Parkinson's disease risks associated with dietary iron, manganese, and other nutrient intakes.

BACKGROUND: Dietary influences on oxidative stress have been thought to play important role in the etiology of PD. OBJECTIVE: To examine associations of PD with dietary nutrients, including minerals, vitamins, and fats. METHODS: A population-based case-control study was conducted among newly diagnosed case (n = 250) and control subjects (n = 388) identified between 1992 and 2002 from enrollees of the Group Health Cooperative health maintenance organization in western Washington state. Controls were frequency matched to cases on sex and age. In-person interviews elicited data on food frequency habits during most of adult life. Nutrient intakes were calculated and analyzed by adjusting each person's nutrient intake by their total energy intake (the nutrient density technique). RESULTS: Subjects with an iron intake in the highest quartile compared with those in the lowest quartile had an increased risk of PD (odds ratio = 1.7, 95% CI: 1.0, 2.7, trend p = 0.016). There was an apparent joint effect of iron and manganese; dietary intake above median levels of both together conferred a nearly doubled risk compared with lower intakes of each nutrient (odds ratio = 1.9, 95% CI: 1.2, 2.9). No strong associations were found for either antioxidants or fats. CONCLUSION: A high intake of iron, especially in combination with high manganese intake, may be related to risk for PD.

MR nerve imaging in a prospective cohort of patients with suspected carpal tunnel syndrome.

OBJECTIVES: To evaluate the reliability and diagnostic accuracy of high-resolution MRI of the median nerve in a prospectively assembled cohort of subjects with clinically suspected carpal tunnel syndrome (CTS). METHODS: The authors prospectively identified 120 subjects with clinically suspected CTS from five Seattle-area clinics. All subjects completed a hand-pain diagram and underwent a standardized nerve conduction study (NCS). The reference standard for determining CTS status was a classic or probable hand pain diagram and NCS with a difference >0.3 ms between the 8-cm median and ulnar peak latencies. Readers graded multiple imaging parameters of the MRI on four-point scales. The authors also performed quantitative measurements of both the median nerve and carpal tunnel cross-sectional areas. NCS and MRI were interpreted without knowledge of the other study or the hand pain diagram. RESULTS: Intrareader reliability was substantial to near perfect (kappa = 0.76 to 0.88). Interreader agreement was lower but still substantial (kappa = 0.60 to 0.67). Sensitivity of MRI was greatest for the overall impression of the images (96%) followed by increased median nerve signal (91%); however, specificities were low (33 to 38%). The length of abnormal signal on T2-weighted images was significantly correlated with nerve conduction latency, and median nerve area was larger at the distal radioulnar joint (15.8 vs 11.8 mm(2)) in patients with CTS. A logistic regression model combining these two MR variables had a receiver operating characteristic area under the curve of 0.85. CONCLUSIONS: The reliability of MRI is high but the diagnostic accuracy is only moderate compared with a research-definition reference standard.

Genetic polymorphisms of microsomal and soluble epoxide hydrolase and the risk of Parkinson's disease.

Oxidative stress is hypothesized to play a major role in the destruction of dopaminergic neurons, which is associated with Parkinson's disease. Epoxides are potentially reactive intermediates formed through the oxidative metabolism of both exogenous and endogenous substances that contribute to cytotoxic damage mediated by oxidative stress. The microsomal (EPHX1) and soluble (EPHX2) epoxide hydrolases function to regulate the oxidation status of a wide range of xenobiotic- and lipid-derived substrates; therefore, interindividual variation in these pathways may mitigate epoxide-related cellular injury. In this investigation, we examined the potential association between the risk of Parkinson's disease and genetic variation within the EPHX1 and EPHX2 genes. Fluorescent 5' nuclease-based assays were developed to identify the allelic status of individuals with respect to specific single nucleotide polymorphisms in exons 3 and 4 of the EPHX1 gene and exons 8 and 13 of the EPHX2 gene. EPHX1 and EPHX2 genotype data were obtained from 133 idiopathic Parkinson's disease patients and 212 control subjects matched on age, gender and ethnicity. No statistically significant differences were found in the distribution of the reference and variant alleles between Parkinson's disease and control subjects, or when results were stratified by gender. Therefore, common polymorphisms within EPHX1 and EPHX2 do not appear to be important risk factors for Parkinson's disease.

Genetic polymorphisms of superoxide dismutase in Parkinson's disease.

