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

  • Author Footnotes
    1 These authors contributed equally to this work.
    Katia Youssov
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Département d'Études Cognitives, École normale supérieure, PSL University, 75005, Paris, France

    Université Paris-Est Créteil, Faculté de médecine, 94000, Créteil, France

    Inserm U955, Institut Mondor de Recherche Biomédicale, Équipe E01 NeuroPsychologie Interventionnelle, 94000, Créteil, France

    Assistance Publique Hôpitaux de Paris (AP-HP), Centre de référence Maladie de Huntington, Service de Neurologie, Hôpital Henri Mondor-Albert Chenevier, 94000, Créteil, France
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Etienne Audureau
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Université Paris-Est Créteil, Faculté de médecine, 94000, Créteil, France

    Assistance Publique Hôpitaux de Paris (AP-HP), Unité de Recherche Clinique (URC Mondor), Service de Santé Publique, Hôpital Henri Mondor-Albert Chenevier, 94000, Créteil, France

    Inserm U955, Institut Mondor de Recherche Biomédicale, CEpiA (Clinical Epidemiology and Ageing) Team, France
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  • Henri Vandendriessche
    Affiliations
    Département d'Études Cognitives, École normale supérieure, PSL University, 75005, Paris, France

    Université Paris-Est Créteil, Faculté de médecine, 94000, Créteil, France

    Inserm U955, Institut Mondor de Recherche Biomédicale, Équipe E01 NeuroPsychologie Interventionnelle, 94000, Créteil, France
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  • Graca Morgado
    Affiliations
    Inserm, Centre d’Investigation Clinique 1430, AP-HP, Hôpital Henri Mondor, Créteil, France
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  • Richard Layese
    Affiliations
    Assistance Publique Hôpitaux de Paris (AP-HP), Unité de Recherche Clinique (URC Mondor), Service de Santé Publique, Hôpital Henri Mondor-Albert Chenevier, 94000, Créteil, France
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  • Cyril Goizet
    Affiliations
    Centre de Reference Maladies Rares « Neurogénétique », Centre de compétence Maladies Rares « Maladie de Huntington », Service de Génétique Médicale, CHU Bordeaux and Univ. Bordeaux, Equipe « Neurogénétique Translationnelle – NRGEN », INCIA CNRS UMR5287 Université Bordeaux, Bordeaux, France
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  • Christophe Verny
    Affiliations
    Service de Neurologie, Centre de référence Huntington, Laboratoire Mitolab UMR CNRS 6015 - Inserm 1083, 49933, CHU d’ANGERS, France
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  • Marie-Laure Bourhis
    Affiliations
    Inserm, Centre d’Investigation Clinique 1430, AP-HP, Hôpital Henri Mondor, Créteil, France

    Inserm U955, Institut Mondor de Recherche Biomédicale, CEpiA (Clinical Epidemiology and Ageing) Team, France
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  • Anne-Catherine Bachoud-Lévi
    Correspondence
    Corresponding author. Service de Neurologie, Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France.
    Affiliations
    Département d'Études Cognitives, École normale supérieure, PSL University, 75005, Paris, France

    Université Paris-Est Créteil, Faculté de médecine, 94000, Créteil, France

    Inserm U955, Institut Mondor de Recherche Biomédicale, Équipe E01 NeuroPsychologie Interventionnelle, 94000, Créteil, France

    Assistance Publique Hôpitaux de Paris (AP-HP), Centre de référence Maladie de Huntington, Service de Neurologie, Hôpital Henri Mondor-Albert Chenevier, 94000, Créteil, France
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  • Author Footnotes
    1 These authors contributed equally to this work.
Open AccessPublished:August 24, 2022DOI:https://doi.org/10.1016/j.parkreldis.2022.08.023

      Highlights

      • Caregiver burden over time in Huntington disease must be considered to improve care.
      • Determinants of the evolution of caregiver burden are not limited to the stage of patients' disease.
      • Patients' stage, psychiatric disorders, and disease's dynamics condition burden.
      • Irritability, obsessions, and depression are major factors in caregiver burden.
      • Entry into the disease causes burden increase for caregivers.

      Abstract

      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.

