Arthur Watts

Urate as a Predictor of the Rate of Clinical Decline in Parkinson Disease

BACKGROUND The risk of Parkinson disease (PD) and its rate of progression may decline with increasing concentration of blood urate, a major antioxidant. OBJECTIVE To determine whether serum and cerebrospinal fluid concentrations of urate predict clinical progression in patients with PD. DESIGN, SETTING, AND PARTICIPANTS Eight hundred subjects with early PD enrolled in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. The pretreatment urate concentration was measured in serum for 774 subjects and in cerebrospinal fluid for 713 subjects. MAIN OUTCOME MEASURES Treatment-, age-, and sex-adjusted hazard ratios (HRs) for clinical disability requiring levodopa therapy, the prespecified primary end point of the original DATATOP trial. RESULTS The HR of progressing to the primary end point decreased with increasing serum urate concentrations (HR for highest vs lowest quintile = 0.64; 95% confidence interval [CI], 0.44-0.94; HR for a 1-SD increase = 0.82; 95% CI, 0.73-0.93). In analyses stratified by alpha-tocopherol treatment (2000 IU/d), a decrease in the HR for the primary end point was seen only among subjects not treated with alpha-tocopherol (HR for a 1-SD increase = 0.75; 95% CI, 0.62-0.89; vs HR for those treated = 0.90; 95% CI, 0.75-1.08). Results were similar for the rate of change in the Unified Parkinsons Disease Rating Scale score. Cerebrospinal fluid urate concentration was also inversely related to both the primary end point (HR for highest vs lowest quintile = 0.65; 95% CI, 0.44-0.96; HR for a 1-SD increase = 0.89; 95% CI, 0.79-1.02) and the rate of change in the Unified Parkinsons Disease Rating Scale score. As with serum urate concentration, these associations were present only among subjects not treated with alpha-tocopherol. CONCLUSIONS Higher serum and cerebrospinal fluid urate concentrations at baseline were associated with slower rates of clinical decline. The findings strengthen the link between urate concentration and PD and the rationale for considering central nervous system urate concentration elevation as a potential strategy to slow PD progression.

Serum Urate as a Predictor of Clinical and Radiographic Progression in Parkinson Disease

OBJECTIVE To determine whether concentration of serum urate, a purine metabolite and potent antioxidant that has been linked to a reduced risk of Parkinson disease (PD), predicts prognosis in PD. DESIGN Prospective study. SETTING The Parkinson Research Examination of CEP-1347 Trial (PRECEPT) study, which investigated the effects of a potential neuroprotectant on rates of PD progression, was conducted between April 2002 and August 2005 (average follow-up time 21.4 months). PARTICIPANTS Eight hundred four subjects with early PD enrolled in the PRECEPT study. MAIN OUTCOME MEASURES The primary study end point was progression to clinical disability sufficient to warrant dopaminergic therapy. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching end point according to quintiles of baseline serum urate concentration, adjusting for sex, age, and other potential covariates. Change in striatal uptake of iodine I 123-labeled 2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]beta-CIT), a marker for the presynaptic dopamine transporter, was assessed with linear regression for a subset of 399 subjects. RESULTS The adjusted HR of reaching end point declined with increasing baseline concentrations of urate; subjects in the top quintile reached the end point at only half the rate of subjects in the bottom quintile (HR, 0.51; 95% confidence interval [CI], 0.37-0.72; P for trend < .001). This association was markedly stronger in men (HR, 0.39; 95% CI, 0.26-0.60; P for trend < .001) than in women (HR, 0.77; 95% CI, 0.39-1.50; P for trend = .33). The percentage of loss in striatal [(123)I]beta-CIT uptake also improved with increasing serum urate concentrations (overall P for trend = .002; men, P = .001; women, P = .43). CONCLUSIONS These findings identify serum urate as the first molecular factor directly linked to the progression of typical PD and suggest that targeting urate or its determinants could be an effective disease-modifying therapy in PD. Trial Registration clinicaltrials.gov Identifier: NCT00040404.

Oral desipramine and topical lidocaine for vulvodynia: a randomized controlled trial.

