Background PBT2 is a metal protein-attenuating compound that might reduce metal-induced aggregation of mutant huntingtin and has prolonged survival in a mouse model of Huntington's disease. We aimed to assess the safety, tolerability, and efficacy of PBT2 in patients with Huntington's disease.Methods In this 26-week, randomised, double-blind, placebo-controlled trial, adults (>= 25 years old) with early-stage to mid-stage Huntington's disease were randomly assigned (1:1:1) by a centralised interactive response system to once daily PBT2 250 mg, PBT2 100 mg, or placebo. Randomisation was stratified by site with a block size of three. Participants, carers, the steering committee, site investigators, study staff, and the study sponsor were masked to treatment assignment. Primary endpoints were safety and tolerability. The safety population consisted of all participants who were randomly assigned and had at least one dose of study drug. The principal secondary endpoint was cognition, measured by the change from baseline to week 26 in the main composite Z score of five cognitive tests (Category Fluency Test, Trail Making Test Part B, Map Search, Symbol Digit Modalities Test, and Stroop Word Reading Test) and scores on eight individual cognitive tests (the five aforementioned plus the Trail Making Test Part A, Montreal Cognitive Assessment, and the Speeded Tapping Test). The intention-to-treat population comprised participants who were randomly assigned and had at least one efficacy assessment after administration of study drug. This trial is registered with ClinicalTrials.gov, NCT01590888.Findings Between April 18, 2012, and Dec 14, 2012, 109 participants were randomly assigned to PBT2 250 mg (n=36), PBT2 100 mg (n=38), or placebo (n=35) at 19 research centres in Australia and the USA. 32 (89%) individuals on PBT2 250 mg, 38 (100%) on PBT2 100 mg, and 34 (97%) on placebo completed the study. Six serious adverse events (acute coronary syndrome, major depression, pneumonia, suicide attempt, viral infection, and worsening of Huntington's disease) occurred in five participants in the PBT2 250 mg group, three (fall with subdural haematoma, suicide attempt, and hospital admission for stabilisation of Huntington's disease) occurred in two participants in the PBT2 100 mg group, and one (increasing aggression) occurred in a participant in the placebo group. The site investigators deemed all, except the worsening of Huntington's disease, as unrelated to study drug. 32 (89%) participants on PBT2 250 mg, 30 (79%) on PBT2 100 mg, and 28 (80%) on placebo had at least one adverse event. Compared with placebo, neither PBT2 100 mg (least-squares mean 0.02, 95% CI-0.10 to 0.14; p=0.772) nor PBT2 250 mg (0.07, -0.05 to 0. 20; p=0. 240) significantly improved the main composite cognition Z score between baseline and 26 weeks. Compared with placebo, the Trail Making Test Part B score was improved between baseline and 26 weeks in the PBT2 250 mg group (17.65 s, 0.65-34.65; p=0. 042) but not in the 100 mg group (0. 79 s improvement, -15.75 to 17.32; p=0.925); neither dose significantly improved cognition on the other tests.Interpretation PBT2 was generally safe and well tolerated in patients with Huntington's disease. The potential benefit on executive function will need to be confirmed in a larger study.

Objective: To determine whether motor, behavioral, or psychiatric symptoms in Huntington disease (HD) predict skilled nursing facility (SNF) placement. Methods: Subjects were participants in the Huntington Study Group’s Unified Huntington Disease Rating Scale Database (Rochester, NY) between January 1994 and September 1999. Specific motor, psychiatric, and behavioral variables in subjects residing at home and in SNF were analyzed using χ2 and Student’s t-tests. For a subset of subjects for whom longitudinal data existed, a Cox proportional hazards model controlling for age, sex, and disease duration was used. Results: Among 4,809 subjects enrolled, 3,070 had clinically definite HD. Of these, 228 (7.4%) resided in SNF. The SNF residents’ average age was 52 years, average disease duration was 8.6 years, and they were predominantly women (63%). The SNF residents had worse motor function (chorea, bradykinesia, gait abnormality, and imbalance, p < 0.0001); were more likely to have obsessions, compulsions, delusions, and auditory hallucinations; and had more aggressive, disruptive (p < 0.0001), and irritable behaviors (p = 0.0012). For 1,559 subjects, longitudinal data existed (average length of follow-up, 1.9 years), and 87 (5%) moved from home to SNF. In the Cox model, bradykinesia (HR 1.965, 95% CI 1.083 to 3.564), impaired gait (HR 3.004, 95% CI 1.353 to 6.668), and impaired tandem walking (HR 2.546, 95% CI 1.460 to 4.439) were predictive of SNF placement. Conclusions: Institutionalized patients with HD are more motorically, psychiatrically, and behaviorally impaired than their counterparts living at home. However, motor variables alone predicted institutionalization. Treatment strategies that delay the progression of motor dysfunction in HD may postpone the need for institutionalization.