      Keywords

      1. Introduction

      Huntington's disease (HD) is an inherited neurodegenerative disease with motor, cognitive and psychiatric impairments. HD causes significant disability and eventually death, with a median survival of 35 years after onset of symptoms in the European population [
      • Rodrigues F.B.
      • et al.
      Survival, mortality, causes and places of death in a European Huntington's disease prospective cohort.
      ]. The decline in cognitive and functional autonomy, the increase of movement disorders and the social issues require adjustments in the organization of patient's life along the course of the disease [
      • Glidden A.M.
      • et al.
      Patient-reported impact of symptoms in Huntington disease.
      ,
      • Ho A.K.
      • Hocaoglu M.B.
      G. European Huntington's Disease Network Quality of Life Working
      Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective.
      ].
      Yet, families face a particular situation related to the autosomal dominant transmission of HD: caregivers might be at risk of HD themselves, and family caregivers might also endorse a caregiving role for several relatives with HD [
      • Kjoelaas S.
      • Tillerås K.H.
      • Feragen K.B.
      The ripple effect: a qualitative overview of challenges when growing up in families affected by Huntington's disease.
      ,
      • Lewit-Mendes M.F.
      • et al.
      Young people living at risk of Huntington's disease: the lived experience.
      ,
      • Mand C.M.
      • et al.
      I'm scared of being like mum”: the Experience of Adolescents Living in Families with Huntington Disease.
      ]. While the burden on caregivers has been reported as higher in HD compared to other neurodegenerative diseases [
      • Mitchell L.A.
      • et al.
      Informal caregivers of clients with neurological conditions: profiles, patterns and risk factors for distress from a home care prevalence study.
      ], data capturing its different dimensions in order to alleviate them remain scarce [
      • Aubeeluck A.
      Caring for the carers: quality of life in Huntington's disease.
      ,
      • Aubeeluck A.V.
      • Buchanan H.
      • Stupple E.J.N.
      ‘All the burden on all the carers’: exploring quality of life with family caregivers of Huntington's disease patients.
      ]. Caregivers’ personal distress [
      • Yu M.
      • et al.
      Assessment of caregiver burden in Huntington's disease.
      ] and pejorative consequences on their personal life are rarely explored [
      • Røthing M.
      • Malterud K.
      • Frich J.C.
      Balancing needs as a family caregiver in H untington's disease: a qualitative interview study.
      ,
      • Williams J.K.
      • et al.
      Family carer personal concerns in Huntington disease.
      ]. High level of burden in caregivers may in turn place the care recipient at risk for poor care at home and cause premature institutionalization [
      • Aneshensel C.S.
      • et al.
      Caregiving careers and stress processes.
      ,
      • Roscoe L.A.
      • et al.
      Well-being of family caregivers of persons with late-stage Huntington's disease: lessons in stress and coping.
      ].
      The components that may affect the burden on caregiver may depend on a variety of factors centred both on the patients and/or on the caregiver him/herself. The most studied are the level of impairment of the person for whom care is provided, and the caregiver involvement in caregiving. Caregiver burden or distress has thus been associated with increasing time providing care, patients’ depression, motor and functional impairment, daily living autonomy loss and behavioral alterations, whereas mixed results have been reported for cognitive functioning [
      • Mitchell L.A.
      • et al.
      Informal caregivers of clients with neurological conditions: profiles, patterns and risk factors for distress from a home care prevalence study.
      ,
      • Schumacher-Kuiper M.M.
      • et al.
      Is there a relation between caregiver burden and cognitive dysfunction in Huntington's disease?.
      ]. Socioeconomic environment and support may also contribute to the burden: being a sole caregiver has been associated with higher burden and a higher risk for burnout [
      • Yu M.
      • et al.
      Assessment of caregiver burden in Huntington's disease.
      ], while satisfaction with social support has been found to be significantly associated with a positive evolution in quality of life in HD caregivers [
      • Ready R.E.
      • et al.
      Patient and caregiver quality of life in Huntington's disease. Movement disorders.
      ]. Other perceived difficulties for caregivers include a lack of understanding about persons with HD in the medical community, the difficult process to get routine care, emergency care and respite care, whereas the sense of mastery, spiritual involvement and beliefs as well as social support have been reported as protective factors against burden heaviness [
      • O'Connor E.J.
      • McCabe M.P.
      Predictors of quality of life in carers for people with a progressive neurological illness: a longitudinal study.
      ].
      Of note, there has been discrepancies in past reports regarding the tools used to assess burden or the focus on the caregiver, the patient or both. Most studies have measured health-related quality of life using self-reported health status scales (e.g., SF36), whereas only a few have used specific caregivers burden instruments such as the Zarit Burden Interview (ZBI) or the Caregiver Burden Inventory (CBI). Moreover, it should be noted that the burden of disease is not a static phenomenon; presumably, the recent and sudden emergence of the disease into the caregiver's life or many years of caregiving do not have the same impact. However, the dynamics of the longitudinal evolution of the burden scores have never been studied to our knowledge. Further, a comprehensive description of such dynamics along with their association with the characteristics of caregivers/patients is still missing, e.g., whether it appears relatively straightforward that professional help may relieve partially the burden, the profile of the pairs patients/caregivers who benefit the most from this help should be described. With that respect, unsupervised clustering approaches based on machine learning can prove useful to reveal typical or less typical subgroups sharing similar features and, possibly, to reveal novel phenotypes or combinations of risk factors.
      To address these questions, we conducted a clustering analysis on a prospective longitudinal multicenter study of caregiver/patient pairs. Our objective was to identify typical profiles and dynamics over a one-year follow-up period and characterize their clinical and perceived burden features, in a view to better understand the components of caregiver burden in HD and provide insights on the potential levers for relieving it.

      2. Methods

      2.1 Participants

      Participants from the Caregiver Burden in Huntington's Disease study (PHRI-HD: NCT02876445) included 179 prospectively and consecutively enrolled caregivers of home-dwelling HD patients, ranging from Stage I to Stage IV according to the Total functional capacity score, from March 2011 to 2015. Caregivers were informed of the study and included at the out-clinic consults and by advertisement in the Neurology Departments from three French centers: the French national reference center of HD (Henri Mondor Hospital, Créteil, N = 162), the reference center of HD (Angers, N = 11) and the competence center of HD (Bordeaux, N = 6).
      To concomitantly analyze data from caregivers participating to the PHRI-HD study and their patients' counterparts, patients' assessments were obtained and linked to those from their caregivers using two preexisting studies, namely Registry, the European multi-center observational study of patients with HD (European Huntington's Disease Network, NCT01590589) and the Biomarkers study (NCT01412125). Participants were informed about the purpose of this study before inclusion, and they gave their informed oral and written consent. This study was approved by the “Comité Consultatif sur le Traitement de l’Information en matière de Recherche dans le domaine de la Santé” (CCTIRS – ref 11–094) and declared to the “Commission Nationale de l'Informatique et des Libertés” (CNIL – ref: EGY/FLR/AR123923).

      2.2 Procedures

      The duration of the study was one year for each participant. Participants were assessed twice, once at baseline and once at the end of the study (caregivers: median 378 days, IQR [355; 433]; patients: median 367 days, IQR [356; 385]).

      2.2.1 Caregiver questionnaires

      We used the Zarit Burden Interview (ZBI) [
      • Zarit S.
      • Orr N.K.
      • Zarit J.M.
      The Hidden Victims of Alzheimer's Disease: Families under Stress.
      ], a 22-item interviewer-administrated questionnaire, designed to assess the degree of burden in caregivers (0 no to 88 max burden) and the Memory and Behavioral Problems Checklist (MBPC) [
      • Zarit S.
      • Zarit J.
      The Memory and Behavior Problems checklist-1987R and the Burden Interview.
      ], a 30-items interviewer-administrated questionnaire intended to assess both the frequency of problems and the impact of these problems on the caregiver (from 0 normal to 68 points the worse), the latter being divided in behavioral and autonomy scores, with respectively 17 and 13 items. Such questionnaires have been extensively used in neurodegenerative diseases [
      • Gilsenan J.
      • Gorman C.
      • Shevlin M.
      Explaining Caregiver Burden in a Large Sample of UK Dementia Caregivers: the Role of Contextual Factors, Behavioural Problems, Psychological Resilience, and Anticipatory Grief.
      ], such as Alzheimer's or Parkinson's disease and have been translated in numerous languages, thus allowing potential comparisons in future studies. In addition, a questionnaire for demographics and socioeconomic status of the caregiver, his/her relationships to the patient, and the life conditions of the care recipients were also provided.

