Predicting High-risk and High-cost Patients for Proactive Intervention.

BACKGROUND: It is well known that 20% of the patients incur 80% of health care costs and many diseases and complications can be prevented or ameliorated with prompt intervention. One of the well-recognized strategies for cost reduction and better outcomes is to predict or identify high-risk and high-cost (HRHC) patients for proactive intervention. OBJECTIVE: The objective of this study was to develop a predictive model that can be used to identify HRHC patients more accurately for proactive intervention. METHODS: This is an observational study using fiscal year (FY) 2018 administrative data to predict FY 2019 total cost at the patient level. All 5,676,248 patients who received care in both FYs 2018 and 2019 from the Veterans Health Administration were included in the analyses. The Veterans Health Administration Corporate Data Warehouse was our main data source. With split-sample analyses, 3 sets of patient comorbidities and 5 statistical models were assessed for the highest predictive power. RESULTS: The Box-Cox regression using comorbidities designated by the expanded CCSR (Clinical Classifications Software Refined) groups as predictors yielded the highest predictive power. The R2 reached 0.51 and 0.37 for the transformed and raw scale cost, respectively. CONCLUSIONS: The predictive model developed in this study exhibits substantially higher predictive power than what has been reported in the literature. The algorithm based on administrative data and a publicly available patient classification system can be readily implemented by other value-based health systems to identify HRHC patients for proactive intervention.

Seizures in juvenile Huntington's disease: frequency and characterization in a multicenter cohort.

Little is known about the epilepsy that often occurs in the juvenile form of Huntington's disease (HD), but is absent from the adult-onset form. The primary aim of this study was to characterize the seizures in juvenile HD (JHD) subjects with regard to frequency, semiology, defining EEG characteristics, and response to antiepileptic agents. A multicenter, retrospective cohort was identified by database query and/or chart review. Data on age of HD onset, primary HD manifestations, number of CAG repeats, the presence or absence of seizures, seizure type(s), antiepileptic drugs used, subjects' response to antiepileptic drugs (AEDs), and EEG results were assembled, where available. Ninety subjects with genetically confirmed JHD were included. Seizures were present in 38% of subjects and were more likely to occur with younger ages of HD onset. Generalized tonic-clonic seizures were the most common seizure type, followed by tonic, myoclonic, and staring spells. Multiple seizure types commonly occurred within the same individual. Data on EEG findings and AED usage are presented. Seizure risk in JHD increases with younger age of HD onset. Our ability to draw firm conclusions about defining EEG characteristics and response to AEDs was limited by the retrospective nature of the study. Future prospective studies are required.

Postural instability/gait disturbance in Parkinson's disease has distinct subtypes: an exploratory analysis.

OBJECTIVE: To test the hypothesis that postural instability with falling (PIF) and freezing of gait (FOG) are distinct subtypes of the postural instability/gait disturbance (PIGD) form of Parkinson's disease (PD). METHODS: 499 PD subjects from the NeuroGenetics Research Consortium were studied using logistic regression to examine, in a cross sectional analysis, predictors of FOG and PIF. Potential predictors were from four spheres; demographic, clinical motor, clinical non-motor and genetic. RESULTS: FOG and PIF were both associated with greater gait subscores and lower tremor subscores on the Unified Parkinson's Disease Rating Scale (p ≤ 0.02). However, they differed with regard to demographic, non-motor and genetic predictors. FOG was associated with greater duration of disease, with ORs of 3.01 (95% CI 1.35 to 6.72) and 4.91 (95% CI 2.29 to 10.54) for third and fourth quartiles of duration, respectively, versus the lowest half of duration. The risk of having psychotic symptoms was also significantly increased (OR 3.02, 95% CI 1.41 to 6.49; p=0.004). FOG was inversely associated with the presence of the CYP2D6*4 allele (OR 0.41, 95% CI 0.21 to 0.80; p=0.009) suggesting a protective effect. PIF was associated with depression (OR 1.08, 95% CI 1.01 to 1.15; p<0.02) and was inversely associated with APOE ε4 (OR 0.21, 95% CI 0.05 to 0.87; p=0.03), again suggesting a protective effect. CONCLUSION: FOG and PIF have different demographic, non-motor and genetic predictors suggesting that they may be pathophysiologically distinct subtypes of PIGD. These findings have implications in the discovery of therapeutic targets for these disabling features as well as for predicting outcomes of PD.

