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BackgroundCognitive impairment is a core feature of Huntington's disease (HD), however, the onset and rate of cognitive decline is highly variable. Apathy is the most common neuropsychiatric symptom of HD, and is associated with cognitive impairment. The aim of this study was to investigate apathy as a predictor of subsequent cognitive decline over 2 years in premanifest and early HD, using a prospective, longitudinal design.MethodsA total of 118 premanifest HD gene carriers, 111 early HD and 118 healthy control participants from the multi-centre TRACK-HD study were included. Apathy symptoms were assessed at baseline using the apathy severity rating from the Short Problem Behaviours Assessment. A composite of 12 outcome measures from nine cognitive tasks was used to assess cognitive function at baseline and after 24 months.ResultsIn the premanifest group, after controlling for age, depression and motor signs, more apathy symptoms predicted faster cognitive decline over 2 years. In contrast, in the early HD group, more motor signs, but not apathy, predicted faster subsequent cognitive decline. In the control group, only older age predicted cognitive decline.ConclusionsOur findings indicate that in premanifest HD, apathy is a harbinger for cognitive decline. In contrast, after motor onset, in early diagnosed HD, motor symptom severity more strongly predicts the rate of cognitive decline.

Background Electrophysiological measures can help understand brain function both in healthy individuals and in the context of a disease. Given the amount of information that can be extracted from these measures and their frequent use, it is essential to know more about their inherent reliability. Objective/Hypothesis To understand the reliability of electrophysiology measures in healthy individuals. We hypothesized that measures of threshold and latency would be the most reliable and least susceptible to methodological differences between study sites. Methods Somatosensory evoked potentials from 112 control participants; long-latency reflexes, transcranial magnetic stimulation with resting and active motor thresholds, motor evoked potential latencies, input/output curves, and short-latency sensory afferent inhibition and facilitation from 84 controls were collected at 3 visits over 24 months at 4 Track-On HD study sites. Reliability was assessed using intra-class correlation coefficients for absolute agreement, and the effects of reliability on statistical power are demonstrated for different sample sizes and study designs. Results Measures quantifying latencies, thresholds, and evoked responses at high stimulator intensities had the highest reliability, and required the smallest sample sizes to adequately power a study. Very few between-site differences were detected. Conclusions Reliability and susceptibility to between-site differences should be evaluated for electrophysiological measures before including them in study designs. Levels of reliability vary substantially across electrophysiological measures, though there are few between-site differences. To address this, reliability should be used in conjunction with theoretical calculations to inform sample size and ensure studies are adequately powered to detect true change in measures of interest.

Structural connectomes derived using diffusion tractography are increasingly used to investigate white matter connectivity in neurological diseases. However inherent biases in diffusion tractography algorithms may lead to both false negatives and false positives in connectome construction. A range of graph thresholding approaches and more recently several streamline filtering algorithms have been developed to address these issues. However there is no consensus in the literature regarding the best available approach. Using a cohort of Huntington’s disease patients and healthy controls we compared the effect of several graph thresholding strategies: proportional, absolute, consensus and consistency thresholding, with and without streamline filtering, using Spherical Deconvolution Informed Filtering of tractograms (SIFT2) algorithm. We examined the effect of thresholding strategies on the stability of graph theory metrics and the sensitivity of these measures in neurodegeneration. We show that while a number of graph thresholding procedures result in stable metrics across thresholds, the detection of group differences is highly variable. We also showed that the application of streamline filtering using SIFT2 resultes in better detection of group differences and stronger clinical correlations. We therefore conclude that the application of SIFT2 streamline filtering without graph thresholding may be sufficient for structural connectome construction.

ObjectiveNeurofilament light (NfL) protein in blood plasma has been proposed as a prognostic biomarker of neurodegeneration in a number of conditions, including Huntington disease (HD). This study investigates the regional distribution of NfL-associated neural pathology in HD gene expansion carriers.MethodsWe examined associations between NfL measured in plasma and regionally specific atrophy in cross-sectional (n = 198) and longitudinal (n = 177) data in HD gene expansion carriers from the international multisite TRACK-HD study. Using voxel-based morphometry, we measured associations between baseline NfL levels and both baseline gray matter and white matter volume; and longitudinal change in gray matter and white matter over the subsequent 3 years in HD gene expansion carriers.ResultsAfter controlling for demographics, associations between increased NfL levels and reduced brain volume were seen in cortical and subcortical gray matter and within the white matter. After also controlling for known predictors of disease progression (age and CAG repeat length), associations were limited to the caudate and putamen. Longitudinally, NfL predicted subsequent occipital gray matter atrophy and widespread white matter reduction, both before and after correction for other predictors of disease progression.ConclusionsThese findings highlight the value of NfL as a dynamic marker of brain atrophy and, more generally, provide further evidence of the strong association between plasma NfL level, a candidate blood biomarker, and pathologic neuronal change.

To summarise the available literature on driving with Alzheimer's disease (AD) and to investigate the relationship between driving and cognitive functioning.Literature review.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.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.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.

Contains fulltext : 174500.pdf (Publisher’s version ) (Open Access) Depression is one of the most prevalent and debilitating psychiatric disorders worldwide. Recently, we showed that both relatively short and relatively long cytosine-adenine-guanine (CAG) repeats in the huntingtin gene (HTT) are associated with an increased risk of lifetime depression. However, to what extent the variations in CAG repeat length in the other eight polyglutamine disease-associated genes (PDAGs) are associated with depression is still unknown. We determined the CAG repeat sizes of ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, ATN1 and AR in two well-characterized Dutch cohorts-the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons-including 2165 depressed and 1058 non-depressed individuals-aged 18-93 years. The association between PDAG CAG repeat size and the risk for depression was assessed via binary logistic regression. We found that the odds ratio (OR) for lifetime depression was significantly higher for individuals with >10, compared with subjects with

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.

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.

