Longitudinal assessment of the Unified Huntington's Disease Rating Scale (UHDRS) and UHDRS-For Advanced Patients (UHDRS-FAP) in patients with late stage Huntington's disease.

BACKGROUND AND PURPOSE: Symptoms and signs in patients with Huntington's disease are usually assessed with the Unified Huntington's Disease Rating Scale (UHDRS). Ceiling and floor effects hamper the measurement of disease progression in patients with late stage Huntington's disease and therefore the UHDRS-For Advanced Patients (UHDRS-FAP) has been developed. The aim of this longitudinal study was to examine if the UHDRS-FAP and UHDRS are sensitive enough to detect change over time in late stage Huntington's disease. METHODS: Forty nursing home residents and patients receiving day-care were assessed with the UHDRS, UHDRS-FAP and Care Dependency Scale (CDS). After 6 months, the assessment scales were completed again in 29 patients. Changes between baseline and follow-up were calculated using paired t tests. Wilcoxon signed-rank tests were used to calculate longitudinal changes for middle and late stage patients separately. RESULTS: The motor and cognitive score of the UHDRS-FAP deteriorated during 6 months' follow-up, whilst the motor and cognitive score of the UHDRS did not show change. Two functional domains of the UHDRS and the CDS also declined. The behavioral score significantly improved with both rating scales in late stage patients. CONCLUSIONS: Our results suggest that the UHDRS-FAP motor and cognitive score, the functional domains of the UHDRS, and the CDS can detect disease progression in late stage Huntington's disease. Therefore, the use of these scores in nursing homes is recommended to optimize care by monitoring disease progression and by evaluating the effect of interventions in clinical care. Psychiatric symptoms seem to fade away as the disease progresses.

The uptake and outcome of prenatal and pre-implantation genetic diagnosis for Huntington's disease in the Netherlands (1998-2008).

We aimed to study reproductive behaviour of couples opting for prenatal diagnosis (PND) and pre-implantation genetic diagnosis (PGD) for Huntington's disease (HD). In the Netherlands, exclusion PND is available for persons at 50% risk, whereas exclusion PGD is not allowed. All 162 couples who underwent PND or PGD for HD between 1998 and 2008 and referrals for exclusion PGD to Belgium were included. Couples' reproductive information was collected until December 2010; 132 couples (81.5%) underwent PND in 262 pregnancies, 54 (33.3%) started PGD, and 25 used both. Sixteen percent of PND couples used exclusion PND and 6% used exclusion PGD. The outcomes were 76.5% of PND couples delivered ≥1 unaffected child(ren) after PND, and 44.4% of PGD couples delivered ≥1 PGD child(ren) (mean 2.5 cycles/couple). Couples opting for PGD secondarily (after a previous pregnancy) had more frequently terminated a pregnancy for HD (87.0%) compared with couples secondarily opting for PND (55.2%; p = 0.015). At-risk or HD expansion carrier males were underrepresented in the group of couples primarily opting for PGD (25%) and overrepresented in the secondary PGD group (64%). We conclude that couples reconsider their choices in every subsequent pregnancy based on their previous experience, personal beliefs and the gender of the at-risk partner.

Prenatal testing for Huntington's disease in the Netherlands from 1998 to 2008.

This study aims to give an overview of the number of prenatal tests for Huntington's disease (HD), test results, and pregnancy outcomes in the Netherlands between 1998 and 2008 and to compare them with available data from the period 1987 to 1997. A total of 126 couples underwent prenatal diagnosis (PND) on 216 foetuses: 185 (86%) direct tests and 31 (14%) exclusion tests. In 9% of direct tests the risk for the foetus was 25%. Four at-risk parents (4%) carried intermediate alleles. Ninety-one foetuses had CAG expansions ≥36% or 50% risk haplotypes: 75 (82%) were terminated for HD, 12 (13%) were carried to term; four pregnancies were miscarried, terminated for other reasons or lost to follow-up. Unaffected pregnancies (122 foetuses) resulted in the birth of 112 children. The estimated uptake of PND was 22% of CAG expansion carriers (≥36 repeats) at reproductive age. PND was used by two new subgroups: carriers of intermediate alleles and 50% at-risk persons opting for a direct prenatal test of the foetus. A significant number of HD expansion or 50% risk pregnancies were continued. Speculations were made on causative factors contributing to these continuations. Further research on these couples' motives is needed.