Disease-related and genetic correlates of psychotic symptoms in Parkinson's disease.

Our aim was to examine disease-related and genetic correlates of the development of psychotic symptoms in a large population of patients with Parkinson's disease. We studied 500 patients with Parkinson's disease from the NeuroGenetics Research Consortium using logistic regression models. Predictors were demographic, clinical (motor/nonmotor features), and genetic, measured as continuous or dichotomous variables. Continuous measures were divided into population-based tertiles. Results are given as odds ratios (95% confidence intervals) for dichotomous variables and by ascending tertile for continuous variables. Psychotic symptoms were associated with increasing age: 4.86 (1.62-14.30) and 6.25 (2.09-18.74) (test for trend: P = 0.01); and duration of disease: 3.81 (1.23-11.76) and 5.33 (1.68-16.89) (test for trend: P = 0.03). For nonmotor features, we demonstrated positive trends with depression: 1.31 (0.47-3.61) and 5.01 (2.04-12.33) (test for trend: P < 0.0001); cognitive dysfunction: 0.69 (0.26-1.84) and 2.51 (1.00-6.29) (test for trend: P = 0.03); and an excess for those with sleep disorders: 2.00 (1.03-3.89) (P = 0.04). Psychotic symptoms were not associated with tremor or postural instability scores, but there was an association with freezing of gait: 3.83 (1.67-8.75) (P < 0.002). Psychotic symptoms were not associated with the presence of any examined polymorphisms in the apolipoprotein, alpha-synuclein, or microtubule associated protein tau genes. This is the largest study to examine correlates of psychotic symptoms in Parkinson's disease. We discovered a novel association with freezing of gait. We demonstrated an association with depression and duration of disease, both of which were inconsistently related in previous studies, and confirmed the association with age, cognitive dysfunction, and sleep disorders.

Occupational exposure to PCBs reduces striatal dopamine transporter densities only in women: a beta-CIT imaging study.

We hypothesize that occupational exposure to PCBs is associated with a reduction in central dopamine (DA) similar to changes previously seen in PCB exposed adult non-human primates. To test that hypothesis, we used [(123)I]beta-CIT SPECT imaging to estimate basal ganglia DA transporter density in former capacitor workers. Women, but not men, showed an inverse relationship between lipid-adjusted total serum PCB concentrations and DA transporter densities in the absence of differences in serum PCB concentrations. These sex differences may reflect age-related reductions in the levels of gonadal hormones since these hormones have been shown experimentally to alter response to DA neurotoxicants. These findings may aid in better understanding the roles that sex and age play in modifying central DA function following exposure, not only to PCBs, but also to other DA neurotoxicants as well as further elucidating the role of gonadal hormones in influencing the initiation and/or progression of neurodegenerative disorders.

Effect of cervical dystonia on employment: A retrospective analysis of the ability of treatment to restore premorbid employment status.

Using a structured interview method, we sought to address the following questions regarding cervical dystonia (CD) and employment: (1) what is the frequency and severity of job impairment in CD; (2) what are the clinical features that contribute to job impairment; (3) how does the effectiveness of botulinum toxin (BTx) compare to oral medications in restoring employment status. In our population of 155 CD patients, employment was affected by CD in 53.3% (31.2% reduced hours or responsibilities, 3.3% changed to different job, 18.9% loss of employment) and 68.9% of patients reported reduced overall productivity. The likelihood of altered employment (P < 0.0006), reduced productivity (P < 0.0001), and seeking disability benefits (P < 0.003) was significantly associated with the presence of neck pain, but not type of employment, spasmodic head motions, or duration of CD symptoms before treatment with BTx. Treatment with BTx was more likely to improve employment status than oral medications (66.1 vs. 18.5%) and much more likely to restore full employment with normal productivity (12.9 vs. 0.0%). These findings suggest that employment status is frequently affected by CD, particularly in patients withneck pain. BTx is significantly more effective than oral medications in restoring premorbid employment status.