      2.2.2 Patients’ assessments

      Patients were evaluated using the Unified Huntington's Disease Rating Scale (UHDRS). It combines demographics information and (i) the total motor score (TMS) assessing chorea, dystonia, oculomotor disorders, gait and walking disorders, etc. (0: normal, 124 maximum disorders); (ii) cognitive scores including the Stroop Word Reading, the Symbol Digit modality Test (SDMT), the literal fluency; with higher scores indicating higher performance; (iii) the psychological and behavioral evaluation including five subscores: depressive mood (depression, low self-esteem, anxiety, and suicidal ideas), aggressiveness/irritability, obsessional/compulsive behavior, psychotic symptoms (delusions and hallucinations), and apathy (higher scores indicating more symptoms), and (iv) three scales evaluating the functional level: the independence scale (IS) from 100 normal to 0 bedridden, the functional assessment scale (FAS) using 25 yes/no questions about the patient current capacity in daily life activities, and the total functional capacity (TFC) about the patient potential capacity from 13 (normal) to 0 (institutionalization and permanent care). Patients' assessment was completed with the Mattis dementia Rating Scale (MDRS).

      2.3 Statistical analyses

      The main part of the analysis sought to identify typical profiles of caregivers based on their perceived burden while also considering the clinical characteristics of the patients' counterparts. To that end, we applied unsupervised (without a priori hypothesis) clustering analysis based on both measurements at the latest follow-up (M12) and the evolution over the past year (change from M0-M12) to account for the dynamics at play. Detailed characteristics used for clustering can be seen in Fig. 1, including all patients assessments from the UHDRS and MDRS as previously described, considering both measurements at the latest follow-up and the quantitative change over the last year. Clustering analysis relied on the building of self-organizing maps (SOMs), a nonparametric approach based on Kohonen's neural networks allowing to convert multidimensional datasets with large numbers of variables into simplified grids displayed as two-dimensional maps.
      Fig. 1
      Fig. 1Clustering analysis by self-organized maps (SOM)
      Results from the clustering analysis by self-organized maps
      - Left part: based on expert-driven visual identification of key patterns in the self-organized maps (SOM) on the right, close districts were combined to provide four suitable clusters of caregivers/patients' pairs. Clusters boundaries are delimited by solid black lines.
      - Right part: unsupervised analysis by SOM placed all pairs of participants identified as globally similar for clinical parameters and self-reported burden within 1 of 66 small groupings (districts) throughout the map. The more participants resemble in terms of global phenotyping, the closer they are placed on the map. Each individual map shows the mean values or proportions per district for each characteristic, blue colors indicating the clinically best average values and red colors the worse, with detailed numbers shown for a selection of representative districts in each SOM.
      SOMs algorithms assign each individual into a specific area on the map based on his/her characteristics, placing similar individuals in close proximity and distinct ones in remote locations and thus allowing to draw visual comparisons of unique or overlapping patients’ characteristics and disease subtypes. The SOMs were constructed applying the approach developed within the Numero package framework for the R statistical platform, by i) building the SOMs with statistical verification of the robustness of the contrasts observed through permutation tests and ii) determining suitable groupings based on the direct visualization of data patterns and key characteristics of the dataset.
      Comparisons in sociodemographic and clinical features between caregivers/patients' groups based on the identified clusters were performed using one-way ANOVA or Kruskall-Wallis tests for continuous data and using Chi-square tests or Fisher's exact tests for categorical data, as appropriate. For illustrative purpose, 2-D biplots were charted to visualize the contrasted characteristics according to disease stage (I to IV) and clusters.
      Missing data rates of variables used for the clustering ranged from 0% (ZBI, TFC) to 53% (MDRS), with most variables having less than 30% missing data. Variables with missing information were imputed for all clustering analyses using the missforest algorithm, a nonparametric imputation method based on random forest that accommodates nonlinearities and interactions. Data were assumed to be missing at random, conditional on the other covariates. Descriptive statistics before/after imputation are given in Supplemental Table 1 in Appendix. A sensitivity analysis was performed discarding all variables with missing rate >40% and found similar results to those from the main analysis; only results from the main analysis are thus showed in the present paper.
      Analyses were performed using Stata 16.1 (StataCorp, Tx, USA) for descriptive analyses and between-groups comparisons, and R 3.6.3 statistical software (R Foundation, Vienna, Austria; missforest, pca3d and Numero packages) for imputation, clustering analyses and visualizations.