BACKGROUND AND PURPOSE: MTI is a quantitative MR imaging technique that has recently demonstrated structural integrity differences between controls and patients with HD. Potentially, MTI can be used as a biomarker for monitoring disease progression. To establish the value of MTI as a biomarker, we aimed to examine the change in these measures during the course of HD. MATERIALS AND METHODS: From the Leiden TRACK-HD study, 25 controls, 21 premanifest gene carriers, and 21 patients with manifest HD participated at baseline and during a 2-year follow-up visit. Brain segmentation of the cortical gray matter, white matter, caudate nucleus, putamen, pallidum, thalamus, amygdala, and hippocampus was performed by using the automated tools FAST and FIRST in FSL. Individual MTR values were calculated from these regions, and MTR histograms were constructed. RESULTS: In the premanifest HD group stage “far from disease onset,” a significant increase in MTR peak height of the putamen was observed with time. During the manifest HD stage, neither the mean MTR nor the MTR peak height showed a significant change during a 2-year follow-up. CONCLUSIONS: MTI-derived measures are not suitable for monitoring in Huntington disease during a 2-year period because there was no decrease in structural integrity detected in any of the manifest HD groups longitudinally. The finding of increased putaminal MTR peak height in the premanifest far from disease onset group could relate to a predegenerative process, compensatory mechanisms, or aberrant development but should be interpreted with caution until future studies confirm this finding.

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 Angehorigen 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.

Evidence for the extent and nature of attentional impairment in premanifest and manifest Huntington’s disease (HD) is inconsistent. Understanding such impairments may help to better understand early functional changes in HD and could have consequences concerning care for HD patients. We investigated attentional control in both early and premanifest HD. We studied 17 early HD subjects (mean age: 51 years), 12 premanifest HD subjects (mean age: 43 years), and 15 healthy controls (mean age: 51 years), using the sustained attention to response task (SART), a simple Go/No-go test reflecting attentional and inhibitory processes through reaction time (RT) and error rates. Simultaneously recorded EEG yielded P300 amplitudes and latencies. The early HD group made more Go errors (p

Summary 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.

De ziekte van Parkinson is een veelvoorkomende ziekte. Het is een chronisch progressieve aandoening gekenmerkt door tremoren, stijfheid van spieren en/of bradykinesie, waardoor de betrokkene in werk en in het priveleven toenemend gehinderd wordt. De ziekte openbaart zich meestal op middelbare leeftijd (tussen de 40 en 60 jaar), maar begint bij een klein aantal patienten al voor het veertigste jaar. Naar schatting zijn er in Nederland ongeveer 45.000 patienten. De prevalentie is 10 per 100.000 bij mensen onder de 50 jaar, maar loopt op tot 600 per 100.000 boven de 65. De incidentie bedraagt voor mannen en vrouwen gelijk 10 per 100.000.

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.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.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.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.

In 24 adults and 29 children both with Gilles de la Tourette syndrome and in 24 control adults and 17 control children we studied auditory event-related potentials (ERP's) evoked in 2 different oddball paradigms: a passive listening paradigm (PLP) in which subjects had only to attend tones (260 standards, 40 deviants), followed by an active discrimination paradigm (ADP) in which subjects had to press a microswitch in response to the deviant tones. In the adult Tourette patients the PLP disclosed between 200-300 msec at all derivations (Fz, Cz, Pz, C3, C4, P3, P4) a significantly more negative activity than in the controls. In the Tourette children such a result was only found at Fz. In the ADP the differences between both adult groups disappeared, but the curves of the control children became now significantly more positive than those of the Tourette ones except at C3 and P3. Between 200-300 msec the curves of all 4 groups were significantly less negative in the ADP than in the PLP. This decrease in negativity was significantly larger in the adult Tourette patients than in the adult controls, but in the children groups the reverse occurred. It is hypothesized that the differences in amplitude between patients and controls and between both paradigms are due to differences in amplitude of an endogenous negative component overlapping the exogenous N100-N200 standard curve. Based on this hypothesis the results could suggest that one of the problems in Tourette syndrome is an increased attention to non-relevant stimuli.

Changes in mood and behaviour form the most variable symptoms of the clinical characteristics of Huntington’s disease (HD).1 Although the diagnosis is usually based on motor signs, behavioural changes occur as a first manifestation of HD in up to half of the patients.2,3 Irritable behaviour, aggression, and depression are most commonly seen in the first phase of the disease.4 Anxiety, obsessions, and apathy are also extremely common in HD. In certain families, major affective disorders may appear as early as 20 years before the onset of chorea and dementia.5 However, with regard to the manifestation of psychiatric signs, there is a known difficulty in distinguishing between an intrinsic and a reactive pattern. The action of the disease is often intertwined with the reaction to the disease in diagnosed patients but also in “asymptomatic” (that is, absence of motor signs) subjects carrying the expansion of the CAG triplet repeat (henceforth referred to as “carriers” compared to “non-carriers”). As far as we are aware, only two studies have been reported regarding psychiatric symptoms in asymptomatic carriers compared to non-carriers.6,7 A controlled psychiatric study reported by Shiwach and Norbury7 showed that there was no significant increase in affective disorder in the former group. However, the whole predictive tested group showed a higher prevalence of psychiatric episodes than their partners. According to the authors it is, therefore, not plausible that depression is an early sign of HD in asymptomatic carriers. Depression and feelings of helplessness are indeed usually seen as a consequence of stressful events related to HD, like predictive testing in both carriers and non-carriers, even years after the predictive test result. Many studies have been reported on mood changes as a reactive pattern in both carriers and non-carriers,8,9 but behavioural changes as …