Exploring gene-environment interactions in Parkinson's disease.

The objective of this study was to explore combined effects of four candidate susceptibility genes and two exposures on Parkinson's disease (PD) risk; namely, alpha-synuclein (SNCA) promoter polymorphism REP1, microtubule-associated protein tau (MAPT) H1/H2 haplotypes, apolipoprotein E (APOE) epsilon2/epsilon3/epsilon4 polymorphism, ubiquitin carboxy-terminal esterase L1 (UCHL1) S18Y variant, cigarette smoking and caffeinated coffee consumption. 932 PD patients and 664 control subjects from the NeuroGenetics Research Consortium, with complete data on all six factors, were studied. Uniform protocols were used for diagnosis, recruitment, data collection and genotyping. A logistic regression model which included gene-exposure interactions was applied. Likelihood ratio tests (LRTs) were used for significance testing and Bayesian inference was used to estimate odds ratios (ORs). MAPT (P = 0.007), SNCA REP1 (P = 0.012), smoking (P = 0.001), and coffee (P = 0.011) were associated with PD risk. Two novel interactions were detected: APOE with coffee (P = 0.005), and REP1 with smoking (P = 0.021). While the individual main effects were modest, each yielding OR < 1.6, the effects were cumulative, with some combinations reaching OR = 12.6 (95% CI: 5.9-26.8). This study provides evidence for the long-held notion that PD risk is modulated by cumulative and interactive effects of genes and exposures. Furthermore, the study demonstrates that while interaction studies are useful for exploring risk relationships that might otherwise go undetected, results should be interpreted with caution because of the inherent loss of power due to multiple testing. The novel findings of this study that warrant replication are the evidence for interaction of coffee with APOE, and of smoking with REP1 on PD risk.

Combined effects of smoking, coffee, and NSAIDs on Parkinson's disease risk.

Inverse associations of Parkinson's disease (PD) with cigarette smoking, coffee drinking, and nonsteroidal anti-inflammatory drug (NSAID) use have been reported individually, but their joint effects have not been examined. To quantify associations with PD for the individual, two-way and three-way combinations of these factors, a case-control association study with 1,186 PD patients and 928 controls was conducted. The study setting was the NeuroGenetics Research Consortium. Subjects completed a structured questionnaire regarding smoking, coffee, and NSAID consumption. Odds ratios were calculated using unconditional logistic regression. Smoking, coffee, and over the counter NSAID use as individual factors exhibited significantly reduced risks of 20% to 30%. The two-way and three-way combinations were associated with risk reduction of 37% to 49%, and 62%, respectively. Smoking and coffee exhibited significant inverse risk trends with increasing cumulative exposures, suggesting dose-response relations. With respect to the combination of all three exposures, persons who were at the highest exposure strata for smoking and coffee and used NSAIDs had an estimated 87% reduction in risk (OR = 0.13, 95% CI = 0.06-0.29). Whether this finding reflects true biologic protection needs to be investigated.

Lack of evidence for an association between UCHL1 S18Y and Parkinson's disease.

UCHL1 has been proposed as a candidate gene for Parkinson's disease (PD). A meta-analysis of white and Asian subjects reported an inverse association between the non-synonymous UCHL1 S18Y polymorphism and PD risk. However, this finding was not replicated in a large case-control study and updated meta-analysis restricted to white subjects. We performed a case-control study of 1757 PD patients recruited from movement disorder clinics and 2016 unrelated controls from four regions of the United States. All subjects self-reported as white. We did not observe evidence for an association between S18Y genotypes and PD (overall P-value for association: P = 0.42). After adjustment for age, sex, and recruitment region, the odds ratio for Y/S versus S/S was 0.91 (95% CI: 0.78-1.06) and for Y/Y versus S/S was 0.87 (95% CI: 0.58-1.29). We also did not observe a significant association for recessive or dominant models of inheritance, or after stratification by age at onset, age at blood draw, sex, family history of PD, or recruitment region. Our results suggest that UCHL1 S18Y is not a major susceptibility factor for PD in white populations although we cannot exclude the possibility that the S18Y variant exerts weak effects on risk, particularly in early-onset disease.