      3. Results

      3.1 Study population and comparative analyses according to disease stage

      Out of an initial number of 179 caregivers enrolled, 3 were secondarily excluded because of withdrawal of consent and 28 did not attend the 12-month follow-up visit (loss to follow-up, N = 22; patient's institutionalization, N = 3; patient's death, N = 2; broken relationship, N = 1) and were left out of the present analysis. Out of the remaining 148 caregivers (83%), linkage of datasets was possible with their patients' counterparts for 105 caregivers (59%), with 77 patients having available clinical data at M0 and M12, 7 at M12 only and 21 at M0 only. A comparison of the main characteristics at inclusion of the 105 caregivers-patients included to the 71 excluded pairs with available data found no statistically significant difference between the two groups (Supplemental Table 2 in the Appendix).
      Characteristics of patients and their caregivers according to disease stage at the latest follow-up are shown in Table 1. As expected, patients with advanced disease stage (III and IV) were older and had the worst clinical scores relating to functional scales, motor examination, cognitive functions, with corresponding caregivers declaring the worst ZBI and MBPC scores at the latest follow-up.
      Table 1Main characteristics of the study population at the latest follow-up, overall and by disease stage.
      N completeTotalDisease stagep-value
      IIIIIIIV
      N = 105N = 21N = 31N = 29N = 24
      Patients characteristics
      Gender, males9846 (46.9%)12 (57.1%)13 (44.8%)12 (48.0%)9 (39.1%)0.681
      Age, years9755.3 (±11.7)48.9 (±10.7)53.6 (±12.0)62.4 (±9.6)56.1 (±10.5)0.001
      UHDRS Total Functional Capacity (TFC)1056.6 (±3.8)11.6 (±1.0)8.5 (±1.4)5.2 (±1.7)1.3 (±0.6)<0.001
      UHDRS Total Motor Score (TMS)8451.3 (±23.1)25.1 (±14.1)42.4 (±11.9)56.4 (±14.0)81.7 (±11.1)<0.001
      Mattis dementia rating scale (MDRS) total score54118.9 (±18.9)134.6 (±8.4)122.3 (±12.9)103.2 (±14.3)60.0 (N = 1)<0.001
      Stroop Word Reading test (SWR)7941.9 (±23.6)65.8 (±17.1)49.0 (±17.6)33.3 (±18.2)19.7 (±17.4)<0.001
      Symbol Digit Modalities Test (SDMT)7415.0 (±12.0)28.1 (±10.0)18.0 (±9.1)8.4 (±6.4)2.3 (±3.4)<0.001
      UHDRS Functional Assessment8414.3 (±7.8)23.5 (±2.0)18.0 (±3.8)12.1 (±4.8)3.5 (±3.3)<0.001
      UHDRS Independence Scale8468.6 (±18.3)92.6 (±8.9)75.0 (±7.2)62.3 (±8.8)45.3 (±10.5)<0.001
      UHDRS-b Depression814.1 (±4.3)5.4 (±4.1)2.2 (±2.2)5.3 (±5.6)4.1 (±4.1)0.046
      UHDRS-b Irritability/aggression811.9 (±3.6)0.9 (±1.4)1.0 (±1.7)2.0 (±2.8)3.8 (±6.5)0.053
      UHDRS-b Apathy812.4 (±2.8)0.7 (±1.1)1.2 (±1.7)3.0 (±2.6)5.0 (±3.2)<0.001
      UHDRS-b Obsessive/compulsive813.0 (±4.1)0.9 (±2.0)1.6 (±2.0)3.6 (±4.4)6.2 (±5.3)<0.001
      UHDRS-b Psychosis810.1 (±0.5)0.0 (±0.0)0.0 (±0.2)0.2 (±0.8)0.1 (±0.2)0.698
      Caregivers characteristics
      Gender, males10537 (35.2%)6 (28.6%)13 (41.9%)10 (34.5%)8 (33.3%)0.786
      Age, years10556.8 (±14.2)51.8 (±14.2)56.2 (±12.0)57.5 (±16.9)60.9 (±12.5)0.193
      Family relationship with the patientPartner10571 (67.6%)16 (76.2%)21 (67.7%)20 (69.0%)14 (58.3%)0.137
      Child12 (11.4%)0 (0.0%)4 (12.9%)3 (10.3%)5 (20.8%)
      Parent16 (15.2%)2 (9.5%)3 (9.7%)6 (20.7%)5 (20.8%)
      Friend6 (5.7%)3 (14.3%)3 (9.7%)0 (0.0%)0 (0.0%)
      Caregiving full responsabilityComplete9747 (48.5%)5 (31.3%)11 (39.3%)15 (51.7%)16 (66.7%)
      Partial50 (51.5%)11 (68.8%)17 (60.7%)14 (48.3%)8 (33.3%)0.105
      If partial, patient caregiving weekly time (hours/week)4714.0 (7.0; 28.0)7.0 (7.0; 14.0)14.0 (7.0; 24.5)14.0 (7.0; 21.0)45.5 (24.5; 71.0)0.003
      Global patient caregiving weekly time (hours/week)94154.0 (14.0; 168.0)14.0 (7.0; 168.0)28.0 (14.0; 168.0)168.0 (14.0; 168.0)168.0 (71.0; 168.0)0.030
      Patient caregiving overall duration (years)986.7 (±5.0)3.1 (±4.0)4.8 (±3.3)7.6 (±4.9)10.2 (±5.1)<0.001
      Total Zarit Burden Interview (/88)10533.8 (±17.4)26.5 (±12.9)27.5 (±15.1)39.7 (±16.2)41.2 (±20.2)0.001
      Mean MBPC-behavior (/16)1021.7 (±1.5)1.3 (±1.3)1.2 (±1.2)2.0 (±1.7)2.4 (±1.7)0.019
      Mean MBPC-autonomy (/16)1022.6 (±3.2)0.6 (±1.0)1.0 (±1.7)4.2 (±3.0)4.8 (±4.1)<0.001
      Support
       Additional caregiver/help10598 (93.3%)15 (71.4%)31 (100.0%)28 (96.6%)24 (100.0%)<0.001
        Additional familial caregiver10526 (24.8%)2 (9.5%)11 (35.5%)7 (24.1%)6 (25.0%)0.209
        Patient's psychological support10519 (18.1%)5 (23.8%)6 (19.4%)5 (17.2%)3 (12.5%)0.797
        Patient's rehabilitation10583 (79.0%)13 (61.9%)25 (80.6%)27 (93.1%)18 (75.0%)0.058
        Care taker/Nurse auxillary/professional care giver10547 (44.8%)3 (14.3%)10 (32.3%)16 (55.2%)18 (75.0%)<0.001
      MBPC: Memory and Behavior Problems Checklist; SD: standard deviation; UHDRS-b: behavioral section of the Unified Huntington's Disease Rating Scale.
      Results are N(%), mean (±standard deviation) or median (interquartile range).