Expansion of a Glutamine (Gln) repeat above a specific critical size in certain proteins gives rise to aggregation-prone proteins that cause neurodegenerative disorders, such as Huntington's disease. However, proteins with long hydrophilic polyglutamine repeats are more frequently found in nature than proteins with long homogeneous repeats of other amino acids, such as hydrophobic (Ala)(n) and (Leu)(n). To explore this finding, the effects of expression in mammalian cells of polyglutamine and polyleucine encoded by mixed DNA repeats were compared. It was found that polyleucine is significantly more toxic than polyglutamine. In addition, we show that polyleucine stretches display a high propensity for aggregation utilizing two complementary biochemical assays and that polyleucine stretches can also be detected by the monoclonal antibody 1C2, which specifically recognizes expanded pathogenic and aggregation-prone glutamine repeats. Together, these results suggest that polyglutamine stretches are in fact relatively well tolerated and that nature may select more strongly against DNA stretches that encode long hydrophobic homopolymeric amino acid stretches, such as polyleucine -- possibly owing to their strong propensity for aggregation. In keeping with this notion, an increasing number of diseases are found to be associated with expansion of stretches of hydrophobic amino acids, including oculopharyngeal muscular dystrophy (OPMD), which is associated with expansion of a hydrophobic polyalanine stretch.

SUMMARY Pseudotumor cerebri, or benign intracranial hypertension, is relatively rare in children. A 12-year-old girl with Hashimoto hyperthyroidism and hypovitaminosis A is described, who fulfilled the diagnostic criteria for pseudotumor cerebri. RESUME Pseudotumeur cerebrate associee a une hypovitaminose A el une hyperthyroidie La pseudotumeur cerebrale, ou hypertension intracranienne benigne est relativement rare chez L'enfant. L'article rapporte le cas d'une fillette de 12 ans avec hyperthyroidie de Hashimoto et hypovitaminose A qui presentait les criteres permettant un diagnostic de pseudotumeur cerebrale. ZUSAMMENFASSUNG Pseudotumor cerebri mit Hypovitaminose A und Hyperthyreose Ein Pseudotumor cerebri oder die benigne intracranielle Hypertension ist bei Kindern relativ selten. Ein 12 Jahre altes Madchen mit einer Hashimoto Hyperthyreose und einer Hypovitaminose A wird dargestellt, das die diagnostischen Kriterien fur einen Pseudotumor cerebri erfullte. RESUMEN Pseudotumor cerebral asociado a hipovitaminosis A y a hipertiroidismo El pseudotumor cerebral a hipertension intracraneana benigna es relativamente rara en ninos. Se describe el caso de una nina de 12 afios de edad con un hipertiroidismo de Hashimoto e hipovitaminosis A, que cumplia los criterios de un diagnostico de pseudotumor cerebral

Background and Purpose —Microvascular changes such as microaneurysms and fibrinoid necrosis have been found in the presence of cerebral amyloid angiopathy (CAA). These CAA-associated microvasculopathies (CAA-AM) may contribute to the development of CAA-associated hemorrhages and/or infarcts, hereafter referred to as “cerebrovascular lesions.” Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D) is an autosomal dominant form of CAA, in which the amyloid angiopathy is pathologically and biochemically similar to sporadic CAA associated with aging and Alzheimer disease. To determine the significance of CAA-AM for CAA-associated cerebrovascular complications, we investigated the association between CAA-AM and cerebrovascular lesions in HCHWA-D patients. Methods —In a previous autopsy study we semiquantitatively scored CAA-AM in 29 HCHWA-D patients. In the present study we reviewed clinical charts and autopsy protocols of these same patients. We investigated whether CAA-AM was associated with age at death, number of cerebrovascular lesions, duration of clinical illness, hypertension, and atherosclerosis. Results —An association was found between CAA-AM and the number of cerebrovascular lesions ( P =0.009). The presence of microaneurysmal degeneration was most strongly associated with the number of cerebrovascular lesions ( P P =0.047). Hypertension was not associated with CAA-AM. Conclusions —Our findings support previous reports suggesting an important role of secondary microvascular degenerative changes in CAA-associated cerebrovascular lesions and suggest an aggravating effect of systemic atherosclerosis, but not hypertension, on the evolution of CAA-AM. These findings may be of relevance to understanding cerebrovascular complications of sporadic or Alzheimer disease–associated CAA.

Objective: To study early motor and cognitive symptoms in Huntington disease. Design: A follow-up cohort study after a DNA test procedure in which gene carriers and noncarriers were identified among people genetically at risk for Huntington disease. Setting: Leiden University Medical Center, Department of Neurology, Leiden, the Netherlands, in cooperation with the Clinical Genetics Center Leiden and the Department of Medical Psychology and Psychotherapy, Erasmus University Rotterdam, Rotterdam, the Netherlands. Participants: Thirty-three individuals: 9 unaffected gene carriers, 6 gene carriers with motor symptoms, and 18 noncarriers of the gene for Huntington disease. Main Outcome Measures: A neuropsychologic examination covering a broad area of cognitive functioning, reaction time procedures, and motor tasks. Results: The neuropsychologic assessment showed no significant differences between presymptomatic gene carriers and noncarriers. Three motor tasks differentiated between these 2 groups on a liberal.05 P level (analysis of variance followed by the Student t test). The affected gene carriers performed less well than the presymptomatic gene carriers and the noncarriers in 10 motor tasks and 7 cognitive tasks. These differences were significant at P Conclusion: Motor symptoms play a more prominent and unequivocal role than cognitive symptoms in early stages of Huntington disease.

Objective assessment of clinical findings of patients with Huntington's disease (HD) is necessary for an evaluation of the individual progression of the disease and the effect of therapy, and it requires specific assessment scales. The Unified Huntington's Disease Rating Scale (UHDRS) is an overall scale to assess clinical performance and functional capacity. In the course of carrying out studies in HD, several items in the motor function section were found to be difficult to score, had high cognitive loading, and appeared to be redundant. The objective of this study was to shorten the motor section of the UHDRS to the smallest number of items, without loss of internal consistency, while still assessing the important clinical features of HD. Shortening the total motor score of the UHDRS was carried out on the UHDRS data set of the Leiden University Hospital using four methods. The first two methods employed principal-component analysis with Varimax rotation. Strongly interrelated test items were uncovered, resulting in a reduction of test items to a smaller set. The third method reduced items so that the internal consistency (Cronbach's alpha) was maximal. The fourth method omitted items subjectively. The results of the Dutch data set were validated on follow-up data and on a data set from the University of Rochester Medical Center, New York. This study determined that the number of items in the motor function section could be reduced from 31 to 15. The reduced set maintains the relationships between the motor and other sections of the UHDRS and still assesses the major clinical features of HD.