Oxidative stress reactions may contribute to the pathogenesis of Parkinson's disease (PD). The superoxide dismutases potentially play significant roles in PD by detoxifying superoxide radical. We developed genomic DNA and cDNA-based sequencing assays to identify genetic variants in the copper/zinc superoxide dismutase (SOD1) and manganese superoxide dismutase (SOD2) genes. No genetic variants were detected in the gene encoding SOD1 in DNA from 45 idiopathic PD cases and 49 controls from a population-based case-control study. However, we identified a previously described polymorphism of the mitochondrial targeting sequence consisting of a C47T in exon 2 of SOD2, which results in an alanine to valine substitution. We analyzed this SOD2 variant in DNA from 155 cases and 231 controls from the same study, using an allele-specific fluorogenic 5' nuclease assay, and found no differences in the distributions of allelic frequencies. These results indicate that SOD gene variants do not contribute to PD pathogenesis.

Mitochondrial ND1 sequence analysis and association of the T4216C mutation with Parkinson's disease.

Mitochondrial dysfunction originating from mutations in Complex I genes may play a role in the pathogenesis of Parkinson's disease (PD). In this study, the entire ND1 coding sequence was sequenced in 84 newly diagnosed PD cases and 127 age/gender-matched controls. Numerous missense mutations were found at low frequency (<5%), whereas a thymidine to cytosine missense mutation at position 4216 that results in the replacement of tyrosine with histidine was found in 25% of the PD case samples and in 18% of the controls. When calculated according to gender, the 4216 mutation was observed in 26% of the male cases versus 16% of male controls (Odds Ratio [OR] = 1.85; 95% CI = 0.79-4.34). In contrast, females exhibited approximately equal frequencies among cases (22.5%) and controls (21%), yielding an OR of 1.08 (95% C.I. = 0.36-3.22). The findings indicate only a weak association of this genetic variant with PD.

Genetic polymorphism of dopamine D2 receptors in Parkinson's disease and interactions with cigarette smoking and MAO-B intron 13 polymorphism.

Genetic polymorphisms of dopamine D2 receptors (DRD2) may be susceptibility factors for Parkinson's disease due to their influence on dopamine response and association with cigarette smoking, which is inversely related to risk of Parkinson's disease. Relations of TaqIA and TaqIB DRD2 genotypes with Parkinson's disease were investigated and tested for interactive effects with smoking and the monoamine oxidase B (MAO-B) intron 13 polymorphism previously found to be related to smoking. Study subjects were 152 cases of idiopathic Parkinson's disease and 231 controls. The smoking history of all genotyped subjects was known. Subjects of genotype B12 were more frequent among cases than controls (27% and 23.8%, respectively), and were more frequent among "ever smokers" than "never smokers", among controls (27.8% and 17.2%, respectively), although these associations were not statistically significant. Neither TaqIA or TaqIB genotypes modified the inverse relation of smoking and Parkinson's disease. When genotypes for DRD2 were considered in combination with genotypes for intron 13 of MAO-B, genotype combinations with high risk of Parkinson's disease were found; although the MAO-B/DRD2 interaction did not reach statistical significance after Bonferroni correction for multiple comparisons, these results are suggestive of a possible synergism between MAOB and DRD2 genes with respect to Parkinson's disease.

Outcome of surgery for thoracic outlet syndrome in Washington state workers' compensation.

OBJECTIVE: To determine the predictors of outcome of thoracic outlet syndrome (TOS) surgery in a population-based cohort of injured workers. METHODS: All injured workers in the Washington State Workers' Compensation system who received TOS surgery during 1986 to 1991 were identified by computerized bill payment records and validated by medical record review (n = 158). The main outcome measure was work disability status 1 year after surgery. Additional functional status and quality of life outcomes were determined by telephone survey an average of 4.8 years after operation. A sample of workers with a TOS diagnosis who did not receive surgery during 1987 to 1989 were identified as a comparison group (n = 95). RESULTS: Sixty percent of workers were still work disabled 1 year after surgery. The strongest predictors of remaining disabled were the amount of work disability before surgery (OR = 1.85; 95% CI, 1.51 to 2.28), longer time between injury and TOS diagnosis (OR = 1.34; 95% CI, 1.09 to 1.64), and older age at injury (OR = 1.07; 95% CI, 1.00 to 1.13). There was no relationship between type of surgery, presence of any provocative tests, or experience of surgeon and work disability outcome. In follow-up surveys an average of 4.8 years after surgery, 72.5% of workers still reported they were "limited a lot" in vigorous activities. Compared with a nonsurgical sample of TOS patients, those receiving surgery had 50% greater medical costs and were three to four times more likely to be work disabled. CONCLUSIONS: The outcome of TOS surgery among injured workers is worse than has generally been reported. The nonspecific neurogenic TOS diagnosis, the complexity of workers' compensation cases, and the adverse event profile are likely substantial contributors to the worse outcomes reported here. Well-designed prospective studies and randomized trials are required to elucidate any role of TOS surgery in nonspecific TOS.