Objective: To determine the inter-rater reliability of a modification of the Memorial Sloan-Kettering (MSK) Staging for HIV-associated cognitive impairment. Methods: Data were abstracted on neurologic, neuropsychological, and functional status on 100 individuals participating at four sites in the Northeast AIDS Dementia (NEAD) Consortium cohort study, a longitudinal study of predictors of cognitive impairment in HIV-infected individuals. Neuropsychological performance was defined 1) based on the neuropsychologist's global impression and 2) solely based on neuropsychological test scores. Raters at each site used the abstracted data to assign an MSK stage to each subject blind to any identifying information. Inter-rater reliability was assessed using kappa statistics. Agreement between computer-generated ratings and site-generated ratings was also assessed. Results: Kappa statistics for pair-wise agreement among the sites regarding MSK stage ranged from 0.70-0.91, representing good to excellent agreement between sites. Agreement between computer-generated ratings and site-generated ratings was in the good to excellent range (0.62-0.79). Conclusions: The authors have modified the MSK rating scale and developed a reliable instrument that can be used in multicenter studies. This instrument will be useful in staging HIV-dementia in future longitudinal studies and will be valuable in increasing accuracy of clinicopathologic studies.

Context: Long-term levodopa therapy for Parkinson disease commonly results in motor complications including "on-off" fluctuations and dyskinesias, but it is still unclear how best to assess treatment effects on dyskinesias in clinical trials.Objective: To compare several methods of rating levodopa-induced dyskinesias to evaluate the effect of remacemide hydrochloride treatment in patients with advanced Parkinson disease.Design: Two-week multicenter randomized, double-blind, placebo-controlled, parallel-group study.Setting: Five academic sites of the Parkinson Study Group.Patients: Thirty-nine subjects at least 30 years old with idiopathic Parkinson disease and disabling dyskinesias.Interventions: Randomly received daily doses of 150 mg, 300 mg, or 600 mg of remacemide hydrochloride or matching placebo for 2 weeks.Main Outcome Measures: The dyskinesia rating scales used were the Modified Goetz Dyskinesia Rating scale (MGDRS), a newly created Lang-Fahn Activities of Daily Living Dyskinesia scale (LFADLDS), and diary dyskinesia ratings.Results: Patient and investigator diaries showed excellent agreement in dyskinesia ratings. The MGDRS score correlated with clinic diary ratings of the percentage of "on" time with dyskinesias, and the LFADLDS score correlated with home and clinic diary assessments of percentage of on time with severe dyskinesias. The MGDRS score did not correlate highly with the LFADLDS score. This pilot study also validated previous results demonstrating the safety and tolerability of remacemide treatment for advanced Parkinson disease but did not result in any demonstrable improvement or worsening in dyskinesia measures.Conclusions: Diaries may provide a valid means of evaluating dyskinesias in clinical trials for Parkinson disease, but there remain other aspects of dyskinesias, as assessed by the MGDRS and LFADLDS, that are not reflected in diary ratings.

BACKGROUND:Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa.METHODS:In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy.RESULTS:Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant.CONCLUSION:Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

Objectives: To determine whether chronic treatment with coenzyme Q(10) or remacemide hydrochloride slows the functional decline of early Huntington's disease (HD). Methods: The authors conducted a multicenter, parallel group, double-blind, 2 X 2 factorial, randomized clinical trial. Research participants with early HD (n = 347) were randomized to receive coenzyme Q(10) 300 mg twice daily, remacemide hydrochloride 200 mg three times daily, both, or neither treatment, and were evaluated every 4 to 5 months for a total of 30 months on assigned treatment. The prespecified primary measure of efficacy was the change in total functional capacity (TFC) between baseline and 30 months. Safety measures included the frequency of clinical adverse events. Results: Neither intervention significantly altered the decline in TFC. Patients treated with coenzyme Q(10) showed a trend toward slowing in TFC decline (13%) over 30 months (2.40- versus 2.74-point decline, p = 0.15), as well as beneficial trends in some secondary measures. There was increased frequency of nausea, vomiting, and dizziness with remacemide and increased frequency of stomach upset with coenzyme Q(10). Conclusions: Neither remacemide nor coenzyme Q(10), at the dosages studied, produced significant slowing in functional decline in early HD.