      3.2 Clustering analysis

      Fig. 1 shows the clustering analysis with the SOM methodology, displaying polarized distributions of patient characteristics across the maps, as evidenced by the contrasting colorings from blue (lowest values) to red (highest values). From these results, four clusters of caregivers-patients’ pairs with homogenous features were built. Cluster boundaries are shown at the top left of Fig. 1 and as solid black lines across the maps, with detailed clinical characteristics presented in Table 2.
      Table 2Main characteristics according to the clusters from the SOM analysis: clinical features.
      Cluster ACluster BCluster CCluster Dp-value
      N = 30N = 22N = 27N = 26
      Mean (±SD)Mean (±SD)Mean (±SD)Mean (±SD)
      Values at one-year follow-up
       Total Zarit Burden Interview (/88)51.8 (±14.0)26.2 (±11.1)17.0 (±9.3)36.8 (±9.5)<0.001
       Mean MBPC-behavior (/16)2.7 (±2.0)1.5 (±1.0)1.0 (±1.0)1.5 (±1.2)0.001
       Mean MBPC-autonomy (/16)4.2 (±3.2)4.6 (±4.1)0.9 (±1.7)1.0 (±1.1)<0.001
       UHDRS Total Functional Capacity (TFC)4.0 (±2.4)2.8 (±2.3)9.2 (±2.3)10.0 (±2.1)<0.001
       UHDRS Total Motor Score (TMS)63.2 (±14.1)75.2 (±15.9)38.4 (±12.5)33.1 (±13.1)<0.001
       Mattis dementia rating scale (MDRS) total score96.7 (±13.5)97.4 (±8.1)123.6 (±12.1)129.4 (±8.6)<0.001
       Stroop Word Reading test (SWR)30.1 (±14.4)17.1 (±14.0)53.4 (±13.7)60.6 (±14.5)<0.001
       Symbol Digit Modalities Test (SDMT)5.8 (±5.2)4.5 (±4.7)19.0 (±8.7)23.4 (±9.8)<0.001
       UHDRS Functional Assessment9.0 (±5.1)6.6 (±4.9)19.3 (±3.4)21.2 (±3.2)<0.001
       UHDRS Independence Scale56.5 (±10.4)52.1 (±11.3)80.0 (±10.1)82.8 (±11.4)<0.001
       UHDRS-b Depression4.4 (±5.3)3.7 (±3.0)3.5 (±2.5)4.5 (±3.8)0.782
       UHDRS-b Irritability/aggression3.6 (±5.2)1.1 (±1.4)0.5 (±0.8)1.0 (±1.5)0.027
       UHDRS-b Apathy3.4 (±2.5)4.7 (±2.7)0.7 (±1.3)0.8 (±0.9)<0.001
       UHDRS-b Obsessive/compulsive5.3 (±4.9)3.7 (±3.4)1.3 (±1.8)1.1 (±1.6)<0.001
       UHDRS-b Psychosis0.0 (±0.0)0.2 (±0.9)0.0 (±0.0)0.0 (±0.2)0.944
      Changes over one-year interval
       Total Zarit Burden Interview (/88)5.9 (±9.3)−9.2 (±11.5)−2.0 (±8.7)11.0 (±10.8)<0.001
       Mean MBPC-behavior (/16)0.0 (±1.7)−0.1 (±1.1)0.0 (±0.8)0.5 (±1.5)0.241
       Mean MBPC-autonomy (/16)−0.1 (±3.7)1.7 (±4.3)0.1 (±0.9)0.4 (±1.1)0.191
       UHDRS Total Functional Capacity (TFC)−1.1 (±1.2)−1.2 (±2.2)−0.9 (±1.2)−0.6 (±1.3)0.627
       UHDRS Total Motor Score (TMS)8.6 (±9.6)6.6 (±5.8)3.3 (±6.3)5.9 (±6.4)0.103
       Mattis dementia rating scale (MDRS) total score−8.1 (±5.8)−10.0 (±3.6)1.3 (±5.5)0.0 (±5.2)<0.001
       Stroop Word Reading test (SWR)−8.3 (±11.1)−10.8 (±8.4)−5.2 (±7.3)−4.0 (±15.8)0.034
       Symbol Digit Modalities Test (SDMT)−4.2 (±3.0)−2.1 (±1.9)−1.8 (±3.7)−2.8 (±6.3)0.008
       UHDRS Functional Assessment−2.3 (±2.6)−2.1 (±3.0)−0.7 (±1.7)−0.9 (±1.8)0.002
       UHDRS Independence Scale−6.3 (±6.3)−4.5 (±5.8)−2.5 (±4.3)−4.4 (±6.1)0.043
       UHDRS-b Depression−1.0 (±6.4)−1.8 (±3.7)−0.8 (±2.2)1.2 (±2.8)0.005
       UHDRS-b Irritability/aggression−1.4 (±5.4)−0.7 (±1.9)−1.4 (±3.4)−0.4 (±2.6)0.383
       UHDRS-b Apathy0.1 (±2.7)−0.4 (±1.9)−0.3 (±1.8)−0.1 (±1.5)0.362
       UHDRS-b Obsessive/compulsive0.1 (±3.7)−1.2 (±3.4)0.3 (±1.9)−0.4 (±3.4)0.103
       UHDRS-b Psychosis−0.3 (±1.6)0.2 (±0.9)0.0 (±0.0)0.0 (±0.2)0.218
      MBPC: Memory and Behavior Problems Checklist; SD: standard deviation; UHDRS-b: behavioral section of the Unified Huntington's Disease Rating Scale.
      Cluster A (N = 30, 29%) and Cluster B (N = 22, 21%) were in the lower area of the maps, comprising patients with the most advanced disease stages as indicated by the higher values in motor score and lower values in TFC, MDRS, Stroop Word Reading, SDMT and FAS. Notably, Clusters A and B differed in key clinical and behavioral components with patients from Cluster A having higher values in UHDRS OCB and irritability and, in turn, corresponding caregivers reporting higher MBPC behavior and Zarit burden interview scores, and patients from Cluster B having the highest UHDRS apathy score. Regarding changes over the past year, patients from Cluster A were also characterized by a more marked decrease in SDMT and increase in motor score. In contrast, even though patients from Cluster B declined cognitively and functionally, their caregivers’ ZBI score improved over a year.
