Occupational categories at risk for Parkinson's disease.

BACKGROUND: The etiology of Parkinson's disease (PD) is considered to have a strong environmental component, but relatively few studies have investigated the potential association between occupation and the disease. METHODS: In a population-based case-control study, we collected comprehensive occupational histories from all study participants, 144 case and 464 control subjects. RESULTS: Chi-square analysis revealed that working in an agricultural occupation increased estimated PD risk (OR = 1.74; 95% CI = 0.85, 3.60). In contrast, a history of ever working in a service occupation was negatively associated with PD risk (OR = 0.69; 95% CI = 0.47, 1.00). Risk estimates were close to one for specific service occupations. Adjusted odds ratios for all non-service occupational and industrial categories were similar, and working in a service occupation was the only significant inverse predictor of PD risk. CONCLUSIONS: Future investigations focusing on lifestyle factors and environmental exposures within the agricultural and service occupational categories are warranted.

Interregional variation of longitudinal relaxation rates in human brain at 3.0 T: relation to estimated iron and water contents.

In a study of interregional variation of the longitudinal relaxation rate (R(1)) in human brain at 3 T, R(1) maps were acquired from 12 healthy adults using a multi-slice implementation of the T one by multiple readout pulses (TOMROP) sequence. Mean R(1) values were obtained from the prefrontal cortex (0.567 +/- 0.020 sec(-1)), caudate head (0.675 +/- 0.019 sec(-1)), putamen (0.749 +/- 0.023 sec(-1)), substantia nigra (0.873 +/- 0.037 sec(-1)), globus pallidus (0.960 +/- 0.034 sec(-1)), thalamus (0.822 +/- 0.027 sec(-1)), and frontal white matter (1.184 +/- 0.057 sec(-1)). For gray matter regions other than the thalamus, R(1) showed a strong correlation (r = 0.984, P < 0.0001) with estimated regional nonheme iron concentrations ([Fe]). These R(1) values also showed a strong correlation (r = 0.976, P < 0.0001) with estimates of 1/f(w) obtained from MRI relative proton density measurements, where f(w) represents tissue water content. When white matter is included in the consideration, 1/f(w) is a better predictor of R(1) than is [Fe]. An analysis based on the fast-exchange two-state model of longitudinal relaxation suggests that interregional differences in f(w) account for the majority of the variation of R(1) across gray matter regions. Magn Reson Med 45:71-79, 2001.

Occupational metal exposures and the risk of Parkinson's disease.

Occupational exposure to specific metals (manganese, copper, lead, iron, mercury, zinc, aluminum and others) appears to be a risk factor for Parkinson's disease (PD) in some, but not all, case-control studies. These epidemiological studies are reviewed. Several methodological issues that may account for the lack of unanimity of findings are discussed, and suggestions for improved case-control methodology are offered. The study of the neurological disease outcome of workers who have had long-term, well-defined occupational exposure to one or more metals is also urged, with collaborative work including industrial hygienists, occupational toxicologists, neurologists, epidemiologists and biostatisticians. Such efforts, employing state-of-the-art case and control ascertainment and enrollment from suitable population bases, neurological diagnostic rigor and exposure assessment, will help to further define the potentially important roles played by metals in PD and other neurodegenerative disorders.

A family history of Parkinson's disease and its effect on other PD risk factors.

Parkinson's disease (PD) is likely a result of both inherited and exogenous factors. In a study of 144 PD cases and 464 controls, we used PD family history as a surrogate for inherited PD susceptibility. Cases were more likely to report a first- or second-degree relative with PD: 16.0 vs. 4.3%; odds ratio (OR) = 4. 2; 95% confidence interval (CI) = 2.3-7.6. A PD family history was a greater risk factor for PD in subjects under age 70 (OR = 8.8; 95% CI = 3.4-22.8) compared with those over 70 (OR = 2.8; 95% CI = 1.3-6. 1) and in men (OR = 8.1; 95% CI = 3.4-19.2) compared with women (OR = 2.6; 95% CI = 1.1-6.0). We also tested whether a PD family history modified the effects of other PD risk factors. In subjects with a PD family history, occupational exposure to copper, lead or iron increased the risk for PD (OR = 3.0; 95% CI = 0.7-13.3), but this was not the case for those without a family history (OR = 1.1; 95% CI = 0.7-1.6). Ever smoking cigarettes was inversely associated with PD in those without a PD family history (OR = 0.6; 95% CI = 0.4-0.9), but was positively associated with PD in those with a PD family history (OR = 1.7; 95% CI = 0.5-5.9). In summary, our results suggest that a PD family history, and perhaps, therefore, an inherited susceptibility, confers a greater risk for PD in men and individuals under 70 years of age and may modify the effects of environmental risk factors for PD.

Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson's disease.