The EcoRV genetic polymorphism of human monoamine oxidase type A is not associated with Parkinson's disease and does not modify the effect of smoking on Parkinson's disease.

We previously observed an association with Parkinson's (PD), and modification of the effect of smoking on PD, by a polymorphism of the monoamine oxidase B (MAO-B) gene. The A form of monoamine oxidase (MAO-A) shares with MAO-B many characteristics that could be relevant to PD, especially proneuroxicant bioactivation and dopamine metabolism. MAO-A is also inhibited by tobacco smoke, which bears an apparent protective effect on PD. We investigated the possibility that MAO-A genetic variants may also be involved in predisposition to PD and in modification of the effect of smoking. Three-hundred and seventy-one subjects--145 idiopathic PD cases and 226 age/gender-matched controls--were genotyped for the EcoRV polymorphism of MAO-A gene which has been related to increased enzyme activity. MAO-A EcoRV polymorphism was neither significantly associated with PD nor did it modify the inverse relationship with smoking. These results suggest that the EcoRV polymorphism of MAO-A is not an important biomarker of PD risk.

Neuropsychological function in retired workers with previous long-term occupational exposure to solvents.

OBJECTIVES: It is plausible that neurodegenerative processes of aging might have a contributing role in the development of chronic effects of exposure to organic solvents. This study evaluated the risk for neuropsychological deficits among retired workers, relative to their histories of exposure to occupational solvents. METHODS: This cross sectional study evaluated retired male workers, 62-74 years of age, including 89 people with previous long-term occupational exposure to solvents (67 retired painters and 22 retired aerospace manufacturing workers), and 126 retired carpenters with relatively minimal previous exposure to solvents. Subjects completed a standardised neuropsychological evaluation and psychiatric interview, structured interviews for histories of occupational exposure and alcohol consumption, and questionnaires assessing neurological and depressive symptoms. RESULTS: By comparison with the carpenters, the painters on average reported greater cumulative alcohol consumption and had lower scores on the WAIS-R vocabulary subtest, usually presumed to reflect premorbid intellectual functioning. These findings, however, were not sufficient to account for the other study findings. Controlling for age, education, vocabulary score, and alcohol use, the painters had lower mean scores on test measures of motor, memory, and reasoning ability; and a subgroup of aerospace workers with moderate to high cumulative exposure to solvents (n = 8) had lower mean scores on measures of visuomotor speed, and motor, attention, memory, and reasoning ability. Subjects were more likely to have an increased number of relatively abnormal test scores (three or more outlier scores on 17 test measures) among both the painter group (odds ratio (OR), 3.1; 95% confidence interval (95% CI) 1.5 to 6.2) and the subgroup of aerospace workers with higher cumulative exposure (OR 5.6; 95% CI 1.0 to 38). The painters, but not the aerospace workers, reported significantly more neurological and depressive symptoms. CONCLUSIONS: The findings are consistent with residual central nervous system dysfunction from long-term exposure to organic solvents, persisting years after the end of exposure.

Dietary factors in Parkinson's disease: the role of food groups and specific foods.

PURPOSE: The association between self-reported past food intake and Parkinson's disease (PD) was investigated in a case-control study of men and women aged 40-89 years. METHODS: Newly diagnosed idiopathic PD cases were ascertained from neurologists, and from outpatient and pharmacy computerized databases, at the Group Health Cooperative (GHC) clinics in the Puget Sound region of Washington state. Control subjects were chosen from the GHC patient roster and had no reported history of diagnosed neurodegenerative disease. Dietary data were obtained from structured questionnaires. RESULTS: An increase in PD risk with increasing intake was noted for foods that contain animal fat and foods containing vitamin D. Intake of fruits, vegetables, meats, bread and cereals, or foods containing vitamins A, C, E, or iron was not significantly related to PD risk. Vitamin use, in general, was also not found to be related to PD risk, although a significant trend of increasing risk of PD was noted for intake of vitamin A supplements. CONCLUSIONS: Although these data support previous findings of no association of past intake with most food groups and PD risk, they confirm an increased risk of PD associated with foods containing animal fat.

A genetic polymorphism of MAO-B modifies the association of cigarette smoking and Parkinson's disease.

In a population-based case-control study, we found a reversal of the association of cigarette smoking with Parkinson's disease (PD) in relation to the monoamine oxidase B intron 13 genetic polymorphism. A reduced PD risk related to pack-years of smoking was detected for persons with the G allele, whereas an opposite effect was found among persons with the A allele. These results indicate an unexplained interaction between cigarette smoking and this genetic polymorphism.