      Cluster C (N = 27, 26%) and Cluster D (N = 26, 25%) included patients from the upper area of the maps, characterized by earlier stages of disease, with corresponding higher values in TFC, Functional assessment, MDRS, Stroop Word reading/SDMT and lower values in motor score. Patients from Cluster D were characterized by higher values in Zarit Burden Interview score. Of note, dynamics over the 1-year follow-up period differed between those two clusters, with Cluster D showing a higher increase in UHDRS-Depression along with a clear increase in Zarit Burden in corresponding caregivers.
      Demographic and socioeconomic characteristics of the four clusters are given in Table 3. Patients from Clusters A and B were older with longer duration of caring, while no significant difference was found regarding gender in both patients and caregivers, or regarding caregivers' professional activity, patients’ living place. Perceived time of caregiving and the professional help (like auxiliary nurses at home) differed across clusters significantly.
      Table 3Main characteristics according to the clusters from the SOM analysis: socioeconomical features.
      Cluster ACluster BCluster CCluster Dp-value
      N = 30N = 22N = 27N = 26
      Patients characteristics
       Age, years61.1 (±8.1)60.1 (±11.9)57.9 (±10.6)48.9 (±12.0)0.001
       Gender, males16 (61.5%)5 (31.3%)8 (40.0%)12 (54.5%)0.206
       Disease stageI0 (0.0%)0 (0.0%)7 (25.9%)14 (53.8%)<0.001
      II3 (10.0%)2 (9.1%)16 (59.3%)10 (38.5%)
      III17 (56.7%)6 (27.3%)4 (14.8%)2 (7.7%)
      IV10 (33.3%)14 (63.6%)0 (0.0%)0 (0.0%)
       Living in the countryside5 (17.2%)10 (45.5%)7 (25.9%)9 (34.6%)0.155
      Caregivers characteristics
       Age, years58.4 (±14.1)58.7 (±16.1)56.1 (±15.0)53.9 (±11.7)0.591
       Gender, males7 (23.3%)8 (36.4%)13 (48.1%)9 (34.6%)0.278
       Number of caregiver's children2.0 (1.0; 2.0)2.0 (1.0; 3.0)2.0 (1.0; 3.0)2.0 (2.0; 2.0)0.851
       Caregiver's children, <18y4 (13.3%)5 (22.7%)5 (18.5%)7 (26.9%)0.626
       Caregiver living at home with patient24 (80.0%)18 (81.8%)21 (77.8%)21 (80.8%)0.987
       Other family members living with the disease23 (76.7%)12 (54.5%)16 (59.3%)19 (76.0%)0.214
       Caring additional patient with the disease4 (13.3%)2 (9.1%)2 (7.4%)8 (32.0%)0.061
       Marital status, living alone6 (20.0%)7 (31.8%)6 (22.2%)6 (23.1%)0.786
       Family relationship with the patientPartner22 (73.3%)11 (50.0%)18 (66.7%)19 (73.1%)0.047
      Child3 (10.0%)4 (18.2%)2 (7.4%)2 (7.7%)
      Parent5 (16.7%)7 (31.8%)2 (7.4%)3 (11.5%)
      Friend0 (0.0%)0 (0.0%)5 (18.5%)2 (7.7%)
       Professional activityNone/Retired16 (53.3%)12 (54.5%)15 (55.6%)9 (34.6%)0.376
      Active14 (46.7%)10 (45.5%)12 (44.4%)17 (65.4%)
       Patient caregiving overall duration (years)9.5 (±5.0)10.0 (±5.6)5.6 (±3.9)5.1 (±3.7)<0.001
       Caregiving full responsabilityComplete19 (63.3%)13 (59.1%)9 (37.5%)7 (31.8%)0.065
      Partial11 (36.7%)9 (40.9%)15 (62.5%)15 (68.2%)
       If partial, patient caregiving weekly time (hours/week)Mean (±SD)28.1 (±19.3)28.4 (±18.2)20.2 (±19.4)23.8 (±24.1)0.745
      Median (IQR)21.0 (14.0; 35.0)22.5 (17.5; 31.5)14.0 (7.0; 28.0)14.0 (7.0; 28.0)0.220
       Global patient caregiving weekly time (hours/week)Mean (±SD)119.8 (±68.6)114.8 (±70.3)75.6 (±74.6)71.9 (±72.3)0.034
      Median (IQR)168.0 (35.0; 168.0)168.0 (28.0; 168.0)28.0 (10.5; 168.0)28.0 (14.0; 168.0)0.024
       Additional caregiver/help29 (96.7%)22 (100.0%)23 (85.2%)24 (92.3%)0.169
        Additional familial caregiver6 (20.0%)8 (36.4%)8 (29.6%)4 (15.4%)0.318
        Patient's psychological support5 (16.7%)4 (18.2%)3 (11.1%)7 (26.9%)0.513
        Patient's rehabilitation25 (83.3%)19 (86.4%)17 (63.0%)22 (84.6%)0.125
        Care taker/Nurse auxillary/professional care giver21 (70.0%)14 (63.6%)5 (18.5%)7 (26.9%)<0.001
      A 2-D biplot representation of the typical characteristics of the patients and caregivers is given in Supplemental Fig. 1 (Appendix), according to disease stage (Supplemental Fig. 1A) and the four clusters (Supplemental Fig. 1B) identified by SOM analysis. In brief, correlations were found between variables (represented as arrows) relating with disease stage (TMS, TFC), MBPC autonomy and UHDRS Apathy, as indicated by the parallel arrows. In contrast, variables relating to burden (ZBI), MBPC behavior, UHDRS irritability and OCB were correlated and orthogonal to disease stage variables, suggesting that burden was not strictly colinear with disease stage. Whereas patients (indicated as dots) colored by disease stage projected along the horizontal axis, patients colored by clusters allowed a more subtle repartition between Clusters A and D located higher along the vertical axis (thus with higher burden), while Clusters B and C were located lower (thus with less burden).

