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Huntington disease (HD) is a late onset ultimately fatal neurodegenerative disorder caused by a cytosine-adenine-guanine ( CAG) triplet repeat expansion in the Huntingtin gene which was discovered in 1993. The PHAROS study is a unique observational study of 1001 individuals at risk for HD who had not been previously tested for HD and who had no plans to do so. In this cohort, 104 (10%) individuals changed their minds and chose to be tested during the course of the study but outside of the study protocol. Baseline behavioral scores, especially apathy, were more strongly associated with later genetic testing than motor and chorea scores, particularly among subjects with expanded CAG repeat length. In the CAG expanded group, those choosing to be tested were older and had more chorea and higher scores on the behavioral section of the unified Huntington's disease rating scale at baseline than those not choosing to be tested. Following genetic testing, 56% of subjects with CAG37 had less depression when compared to prior to testing, but depression generally stayed the same or increased for 64% of subjects in the expanded group. This finding suggests that approaches to testing must continue to be cautious, with appropriate medical, psychological and social support.

Abundant preclinical evidence suggests that serotonin-containing neural systems may participate in the regulation of both extrapyramidal and neuroendocrine function. In an attempt to examine these possibilities in man, patients with various neurologic disorders received drugs believed to facilitate or inhibit serotonergic function. Extrapyramidal signs in patients with parkinsonism or Huntington's disease showed no consistent change with L-tryptophan or parachlorophenylalanine. Unexpectedly, L-5-hydroxytryptophan, given in combination with a peripheral decarboxylase inhibitor, caused a worsening of parkinsonian akinesia and rigidity. Fenfluramine, at doses which appeared to diminish central serotonin but not dopamine turnover, had no consistent effect on the severity of involuntary movements in patients with Huntington's chorea, but did produce a significant rise in plasma prolactin.

We analyzed plasma 8OHdG concentrations in 20 individuals enrolled in the Pre-2CARE study before and after treatment with CoQ. Treatment resulted in a mean reduction in 8OHdG of 2.9 ± 2.9 pg/ml for the cohort (p = 0.0003) and 3.0 ± 2.6 pg/ml, for the HD group (p = 0.002). Baseline 8OHdG levels were not different between individuals with HD and controls (19.3 ± 3.2 pg/ml vs. 19.5 ± 4.7 pg/ml, p = 0.87) though baseline CoQ levels were elevated in HD compared with controls (p < 0.001). CoQ treatment reduces plasma 8OHdG and this reduction may serve as a marker of pharmacologic activity of CoQ in HD.

The Genetic Information Nondiscrimination Act (GINA) of 2008 was the first US legislation to address genetic discrimination. We sought to assess understanding of GINA among individuals affected by the autosomal dominant condition, Huntington disease (HD). We conducted a cross-sectional survey of individuals with varying risk of HD to assess their familiarity with GINA. As a control, individuals were surveyed about their familiarity with the Health Insurance Portability and Accountability Act (HIPAA). Those who reported familiarity with GINA were asked about their knowledge of specific provisions of the legislation. The survey was offered to 776 participants and completed by 410 (response rate 53%). Respondents across all groups were less familiar with GINA (41% slightly, somewhat, or very familiar) than with HIPAA (65%; p 0.0001). Of individuals with or at risk for HD who reported some familiarity with GINA, less than half correctly identified GINA's protections, and less than 15% correctly identified its limitations. Thus, among individuals affected by HD, familiarity with and knowledge of GINA are low. The effectiveness of the legislation may be limited by this lack of knowledge.