OBJECTIVE: To estimate the efficacy of common treatments for vulvodynia: topical lidocaine monotherapy, oral desipramine monotherapy, and lidocaine-desipramine combined therapy. METHODS: A 12-week randomized, double-blinded, placebo-controlled trial was conducted on 133 vulvodynia-afflicted women assigned to four treatment arms: placebo tablets–placebo cream, desipramine tablets–placebo cream, placebo tablets–lidocaine cream, and desipramine tablets–lidocaine cream. The tampon test was selected as primary end point using a modified intention-to-treat analysis. Twelve secondary end points were also examined. At completion of the 12-week randomized phase, women were examined “open label” through 52 weeks postrandomization. RESULTS: All treatment arms reported substantial tampon-test pain reduction: 33% reduction placebo cream–placebo tablet, 20% reduction lidocaine cream–placebo tablet, 24% reduction placebo cream–desipramine tablet, and 36% reduction lidocaine cream–desipramine tablet. Compared with placebo, we found no significant difference in tampon-test pain reduction with desipramine (t=0.90; P=.37) or lidocaine (t=1.27; P=.21). Of the remaining 12 outcome measures, only the Index of Sexual Satisfaction, improved with desipramine compared with placebo (t=-2.81; P=.006). During the open-label phase, women undergoing vestibulectomy surgery reported significantly improved pain as measured by cotton swab test and the McGill Pain Scale compared with nonsurgical alternatives. CONCLUSION: Oral desipramine and topical lidocaine, as monotherapy or in combination, failed to reduce vulvodynia pain more than placebo. Placebo or placebo-independent effects are behind the substantial pain improvement seen in all treatment allocations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00276068. LEVEL OF EVIDENCE: I

Safety and tolerability of high-dosage coenzyme Q10 in Huntington's disease and healthy subjects.

Coenzyme Q10 (CoQ10), a potential neuroprotective compound, was previously investigated at a dosage of 600 mg/day in Huntingtons disease (HD) patients and demonstrated a trend toward slowing disease progression. Higher CoQ10 dosages may prove beneficial. We investigated the tolerability and blood levels associated with 1,200, 2,400, and 3,600 mg/day of CoQ10 in HD and healthy subjects. Twenty‐eight subjects (20 HD, 8 healthy) enrolled in a 20‐week open‐label trial. Subjects started on 1,200 mg/day of CoQ10, increasing every 4 weeks by 1,200 mg to a maximum dosage of 3,600 mg/day. Monthly evaluations included review of adverse events and CoQ10 blood levels. Twenty‐three subjects (82%) achieved the target dosage of 3,600 mg/day. Six subjects (2 healthy, 4 HD) withdrew prematurely (gastrointestinal (GI) symptoms in 3, worsening HD in 2, and 1 because of a fall). All three serious adverse events occurred in a single subject, and were deemed unrelated to CoQ10. The most common adverse events seen were GI symptoms. Mean (± SD) CoQ10 blood levels achieved over the course of the trial were as follows: 1.26 ± 1.27 μg/mL (baseline, n = 28), 5.59 ± 2.24 μg/mL (1,200 mg/day, week 4, n = 26), 6.38 ± 3.25 μg/mL (2,400 mg/day, week 8, n = 25), 7.49 ± 4.09 μg/mL (3,600 mg/day, week 12, n = 23), and 6.78 ± 3.36μg/mL (3,600 mg/day, week 20, n = 20). CoQ10 was well tolerated with over 80% of subjects achieving the target dosage. Dosages of 2,400 mg/day may provide the best balance between tolerability and blood level achieved. Further studies examining the efficacy of 2,400 mg/day are planned.

A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington's disease

We examined the effects of 3 dosages of pridopidine, a dopamine‐stabilizing compound, on motor function and other features of Huntingtons disease, with additional evaluation of its safety and tolerability. This was a randomized, double‐blind, placebo‐controlled trial in outpatient neurology clinics at 27 sites in the United States and Canada. Two hundred twenty‐seven subjects enrolled from October 24, 2009, to May 10, 2010. The intervention was pridopidine, either 20 (n=56), 45 (n=55), or 90 (n=58) mg daily for 12 weeks or matching placebo (n=58). The primary outcome measure was the change from baseline to week 12 in the Modified Motor Score, a subset of the Unified Huntingtons Disease Rating Scale Total Motor Score. Measures of safety and tolerability included adverse events and trial completion on the assigned dosage. After 12 weeks, the treatment effect (relative to placebo, where negative values indicate improvement) of pridopidine 90 mg/day on the Modified Motor Score was −1.2 points (95% confidence interval [CI], −2.5 to 0.1 points; P = .08). The effect on the Total Motor Score was −2.8 points (95% CI, −5.4 to −0.1 points; nominal P = .04). No significant effects were seen in secondary outcome measures with any of the active dosages. Pridopidine was generally well tolerated. Although the primary analysis did not demonstrate a statistically significant treatment effect, the overall results suggest that pridopidine may improve motor function in Huntingtons disease. The 90 mg/day dosage appears worthy of further study. Pridopidine was well tolerated.