We evaluated whether the self-reported reduction of physical activity associated with fatigue in Parkinson's disease (PD) could be quantified with a wrist-worn activity monitor in 69 non-depressed PD patients. A questionnaire was used to assess the presence of fatigue. Outcome measures reflected activity, immobility and sustained activity above preset thresholds. Thirty PD patients suffering from fatigue did not differ from 39 PD patients (with similar disease severity) who were not suffering from fatigue. These results emphasize the need to explore the role of the mental aspects of fatigue in PD.

Objectives - To establish the effect of the atypical neuroleptic clozapine on chorea, voluntary motor performance, and functional disability in patients with Huntington's disease. Methods - Thirty three patients with Huntington's disease participated in a double blind randomised trial. A maximum of 150 mg/day clozapine or placebo equivalent was given for a period of 31 days. Assessments were performed in the week before and at the last day of the trial. Chorea was scored using the abnormal involuntary movement scale (AIMS), the chorea score of the unified Huntington's disease rating scale (UHDRS), and judgement of video recordings. Voluntary motor performance was assessed using the UHDRS motor scale. Patients and their partners completed a questionnaire regarding functional disability. Twelve patients already used other neuroleptic medication, which was kept unchanged during the trial period. Results of neuroleptic naive and neuroleptic treated patients were analysed separately. Results - Clozapine tended to reduce chorea in neuroleptic naive patients only (AIMS); improvement seemed more pronounced in patients receiving higher doses of clozapine. Other measures of chorea (UHDRS chorea score, video ratings) showed no improvement. Clozapine had no beneficial effect on chorea in patients already receiving neuroleptic medication. Voluntary motor performance did not improve with clozapine. Neuroleptic naive patients reported aggravation of functional disability, possibly reflecting the frequent occurrence of side effects. Adverse reactions forced trial termination in six patients and dose reduction in another eight, and consisted mainly of drowsiness, fatigue, anticholinergic symptoms, and walking difficulties. Conclusions - Clozapine has little beneficial effect in patients with Huntington's disease, although individual patients may tolerate doses high enough to reduce chorea. Because adverse reactions are often encountered, clozapine should be used with restraint in this patient group.

With the prospect of potential treatments for Huntington's disease (HD), non-invasive markers of disease progression are needed. Cognitive impairment has long been recognised as one of the core symptoms of HD. The first aim of this review is to provide insight into the onset and nature of cognitive loss in the progressing stages of HD. The second aim is to provide an overview of the cognitive functions that have been examined in an attempt to identify those areas that have the most potential to yield a cognitive biomarker. Literature, consisting of 110 studies, since the implementation of genetic testing until the beginning of 2011 has been included in this review. The clinical features of premanifest HD include deficits in psychomotor speed, negative emotion recognition and to some extent in executive functioning. The clinical profile of manifest HD includes impairment in memory, psychomotor speed, negative emotion recognition and executive functioning. Furthermore, potential candidate biomarkers should be most expected from such domains as working memory, psychomotor speed, recognition of negative emotions, attentional and visuospatial executive functions.

A new formulation of a sublingual tablet with 10 mg apomorphine was examined in 13 patients with Parkinson's disease. Vitamin C (250 mg) was added sublingually to lower the salivary pH. Four patients received sublingual apomorphine and nine received sublingual apomorphine as well as vitamin C. Subcutaneous apomorphine was given to all patients. The study was designed as a randomized three-way cross-over study. Tmax, Cmax, and bioavailability (F) were determined. Clinical efficacy was assessed by hand-tapping during 30 s, walking time over 25 m, and a 4-point tremor score. The mean Tmax after subcutaneous apomorphine was 14.5 +/- 1.9 min with a mean Cmax of 19.2 +/- 3.8 ng/ml. The mean clearance of all patients was 3.8 +/- 0.6 L/min. The mean Tmax after sublingual apomorphine was 61.1 +/- 6.9 min vs. 61.7 +/- 8.2 min with vitamin C. The mean Cmax was 7.4 +/- 1.0 ng/ml (- vitamin C) vs. 4.3 +/- 1.3 ng/ml (+ vitamin C). These data resulted consequently in a not significantly different mean bioavailability, varying from 17.6% (- vitamin C) to 6.1% (+ vitamin C). The latency of onset of clinical efficacy varied between 25.0 +/- 8.5 min (- vitamin C) and 26.0 +/- 5.3 min (+ vitamin C). The duration of effect was lower (not significantly) when vitamin C was added: 88.0 +/- 12.5 min (- vitamin C) vs. 61.0 +/- 11.9 min (+ vitamin C). These data show that 10 mg apomorphine sublingually was effective in 56% of the patients. The combination with vitamin C did not significantly change the latency of onset or duration of clinical efficacy. Sublingual apomorphine should be considered as an alternative in the treatment of "off"-periods in Parkinson's disease, in particular when patients have the capacity to anticipate their off-periods.