Background Cognitive and behavioral adverse events (AEs) such as hallucinations, confusion, depression, somnolence and other sleep disorders commonly limit effective management of motor symptoms in PD. Rasagiline (N-propargyl-1(R)-aminoindan) mesylate is a novel, second-generation, selective, irreversible monoamine oxidase type B inhibitor, demonstrated in monotherapy and adjunctive trials to be effective for PD with excellent tolerability. Methods The occurrence of cognitive and behavioral AEs and the change from baseline in the Unified Parkinson's Disease Rating Scale (UPDRS) part I mental subscores were reviewed in two multicenter, randomized, placebo-controlled, 26-week trials of rasagiline for early and moderate-to-advanced patients with PD. The UPDRS is a multi-item rating scale specific to PD; part I rates the patient's intellectual impairment, thought disorders, depression and motivation/initiative. Results The TEMPO study evaluated rasagiline monotherapy in early PD patients (n = 404). The PRESTO study evaluated rasagiline as adjunctive therapy in moderate-to-advanced PD patients with motor complications who were receiving optimized levodopa/carbidopa (n = 472). In the analysis of adverse event reporting for both studies, no cognitive and behavioral AE in either the rasagiline 1 mg or placebo groups exceeded 10% of the study population and the frequency differences between rasagiline 1 mg and placebo never exceeded 3%. There was no adverse effect on the UPDRS mental subscore relative to placebo in either of the two studies. Conclusion Rasagiline 1 mg once daily improves PD symptoms and motor fluctuations in early and moderate-to-advanced PD patients without causing significant cognitive and behavioral AE or adverse changes in mentation, behavior and mood.

A 44-year-old female is described who developed persistent upper extremity and orolingual dystonia several weeks after suspected onset of central pontine myelinolysis (CPM), later confirmed by characteristic pontine lesions on MRI. No foci of the extrapontine myelinolysis were evident. This case confirms that dystonia may be a late and persistent sequela of CPM and may occur in the absence of visible lesions outside the brainstem.

To determine the rate of functional decline in a large cohort of patients with Huntington's disease (HD) followed at 43 sites by the Huntington Study Group (HSG).The annual rate of functional decline was measured using the Total Functional Capacity Scale (TFC) and the Independence Scale (IS) in 960 patients with definite HD followed prospectively for a mean of 18.3 months. All patients were rated with the Unified Huntington's Disease Rating Scale (UHDRS). Sample size calculations for hypothetical clinical trials were calculated.A factor analysis of the UHDRS at baseline yielded 15 factors accounting for 77% of the variance. The TFC score declined at a rate of 0.72 units/year (standard error [SE] 0.04) and the IS score declined at a rate of 4.52 units/year (SE 0.23). Lower TFC score at baseline, indicating more severe impairment, was associated with less rapid annual decline in TFC score, perhaps reflecting the floor effect of the scale. The annual rate of decline for 575 patients with baseline TFC scores of 7 to 13 was 0.97 (SE 0.06), was 0.38 (SE 0.08) for 270 patients with baseline TFC scores of 3 to 6, and was 0.06 (SE 0.1) for 101 patients with TFC scores of 0 to 2. In multivariate analysis (n = 960), longer disease duration and better cognitive status at baseline were associated with a less rapid rate of decline in TFC score, whereas depressive symptomatology was the only factor associated with more rapid decline on the IS score. Age at onset of HD, sex, weight, and education did not affect decline on either score.The comparable rates of decline on the TFC and the IS scores with other published studies suggest that these estimates of functional decline are representative of HD patients who are evaluated at HSG research sites. In longitudinal analysis, longer disease duration and better neuropsychological performance at baseline were associated with a less rapid rate of decline in TFC score, whereas depressive symptomatology at baseline was associated with a more rapid decline in the IS score. These rates of functional decline and the covariates that modify them should be considered in estimating statistical power and designing future therapeutic trials involving HD patients with early or moderately severe disease.

In 1987, the DATATOP clinical trial was initiated to examine the benefits of deprenyl (selegiline) and alpha-tocopherol in slowing the progression of Parkinson's disease (PD). After 14 +/- 6 (mean +/- SD) months of controlled observation, deprenyl 10 mg/day was found to significantly delay the time until enough disability developed to warrant the initiation of levodopa therapy. This effect was largely sustained during the overall 8.2 years of observation, including open-label deprenyl treatment and a second treatment randomization to continue deprenyl or switch to placebo. There were no accompanying benefits of deprenyl in postponing levodopa-related adverse effects or extending life. Alpha-tocopherol produced no benefits. The 2.1% per year mortality rate of the DATATOP cohort was remarkably low, about the same as an age-matched population without PD. Neuroprotective therapy remains an elusive goal for the experimental therapeutics of PD. Advances in understanding pathogenesis, a robust pipeline of rational treatments, and the advent of valid and reliable biologic markers hold promise in the coming decade for developing and achieving neuroprotective therapies for PD.