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial

IMPORTANCE Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. OBJECTIVE To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. DESIGN, SETTING, AND PARTICIPANTS Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. INTERVENTIONS Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. MAIN OUTCOMES AND MEASURES Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test. RESULTS Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. CONCLUSIONS AND RELEVANCE Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01795859.

Concomitant Forms of Abuse and Help-Seeking Behavior Among White, African American, and Latina Women Who Experience Intimate Partner Violence:

This study uses National Violence against Women Survey data to investigate the differential impact of concomitant forms of violence (sexual abuse, stalking, and psychological abuse) and ethnicity on help-seeking behaviors of women physically abused by an intimate partner (n = 1,756). Controlling for severity of the physical abuse, women who experienced concomitant sexual abuse are less likely to seek help, women who experienced concomitant stalking are more likely to seek help, whereas concomitant psychological abuse is not associated with help seeking. Ethnic differences are found in help seeking from friends, mental health professionals, police, and orders of protection. Implications for service outreach are discussed.

Biosignatures for Parkinson’s Disease and Atypical Parkinsonian Disorders Patients

Diagnosis of Parkinson’ disease (PD) carries a high misdiagnosis rate due to failure to recognize atypical parkinsonian disorders (APD). Usually by the time of diagnosis greater than 60% of the neurons in the substantia nigra are dead. Therefore, early detection would be beneficial so that therapeutic intervention may be initiated early in the disease process. We used splice variant-specific microarrays to identify mRNAs whose expression is altered in peripheral blood of early-stage PD patients compared to healthy and neurodegenerative disease controls. Quantitative polymerase chain reaction assays were used to validate splice variant transcripts in independent sample sets. Here we report a PD signature used to classify blinded samples with 90% sensitivity and 94% specificity and an APD signature that resulted in a diagnosis with 95% sensitivity and 94% specificity. This study provides the first discriminant functions with coherent diagnostic signatures for PD and APD. Analysis of the PD biomarkers identified a regulatory network with nodes centered on the transcription factors HNF4A and TNF, which have been implicated in insulin regulation.

Stressful life events and suicidal behavior in adults with alcohol use disorders: Role of event severity, timing, and type

BACKGROUND Stressful life events (SLEs) play a key role in suicidal behavior among adults with alcohol use disorders (AUD), yet there are meager data on the severity of SLEs preceding suicidal behavior or the timing of such events. METHOD Patients in residential substance use treatment who made a recent suicide attempt (cases, n=101) and non-suicidal controls matched for site (n=101) were recruited. SLEs that occurred within 30 days of the attempt and on the day of the attempt in cases were compared to SLEs that occurred in the corresponding periods in controls. SLEs were categorized by type (interpersonal, non-interpersonal) and severity (major, minor) and were dated to assess timing. Degree of planning of suicide attempts was also assessed. RESULTS Major interpersonal SLEs conferred risk for a suicide attempt, odds ratio (95% CI)=5.50 (1.73, 17.53), p=0.005. Cases were also more likely to experience an SLE on the day of the attempt than on the corresponding day in controls, OR (95% CI)=6.05 (1.31, 28.02), p=0.021. However, cases that made an attempt on the day of a SLE did not make lower planned suicide attempts compared to other cases, suggesting that suicide attempts that are immediately preceded by SLEs cannot be assumed to be unplanned. CONCLUSIONS Results suggest the central importance of major interpersonal SLEs in risk among adults with AUD, a novel finding, and documents that SLEs may lead to suicide attempts within a short window of time (i.e., same day), a daunting challenge to prevention efforts.

Interpersonal psychotherapy for depressed women with sexual abuse histories: a pilot study in a community mental health center.

Depression among women with childhood sexual abuse histories has a chronic and treatment-refractory course, and is accompanied by high rates of comorbid illness and adult trauma exposures. Reducing the disproportionate burden of serious mental illness among depressed, traumatized women must be a priority in community mental health settings. Effective treatments are needed. The feasibility and effects of interpersonal psychotherapy (IPT) for women with major depression and childhood trauma histories were tested. Twenty-five women in a community mental health center were enrolled in a 16-session course of IPT. Symptoms, functioning, and feasibility (e.g., participation rates) were measured at baseline, 10 weeks, 24 weeks, and 36 weeks. Fifteen of the 25 participants completed eight or more sessions. Significant improvements in depression and psychological functioning, but not in social functioning, were observed. Although a 16-session course of IPT appears feasible and promising, modifications may be needed to reduce barriers to care and enhance treatment potency.