Genetic association between alpha-synuclein and idiopathic Parkinson's disease.

Point mutations and copy number variations in SNCA, the gene encoding alpha-synuclein, cause familial Parkinson's disease (PD). A dinucleotide polymorphism (REP1) in the SNCA promoter may be a risk factor for common forms of PD. We studied 1,802 PD patients and 2,129 controls from the NeuroGenetics Research Consortium, using uniform, standardized protocols for diagnosis, subject recruitment, data collection, genotyping, and data analysis. Three common REP1 alleles (257, 259, and 261 bp, with control frequencies of 0.28, 0.65, and 0.06) and several rare alleles (combined frequency <0.01) were detected. We confirmed association of REP1 with PD risk [odds ratio (OR) = 0.86, P = 0.006 for 257-carriers; OR = 1.25, P = 0.022 for 261-carriers]. Using a normalization procedure, we showed that the 257 and 261 alleles are both independently associated with PD risk (for 257, P = 0.002 in overall data, 0.003 in non-familial PD, 0.001 in early-onset PD; for 261, P = 0.056 in overall data, 0.024 in non-familial PD, 0.052 in early-onset PD). The 257-associated risk was consistent with a dominant model [hazard ratio (HR) = 0.99, P = 0.91 for 257/257 vs. 257/X where X denotes all other common alleles; HR = 1.16, P = 0.004 for X/X vs. 257/X]. The 261-associated risk was consistent with a recessive model (HR = 1.89, P = 0.026 for 261/261 vs. 261/X; HR = 0.95, P = 0.42 for X/X vs. 261/X). Genotype-specific mean onset ages (+/-SD) ranged from 54.8 +/- 12.1 for 261/261 to 59.4 +/- 11.5 for 257/257, displaying a trend of decreasing onset age with increasing allele size (P = 0.055). Genetic variation in SNCA and its regulatory regions play an important role in both familial and sporadic PD.

Independent home use of a brain-computer interface by people with amyotrophic lateral sclerosis.

OBJECTIVE: To assess the reliability and usefulness of an EEG-based brain-computer interface (BCI) for patients with advanced amyotrophic lateral sclerosis (ALS) who used it independently at home for up to 18 months. METHODS: Of 42 patients consented, 39 (93%) met the study criteria, and 37 (88%) were assessed for use of the Wadsworth BCI. Nine (21%) could not use the BCI. Of the other 28, 27 (men, age 28-79 years) (64%) had the BCI placed in their homes, and they and their caregivers were trained to use it. Use data were collected by Internet. Periodic visits evaluated BCI benefit and burden and quality of life. RESULTS: Over subsequent months, 12 (29% of the original 42) left the study because of death or rapid disease progression and 6 (14%) left because of decreased interest. Fourteen (33%) completed training and used the BCI independently, mainly for communication. Technical problems were rare. Patient and caregiver ratings indicated that BCI benefit exceeded burden. Quality of life remained stable. Of those not lost to the disease, half completed the study; all but 1 patient kept the BCI for further use. CONCLUSION: The Wadsworth BCI home system can function reliably and usefully when operated by patients in their homes. BCIs that support communication are at present most suitable for people who are severely disabled but are otherwise in stable health. Improvements in BCI convenience and performance, including some now underway, should increase the number of people who find them useful and the extent to which they are used.

Quality of Care for Veterans With Transient Ischemic Attack and Minor Stroke.