Neuroprotective therapies are interventions that produce enduring benefits by favorably influencing underlying etiology or pathogenesis of neurodegenerative disorders. Neuroprotection remains an unachieved goal of experimental therapeutics. A variety of pathogenetic mechanisms and propagating factors have been implicated in the emergence and progression of Parkinson's disease (PD). Antioxidative strategies have been the focus of neuroprotective trials for PD, but interpretation of the outcomes has been controversial. Traditional end points that respond to enhanced dopaminergic activity may not be suitable for distinguishing symptomatic from neuroprotective effects. Inferences supporting neuroprotective effects in clinical trials would be strengthened by attention to unmet therapeutic needs or relevant clinical end points that are not currently amenable to dopaminergic treatments. Progressive postural instability and intellectual impairment (dementia) represent two major unmet therapeutic needs in PD that are worthy outcomes in therapeutic trials. Imaging tools such as [18F]-dopa PET and [123I] B-CIT SPECT may provide valid and reliable biologic markers of nigrostriatal degeneration. Controlled clinical trials focused on unmet therapeutic needs, and involving valid biologic markers is expected to play a central role in development of neuroprotective therapy for PD.

Clinical research in neurology may be based on observation or intervention. Basic science and observational clinical studies often address questions of cause and pathogenesis, whereas interventional clinical experiments normally are required to establish the safety, tolerability, and efficacy of therapies. This article outlines various study paradigms and discusses the concepts of intervention, randomization, blinding, and control in the context of clinical trial design. Accurate interpretation of trial results is predicated on the care with which experimental therapeutic studies are designed and conducted.

Three hundred and seventy-six subjects with advanced Parkinson's disease participated in a prospective, double-blind placebo-controlled study of the dopamine agonist pergolide mesylate as an adjunct to Sinemet. At 6 months, patients randomized to pergolide had a statistically significant improvement in total Parkinson's score, scores of activities of daily living, motor function, number of "off" hours, Hoehn and Yahr stage, and numerous parameters of parkinsonian function including bradykinesia, rigidity, gait, and dexterity. This benefit was obtained with the addition of a mean dose of 2.94 mg of pergolide, which permitted a 24.7% reduction in dose of levodopa. Adverse reactions were, for the most part, mild, reversible, and not of major clinical significance. No significant cardiac or electrocardiographic abnormalities were detected. This study demonstrates that pergolide mesylate, as an adjunct to levodopa, is an effective antiparkinsonian agent that provides clinical improvement while permitting a reduction in levodopa dose.

The initial observation of an expanded and unstable trinucleotide repeat in the Huntington's disease gene has now been confirmed and extended in 150 independent Huntington's disease families. HD chromosomes contained 37-86 repeat units, whereas normal chromosomes displayed 11-34 repeats. The HD repeat length was inversely correlated with the age of onset of the disorder. The HD repeat was unstable in more than 80% of meiotic transmissions showing both increases and decreases in size with the largest increases occurring in paternal transmissions. The targeting of spermatogenesis as a particular source of repeat instability is reflected in the repeat distribution of HD sperm DNA. The analysis of the length and instability of individual repeats in members of these families has profound implications for presymptomatic diagnosis.

While participating in a controlled study of baclofen as protective therapy, 39 Huntington's disease (HD) patients underwent measurements of horizontal saccade latency and velocity, repeated longitudinally over a 2-year period. Significant worsening of saccade latency and of mean velocity was detected in untreated patients. Although individual variation was great, initial velocity impairment was found to be more prominent in younger patients. Factors are identified that may affect the rate of decline in supranuclear oculomotor function, including age and the severity of illness at the time of initial assessment. We propose that serial quantitative measurement of saccade performance is a useful clinical marker of the rate of disease progression against which the efficacy of treatments may be tested.