OBJECTIVE: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).METHODS: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.RESULTS: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.CONCLUSIONS: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.

Background: Preclinical evidence suggests that manipulation of the glutamatergic system may provide an alternative strategy for therapeutic intervention in PD. Remacemide hydrochloride is a low affinity NMDA channel blocker that might improve parkinsonian symptoms by modulating glutamatergic overactivity in the basal ganglia or slow worsening by decreasing excitotoxicity. Methods: The authors performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study of remacemide in patients with early PD who were not yet receiving levodopa or dopamine agonists. The primary objective was to assess the short-term tolerability and safety of three dosage levels of remacemide. Two hundred patients were randomized to receive either remacemide 150 mg, 300 mg, or 600 mg, or matching placebo daily for 5 weeks. Results: Significantly fewer patients receiving remacemide 600 mg daily were able to tolerate 5 weeks of their assigned treatment on a BID schedule compared with patients receiving placebo (64% versus 94%,p = 0.0002). Most patients who experienced intolerable side effects on the BID schedule, however, could tolerate the same daily dosage on a QID schedule. The most common adverse events were dizziness and nausea. There were no serious adverse events or clinically significant treatment-related changes in vital signs, laboratory values, or electrocardiograms. There was no evidence of improvement in PD signs or symptoms associated with remacemide monotherapy. Conclusion: Remacemide was generally well tolerated and safe in this 5-week trial. There was no evidence for a symptomatic effect of remacemide monotherapy in patients with early PD. Based on its favorable safety profile and several animal studies, further studies of remacemide are warranted as symptomatic therapy in levodopa-treated patients and as a neuroprotective agent.

Background: In vivo imaging of the dopamine transporter (DAT) with SPECT is a quantitative biomarker for PD onset and severity. Objective: To use a multicenter study to evaluate the diagnostic accuracy of DOPASCAN and SPECT in patients with PD, progressive supranuclear palsy (PSP), and essential tremor (ET), and in healthy controls (HC. Methods: Ninety-six individuals with known clinical diagnosis were imaged with DOPASCAN at five sites with different multidetector SPECT systems. Both masked visual interpretation and region of interest (ROI) analysis were performed at each site and at a core analysis center. Results: Visual interpretation of the images by an expert panel demonstrated a sensitivity of 0.98 and specificity of 0.83 comparing parkinsonian (PD + PSP) versus nonparkinsonian (ET + HC) controls. Quantitative analysis of putamen and caudate DOPASCAN uptake for each region in the PD or PSP groups was significantly reduced compared to the ET or HC groups. Comparison of parkinsonian (PD + PSP) versus nonparkinsonian (ET + HC) individuals demonstrated a reduction of 76% in mean putamen and 48% in mean caudate DOPASCAN uptake. Conclusions: DOPASCAN and SPECT imaging reliably and effectively distinguish between subjects with Parkinson's syndrome (PD + PSP) and without Parkinson's syndrome (RC + ET). This is the first multicenter assessment of dopamine transporter imaging demonstrating that this tool may be used widely to assess dopaminergic degeneration in patients with parkinsonism.

The authors randomized 10 patients (age range, 7 to 13 years) with Tourette's syndrome who had achieved a stable level of tic control on open-label pimozide to continue on pimozide (n = 6) or be withdrawn from therapy (n = 4) in a double-blind study. The median time to end point (the time when an increased dose of study medication was required to control ties) was 231 days (continued) versus 37 days (withdrawn), and the survival curves were significantly different (p = 0.02). Chronic, longer term treatment with pimozide appears to be more effective in controlling the course of ties than using the drug acutely to treat an exacerbation.