Importance: The timely delivery of guideline-concordant care may reduce the risk of recurrent vascular events for patients with transient ischemic attack (TIA) and minor stroke. Although many health care organizations measure stroke care quality, few evaluate performance for patients with TIA or minor stroke, and most include only a limited subset of guideline-recommended processes. Objective: To assess the quality of guideline-recommended TIA and minor stroke care across the Veterans Health Administration (VHA) system nationwide. Design, Setting, and Participants: This cohort study included 8201 patients with TIA or minor stroke cared for in any VHA emergency department (ED) or inpatient setting during federal fiscal year 2014 (October 1, 2013, through September 31, 2014). Patients with length of stay longer than 6 days, ventilator use, feeding tube use, coma, intensive care unit stay, inpatient rehabilitation stay before discharge, or receipt of thrombolysis were excluded. Outlier facilities for each process of care were identified by constructing 95% CIs around the facility pass rate and national pass rate sites when the 95% CIs did not overlap. Data analysis occurred from January 16, 2016, through June 30, 2017. Main Outcomes and Measures: Ten elements of care were assessed using validated electronic quality measures. Results: In the 8201 patients included in the study (mean [SD] age, 68.8 [11.4] years; 7877 [96.0%] male; 4856 [59.2%] white), performance varied across elements of care: brain imaging by day 2 (6720/7563 [88.9%]; 95% CI, 88.2%-89.6%), antithrombotic use by day 2 (6265/7477 [83.8%]; 95% CI, 83.0%-84.6%), hemoglobin A1c measurement by discharge or within the preceding 120 days (2859/3464 [82.5%]; 95% CI, 81.2%-83.8%), anticoagulation for atrial fibrillation by day 7 after discharge (1003/1222 [82.1%]; 95% CI, 80.0%-84.2%), deep vein thrombosis prophylaxis by day 2 (3253/4346 [74.9%]; 95% CI, 73.6%-76.2%), hypertension control by day 90 after discharge (4292/5979 [71.8%]; 95% CI, 70.7%-72.9%), neurology consultation by day 1 (5521/7823 [70.6%]; 95% CI, 69.6%-71.6%), electrocardiography by day 2 or within 1 day prior (5073/7570 [67.0%]; 95% CI, 65.9%-68.1%), carotid artery imaging by day 2 or within 6 months prior (4923/7685 [64.1%]; 95% CI, 63.0%-65.2%), and moderate- to high-potency statin prescription by day 7 after discharge (3329/7054 [47.2%]; 95% CI, 46.0%-48.4%). Performance varied substantially across facilities (eg, neurology consultation had a facility outlier rate of 53.0%). Performance was higher for admitted patients than for patients cared for only in EDs with the greatest disparity for carotid artery imaging (4478/5927 [75.6%] vs 445/1758 [25.3%]; P < .001). Conclusions and Relevance: This national study of VHA system quality of care for patients with TIA or minor stroke identified opportunities to improve care quality, particularly for patients who were discharged from the ED. Health care systems should engage in ongoing TIA care performance assessment to complement existing stroke performance measurement.

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease.

OBJECTIVE: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. METHODS: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. RESULTS: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. CONCLUSIONS: These data do not justify use of CoQ as a treatment to slow functional decline in HD. CLINICALTRIALSGOV IDENTIFIER: NCT00608881. CLASSIFICATION OF EVIDENCE: This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD.

Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: a large-scale international study.

BACKGROUND: A genome-wide association study identified 13 single-nucleotide polymorphisms (SNPs) significantly associated with Parkinson's disease. Small-scale replication studies were largely non-confirmatory, but a meta-analysis that included data from the original study could not exclude all SNP associations, leaving relevance of several markers uncertain. METHODS: Investigators from three Michael J Fox Foundation for Parkinson's Research-funded genetics consortia-comprising 14 teams-contributed DNA samples from 5526 patients with Parkinson's disease and 6682 controls, which were genotyped for the 13 SNPs. Most (88%) participants were of white, non-Hispanic descent. We assessed log-additive genetic effects using fixed and random effects models stratified by team and ethnic origin, and tested for heterogeneity across strata. A meta-analysis was undertaken that incorporated data from the original genome-wide study as well as subsequent replication studies. FINDINGS: In fixed and random-effects models no associations with any of the 13 SNPs were identified (odds ratios 0.89 to 1.09). Heterogeneity between studies and between ethnic groups was low for all SNPs. Subgroup analyses by age at study entry, ethnic origin, sex, and family history did not show any consistent associations. In our meta-analysis, no SNP showed significant association (summary odds ratios 0.95 to 1.08); there was little heterogeneity except for SNP rs7520966. INTERPRETATION: Our results do not lend support to the finding that the 13 SNPs reported in the original genome-wide association study are genetic susceptibility factors for Parkinson's disease.