The pathogenesis of Parkinson's disease (PD) has been linked to oxidative-mediated events including increased monoamine oxidase (MAO) and free-radical generation. We are investigating the ability of the MAO inhibitor, selegiline (deprenyl), and of the free-radical scavenger, tocopherol, to delay the onset of disability requiring levodopa therapy (primary end point) in patients with early PD. Eight hundred patients with early, untreated PD were enrolled in the multi-center placebo-controlled, double-blind clinical trial 'Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP)'. Subjects were assigned by 2 x 2 factorial design to receive selegiline (10 mg/day), tocopherol (2,000 IU/day), a combination of both drugs, or placebo, and followed to determine if and when disability occurred requiring levodopa therapy. After 12 +/- 5 months of observation, independent monitoring prompted a preliminary analysis indicating that selegiline 10 mg/day significantly extended the time to the primary end point. Selegiline therapy, alone or in combination with tocopherol, resulted in a 57% reduction in the rate of developing disability requiring levodopa therapy (p10(-10)) and a 50% reduction in the rate of loss of full-time employment (p = 0.01). Deterioration of motor and mental features was significantly less in selegiline-treated subjects. Adverse effects were minor and infrequent. We conclude from these preliminary results that selegiline (10 mg/day) delays the onset of disability associated with early, otherwise untreated PD. It remains unclear whether these benefits derive from mechanisms that are symptomatic (dopaminergic), protective (anti-neurotoxic), or both. The DATATOP study is ongoing to examine the long-term effects of selegiline and the independent and interactive effects of tocopherol.

The DATATOP database, which includes clinical information on 800 patients with early untreated Parkinson's disease (PD), is well suited to explore clinical heterogeneity in PD. Patients with early-onset PD (less than or equal to 40 years, N = 33) reached the same level of disability as the late-onset PD (greater than or equal to 70 years, N = 85) group at a significantly slower rate (2.9 vs. 1.7 years). Early-onset PD patients functioned cognitively better than late-onset PD patients. Bradykinesia, and postural instability and gait difficulty (PIGD), were more common at onset in patients with a rapid rate of disease progression ("malignant PD"; duration of symptoms less than 1 year and Hoehn/Yahr stage of 2.5, N = 11) as compared with those with a relatively slow rate of progression ("benign PD"; duration of symptoms greater than 4 years, N = 65). Comparisons of tremor-dominant PD (mean tremor score/mean PIGD score less than or equal to 1.5, N = 441) with the PIGD-dominant type (mean tremor score/mean PIGD score greater than or equal to 1.0, N = 233) provided support for the existence of clinical subtypes. The PIGD group reported significantly greater subjective intellectual, motor, and occupational impairment than the tremor group. Stage II patients had higher depression scores than stage I patients. Among the patients participating in the DATATOP, older age at onset with bradykinesia, or with the PIGD form of PD, is associated with more functional disability than when the symptoms are dominated by tremor or begin at a younger age.

The ability of orally administered clonidine, an alpha noradrenergic agonist, to modify the therapeutic efficacy of l -DOPA or piribedil was studied in Parkinsonian patients. At doses which produced unequivocal cardiovascular changes, clonidine significantly diminished the anti-Parkinsonian potency of either drug. Anticholinergic agents markedly reduced this effect of clonidine. The results suggest that clonidine possesses cholinergic as well as noradrenergic activity and cast doubt on the accuracy of the l -DOPA potentiation test in rodents as a predictor of therapeutic efficacy in patients with Parkinson's disease.

A double-blind trial of orally administered fenfluramine was conducted in 7 non-obese adults with various neurological disorders. Caloric intake and body weight fell significantly after 8 days of treatment although there was no definite change in appetite ratings. Average central turnover of serotonin, as estimated by the cerebrospinal fluid (CSF) accumulation of 5-hydroxyindoleacetic acid (5-HIAA) during probenecid loading, decreased by 66%. No significant change in homovanillic acid, the major dopamine product, was apparent. The results support the contention that the effect of fenfluramine on human dietary intake may be mediated by alterations in serotonergic rather than dopaminergic mechanisms.

Abundant preclinical evidence suggests that serotonin-containing neural systems may participate in the regulation of both extrapyramidal and neuroendocrine function. In an attempt to examine these possibilities in man, patients with various neurologic disorders received drugs believed to facilitate or inhibit serotonergic function. Extrapyramidal signs in patients with parkinsonism or Huntington's disease showed no consistent change with L-tryptophan or parachlorophenylalanine. Unexpectedly, L-5-hydroxytryptophan, given in combination with a peripheral decarboxylase inhibitor, caused a worsening of parkinsonian akinesia and rigidity. Fenfluramine, at doses which appeared to diminish central serotonin but not dopamine turnover, had no consistent effect on the severity of involuntary movements in patients with Huntington's chorea, but did produce a significant rise in plasma prolactin.