Summary: The relationship between cognitive deterioration and abnormalities detected by magnetic resonance imaging (MRI) was investigated to determine the radiological correlates of cognitive deterioration in hereditary cerebral hemorrhage with amyloidosis- Dutch type (HCHWA-D). Twenty HCHWA-D subjects (12 patients who had suffered one or more strokes and eight who had not suffered a stroke) were studied with MRI and underwent extensive neuropsychological examination. On MRI the number of focal lesions was counted, and white matter hyperintensities (WMHs) were scored semiquantitatively. A significant correlation between cognitive deterioration and WMH score and number of focal lesions was found. However, cognitive deterioration, WMH score, and the number of focal lesions all increase with age, and therefore their mutual correlation can be explained as an age effect. This study shows that cognitive deterioration in HCHWA-D is not correlated with abnormalities detected by MRI (number of focal lesions and subcortical WMHs) independently of age. Although a contribution of white matter changes and/or focal lesions, possibly in combination with age, to cognitive deterioration cannot be excluded. Cognitive deterioration in these HCHWA-D patients is probably primarily the result of chronic damage of amyloid angiopathy to the brain, to which may be superimposed cognitive impairment from focal cerebral hemorrhage or infarction

The pharmacokinetics and clinical effects of apomorphine after rectal administration were determined in five patients with idiopathic Parkinson's disease (PD). Three different pharmaceutical formulations were tested: a rectal solution of apomorphine (10 or 15 mg), a gelatin suppository (25 and 50 mg), and a Witepsol-H15 suppository (50 and 100 mg). The pharmacokinetics of apomorphine were determined by measuring plasma concentrations using a sensitive and specific high-performance liquid chromatography method. The mean bioavailability varied between 14.7% and 40.2%, which was the bioavailability until the end of clinical benefit. Also, despite the differences in dose, the values of the Cmax were similar, with average values of 12.7-25.6 ng/ml. Wide differences in Tmax were observed, with values varying between 16 min for the enema and 127.5 min for the Witepsol-H15 100-mg suppository. The time course of the clinical effect was determined by assessing the time needed for walking a 25-m course and by calculating a tremor and dyskinesia score. Onset of effect was similar for each of the preparations, with an average onset time of 14-28 min. Significant differences with respect to the duration of the effect were observed. The duration of effect after administration of the Witepsol-H15 100-mg suppository was 156 +/- 43 min versus 50 +/- 13 min after rectal administration of the apomorphine solution. These results show that rectal administration of apomorphine may present an alternative to subcutaneous administration. The sustained-release properties of the Witepsol-H15 suppositories are especially of interest in the treatment of on-off fluctuations in PD.

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.

BACKGROUND AND PURPOSE: MTI has the potential to detect abnormalities in normal-appearing white and gray matter on conventional MR imaging. Early detection methods and disease progression markers are needed in HD research. Therefore, we investigated MTI parameters and their clinical correlates in premanifest and manifest HD. MATERIALS AND METHODS: From the Leiden TRACK-HD study, 78 participants (28 controls, 25 PMGC, 25 MHD) were included. Brain segmentation of cortical gray matter, white matter, caudate nucleus, putamen, pallidum, thalamus, amygdala, and hippocampus was performed using FSL's automated tools FAST and FIRST. Individual MTR values were calculated from these regions and MTR histograms constructed. Regression analysis of MTR measures from all gene carriers with clinical measures was performed. RESULTS: MTR peak height was reduced in both cortical gray (P = .01) and white matter (P = .006) in manifest HD compared with controls. Mean MTR was also reduced in cortical gray matter (P = .01) and showed a trend in white matter (P = .052). Deep gray matter structures showed a uniform pattern of reduced MTR values (P < .05). No differences between premanifest gene carriers and controls were found. MTR values correlated with disease burden and motor and cognitive impairment. CONCLUSIONS: Throughout the brain, disturbances in MTI parameters are apparent in early HD and are homogeneous across white and gray matter. The correlation of MTI with clinical measures indicates the potential to act as a disease monitor in clinical trials. However, our study does not provide evidence for MTI as a marker in premanifest HD.

This study assessed the 6-month follow-up effects of presymptomatic DNA testing for Huntington's disease (HD) in 73 individuals at 50% prior risk who were identified either as carriers of the HD gene (N = 29) or as noncarriers (N = 44). The subject's knowledge of being a gene carrier was expected to induce intrusive emotions, denial-avoidance behavior, and pessimistic expectancies of the future and adjustment problems. The Impact of Event Scale, the Beck Hopelessness Scale, and the General Health Questionnaire were used as standard measures of psychological distress. At the disclosure of the test results, carriers had a strong increase in pessimistic expectations but showed a decline to baseline levels 6 months later. Noncarriers reported a steep decline in hopelessness compared with their pretest conditions but had increased scores after 6 months. Six months after the disclosure of the test results, both gene carriers and noncarriers reported a significant decrease in unwanted intrusive thoughts about HD. Carriers showed a slight increase in denial-avoidance behavior, whereas noncarriers showed a clear decrease. Our observations might indicate that tested individuals found relief from the prior psychological distress and that they were able to acknowledge the impact of the test result on their future. An unresolved question is how the foreknowledge will affect carriers as they approach the impending onset of the disease. Longer observation periods (> 6 months after disclosure) are required to study changes of the impact of DNA test results over time.

Plaque-like lesions and amyloid angiopathy were investigated in the frontal cerebral cortex of four patients with hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D), using immunohistochemical [antibodies to beta amyloid protein (A beta), beta protein precursor (beta PP), synaptophysin, ubiquitin (UBQ), cathepsin D, paired helical filaments (PHF) and glial fibrillary acidic protein (GFAP)], enzymehistochemical (acid phosphatase) and silver [methenamine silver (MS) and Palmgren] staining methods. Whereas A beta- and MS-positive diffuse plaques were found in all patients, only the three older patients showed neuritic or congophilic plaques, which were acid phosphatase and cathepsin D positive and contained beta PP-, synaptophysin- and UBQ-positive, but PHF-negative neurites. These plaques were surrounded by reactive astrocytes. Similar immuno- and enzymereactivity was found around congophilic blood vessels. Thus, apart from neuronal degeneration in a subset of plaque-like lesions and around blood vessels, this study shows an age-related morphology of the plaques in HCHWA-D, corresponding to that in Down's syndrome (DS), with the difference that neurofibrillary (NF) pathology is absent in HCHWA-D in contrast to DS. HCHWA-D may be considered as a model for congophilic plaque formation not associated with NF pathology.

In hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D) (5/A4 amyloid deposition is found in meningocortical blood vessels and in diffuse plaques in the cerebral cortex. Diffuse plaques putatively represent early stages in the formation of senile plaques. Microglia are intimately associated with congophilic plaques in Alzheimer's disease (AD), but microglial involvement in diffuse plaque formation is controversial. Therefore, we studied the relationship between microglia and diffuse plaques in the cerebral cortex of four patients with HCHWA-D using a panel of macrophage/microglia markers (mAbs LCA, LeuM5, LeuM3, LN3, KP1, OKIa, CLB54, Macl, Ki-M6, AMC30 and the lectin RCA-1). Eight AD patients, one demented Down's syndrome (DS) patient and four non-demented controls were included for comparison. In controls and HCHWA-D patients ramified or "resting" microglia formed a reticular array in cortical gray and subcortical white matter. Microglial cells in or near HCHWA-D diffuse plaques retained their normal regular spacing and ramified morphology. In AD/DS gray matter more microglial cells were stained than in controls and HCHWA-D patients. Intensely immunoreactive microglia with enlarged cell bodies and short, thick processes clustered in congophilic plaques. In contrast to the resting microglia, these "activated microglia" strongly expressed class II major histocompatibility complex antigen, HLA-DR, and were AMC30-immunoreactive. These findings support the view that microglia play a role in the formation of congophilic plaques but do not initiate diffuse plaque formation. Another finding in this study is the presence of strong monocyte/macrophage marker immunoreactivity in the wall of cortical congophilic blood vessels in HCHWA-D.

In this study we evaluate the feasibility of measures that reflect different characteristics of motor activity and immobility in the objective quantification of hypokinesia. Because by definition hypokinesia can only be assessed over a period of time, continuous activity monitoring was used during 5 successive days in the home setting in 64 patients with Parkinson's disease (PD) and 104 healthy elderly subjects. In the patients we also evaluated the relation between the monitor measures and subjective measures of hypokinesia and age. Compared to the healthy elderly subjects, PD patients have a decreased activity level, increased proportion of time without movement, elevated mean duration of immobility, and decreased percentage of short-lasting immobility periods. Differences between both groups were most prominent for those measures that incorporate or reflect immobility. Moreover, in the PD patients the mean duration of immobility and percentage of short-lasting immobility periods show an apparent lack of relation with age and clinical ratings obtained from the UPDRS. In conclusion, our findings underscore the poor representation of hypokinesia in the UPDRS and value of objective quantification of this fundamental impairment of PD.

Although the Unified Parkinson's Disease Rating Scale (UPDRS) is widely used to monitor disease progression and drug efficacy, no attempts have been made to evaluate its scientific and clinical quality. Poor clinical sensibility of items in the activities of daily living (ADL) section and redundancy of items in the motor examination (ME) section prompted us to determine if the number of items in these sections could be reduced to a smaller, equally sensitive set that would describe the data as reliably as did the original set of items. Therefore, we assessed 111 patients with idiopathic Parkinson's disease on the UPDRS and Hoehn and Yahr staging scales. Our results show that the ADL (13 items) and ME (14 items) sections can be reduced to 8 items each without loss of reliability or validity. Our report is preliminary and needs validation.

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.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.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.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.

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. 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. 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). 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.

Recently, a massive loss of both hypocretin and melanin-concentrating hormone (MCH) neurones was found in the hypothalamus of Parkinson's disease (PD) patients. Because both hypocretin and MCH play a key role in the regulation of sleep, energy homeostasis and autonomic function, partly by modulation of the somatotrophic, thyrotrophic and lactotrophic axes, neuroendocrine dysregulation may contribute to some of the non-motor features of PD. In eight de novo, medication-free PD patients and eight age-, sex- and body mass index-matched controls, we measured serum levels of growth hormone (GH), thyroid-stimulating hormone (TSH) and prolactin every 10 min for 24 h. Auto-deconvolution, cosinor and approximate entropy analysis were applied to quantify GH, TSH and prolactin secretion rates, diurnal rhythmicity, as well as regularity of hormone release. Sleep was polygraphically-recorded throughout the night. Total 24-h secretion of GH (191 ± 31 versus 130 ± 39 mU/l/24 h), TSH (38 ± 9 versus 36 ± 2 mU/l/24 h) and prolactin (102 ± 14 versus 116 ± 17 μg/l/24 h), as well as their diurnal rhythmicity and regularity of release, were not significantly different between PD patients and controls (all P ≥ 0.12). Fasting levels of insulin-like growth factor-1 were also unaltered in PD patients. However, free thyroxine (T(4) ) levels were significantly higher in PD patients compared to controls (16.19 ± 0.80 versus 13.88 ± 0.40 pmol/l; P = 0.031). In PD patients, prolactin levels were related to disease duration (r = 0.76, P = 0.028), whereas both GH (r = -0.91, P = 0.002) and free T(4) (r = -0.71, P = 0.050) levels correlated inversely with body fat content. Apart from a mild increase in free T(4) levels, we found no indications for altered somatotrophic, thyrotrophic and lactotrophic axes activity in early-stage PD patients.