Oxidative damage due to free-radical generation in the setting of underlying defects of neuronal energy metabolism has been implicated as a pathogenetic mechanism for Huntington's disease (HD). The authors conducted a randomized, double-blind, placebo-controlled, multicenter trial of the tolerability of OPC-14117, a lipophilic free-radical scavenger that concentrates in the brain. Ambulatory patients with HD received OPC-14117 60 mg/d, 120 mg/d, 240 mg/d, or placebo and were assessed by the Unified Huntington's Disease Rating Scale (UHDRS) for 20 weeks, including 12 or 16 weeks of assigned treatment and 8 or 4 weeks of blinded withdrawal of the study drug. Tolerability was measured by the proportion of patients completing the initial 12-week course of treatment on their originally assigned regimen. Sixty-four patients were enrolled in the study, 56 of whom completed the 12 weeks of treatment. Treatment was discontinued in four patients (1 placebo, 1 60 mg/d, 2 240 mg/d) due to asymptomatic but persistent serum elevations of liver transaminase. Two patients (1 60 mg/d and 1 120 mg/d) withdrew because of increased involuntary movements, one patient (60 mg/d) withdrew due to persistent dry eyes, and one patient (120 mg/d) withdrew because of persistent vomiting. There were no significant differences between treatment arms in the primary measures of tolerability, the frequency and types of clinical adverse events, or the clinical/functional features of HD. OPC-14117 was safe and generally well tolerated; however, elevations of liver transaminase suggested that continued surveillance monitoring is warranted in conducting more long-term studies of this antioxidant therapy.

Cognitive impairment is a frequent manifestation of advanced human immunodeficiency virus (HIV) infection. The response to antiretroviral medication is often partial and poorly sustained. Recent studies suggest that free radical production within the CNS and neuronal apoptosis may play important roles in the pathogenesis of HN dementia. We conducted a randomized double-blind, placebo-controlled trial using a parallel group, 2 x 2 factorial design evaluating deprenyl, a monoamine oxidase B inhibitor and putative anti-apoptotic agent, and thioctic acid, an antioxidant, in 36 patients with HIV-associated cognitive impairment. Both deprenyl and thioctic acid were well tolerated with few adverse events. Deprenyl recipients showed significant improvement on tests of verbal memory compared with patients not taking deprenyl. Thioctic acid treatment did not improve cognitive function. These results suggest that deprenyl treatment is associated with cognitive improvement in subjects with mild HN-associated cognitive impairment, whereas thioctic acid has no benefit. A larger efficacy trial is needed to assess the long-term effect of deprenyl on cognitive performance in patients with HIV infection.

Cognitive impairment is a common and disabling complication of advanced HIV infection. Antiretroviral agents are the only proven therapies currently used for the treatment of HIV dementia, but the response to these agents is frequently unsatisfactory, short-lived, or complicated by intolerable side effects. We hypothesized that OPC-14117, a lipophilic antioxidant that acts to scavenge superoxide anion radicals, might ameliorate the toxic interactions between HIV infected macrophages and neurons. We conducted a double-blind, placebo-controlled, randomized clinical trial to assess the safety and tolerability of OPC-14117 240 mg per day. All 30 patients enrolled (15 per group) had cognitive impairment based on performance on neuropsychological tests. The primary outcome was tolerability of the study drug as measured by the proportion of subjects able to complete the study on their assigned dosage of experimental medication. Overall OPC-14117 was as well tolerated as placebo. Five subjects withdrew because of adverse experiences (two placebo, three OPC-14117). The OPC-14117-treated group had better scores on a clinical global impression scale, compared with the placebo group. There were trends toward improvement in the cognitive test scores; however, these changes were not statistically significant. These results demonstrate that this antioxidant intervention is well tolerated in cognitively impaired patients with advanced HIV infection, and suggest that a larger efficacy trial to assess the impact of OPC-14117 on cognitive performance is warranted.

Motor fluctuations associated with levodopa therapy are common problems encountered in the long-term treatment of Parkinson's disease (PD). Entacapone, a peripherally acting, reversible inhibitor of catechol-O-methyltransferase, slows the elimination of levodopa in humans by reducing the formation of 3-O-methyldopa. We conducted a placebo-controlled, double-blind, parallel-group, multicenter trial of entacapone in PD patients with motor fluctuations. Two hundred five patients were randomized to receive either entacapone 200 mg or matching placebo with each dose of levodopa and were followed for 24 weeks. The primary measure of efficacy was the change in percentage of ''on'' time (relief of parkinsonism) while awake, as recorded by subjects at home in diaries completed at 30-minute intervals. At baseline, patients averaged approximately 10 hours of ''on'' time per day while awake (60.5% ''on'' time), and entacapone treatment increased the percent ''on'' time by 5.0 percentage points. The effect of entacapone was more prominent in patients with a smaller percent ''on'' time (<55%) at baseline, and increased as the day wore on. Entacapone is effective at increasing the duration of response to levodopa and at relieving parkinsonism in patients experiencing motor fluctuations and was well tolerated during the 24 weeks of treatment.