The neuroanatomy of subthreshold depressive symptoms in Huntington's disease: a combined diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) study.

BACKGROUND: Depressive symptoms are prominent psychopathological features of Huntington's disease (HD), making a negative impact on social functioning and well-being. METHOD: We compared the frequencies of a history of depression, previous suicide attempts and current subthreshold depression between 61 early-stage HD participants and 40 matched controls. The HD group was then split based on the overall HD group's median Hospital Anxiety and Depression Scale-depression score into a group of 30 non-depressed participants (mean 0.8, s.d. = 0.7) and a group of 31 participants with subthreshold depressive symptoms (mean 7.3, s.d. = 3.5) to explore the neuroanatomy underlying subthreshold depressive symptoms in HD using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). RESULTS: Frequencies of history of depression, previous suicide attempts or current subthreshold depressive symptoms were higher in HD than in controls. The severity of current depressive symptoms was also higher in HD, but not associated with the severity of HD motor signs or disease burden. Compared with the non-depressed HD group DTI revealed lower fractional anisotropy (FA) values in the frontal cortex, anterior cingulate cortex, insula and cerebellum of the HD group with subthreshold depressive symptoms. In contrast, VBM measures were similar in both HD groups. A history of depression, the severity of HD motor signs or disease burden did not correlate with FA values of these regions. CONCLUSIONS: Current subthreshold depressive symptoms in early HD are associated with microstructural changes - without concomitant brain volume loss - in brain regions known to be involved in major depressive disorder, but not those typically associated with HD pathology.

Evaluation of exclusion prenatal and exclusion preimplantation genetic diagnosis for Huntington's disease in the Netherlands.

Individuals at 50% risk of Huntington's disease (HD) who prefer not to know their carrier status, might opt for exclusion prenatal diagnosis (ePND) or exclusion preimplantation genetic diagnosis (ePGD). This study aims to provide a better understanding of couples' motives for choosing ePND or ePND, and surveys couples' experiences in order to make recommendations for the improvement of counselling for exclusion testing. This qualitative retrospective interview study focussed on couples who underwent ePND or ePGD for HD in the period 1996-2010. Seventeen couples were included of which 13 had experienced ePND and 6 ePGD. Mean time-interval since exclusion-testing was 3.9 years. Couples' moral reservations regarding termination of pregnancy (TOP) or discarding healthy embryos were counterbalanced by the wish to protect their future child against HD. Seven couples had terminated a total of 11 pregnancies with a 50% HD risk, none showed regret. ePGD was used by couples who wanted to avoid (another) TOP. ePND and ePGD are acceptable reproductive options for a specific group of counsellees. To guarantee sound standards of care, it is imperative that candidate couples be given in-depth non-directive counselling about all possible scenarios, and adequate professional and psychological support prior to, during and after ePND/ePGD.

Psychiatric disorders in Huntington's disease: a 2-year follow-up study.

OBJECTIVE: This study investigates the presence and course of formal psychiatric disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) in 142 Huntington's disease (HD) mutation carriers in a two-year follow-up design. METHOD: Of the 142 mutation carriers, 106 (75%) participated in the second measurement of an ongoing cohort study on psychopathology in HD. Presence of psychiatric disorders was assessed using the Composite International Diagnostic Interview. RESULTS: Of the 91 patients without a formal psychiatric disorder at baseline, 14 (15%) had a psychiatric disorder after 2 years, mostly a major depressive disorder (MDD) (64%). The baseline characteristics of lower education, having no children, a lower level of global daily functioning, a lifetime psychiatric diagnosis, and the use of psychotropic medication were predictive of incident psychiatric disorders after 2 years. Of the 15 patients with a psychiatric diagnosis at baseline, eight (53%) no longer had a psychiatric disorder at follow-up. All seven patients (47%) with a persistent psychiatric disorder were female and their most prevalent diagnosis was generalized anxiety disorder. CONCLUSION: This cohort study confirms that psychiatric disorders, in particular MDD, frequently occur in patients with HD. Professionals working with HD patients should therefore be aware of the high risk of psychopathology in HD because early diagnosis and treatment of psychiatric disorders may improve the quality of life of patients and their caregivers.

