was to inform the design of randomized clinical trials in early-stage manifest Huntington's disease through analysis of longitudinal data from TRACK-Huntington's Disease (TRACK-HD), a multicenter observational study. We compute sample sizes required for trials with candidate clinical, functional, and imaging outcomes, whose aims are to reduce rates of change. The calculations use a 2-stage approach: first using linear mixed models to estimate mean rates of change and components of variability from TRACK-HD data and second using these to predict sample sizes for a range of trial designs. For each outcome, the primary drivers of the required sample size were the anticipated treatment effect and the duration of treatment. Extending durations from 1 to 2 years yielded large sample size reductions. Including interim visits and incorporating stratified randomization on predictors of outcome together with covariate adjustment gave more modest, but nontrivial, benefits. Caudate atrophy, expressed as a percentage of its baseline, was the outcome that gave smallest required sample sizes. Here we consider potential required sample sizes for clinical trials estimated from naturalistic observation of longitudinal change. Choice among outcome measures for a trial must additionally consider their relevance to patients and the expected effect of the treatment under study. For all outcomes considered, our results provide compelling arguments for 2-year trials, and we also demonstrate the benefits of incorporating stratified randomization coupled with covariate adjustment, particularly for trials with caudate atrophy as the primary outcome. The benefits of enrichment are more debatable, with statistical benefits offset by potential recruitment difficulties and reduced generalizability. © 2017 International Parkinson and Movement Disorder Society

A cross-sectional testing of The Iowa Personality Disorder Screen in a psychiatric outpatient setting

<p>Abstract</p> <p>Background</p> <p>Patients suspected of personality disorders (PDs) by general practitioners are frequently referred to psychiatric outpatient clinics (POCs). In that setting an effective screening instrument for PDs would be helpful due to resource constraints. This study evaluates the properties of The Iowa Personality Disorder Screen (IPDS) as a screening instrument for PDs at a POC.</p> <p>Methods</p> <p>In a cross-sectional design 145 patients filled in the IPDS and were examined with the SCID-II interview as reference. Various case-findings properties were tested, interference of socio-demographic and other psychopathology were investigated by logistic regression and relationships of the IPDS and the concept of PDs were studied by a latent variable path analysis.</p> <p>Results</p> <p>We found that socio-demographic and psychopathological factors hardly disturbed the IPDS as screening instrument. With a cut-off ≥4 the 11 items IPDS version had sensitivity 0.77 and specificity 0.71. A brief 5 items version showed sensitivity 0.82 and specificity 0.74 with cut-off ≥ 2. With exception for one item, the IPDS variables loaded adequately on their respective first order variables, and the five first order variables loaded in general adequately on their second order variable.</p> <p>Conclusion</p> <p>Our results support the IPDS as a useful screening instrument for PDs present or absent in the POC setting.</p

Motor, cognitive, and functional decline contribute to a single progressive factor in early HD

Objective: To identify an improved measure of clinical progression in early Huntington disease (HD) using data from prospective observational cohort studies and placebo group data from randomized double-blind clinical trials. / Methods: We studied Unified Huntington Disease Rating Scale (UHDRS) and non-UHDRS clinical measures and brain measures of progressive atrophy in 1,668 individuals with early HD followed up prospectively for up to 30 to 36 months of longitudinal clinical follow-up. / Results: The results demonstrated that a composite measure of motor, cognitive, and global functional decline best characterized clinical progression and was most strongly associated with brain measures of progressive corticostriatal atrophy. / Conclusions: Use of a composite motor, cognitive, and global functional clinical outcome measure in HD provides an improved measure of clinical progression more related to measures of progressive brain atrophy and provides an opportunity for enhanced clinical trial efficiency relative to currently used individual motor, cognitive, and functional outcome measures

A SNP in the HTT promoter alters NF-kappa B binding and is a bidirectional genetic modifier of Huntington disease

Cis-regulatory variants that alter gene expression can modify disease expressivity, but none have previously been identified in Huntington disease (HD). Here we provide in vivo evidence in HD patients that cis-regulatory variants in the HTT promoter are bidirectional modifiers of HD age of onset. HTT promoter analysis identified a NF-κB binding site that regulates HTT promoter transcriptional activity. A non-coding SNP, rs13102260:G > A, in this binding site impaired NF-κB binding and reduced HTT transcriptional activity and HTT protein expression. The presence of the rs13102260 minor (A) variant on the HD disease allele was associated with delayed age of onset in familial cases, whereas the presence of the rs13102260 (A) variant on the wild-type HTT allele was associated with earlier age of onset in HD patients in an extreme case–based cohort. Our findings suggest a previously unknown mechanism linking allele-specific effects of rs13102260 on HTT expression to HD age of onset and have implications for HTT silencing treatments that are currently in development

Exploratory 7-Tesla magnetic resonance spectroscopy in Huntington’s disease provides in vivo evidence for impaired energy metabolism

Huntington’s disease (HD) is a neurodegenerative genetic disorder that affects the brain. Atrophy of deep grey matter structures has been reported and it is likely that underlying pathologic processes occur before, or in concurrence with, volumetric changes. Measurement of metabolite concentrations in these brain structures has the potential to provide insight into pathological processes. We aim to gain understanding of metabolite changes with respect to the disease stage and pathophysiological changes. We studied five brain regions using magnetic resonance spectroscopy (MRS) using a 7-Tesla MRI scanner. Localized proton spectra were acquired to obtain six metabolite concentrations. MRS was performed in the caudate nucleus, putamen, thalamus, hypothalamus, and frontal lobe in 44 control subjects, premanifest gene carriers and manifest HD. In the caudate nucleus, HD patients display lower NAA (p = 0.009) and lower creatine concentration (p = 0.001) as compared to controls. In the putamen, manifest HD patients show lower NAA (p = 0.024), lower creatine concentration (p = 0.027), and lower glutamate (p = 0.013). Although absolute values of NAA, creatine, and glutamate were lower, no significant differences to controls were found in the premanifest gene carriers. The lower concentrations of NAA and creatine in the caudate nucleus and putamen of early manifest HD suggest deficits in neuronal integrity and energy metabolism. The changes in glutamate could support the excitotoxicity theory. These findings not only give insight into neuropathological changes in HD but also indicate that MRS can possibly be applied in future clinical trails to evaluate medication targeted at specific metabolic processes