Occupational hearing loss in Washington state, 1984-1991: I. Statewide and industry-specific incidence.

This study examined non-federal workers' compensation claims accepted for hearing-related conditions in Washington state during 1984-1991. Seventy percent of 6,539 filed claims were accepted (n = 4,547); most accepted claims resulted in disability compensation (n = 3,660; 80%). A transient 50-fold increase in claims from one worksite accounted for one-third of all hearing-related claims in the state for 2 years. The number and incidence of accepted claims from all other worksites increased significantly across the study period. The incidence was 0.3 per 10(3) workers per year, overall, but was at least five-fold higher in industries that accounted for half of accepted claims, and reached 38- to 71-fold higher in some industries. This study indicates: 1) workers' compensation claims under-estimate the true frequency of occupational illness, representing only the "tip of the iceberg;" 2) hearing loss is a growing problem in occupational health; and 3) workers' compensation data are potentially useful to identify specific high-incidence industries for possible interventions.

Occupational hearing loss in Washington state, 1984-1991: II. Morbidity and associated costs.

This study examined 4,547 workers' compensation claims accepted for hearing-related conditions in Washington state between 1984 and 1991; 80% resulted in disability compensation (n = 3,660). Acute hearing-related conditions comprised 11% of accepted conditions (95% confidence interval [CI], 2-15%); most claims were for chronic noise-related hearing loss. Tinnitus was reported in 64% of accepted claims (95% CI, 54-75%). The median binaural-equivalent hearing loss in compensated claims was 12.5% (inter-quartile interval, 5-22%; 90th percentile, 34%), although it declined by 30% during the study period. The number of claims and associated impairment increased with claimant age, but the number of claims dropped dramatically after age 65. Annual total disability settlements almost tripled in 8 years, totaling $22.8 million. This study indicates that occupational hearing-related conditions: 1) are manifested by mild to moderate hearing loss, accompanied by tinnitus in a majority of cases; 2) may be under-recognized in older, formerly noise-exposed individuals; and 3) were associated with substantial increases in compensation and medical costs over time, through 1991.

Association of a polymorphism in intron 13 of the monoamine oxidase B gene with Parkinson disease.

Monoamine oxidase B (MAO-B) is an enzyme that has relevance for Parkinson disease (PD) because of its roles in catabolizing dopamine and potentially activating exogenous neurotoxicants. A polymorphism of the gene encoding MAO-B has been identified as a single base change (A or G) in intron 13 of the X chromosome. The A allele was previously associated with an approximately twofold risk of PD. The present study compared A and G allele frequencies between newly diagnosed idiopathic PD cases and a control group free of neurodegenerative diseases. All study subjects were Caucasian. Cases were 37 men and 25 women, age 37-80 years; controls were 50 men and 29 women, age 45-82 years. MAO-B genotype was determined by the allele-specific polymerase chain reaction on DNA extracted from peripheral lymphocytes. In complete contrast to previous studies, elevated risks were detected with the G allele. The age-adjusted odds ratio for the G allele in males was 1.87 ((95% confidence interval) 0.78-4.47). Among females the age-adjusted odds ratios were 5.00 ((95% confidence interval) 1.13-22.1) for the GA genotype and 5.60 ((95% confidence interval) 1.01-30.9) for the GG genotype. These findings, although of limited statistical precision, suggest that the G allele of this MAO-B polymorphism may relate to PD risk.

Selegiline and lymphocyte superoxide dismutase activities in Parkinson's disease.

Superoxide dismutases (SODs) are metalloenzymes that detoxify superoxide radicals, and occur in cytosolic (Cu,Zn-SOD) and mitochondrial (Mn-SOD) forms in multiple tissues, including brain. A neuroprotective effect against oxide stressor exposures may be provided by SOD, although excessive enzyme activity can produce cell injury by formation of hydroxyl radical from hydrogen peroxide. We measured Cu,Zn-SOD and Mn-SOD activities in peripheral lymphocytes of 43 newly diagnosed idiopathic Parkinson's disease (PD) cases and 62 age- and sex-matched controls free of neurodegenerative disorders. Significant excesses of both SOD forms were found among PD cases compared with controls; however, the excesses were found exclusively among PD patients treated with the monoamine oxidase inhibitor selegiline (L-deprenyl). Enzyme-linked immunosorbent assays (ELISAs) confirmed that the activity excesses were due to increased protein rather than more highly reactive enzymes in lymphocytes of PD cases. Our findings clearly indicate the importance of selegiline on measured Cu,Zn-SOD and Mn-SOD activity in peripheral lymphocytes. Characterizing a possible therapeutic value of SOD will require longitudinal assessments of SOD in relation to PD progression.