Validity and utility of a LRRK2 G2019S mutation test for the diagnosis of Parkinson's disease.

The G2019S mutation in the LRRK2 gene, the most common known cause of Parkinson's disease (PD), will soon be widely available as a molecular clinical test for PD. The objective of this study was to assess performance characteristics of G2019S as a clinical test for PD in the setting of typical movement disorder clinics in the United States. Subjects included 1,518 sequentially recruited PD patients from seven movement disorder clinics in the United States, and 1,733 unaffected subjects. All 3,251 subjects were genotyped for the G2019S mutation using a TaqMan assay, and mutations were verified by direct sequencing. Test validity estimates were calculated using standard methods. A total of 20/1518 patients and 1/1733 controls carried the G2019S mutation. Specificity was 99.9% (95% CI, 99.6-100%), sensitivity was 1.3% (0.8-2.1%), and the positive likelihood ratio was 22.8. A positive family history of PD increased the positive likelihood ratio to 82.5. Information on gender, age at disease onset, or age at testing did not improve test performance. The gene test was highly accurate in classifying mutation carriers as PD, but it performed poorly in predicting the phenotype of non-mutation carriers. A G2019S molecular test for PD would be highly specific, technically simple, and inexpensive. Test interpretation is straightforward when used for diagnosis of symptomatic individuals, but is more complex for risk assessment and predictive testing in asymptomatic individuals. Test results can have psychological, social, and economical ramifications; thus, proper counseling is essential.

The RAB39B p.G192R mutation causes X-linked dominant Parkinson's disease.

OBJECTIVE: To identify the causal gene in a multi-incident U.S. kindred with Parkinson's disease (PD). METHODS: We characterized a family with a classical PD phenotype in which 7 individuals (5 males and 2 females) were affected with a mean age at onset of 46.1 years (range, 29-57 years). We performed whole exome sequencing on 4 affected and 1 unaffected family members. Sanger-sequencing was then used to verify and genotype all candidate variants in the remainder of the pedigree. Cultured cells transfected with wild-type or mutant constructs were used to characterize proteins of interest. RESULTS: We identified a missense mutation (c.574G > A; p.G192R) in the RAB39B gene that closely segregated with disease and exhibited X-linked dominant inheritance with reduced penetrance in females. The mutation occurred in a highly conserved amino acid residue and was not observed among 87,725 X chromosomes in the Exome Aggregation Consortium dataset. Sequencing of the RAB39B coding region in 587 familial PD cases yielded two additional mutations (c.428C > G [p.A143G] and c.624_626delGAG [p.R209del]) that were predicted to be deleterious in silico but occurred in families that were not sufficiently informative to assess segregation with disease. Experiments in PC12 and SK-N-BE(2)C cells demonstrated that p.G192R resulted in mislocalization of the mutant protein, possibly by altering the structure of the hypervariable C-terminal domain which mediates intracellular targeting. CONCLUSIONS: Our findings implicate RAB39B, an essential regulator of vesicular-trafficking, in clinically typical PD. Further characterization of normal and aberrant RAB39B function might elucidate important mechanisms underlying neurodegeneration in PD and related disorders.

Tibial bone lead, but not serum polychlorinated biphenyl, concentrations are associated with neurocognitive deficits in former capacitor workers.

OBJECTIVE: To determine the relationships between tibial bone lead and serum polychlorinated biphenyl (PCB) concentrations and neurocognitive function. METHODS: The study population consisted of men and women former capacitor workers had been employed by the General Electric Corporation between 1946 and 1977. Regression analyses evaluated the association between neurocognitive function and lipid-adjusted serum PCB and tibia lead concentrations. RESULTS: Tibia lead, but not serum PCBs, was significantly correlated with deficits in neurocognitive function. Women showed more associations between tibia lead and neurocognitive function than men, especially regarding executive function. CONCLUSIONS: These results demonstrate that low levels of tibia lead, but not serum PCBs, are associated with neurocognitive deficits and that postmenopausal women show a greater number of deficits in executive function than men.

Estimating the half-lives of PCB congeners in former capacitor workers measured over a 28-year interval.