Treatment effect modifiers for the patient education programme for Parkinson's disease.

AIM: A recent randomised controlled trial showed significant benefits for Parkinson's disease (PD) caregivers' psychosocial problems and need for help and a trend towards significant improvement of patients' quality of life after participation in the Patient Education Programme for Parkinson's disease (PEPP). Large variations in change scores were found, indicating variation in benefit. The aim of this study was to search for treatment effect modifiers. METHODS: Outcome measures were patients' quality of life [Parkinson's Disease Questionnaire (PDQ)-39] and caregivers' psychosocial burden [Belastungsfragebogen Parkinson Angehörigen kurzversion (BELA-A-k)]. Candidate treatment effect modifiers were participants' characteristics and baseline scores on psychological questionnaires (BELA-P/A-k, PDQ-39, EQ-5D, Self-rating Depression Scale) and patients' neuropsychological test scores (Mini Mental State Examination, National Adult Reading Test, Dutch version, Word Test, Behavioural Assessment of the Dysexecutive Syndrome rule shift, Trail Making Test, Stroop). Secondary analyses of data from a randomised controlled trial with 64 patients and 46 caregivers were performed using regression analyses with treatment group interaction terms. RESULTS: No significant modifiers were found for the patients. In the caregiver group, a higher MMSE score of the patient at baseline was found to be a significant predictor of a lower BELA-A-k Bothered by score post-intervention of the caregiver. CONCLUSIONS: A potential predictor of treatment benefit was found for caregivers of PD patients with better cognitive functioning. This study did not find treatment effect modifiers for PD patients: demographics, disease stage and time of diagnosis, cognitive functioning, level of baseline psychosocial burden, participating with or without a caregiver, and caregiver changes did not influence treatment outcome. The PEPP seems suitable for the majority of patients.

Dysphagia, Fear of Choking and Preventive Measures in Patients with Huntington's Disease: The Perspectives of Patients and Caregivers in Long-Term Care.

OBJECTIVES: To explore the prevalence of dysphagia and fear of choking in patients with Huntington's disease (HD) as well as preventive measures, both those applied and those not included in managing dysphagia. Also, to investigate related problems encountered by their formal and informal caregivers. DESIGN: A multi-center observational cross-sectional study. SETTING AND PARTICIPANTS: 158 HD patients, recruited from six Dutch nursing homes specialized in HD, and their formal and informal caregivers. MEASUREMENTS: Patients were assessed by means of questionnaires enquiring about dysphagia, fear of choking and measures to manage dysphagia. Also, questionnaires were administered about awareness of dysphagia symptoms, cognition and anxiety. Because we expected individuals with greater care dependency to have a higher severity of dysphagia, we distinguished between a care-independent and a care-dependent group of HD patients. RESULTS: In the total group, 90.5% of HD patients had one or more dysphagia symptoms. The prevalence of FoC in HD patients and the formal and informal caregivers' fears about choking in HD patients was 45.7%, 19.0% and 59.5%, respectively, for care-independent patients and 58.7%, 50.1% and 77.5% for care-dependent patients. The score on the Huntington's Disease Dysphagia Scale was a predictor for fear of FoC in care-independent patients. Speech-language therapy, supervision during eating and drinking and adaptation of food and drink consistency were the most frequently applied measures to manage dysphagia, a combination was used in most HD patients. CONCLUSIONS: In HD patients, the prevalence of dysphagia is high and fear of choking is common among both patients and caregivers. A more severe degree of dysphagia is a predictor of FoC in care-independent HD patients. A combination of measures was used to manage dysphagia in most HD patients.