      4. Discussion

      4.1 Main findings

      We performed a one-year longitudinal study exploring the subjective burden of caregivers of patients with HD at various stages of their disease. By pooling an evaluation of 105 caregivers to the clinical assessment of the patients they cared for, we conducted a clustering analysis to explore the associations between burden scores obtained from the ZBI and the MBPC, and the motor, cognitive, behavioral, and functional assessment of patients with HD as well as their sociodemographic data. Out of the four clusters identified, two included severe patients in advanced disease stages showing contrasted levels and evolution in burden score: in Cluster A characterized by remarkedly high levels in patients' irritability and obsessive-compulsive behaviors, burden was heavy and increased over time, while burden was relatively low and relieved over time in Cluster B, where patients' apathy levels were the highest. Clusters C and D both consisted of patients at earlier stages with only low to moderate impairments, but with opposite directions in burden score evolution: stable in Cluster C but notably increasing in Cluster D along with a marked increase in patients' depression scores. Our findings are indicative of the complex dynamics influencing caregivers' perceived burden, demonstrating the importance of both patients’ disease stage and quantitative level of impairment, but also highlighting the influence of specific psychiatric and behavioral disorders.

      4.2 Influence of disease stage and behavioral components

      Some of our findings were comparable to those from previous studies [
      • Domaradzki J.
      The impact of Huntington disease on family carers: a literature overview.
      ]: the characteristics of the study population by disease stages showed that the burden for the caregiver correlated with the progression of HD symptom (motor, cognitive and functional) along with the age of the patient and the overall patient caregiving duration. Accordingly in our clustering analysis, the caregivers of the oldest patients with advanced stages and more marked psychiatric disorders (Cluster A) had the highest level of burden. Of note, the clustering analysis revealed more complex associations between disease stage and caregiver strain, as indicated by the heavy burden perceived by caregivers of patients from Cluster A showing more prevalent behavioral manifestations such as irritability and OCB, in contrast with the low burden levels observed in Cluster B where patients' apathy prevailed. This possible influential role of patients' irritability on caregivers’ burden is consistent with past reports [
      • Yu M.
      • et al.
      Assessment of caregiver burden in Huntington's disease.
      ].
      Further supporting the lack of a strict correlation between age/stage disease and burden, our analysis also identified a subgroup of caregivers of the youngest patients (Cluster D) who could also have a significant burden, despite the relatively early stage of patients, and higher than caregivers from Clusters B and C. In a recent cross-sectional study, conducted in 50 pairs of HD patients with their caregivers [
      • Hergert D.C.
      • Cimino C.R.
      Predictors of caregiver burden in Huntington’s disease.
      ], young age of caregivers was associated with increased burden when controlling for symptoms severity. This observation might be at least partially explained by the high level of stress and emotional burden in young caregivers more often dealing with a relatively recent diagnosis, at a time in their life when some of their main concerns are parenthood, children's education and professional life, and when they rely on the support of their relatives [
      • Kanuit A.
      The Experiences of Huntington's Disease Caregivers.
      ].

      4.3 Depression trends over one-year interval in earlier stages

      The data obtained in the intermediate clusters reinforce the hypothesis according to which the entry of the disease into the family contributes to the feeling of the burden. First, the significant worsening of depression measured by the UHDRS in patients from Cluster D is a likely contributor to the increase in burden over time in early stages patients' caregivers. The link between depression in patients and caregivers' burden has already been reported [
      • Mitchell L.A.
      • et al.
      Informal caregivers of clients with neurological conditions: profiles, patterns and risk factors for distress from a home care prevalence study.
      ]; here, the intensity of the burden experienced by caregivers was related to the increase in patients' depression between the two assessments. This may reflect the difficulty of facing the disease at the beginning of the disease when coping strategies have not yet reduced the psychological burden. The lack of longitudinal evaluation of mood in caregivers in our study limits the interpretation. Presumably, especially in the early stage, the change in the patient's mood may impact the mood of the caregiver, hence the perceived burden. Yet, it is also possible to assume the opposite: that a drop in mood in the caregiver (which causes an increase in the burden) leads to a drop in mood in the care receiver. Both explanations are consistent with the prevalence of self-reported depression among the family controls (N = 2358) participating to the global registry study, Enroll-HD, being mostly family caregivers. Interestingly those family controls also suffered from cognitive impairment, probably related to the burden and/or to the depressive mood [
      • Achenbach J.
      • Saft C.
      Another perspective on Huntington's disease: disease burden in family members and pre-manifest HD when compared to genotype-negative participants from ENROLL-HD.
      ].
      These findings support the interest of considering the temporal dynamics of caregiving. Our longitudinal analysis unmasked the potential effect on burden of worsening trends in depression, which may help clarify their link with the burden score from previous studies (see Ref. [
      • Schumacher-Kuiper M.M.
      • et al.
      Is there a relation between caregiver burden and cognitive dysfunction in Huntington's disease?.
      ] for negative results). Beyond considering the effect of a single influential factor such as irritability, there is a need to further study the combination of various factors and their evolution over time to better understand the factors that affect the lives of caregivers.

      4.4 Other factors

      Additional factors were investigated. In our study, we did not find any association between gender and burden. However, gender was equally distributed among the patients (48% women), while caregivers were mostly women (63%). Among possible explanations, it might be the case that men caregivers have given up caring earlier than women or alternatively that they died earlier.
      Significant associations were found between advanced disease stages (i.e., stages III and IV vs. I and II; Clusters A and B vs. C and D) and the amount of additional help setup (any kind or nurse auxiliary). Of note, we did not find a direct association between burden and the amount of professional help at home, as indicated by Clusters A and D having the worst burden levels whilst Clusters A and B had the highest levels of help, in keeping with the more advanced disease stages of these two groups. This does not imply that this help is not needed, rather it could suggest that the establishment and increase of professional assistance follows the needs without completely easing the burden on caregivers. Indeed, counterintuitively the frequency of seeking psychological support decreases as stage of the disease increases. This could underline that psychological support is even more useful in the early stages at the moment coping skills coming to be established.