DATATOP is a double-blind, multi-center, placebo-controlled clinical trial aimed at slowing the decline of patients who are in the early stages of Parkinson's disease (PD). The specific aim is to determine whether or not chronic administration of deprenyl 10 mg per day and/or tocopherol 2000 IU per day to early, otherwise untreated PD patients will prolong the time until levodopa therapy is required to treat emerging disability. Deprenyl and tocopherol exert antioxidative effects through separate but complementary mechanisms of action. A 2 X 2 factorial design allocates eligible subjects to one of four treatment groups: 1) deprenyl alone, 2) tocopherol alone, 3) deprenyl plus tocopherol, or 4) placebo. Eligible subjects include early PD patients (illness duration less than 5 years and in stages I and II), aged 30 to 79, who are not taking or requiring any anti-PD medications. The major response variable is the time period from randomization until the blinded investigator judges levodopa necessary to treat emerging parkinsonian disability. Randomization is stratified to ensure that treatment assignments are balanced for each blinded investigator. Cerebrospinal fluid is sampled just prior to randomization and one month after washout of experimental medications in order to help distinguish between symptomatic and protective effects of interventions. Based on pilot studies it is estimated that approximately 85% of untreated PD patients will require levodopa within two years and a total sample size of 800 subjects will provide a 95% likelihood for detecting a 10% "survival" difference between experimental medications and placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients with PD who experience on-off effects have higher erythrocyte catechol-O-methyltransferase (COMT) activities and plasma 3-O-methyldopa concentrations than do patients without these levodopa-related motor fluctuations. We therefore administered ascorbic acid, a weak competitive inhibitor of COMT, to six PD patients with on-off effects. In this double-blind crossover investigation, ascorbic acid produced a modest improvement in functional performance. However, no fundamental change was observed in the pattern of on-off effects, severity of parkinsonism/dyskinesia, or self-assessment ratings. Ascorbic acid therapy reduced plasma concentrations of levodopa and 3-O-methyldopa but did not alter erythrocyte COMT activity. These findings are discussed in the context of the pharmacokinetic and pharmacodynamic factors that contribute to the pathogenesis of levodopa-induced dyskinesias and on-off motor fluctuations.

Huntington'S disease (HD) is an autosomal dominant disorder associated with neuronal degeneration especially involving the basal ganglia and cerebral cortex. The cardinal signs of dementia and involuntary movements usually appear in middle life. Although the pathogenesis of this disease remains unknown, its course progres­ sive, and the efficacy of available treatments limited, a recent surge of investigative interest has yielded significant information about HD and related central degenera­ tive disorders.

In a patient with essential cryoglobulinemia with systemic, cutaneous, and neurologic manifestations and a mixed IgG-IgM cryoprotein, elimination of systemic and cutaneous disease manifestations, as well as notable reversal of neurologic impairment, followed therapy with melphalan. Levels of circulating cryoprotein decreased, but protein structure was unchanged by chemotherapy. Experience to date with alkylating agents suggests that this mode of treatment is the most effective currently available.

The development of levodopa therapy for Parkinson’s disease (PD) has spawned substantive clinical and scientific gains related to the experimental therapeutics of neurodegenerative disorders. Levodopa therapy has resulted in symptomatic benefit and increased life expectancy for the majority of PD patients. The rational development of levodopa therapy and related therapies to rectify the consequences of reduced dopaminergic neurotransmission in PD has also served as a prototype for the experimental therapeutics of other neurologic disorders associated with neurotransmitter deficits. In spite of these advances, the clinical and scientific limitations of replacement therapies have become increasingly evident. Symptomatic anti-PD benefits have proved transient, and clinical features intensify eventually in the setting of progressive neuronal degeneration. Disabling adverse effects, such as mental status disturbances, involuntary movements, and autonomic instability, further preclude or limit the use of dopaminergic therapies. The application of rational replacement therapy to other neurologic disorders has been constrained by the progressive and often multiple transmitter disturbances arising from neurode-generation.

In dem Vortrag wurde das Design einer amerikanisch/kanadischen Multicenter-Studie vorgestellt. Die Studie basiert auf einem hypothetischen Schadigungsmechanismus der Substantia nigra uber Radikale. Ihr Ziel ist es, die Wirkung einer Radikal-vermindernden Therapie zu uberprufen.