Analysis of the distribution of normal and expanded alleles of the polymorphic (CAG)n repeat in the IT15 gene in the Dutch population confirmed the presence of an expanded repeat on all Huntington's disease (HD) chromosomes. Our results show that the size distributions of normal and affected alleles overlap. Normal alleles range from 11 to 37 repeats and HD alleles contain 37 to 84 repeats. A clear correlation is found between age at onset and repeat length, but the spread of the age at onset in the major repeat range producing characteristic HD is too wide to be of diagnostic value. In the available parent-offspring pairs, maternal HD alleles show a moderate instability with a slight preponderance of size increase over size decrease. Paternal alleles have a bimodal distribution: the majority (69%) behave similarly to the maternal alleles, while the remainder (31%) show a dramatic expansion, the degree of which appears proportional to the initial size. This is shown in three out of four juvenile patients, who have repeats of 71, 74, and 84 copies, respectively, originating from expanded paternal HD alleles in the previous generation. Two sporadic cases are caused by expansion of 'large' normal paternal alleles of 32 and 34 repeats, respectively, to 46 copies. This not only confirms the diagnosis of HD in two de novo cases, but it also underlines the increased paternal instability. In addition paternal repeat instability was once detected within the normal range in two sibs who inherited 21 and 22 repeats, respectively, on the same paternal chromosome. In two Dutch HD families the segregation of the expanded (CAG)n repeat was found. Analysis of the (CAG)n repeat in our previously reported recombinants confirmed their disease status.

Heart rate variability at rest, during deep breathing, or standing up and with the Valsalva manoeuvre did not differ significantly between 67 patients with idiopathic Parkinson's disease (PD) and 31 healthy age matched controls. Blood pressure (BP) responses to standing up and sustained handgrip revealed diminished autonomic function in the PD group. In a preliminary analysis of the PD group older age, anti-Parkinson medication and higher Hoehn and Yahr (HY) stages were each associated with poor autonomic responsiveness. Disease duration was only related to the systolic BP fall on standing up. Multiple stepwise regression analysis showed that older age explained most of the variance of heart rate variability (up to 36%), and the only significant PD related factor was the use of medication, which explained less than 7%. The HY stage accounted for 12.7% of the variance in the standing up BP test, and the use of medication explained 10.6% of the variance of the systolic BP change in the sustained hand grip test. The unmedicated PD subgroup (n = 33), who had mild disease of short duration, showed no evidence of autonomic dysfunction. Cardiovascular autonomic dysfunction in PD is mild, mainly affects blood pressure responses, and occurs only in advanced cases.

The aim of this study was to evaluate the role of the site of attachment of activity monitors. We compared mean diurnal and nocturnal motor activity measures as well as the daily pattern of motor activity of dominant and non-dominant wrist recordings over 5 successive days of 10 healthy right-handed and 10 left-handed subjects. In a second study we evaluated the relationship between truncal motor activity and wrist motor activity. No differences emerged between the diurnal and nocturnal measures as well as the diurnal activity pattern of the dominant and the non-dominant wrist. Additionally, no differences were found in relation to handedness. Our results show that it is inaccurate to regard wrist motor activity measurements as representative of an invariable percentage of truncal motor activity; the relation between the measurements of these two recording sites varies across the daytime period. During the nocturnal period bilateral wrist motor activity occurred frequently in absence of truncal motor activity. The reverse situation, however, may occur sporadically. This finding most likely reflects that integrated generalized movements like postural shifts are measured at all recording sites, while the small movements that occur at the distal extremites are predominantly recorded by wrist-worn monitors. In conclusion, it is apparent that for both diurnal and nocturnal studies on the assessment of motor activity, either wrist can be chosen as the recording site. Across the diurnal period the relation between motor activity recorded at the wrist and waist is subject to considerable variability. During the nocturnal period motor activity can best be recorded at the wrist because this recording site detects both integrated generalized movements and movements that occur at the distal extremities.

The objective of this questionnaire-based survey was to evaluate the prevalence and causes of sleep disturbances in 90 nondepressive patients with Parkinson's disease (PD) and 71 age-matched healthy subjects. We also assessed the prevalence and characteristics of excessive daytime sleepiness (both groups) and excessive fatigue (PD patients). A high prevalence of sleep disturbances in PD patients was found; this is to a large extent probably the result of aging. As compared with controls, patients had a more severely disturbed sleep maintenance because of nycturia, pain, stiffness, and problems with turning in bed. The prevalence of excessive dreaming is similar in both groups, but altered dream experiences almost exclusively occurred in PD. Patients rated themselves more often to be morning-types than controls. This finding may account for the reported adaptation effects in experimental settings and the reduced REM latency in PD patients. The prevalence of daytime sleepiness was similar in both groups. Excessive daytime sleepiness showed a clear diurnal pattern with a peak in the early afternoon. As for excessive fatigue, the majority of the patients did not report a preferential time for this symptom. Our findings further argue against an association of fatigue with any circadian factor, and instead suggest a relationship with the motor deficits of PD.

We studied the influence of dietary protein intake on the plasma level profile of levodopa, carbidopa, and 3-O-methyldopa and clinical efficacy in 12 patients with idiopathic Parkinson's disease after intake of one levodopa-carbidopa 200/50 controlled release tablet (Sinemet CR; LC-CR). The tablet was given 1 h before the protein rich meal on one day (fasted) and together with the meal on an other day (non-fasted). Higher levodopa and carbidopa concentrations were reached when the LC-CR was taken 1 h before the meal, but the plasma level profile for levodopa was flatter in the non-fasted state. The area under the curve for levodopa was slightly higher in the fasted condition. For the clinical variables walking and tapping slightly better clinical results (P = 0.08) were found in the fasted condition with the higher levodopa levels. If the patient on levodopa is in a clinically satisfactory condition, then non-fasted condition could be preferred because of the smooth plasma level profile demonstrated. However, if the initial levodopa concentrations are not in the critical range to be effective for the patient, the advice should be to take the drug in a fasted condition.

Five patients with idiopathic Parkinson's disease with severe response fluctuations were selected for a randomized double-blind placebo-controlled study, concerning the clinical effects of subcutaneous apomorphine and its assessment in `off¿-periods. The study was designed as five n = 1 studies, in which every patient was his own control. The effect of apomorphine was studied by using the Columbia rating scale and quantitative assessments, using tapping, walking and pinboard. There was a significant positive effect of apomorphine, in a mean optimal dose of 2.7 mg, with a mean latency of onset of 7.3 min and a mean duration of response of 96 min. After pretreatment with domperidone, no significant adverse effects were observed. Tapping showed the highest correlation with rigidity and bradykinesia. Walking showed a high correlation with stability and gait. Pinboard testing did not give additional information. The first conclusion was that apomorphine proved to be a significantly effective dopamine agonist, proven now also by a double blind placebo-controlled study. Secondly it was concluded that assessment of clinical effect in parkinsonian patients can be performed best by combining the Columbia item tremor with tapping and walking scores.