We conducted a randomized, double-blind, placebo-controlled tolerability study of a N-methyl-D-aspartate (NMDA) glutamate receptor ion-channel blocker, remacemide hydrochloride, in 31 independently ambulatory patients (18 men, 13 women) with Huntington's disease (HD). Subjects were randomized to receive either placebo or active remacemide at dosages of 200 mg/day or 600 mg/day. The primary outcome measure was the proportion of subjects able to complete the study with the assigned treatment. Remacemide was generally well tolerated, and no significant differences between the treatment arms were found in the primary outcome measure. A trend toward improvement in chorea was observed among subjects administered remacemide 200 mg/day. Based on the tolerability and safety demonstrated during this short-term trial, remacemide warrants more extended controlled investigation in patients with HD.

In the controlled trial Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP), 310 of the 800 enrolled subjects did not reach the primary end point of disability requiring levodopa therapy during 21 +/- 4 (mean +/- SD) months of observation or need early initiation of deprenyl (selegiline) during a 2-month withdrawal of experimental treatments. While maintaining the blindness of their original deprenyl and tocopherol treatment assignments, these 310 subjects were administered deprenyl 10 mg/day (open label) and were monitored systematically at 1- to 3-month intervals for up to 18 months (12 +/- 5 mo). During this extended trial, the 189 subjects who had been assigned originally to active deprenyl tended to reach the end point of disability faster than the 121 subjects who had not been assigned originally to deprenyl (hazard ratio, 1.43; 95% CI, 0.98, 2.09; p = 0.065). However, the differential rates of reaching the end point may have been due in part to the more severe baseline impairment of deprenyl-assigned subjects, who benefited originally from deprenyl but who were more likely to require levodopa during this extended period of observation. Prior treatment with deprenyl did not lead to superior survival with respect to the end point of disability requiring levodopa, suggesting that the initial advantages of deprenyl were not sustained.

The Unified Huntington's Disease Rating Scale (UHDRS) was developed as a clinical rating scale to assess four domains of clinical performance and capacity in HD: motor function, cognitive function, behavioral abnormalities, and functional capacity. We assessed the internal consistency and the intercorrelations for the four domains and examined changes in ratings over time. We also performed an interrater reliability study of the motor assessment. We found there was a high degree of internal consistency within each of the domains of the UHDRS and that there were significant intercorrelations between the domains of the UHDRS, with the exception of the total behavioral score. There was an excellent degree of interrater reliability for the motor scores. Our limited longitudinal database indicates that the UHDRS may be useful for tracking changes in the clinical features of HD over time. The UHDRS assesses relevant clinical features of HD and appears to be appropriate for repeated administration during clinical studies.

Objective: Our goal was to put into operation the American Academy of Neurology (AAN) algorithm for the definition of minor cognitive/motor disorder and human immunodeficiency virus type 1 (HIV-1)-associated dementia complex (ADC) and examine the neuropsychological, neurologic, psychiatric, and functional deficits in affected subjects. Design: Two hundred seventy-one HIV-positive men and women with CD4 count of <200 or demonstrated cognitive impairment were recruited from three sites (Columbia University, The Johns Hopkins University, and the University of Rochester) and underwent standardized assessments. Results: Sixty-five subjects met criteria for ADC (cognitive, functional, and neurologic or behavioral), 56 met criteria for minor cognitive/motor disorder, and 150 met criteria for neither. Seventy-eight subjects met neuropsychological and neurologic/behavioral criteria but did not demonstrate functional impairment. Those with ADC performed significantly worse on speeded motor and verbal memory tests and demonstrated more extrapyramidal signs and behavioral symptoms than did the other two groups. Both ADC and minor cognitive/motor disorder were independently predictive of poor physical function, after adjustment for age, gender, years of education, log (CD4 count), hemoglobin, number of HIV diagnoses and medications, and depression. Conclusions: The operationalization of AAN criteria demonstrates that it is rare to have both cognitive and functional impairment without associated neurologic and/or behavioral deficits. Functional impairment in isolation is also rare. Dementia is an independent predictor of physical function.