      4.5 Implications

      Our comprehensive longitudinal study confirms the pejorative role of high staging and the wear of the caregiver after long-lasting caregiving duration but also, in contrast, the difficulties encountered at disease entry at a stage where patients and their family try to keep “normal” life as much as possible.
      The relatively low burden in Cluster B (in which patients are quite severe) might also rely on the balance between the stressfulness of the situation and the perceived benefits in caregiving for some more resilient caregivers, as it was already found previously [
      • Roscoe L.A.
      • et al.
      Well-being of family caregivers of persons with late-stage Huntington's disease: lessons in stress and coping.
      ], indicating that it could be a valuable strategy to reinforce efficient coping strategies and the social support to help the caregivers at later stages.
      However, social and psychological support does not sum up the panoply of possibilities for helping patients and their families. Medicines must also be adapted. For example, irritability is currently one of the symptoms most monitored by experts in view to prevent family burden and social impact [
      • Karagas N.E.
      • Rocha N.P.
      • Stimming E.F.
      Irritability in Huntington's disease.
      ]. When high irritability or aggression scores are detected, the pharmacological response must be adapted according to the most recent recommendations, i.e. taking into account the interest of the treatments (pharmacological and non-pharmacological) that have the greatest effect on patient anxiety [
      • Bachoud-Lévi A.-C.
      • et al.
      International guidelines for the treatment of Huntington's disease.
      ]. Finding ways of moderating this symptom as early as possible and throughout the course of the disease by making patients and their caregivers aware of this salient aspect of Huntington's disease is useful.
      Detecting and treating mood disorders, anxiety, and depression in patients and in their caregivers also appears to be a major lever in overall management. Whatever the causal link between the caregiver's mood and the patient's mood, reducing the depression in one of the members of the pair should alleviate depression in the other member and may also have an impact on the survival of everyone. Indeed, in a non-HD study [
      • Schulz R.
      • Beach S.R.
      • Friedman E.M.
      Caregiving factors as predictors of care recipient mortality.
      ], caregiver burden and care recipient depression were found as independent predictors of care recipient mortality in 1262 adults dealing with disability, and their caregivers, over 65 years old. The same authors had previously demonstrated [
      • Schulz R.
      • Beach S.R.
      Caregiving as a risk factor for mortality.
      ] that being a caregiver is an independent risk factor of mortality among elderly caregivers (spouses).
      Otherwise, if being married is possibly a factor that favors home care [
      • Winder J.Y.
      • Achterberg W.P.
      • Roos R.A.C.
      Marriage as protector for nursing home admission in Huntington's disease.
      ], spouses must be supported from the early stages of HD, since the impact on the caregiver can be felt in a marked way and worsen over time. Similarly, unmarried patients should receive early professional help to achieve a level of comfort and security close to that of living with a family, perhaps ensuring a longer stay at home. Further research on the living place and its potential impact on daily life and social environment is needed to increase our knowledge on the difficulties and advantages of each lifestyle and create opportunities for home adaptation, community contact, support for transportation, etc. that might help the caregiver-patient pair to keep their way of living as long as possible.
      The need for both professional help for daily life, and psychological support has been raised in some studies on actual care provision and HD community unmet needs [
      • Etchegary H.
      Healthcare experiences of families affected by Huntington disease: need for improved care.
      ,
      • Soltysiak B.
      • Gardiner P.
      • Skirton H.
      Exploring supportive care for individuals affected by Huntington disease and their family caregivers in a community setting.
      ]: it seems that education of the patient (and of the caregiver) to cope with the disease, and psychologic support remain insufficient. Our results suggests that the earlier the caregiver is discharged from some daily activities by professional helps the better.
      However, to disentangle all aspects of caregiver burden, quantitative data on the dynamics of home care would be useful. While the amount of support time provided by professionals and non-professionals has been documented, questions about the use of support could perhaps refine the factors of burden of care. Although Zarit's interview on burden [
      • Zarit S.
      • Orr N.K.
      • Zarit J.M.
      The Hidden Victims of Alzheimer's Disease: Families under Stress.
      ] has many benefits for dissemination, it does not address the mechanisms of burden. Collecting each change rather than just at the beginning and end of the study (demographic, economic, clinical and care data, including medication) would likely strengthen our conclusions. This would likely require the study of a large cohort of patient-caregiver pairs to enable machine learning statistics. However, such a study might seem disproportionate if it is not endorsed by health policy at its inception.
      This sustains the need for others longitudinal studies in view to better assess the suspected link between caregiver burden, and environmental factors as living place, professional help, as well as caregiver mood. Meanwhile, mainstream publications, diffusion of guidelines for well-being and “know-how” are required to assist every user, family (patients, partners, children, friend), social environment, professional caregivers who are beginners in HD community. It is particularly urgent to strengthen the capacity of caregivers to manage daily life and to experience less burden, since they carry at home, for years, a large part of the responsibility for the daily stimulation necessary for a more active cognitive lifestyle as well as for the installation and maintenance of physical activities, which are both now presumed to have a neuroprotective potential [
      • Garcia-Gorro C.
      • et al.
      An active cognitive lifestyle as a potential neuroprotective factor in Huntington's disease.
      ]. Recent development of patient-education programs for HD in France (as previously published in the Nederland regarding the PEP-HD program [
      • A'Campo L.E.
      • Spliethoff-Kamminga N.G.
      • Roos R.A.
      The patient education program for Huntington's disease (PEP-HD).
      ]), started from reference centers well trained in HD, then using e-programs to help to spread the good practices on rural locations for instance, will help both for empowerment of patients and caregivers. The community would benefit from its emergence as a next “gold standard” for care, including implementation of palliative care approach as well as the development of trials in emerging and advanced therapies.

      Author contributions

      (1) The conception and design of the study, or acquisition of data, or analysis and interpretation of data.
      (2) Drafting the article or revising it critically for important intellectual content.
      (3) Final approval of the version to be submitted.
      KY: 1, 2,3; EA: 1, 2, 3; HV: 1, 3; GM:1,3; RL: 2, 3; CG: 1, 3; CV: 1, 3; MLB: 1, 3; ACBL 1, 2,3.

      Funding

      The PHRI-HD study was supported by a grant from the French Ministry of Health (Hospital Program for Nursing Research PHRI 2010) and the Bio-HD study by the Henri-Mondor Hospital National Reference Centre for Huntington's disease (Ministry of Health) . The team is supported by l'Agence Nationale pour la recherche (the French national Research Agency) though 3 contracts: NeurATRIS ANR-11-INBS-0011 ; ANR-17-EURE-0017 Frontcog ; ANR-10-IDEX-0001-02 PSL* .

      Declaration of competing interests

      No conflict of interest.

      Acknowledgements

      We thank David Schmitz, Tiffany Monnier, Rima Belhamdi, and Cecile Focseneau for their invaluable help in data collection and reglementary issues.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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