Background Macrostructural and microstructural neuroimaging measures are potential biomarkers in Huntington’s disease (HD). Macrostructural measures are generally derived from structural T1-weighted magnetic resonance imaging (MRI), while microstructure can be measured using diffusion tensor imaging (DTI), which indexes the properties of water molecules within white matter (WM) tissue. HD is associated with WM volume and integrity loss but how these two measures interact is not fully understood. Aims To investigate the relationship between diffusion metrics and brain volume in healthy controls. Methods 3T MRI and DTI data from 51 control subjects taken from the TRACK-HD and PADDINGTON studies were analysed. Regression analysis and Tract Based Spatial Statistics (TBSS) were used to assess the associations between whole brain diffusion metrics: fractional anisotropy; mean diffusivity; axial diffusivity and radial diffusivity, and volumetric measures: whole brain volume; WM and grey matter (GM) volumes (all adjusted for total intracranial volume). Results Regression analysis revealed a significant relationship between all diffusion metrics and both whole brain and WM volumes. No significant relationship was found between GM and FA. Preliminary TBSS results suggest a significant positive association between whole brain volume and FA in several regions, including the cingulate gyrus, pre- and post central gyri and the putamen. Conclusions We demonstrated an association between whole brain and WM volume and diffusion-based measures of tissue integrity; this relationship is present in the absence of any disease-related changes. These results may aid our understanding of the underlying pathology and heterogeneity in HD and have implications for biomarker development in the condition.

Background Since there is no cure for Huntington’s disease (HD) yet the intention of all forms of treatment is to improve quality of life. All treatment must be individually tailored, as the symptoms and signs are different for each person and change over time. Music therapy (MT) recognises individual needs and can be adapted to meet them. The aim is to maintain function and provide opportunities for compensatory behaviour. In MT functional training can be combined with cognitive, emotional and communicative/relational approaches. Practice based evidence has shown that MT could be a suitable non-pharmacological intervention to improve quality of life in every stage. Aims This will be the first randomised controlled trial (RCT) to study the efficacy of MT, to be executed in three different long care facilities in The Netherlands, specialised in HD. The aim is to determine whether MT can improve expressive and communicative skills, and if so, whether these improvements lead to behavioural change. Methods Sixty patients will be included and randomised: the experimental MT and the control group. The basic principle is to challenge expressive and communicative skills. Results The primary outcome measures are the Behaviour Observation Scale Huntington and the Problem Behaviour Assessment. Assessments will take place at baseline and will be repeated after session 8 and 16, and 3 months after the last intervention. Conclusions Music therapy is promising for improving QOL in HD, but not evidence based. This study aims to test it’s effectiveness in a RCT.

Background Previous Huntington’s disease studies have revealed occipital lobe atrophy and cortical thinning, although it is unclear when this develops and whether it is uniform across the lobe. Visual deficits are not typical of HD symptomatology, however it is possible that more subtle visual functions are impaired and, in turn, influence performance on cognitive tasks with a visual component. Aims To identify the regional distribution of disease-related occipital cortical thinning and investigate associations with cognitive and motor impairment. Methods T1-weighted 3T MR scans from controls (n = 107), pre-HD (n = 116) and early HD subjects (n = 90) from the TRACK-HD study were processed using the FreeSurfer software; cuneus, pericalcarine, lingual and lateral occipital regions were outputted. Generalised least squares regression models were fitted to assess between-group differences. Relationships between visual cognitive and motor task performance and cortical occipital thinning in gene-positive participants were assessed using general linear regression models. Results The occipital cortex was significantly thinner in pre-HD and early HD participants. These between-group differences were heterogeneous across regions, with the lateral occipital region showing the most pronounced effects. Significant associations were found between reduced occipital cortical thickness and poorer performance on a number of cognitive tasks involving a visual component. No association was found with finger tapping. Conclusions Regionally-specific thinning of the occipital cortex was evident more than a decade before estimated HD symptom onset. Associations were found with cognitive tasks, but not finger tapping, suggesting that occipital thickness plays an important role in cognitive tasks with a visual component. This has implications for the interpretation of impaired cognitive performances in HD, which is typically attributed to frontal and executive circuits, rather than to visual regions.

Background Huntington’s disease (HD) is commonly associated with psychiatric disturbance. Often evident in premanifest gene-carriers, little is understood about the neural bases underlying these HD symptoms. While structural imaging has so far failed to provide any major insight, Diffusion Tensor Imaging (DTI) can be used to investigate connectivity between brain regions and any putative microstructural changes that may occur in HD. Aims To examine structural connectivity associated with depression, apathy and irritability in HD gene-carriers. Methods DTI data was collected from 39 premanifest and 45 early-HD participants, as part of the TrackHD study and was analysed using whole-brain Tract-Based Spatial Statistics to extract fractional anisotropy (FA) values – a surrogate marker for tract integrity and efficacy of communication between brain regions. Regression analyses were performed on all gene-carriers using HADS depression and PBA apathy and irritability scores. Results High disease load (measured by CPO) was associated with highly significant, whole-brain corrected correlations between depression scores and reduced FA in the bilateral splenium of the corpus callosum. There were significant widespread negative associations between irritability scores and FA. Interestingly, low disease load participants demonstrated significant correlations between irritability scores and FA reduction. There were no significant associations between apathy and FA. Conclusions Both depression and irritability are associated with reductions in white matter integrity in HD. The opposite relationships between FA and measures of depression and irritability as a function of disease progression suggest that diverse mechanisms associated with both the onset and progression of psychiatric disturbance in HD.