Basal ganglia volume is strongly related to P3 event-related potential in premanifest Huntington's disease.

BACKGROUND: The P3 event-related potential (ERP) is presumably partly generated by the basal ganglia. Because degeneration of these brain structures starts many years before clinical disease onset in Huntington's disease (HD), studying the interplay between P3 characteristics and basal ganglia volumes in 'premanifest' carriers might lead to new insights into the disease process. METHODS: Fourteen premanifest\ HD mutation carriers and twelve non-mutation carriers underwent clinical, MRI and P3-ERP investigations. The P3 was measured during the Sustained Attention to Response Task. RESULTS: P3 amplitude and latency did not differ between groups. In carriers, longer P3 latency during Go-trials was strongly associated with smaller caudate, putamen and globus pallidus volumes (r values up to -0.827, P ≤ 0.001). CONCLUSION: The exceptionally strong relations of P3 latency with basal ganglia volumes in carriers suggest that the P3 may provide a marker for disease progression in HD.

An evaluation of the patient education programme for Parkinson's disease in clinical practice.

AIM: The Patient Education Programme for Parkinson's disease (PEPP) was assessed in a recent randomised controlled trial (RCT). In this study, a trend was identified towards significant improvement of patients' quality of life (Qol) as well as a significant reduction of caregivers' psychosocial burden and need for help. This study is aimed at evaluating the effectiveness of the PEPP in clinical practice as compared with the RCT in an academic setting. The second aim is to assess its effectiveness in clinical practice at 6-month follow-up. METHODS: Fifty-five patients and 50 caregivers from nine clinical settings participated in the PEPP consisting of eight weekly sessions of 90 min. Self-report questionnaires were used to assess patients' Qol (PDQ-39) and caregivers' psychosocial burden and need for help (BELA-A-k) at baseline, directly after the programme and at 6-month follow-up. To compare the baseline data and short-term effects, data were used from an RCT study which included 64 Parkinson's disease patients and 46 caregivers. RESULTS: Compared with the RCT control group, significant effects, after Bonferoni adjustment, were found for patients' Qol as well as for caregivers' psychosocial burden and need for help. No significant changes were found between baseline scores compared with 6-month follow-up. Scores returned to baseline levels at 6-month follow-up. CONCLUSIONS: Effects from the RCT study were replicated and the effect on patients' Qol was now significant. However, at 6-month follow-up, scores returned to baseline levels, indicating the need for some form of a booster session.

Autonomic symptoms in patients and pre-manifest mutation carriers of Huntington's disease.

BACKGROUND AND PURPOSE: Although autonomic function tests have revealed abnormalities of the autonomic nervous system in Huntington's disease (HD), autonomic symptoms and their association with other symptoms and signs of HD have not yet been assessed in large groups of patients or pre-manifest mutation carriers. Therefore, we aimed at delineating the characteristics and correlates of autonomic symptoms in HD. METHODS: Using the scales for outcomes in Parkinson's disease-autonomic symptoms (SCOPA-AUT) and Beck Depression Inventory questionnaires, autonomic symptoms and depressed mood were assessed in 63 patients with HD, 21 pre-manifest mutation carriers, and 85 controls. The Unified Huntington's Disease Rating Scale was used to assess other HD symptoms and signs. RESULTS: Relative to controls, patients with HD experienced significantly more gastrointestinal, urinary, cardiovascular and, in men, sexual problems. The most prevalent symptoms were swallowing difficulties, erection and ejaculation problems, dysphagia, sialorrhea, early abdominal fullness, straining for defecation, fecal and urinary incontinence, urgency, incomplete bladder emptying, and light-headedness whilst standing. Pre-manifest mutation carriers experienced significantly more swallowing difficulties and light-headedness on standing up compared with controls. In patients with HD, autonomic symptoms were associated with a greater degree of functional disability, more severe depression, and antidepressant drugs use. However, depression was the only independent predictor of autonomic dysfunction. CONCLUSIONS: Autonomic symptoms are highly prevalent in patients with HD and may even precede the onset of motor signs. Moreover, autonomic dysfunction is related to functional disability and depression in HD.