To date, most estimates of the half-life of polychlorinated biphenyls (PCBs) in humans have been based on relatively short follow-up periods. To address this issue, we determined the half-lives of PCB congeners of occupational origin in the serum of former capacitor workers as part of a study conducted in 2003-2006--approximately 28 years after their last occupational exposure. A total of 241 persons from a source population of 6798 former capacitor workers were interviewed and asked to donate a blood sample for serum PCB congener analysis. A subgroup of 45 participants also had serum archived from 1976 and reanalyzed for the same 27 PCB congeners by the same laboratory. Our estimates of the half-lives of the congeners among these 45 persons were longer than those reported by Wolff et al. (1992), due primarily to the much longer interval between exposure and determination of serum PCB concentrations. Half-lives were significantly greater for the heavy versus light occupational congeners, for women versus men and for those with low versus high initial exposure. Current serum total PCB concentrations, expressed as the geometric mean of wet weight data, averaged 6.7 ng/g for the entire 241-person cohort, which represents a 10-fold decrease from values reported in the late 1970s, but is still nearly twice the average for persons of similar age residing in the same area, but without occupational exposure. In addition, current serum PCB concentrations remained significantly and positively associated with earlier occupational exposure, but were not associated with fresh water fish consumption. In general, the results support a consistent and long-duration trend of increased PCB body burden in this cohort of former capacitor workers compared with non-occupationally exposed individuals. The results may aid in further understanding the toxicological/epidemiological consequences of exposure to PCBs in humans.

SNCA variant associated with Parkinson disease and plasma alpha-synuclein level.

BACKGROUND: A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson disease (PD). There is also increasing evidence that single-nucleotide polymorphisms (SNPs) elsewhere in the gene are associated with PD risk. OBJECTIVES: To further explore the association of common SNCA SNPs with PD susceptibility, to determine whether evidence of allelic heterogeneity exists, and to examine the correlation between PD-associated variants and plasma α-synuclein levels. DESIGN: Two-tiered analysis. SETTING: Academic research. PATIENTS: Patients and control subjects from the NeuroGenetics Research Consortium. MAIN OUTCOME MEASURES: We performed a 2-tiered analysis of 1956 patients with PD and 2112 controls from the NeuroGenetics Research Consortium using a comprehensive tag SNP approach. Previously published REP1 genotypes were also included. Plasma α-synuclein was assayed in 86 patients with PD and 78 controls using a highly sensitive Luminex assay. RESULTS: Five of 15 SNPs genotyped were associated with PD under an additive model in tier 1 (α = .05). Of these, 4 were successfully replicated in tier 2. In the combined sample, the most significant marker was rs356219 (odds ratio, 1.41; 95% confidence interval, 1.28-1.55; P = 1.6 × 10(-12)), located approximately 9 kilobases downstream from the gene. A regression model containing rs356219 alone best fit the data. The linkage disequilibrium correlation coefficient between this SNP and REP1 was low (r(2) = 0.09). The risk-associated C allele of rs356219 was also correlated with higher transformed plasma α-synuclein levels in patients under an adjusted additive model (P = .005). CONCLUSIONS: Our data suggest that 1 or more unidentified functional SNCA variants modify risk for PD and that the effect is larger than and independent of REP1. This variant(s), tagged by rs356219, might act by upregulating SNCA expression in a dose-dependent manner.

Botulinum toxin in the management of dystonia.

Dystonia is a neurologic disorder that can occur at any age and often results in significant disability. The therapeutic application of botulinum toxin has revolutionized the treatment of this disorder, particularly for the adult-onset focal forms such as cervical dystonia and blepharospasm. The two available commercial preparations, botulinum toxin types A and B, have been shown to be equally efficacious in cervical dystonia and are both reasonable first-line choices for treating other forms of focal dystonia. Preliminary studies have suggested that differences in tolerability and immunogenicity may exist between the two preparations, but this has not been adequately evaluated. Because of high cost, complicated administration, potentially serious side effects, and the risk of developing immunoresistance, this treatment should be administered only by a physician with sufficient background in the diagnosis and treatment of dystonia, to ensure optimal outcomes.