Graph methods to infer spatial disturbances: Application to Huntington's Disease's speech.

OBJECTIVE: Huntington's Disease (HD) is an inherited neurodegenerative disease caused by the mutation of the Htt gene, impacting all aspects of living and functioning. Among cognitive disabilities, spatial capacities are impaired, but their monitoring remains scarce as limited by lengthy experts' assessments. Language offers an alternative medium to evaluate patients' performance in HD. Yet, its capacities to assess HD's spatial abilities are unknown. Here, we aimed to bring proof-of-concept that HD's spatial deficits can be assessed through speech. METHODS: We developed the Spatial Description Model to graphically represent spatial relations described during the Cookie Theft Picture (CTP) task. We increased the sensitivity of our model by using only sentences with spatial terms, unlike previous studies in Alzheimer's disease. 78 carriers of the mutant Htt, including 56 manifest and 22 premanifest individuals, as well as 25 healthy controls were included from the BIOHD & (NCT01412125) & Repair-HD (NCT03119246) cohorts. The convergence and divergence of the model were validated using the SelfCog battery. RESULTS: Our Spatial Description Model was the only one among the four assessed approaches, revealing that individuals with manifest HD expressed fewer spatial relations and engaged in less spatial exploration compared to healthy controls. Their graphs correlated with both visuospatial and language SelfCog performances, but not with motor, executive nor memory functions. CONCLUSIONS: We provide the proof-of-concept using our Spatial Description Model that language can grasp HD patient's spatial disturbances. By adding spatial capabilities to the panel of functions tested by the language, it paves the way for eventual remote clinical application.

A new approach to digitized cognitive monitoring: validity of the SelfCog in Huntington's disease.

Cognitive deficits represent a hallmark of neurodegenerative diseases, but evaluating their progression is complex. Most current evaluations involve lengthy paper-and-pencil tasks which are subject to learning effects dependent on the mode of response (motor or verbal), the countries' language or the examiners. To address these limitations, we hypothesized that applying neuroscience principles may offer a fruitful alternative. We thus developed the SelfCog, a digitized battery that tests motor, executive, visuospatial, language and memory functions in 15 min. All cognitive functions are tested according to the same paradigm, and a randomization algorithm provides a new test at each assessment with a constant level of difficulty. Here, we assessed its validity, reliability and sensitivity to detect decline in early-stage Huntington's disease in a prospective and international multilingual study (France, the UK and Germany). Fifty-one out of 85 participants with Huntington's disease and 40 of 52 healthy controls included at baseline were followed up for 1 year. Assessments included a comprehensive clinical assessment battery including currently standard cognitive assessments alongside the SelfCog. We estimated associations between each of the clinical assessments and SelfCog using Spearman's correlation and proneness to retest effects and sensitivity to decline through linear mixed models. Longitudinal effect sizes were estimated for each cognitive score. Voxel-based morphometry and tract-based spatial statistics analyses were conducted to assess the consistency between performance on the SelfCog and MRI 3D-T1 and diffusion-weighted imaging in a subgroup that underwent MRI at baseline and after 12 months. The SelfCog detected the decline of patients with Huntington's disease in a 1-year follow-up period with satisfactory psychometric properties. Huntington's disease patients are correctly differentiated from controls. The SelfCog showed larger effect sizes than the classical cognitive assessments. Its scores were associated with grey and white matter damage at baseline and over 1 year. Given its good performance in longitudinal analyses of the Huntington's disease cohort, it should likely become a very useful tool for measuring cognition in Huntington's disease in the future. It highlights the value of moving the field along the neuroscience principles and eventually applying them to the evaluation of all neurodegenerative diseases.

The striatum in time production: The model of Huntington's disease in longitudinal study.

The unified model of time processing suggests that the striatum is a central structure involved in all tasks that require the processing of temporal durations. Patients with Huntington's disease exhibit striatal degeneration and a deficit in time perception in interval timing tasks (i.e. for duration ranging from hundreds of milliseconds to minutes), but whether this deficit extends to time production remains unclear. In this study, we investigated whether symptomatic patients (HD, N = 101) or presymptomatic gene carriers (Pre-HD, N = 31) of Huntington's disease had a deficit in time production for durations between 4 and 10 s compared to healthy controls and whether this deficit developed over a year for patients. We found a clear deficit in temporal production for HD patients, whereas Pre-HD performed similarly to Controls. For HD patients and Pre-HD participants, task performance was correlated with grey matter volume in the amygdala and caudate, bilaterally. These results confirm that the striatum is involved in interval timing not only in perception but also in production, in accordance with the unified model of time processing. Furthermore, exploratory factor analyses on our data indicated that temporal production was associated with clinical assessments of psychomotor and executive functions. Finally, when retested twelve months later, the deficit of HD patients remained stable, although striatal degeneration was more pronounced. Thus, the simple, short and language-independent temporal production task may be a useful clinical tool to detect striatal degeneration in patients in early stages of Huntington's disease. However, its usefulness to detect presymptomatic stages or for monitoring the evolution of HD over a year seems limited.