Growth hormone and ghrelin secretion are associated with clinical severity in Huntington's disease.

BACKGROUND AND PURPOSE: Huntington's disease (HD) is a fatal hereditary neurodegenerative disorder caused by an increased CAG repeat size in the huntingtin gene. Apart from neurological impairment, the disease is also accompanied by progressive weight loss, abnormalities in glucose homeostasis and a higher prevalence of diabetes mellitus, which may partly be caused by disturbed growth hormone (GH) and ghrelin secretion. Therefore, we aimed to perform a detailed analysis of GH and ghrelin secretion in HD patients in relation to clinical signs and symptoms. METHODS: In nine early-stage, medication-free HD patients and nine age-, gender- and body mass index-matched controls, we measured serum GH levels every 10 min for 24 h and assessed ghrelin response to food intake. Multi-parameter auto-deconvolution and approximate entropy analysis were applied to quantify basal, pulsatile, and total GH secretion rates as well as the regularity of GH secretion. RESULTS: We found no significant differences in GH and ghrelin secretion characteristics between HD patients and controls (total GH secretion: 137 +/- 36 vs. 181 +/- 43 mU/l/24 h, respectively; P = 0.439). However, in HD patients, both GH secretion and its irregularity as well as the degree of postprandial ghrelin suppression significantly increased with worsening motor and functional impairment (all P < 0.05). Moreover, postprandial ghrelin suppression also increased with decreasing body weight and higher CAG repeat number (both P < 0.05). CONCLUSIONS: These findings suggest changes in the regulation of GH and ghrelin secretion dynamics in early stage HD patients that could become more prominent in the later stages of the disease.

Correlates of apathy in Huntington's disease.

The authors aim to study prevalence and clinical correlates of apathy in Huntington's disease. Apathy was defined as an Apathy Scale score > or =14 points in 152 Huntington's disease mutation carriers and 56 noncarriers. Correlates of apathy were analyzed cross-sectionally in mutation carriers using multivariable logistic regression analysis. Forty-nine (32%) Huntington's disease mutation carriers showed apathy compared to none of the noncarriers. After exclusion of 10 depressed patients, apathy was independently associated with male sex, worse global functioning, and higher use of neuroleptics and benzodiazepines.

Caregiver education in Parkinson's disease: formative evaluation of a standardized program in seven European countries.

PURPOSE: The formative evaluation of a standardized psychosocial education program for patients with Parkinson's disease (PD) and their caregivers. The results of the participation of the caregivers are presented next to the data of the patients. METHODS: Caregivers (n = 137) and patients with PD (n = 151) participated in the 8-week program in separate groups. Measurements were performed on psychosocial problems (BELA-P/A-k), health state (EQ-5D VAS), quality of life (PDQ-39) and depression (SDS) 1 week before and 1 week after the program. Participants rated their mood on a visual analogue scale before and after each session, and they filled in an evaluation questionnaire after the last session. RESULTS: Scores on the BELA-P/A-k improved significantly on the 'bothered by scale' as well as the 'need for help scale'. No improvements were found on EQ-5D VAS, PDQ-39 and SDS. Mood ratings improved significantly after each session. Most participants evaluated the program as positive. Feedback led to improvements in the program, which are incorporated in a final manual. CONCLUSIONS: The program was feasible to run in the different countries. This exploratory study led to improvements in the program and recommendations for further research. A study on the effectiveness of the program is the next step.

Changes in striatal dopamine D2 receptor binding in pre-clinical Huntington's disease.

BACKGROUND: Carriers of the Huntington disease (HD) mutation develop a progressive neurodegenerative disorder after a pre-clinical phase. We examined the value of (11)C-raclopride PET (RAC) as a biomarker for pre-clinical HD pathophysiology. METHODS: In a prospective cohort study with clinical and neuropsychological assessment we collected complete RAC data in 18 pre-clinical mutation carriers (HD-PMC) and 11 controls. Follow-up was 2 years. We calculated striatal RAC binding potential (BP) to measure dopamine D2 receptor availability. RESULTS: No HD-PMC had overt neuropsychological dysfunction. RAC-BP in putamen was abnormal in up to 44% of HD-PMC. The rate of RAC-BP decline (2.6% per year) was not significantly higher than in controls. Follow-up putaminal BP correlated weakly with predicted distance to onset of clinical HD (P = 0.034), but the rate of decline did not. Three HD-PMC developed motor abnormalities suspect for HD but did not show an increased rate of decline of putaminal BP. CONCLUSIONS: Many HD-PMC have striatal abnormalities but we found no clearly increased rate of D2 receptor changes around the onset of clinical HD. A longer follow-up of the present study cohort is needed to establish the value of RAC-BP in assessing the risk of clinical conversion from striatal D2 binding data.

[A female patient with late-onset schizophrenia and fear of Katwijk disease]. / Een patiënte met laat ontstane schizofrenie en angst voor de Katwijkse ziekte.

A 66-year-old patient had suffered from late-onset schizophrenia from the age of 44. Her family history included reports of brain haemorrhages, possibly resulting from hereditary amyloidal angiopathy of the Dutch type (Katwijk disease). She was very afraid for having this disease. The progression of the psychiatric symptoms and the age at which they began, led us to suspect an organic process. Differential diagnoses that were discussed included cerebral amyloidal angiopathy, frontal lobe dementia and Huntington's disease.

Hypothalamic dysfunction and neuroendocrine and metabolic alterations in Huntington's disease: clinical consequences and therapeutic implications.

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by cognitive, psychiatric, behavioural and motor disturbances. Although the course of HD is also frequently complicated by unintended weight loss, sleep disturbances and autonomic nervous system dysfunction, the aetiology of these signs and symptoms remains largely unknown. In recent years, many novel findings from both animal and human studies have emerged that indicate considerable hypothalamic, endocrine and metabolic alterations in HD. However, a comprehensive overview of these findings is lacking and their precise clinical significance is far from clear. Therefore, in this review we attempt to put these recent developments in the field into perspective by integrating them with previous findings in a comprehensible manner, and by discussing their clinical relevance, with a special focus on body weight, sleep and autonomic functions in HD, which will also allow for the identification of future lines of research in this area.

Hypocretin-1 and secondary signs in Huntington's disease.

Huntington's disease is characterised by unwanted movements, psychiatric disturbances and cognitive decline. Less well recognised symptoms and signs are weight loss, autonomic dysfunction and sleep disorders. In this study we focus on hypocretin-1 and hypothalamus functions. We found a reduction by about 30% in hypocretin signalling in patients with HD. However, it remains unclear whether this moderate decrease in hypocretin signalling contributes to clinical symptoms.

[Driving with Alzheimer's disease]. / Autorijden met de ziekte van Alzheimer.

OBJECTIVE: To summarise the available literature on driving with Alzheimer's disease (AD) and to investigate the relationship between driving and cognitive functioning. DESIGN: Literature review. METHOD: A systematic search of the electronic databases PubMed/MEDLINE was conducted to select the relevant literature on the driving competence of patients with Alzheimer's disease. RESULTS: A total of 31 studies were selected that investigated driving competence in AD using either an on-road driving assessment or a driving simulator. The driving competence of patients with AD was less accurate compared with controls. The most commonly made errors included errors in staying in lane, lane changing, slower reaction times, and more fluctuations in speed. Cognitive functioning was more predictive of driving competence than a diagnosis of AD alone. CONCLUSION: Based on the available literature it is difficult to determine when patients with AD should be restricted in their driving. In addition, there is currently no consensus on which neuropsychological tests are useful in clinical practice to predict driving competence. Specific practical guidelines that can be implemented in daily practice are still lacking.