The burden of Huntington's disease: A prospective longitudinal study of patient/caregiver pairs.

BACKGROUND: Caregiver burden is widely recognized in Huntington's disease, but little is known about the factors determining its evolution over time in the absence of longitudinal studies. Our objective was to identify typical patterns of caregiver burden level and evolution using both patients' and caregivers' characteristics over a one-year period to identify potential levers for alleviation. METHODS: We conducted a prospective multicenter longitudinal study in caregiver/patient pairs in Huntington's disease (NCT02876445) between March 2011 and May 2015. Caregiver data were derived from two questionnaires at one-year interval on perceived burden (Zarit Burden Interview), social environment and support. Caregiver data were linked to clinical and demographic data from patients included in the Biomarker study (NCT01590589). Unsupervised clustering analysis was performed using self-organizing maps. RESULTS: 105 caregiver/patient pairs were included in the analysis. We identified four clusters. Of the two clusters of patients with advanced disease, cluster A was characterized by high levels of irritability and obsessive-compulsive behaviors, with high and increasing burden (N = 30; 29%), cluster B, the more apathetic group, with low and decreasing burden (N = 22; 21%). Clusters C (N = 27; 26%) and D (N = 26; 25%) were composed of patients in earlier stages, associated with a stable burden in group C but a notably increasing one in group D driven by patients' depression scores increase. CONCLUSIONS: Our results revealed the dynamics of caregiver burden over time in Huntington's disease, combining the stage of the disease, the severity of the patients' decline, psychiatric and behavioral disorders, and their evolution over time.

Cognitive decline in Huntington's disease in the Digitalized Arithmetic Task (DAT).

BACKGROUND: Efficient cognitive tasks sensitive to longitudinal deterioration in small cohorts of Huntington's disease (HD) patients are lacking in HD research. We thus developed and assessed the digitized arithmetic task (DAT), which combines inner language and executive functions in approximately 4 minutes. METHODS: We assessed the psychometric properties of DAT in three languages, across four European sites, in 77 early-stage HD patients (age: 52 ± 11 years; 27 females), and 57 controls (age: 50 ± 10, 31 females). Forty-eight HD patients and 34 controls were followed up to one year with 96 participants who underwent MRI brain imaging (HD patients = 46) at baseline and 50 participants (HD patients = 22) at one year. Linear mixed models and Pearson correlations were used to assess associations with clinical assessment. RESULTS: At baseline, HD patients were less accurate (p = 0.0002) with increased response time (p<0.0001) when compared to DAT in controls. Test-retest reliability in HD patients ranged from good to excellent for response time (range: 0.63-0.79) and from questionable to acceptable for accuracy (range: r = 0.52-0.69). Only DAT, the Mattis Dementia Rating Scale, the Symbol Digit Modalities Test, and Total Functional Capacity scores were able to detect a decline within a one-year follow-up in HD patients (all p< 0.05). In contrast with all the other cognitive tasks, DAT correlated with striatal atrophy over time (p = 0.037) but not with motor impairment. CONCLUSIONS: DAT is fast, reliable, motor-free, applicable in several languages, and able to unmask cognitive decline correlated with striatal atrophy in small cohorts of HD patients. This likely makes it a useful endpoint in future trials for HD and other neurodegenerative diseases.

Effectiveness of anti-psychotics and related drugs in the Huntington French-speaking group cohort.

PURPOSE: Huntington's disease is a rare condition. Patients are commonly treated with antipsychotics and tetrabenazine. The evidence of their effect on disease progression is limited and no comparative study between these drugs has been conducted. We therefore compared the effectiveness of antipsychotics on disease progression. METHODS: 956 patients from the Huntington French Speaking Group were followed for up to 8 years between 2002 and 2010. The effectiveness of treatments was assessed using Unified Huntington's Disease Rating Scale (UHDRS) scores and then compared using a mixed model adjusted on a multiple propensity score. RESULTS: 63% of patients were treated with antipsychotics during the survey period. The most commonly prescribed medications were dibenzodiazepines (38%), risperidone (13%), tetrabenazine (12%) and benzamides (12%). There was no difference between treatments on the motor and behavioural declines observed, after taking the patient profiles at the start of the drug prescription into account. In contrast, the functional decline was lower in the dibenzodiazepine group than the other antipsychotic groups (Total Functional Capacity: 0.41 ± 0.17 units per year vs. risperidone and 0.54 ± 0.19 vs. tetrabenazine, both p<0.05). Benzamides were less effective than other antipsychotics on cognitive evolution (Stroop interference, Stroop color and Literal fluency: p<0.05). CONCLUSIONS: Antipsychotics are widely used to treat patients with Huntington's disease. Although differences in motor or behavioural profiles between patients according to the antipsychotics used were small, there were differences in drug effectiveness on the evolution of functional and cognitive scores.