A population-based case-control study was conducted in the Henry Ford Health System (HFHS) in metropolitan Detroit to assess occupational exposures to manganese, copper, lead, iron, mercury and zinc as risk factors for Parkinson's disease (PD). Non-demented men and women 50 years of age who were receiving primary medical care at HFHS were recruited, and concurrently enrolled cases (n = 144) and controls (n = 464) were frequency-matched for sex, race and age (+/- 5 years). A risk factor questionnaire, administered by trained interviewers, inquired about every job held by each subject for 6 months from age 18 onward, including a detailed assessment of actual job tasks, tools and environment. An experienced industrial hygienist, blinded to subjects' case-control status, used these data to rate every job as exposed or not exposed to one or more of the metals of interest. Adjusting for sex, race, age and smoking status, 20 years of occupational exposure to any metal was not associated with PD. However, more than 20 years exposure to manganese (Odds Ratio [OR] = 10.61, 95% Confidence Interval [CI] = 1.06, 105.83) or copper (OR = 2.49, 95% CI = 1.06,5.89) was associated with PD. Occupational exposure for > 20 years to combinations of lead-copper (OR = 5.24, 95% CI = 1.59, 17.21), lead-iron (OR = 2.83, 95% CI = 1.07,7.50), and iron-copper (OR = 3.69, 95% CI = 1.40,9.71) was also associated with the disease. No association of occupational exposure to iron, mercury or zinc with PD was found. A lack of statistical power precluded analyses of metal combinations for those with a low prevalence of exposure (i.e., manganese, mercury and zinc). Our findings suggest that chronic occupational exposure to manganese or copper, individually, or to dual combinations of lead, iron and copper, is associated with PD.

MR imaging of human brain at 3.0 T: preliminary report on transverse relaxation rates and relation to estimated iron content.

PURPOSE: To determine the transverse relaxation rates R2 and R2' from several gray matter regions and from frontal cortical white matter in healthy human brains in vivo and to determine the relationship between relaxation rates and iron concentration [Fe]. MATERIALS AND METHODS: Six healthy adults aged 19-42 years underwent thin-section gradient-echo sampling of free induction decay and echo magnetic resonance (MR) imaging at 3.0 T. Imaging covered the mesencephalon and basal ganglia. RESULTS: Relaxation rates (mean +/- SD) were highest in globus pallidus (R2 = 25.8 seconds-1 +/- 1.1, R2' = 12.0 seconds-1 +/- 2.1) and lowest in prefrontal cortex (R2 = 14.4 seconds-1 +/- 1.8, R2' = 3.4 seconds-1 +/- 1.1). Frontal white matter measurements were as follows: R2 = 18.0 seconds-1 +/- 1.2 and R2' = 3.9 seconds-1 +/- 1.2. For gray matter, both R2 and R2' showed a strong correlation (r = 0.92, P < .001 and r = 0.90, P < .001, respectively) with [Fe]. Although the slopes of the regression lines for R2' versus [Fe] and for R2 versus [Fe] were similar, the iron-independent component of R2' (2.2 seconds-1 +/- 0.6), the value when [Fe] = 0, was much less than that of R2 (12.7 seconds-1 +/- 0.7). CONCLUSION: The small iron-independent component R2', as compared with that of R2, is consistent with the hypothesis that R2' has higher iron-related specificity.

Smoking and Parkinson's disease: a dose-response relationship.

OBJECTIVE: To determine whether an inverse dose-response relationship exists between cigarette smoking and PD among ever-smokers and ex-smokers. METHODS: Smoking and alcohol consumption were analyzed in 144 PD patients and 464 control subjects, who were frequency matched for sex, race, and age (+/-5 years), in a population-based case-control study of men and women > or =50 years old in the Henry Ford Health System. RESULTS: With never-smokers as the reference category, there was an inverse association between current light smokers (>0 to 30 pack-years) and PD patients (odds ratio [OR], 0.59; 95% CI, 0.23 to 1.53), and a stronger inverse association of PD with current heavy smokers (>30 pack-years; OR, 0.08; 95% CI, 0.01 to 0.62). When former >30-pack-year smokers were stratified by the interval since quitting, there was an inverse association between those who stopped >20 years ago and PD (OR, 0.86; 95% CI, 0.42 to 1.75), and a greater inverse relationship with those who stopped 1 to 20 years ago (OR, 0.37; 95% CI, 0.19 to 0.72). Alcohol consumption had no independent, significant association with PD, but heavy drinking (>10 drink-years) had a greater effect than light-moderate drinking in reducing but not eliminating the inverse association between smoking and PD. CONCLUSIONS: The inverse dose-response relationship between PD and smoking and its cessation is unlikely to be due to bias or confounding, as discussed, providing indirect evidence that smoking is biologically protective.

Validity of the Dementia Rating Scale in assessing cognitive function in Parkinson's disease.

Two studies examined the validity of the Dementia Rating Scale (DRS) as a measure of cognitive functioning among patients with Parkinson's disease (PD). The DRS accounted for more variation in the level of cognitive functioning of PD patients than either the Mini-Mental Status Examination or a battery of tests selected to assess specific cognitive deficits associated with PD. Further, DRS subtests displayed strong convergent and discriminant validity with a comprehensive Criterion Neuropsychology Battery. The DRS subtests appear to be valid measures of attention, perseveration, conceptualization, and memory among PD patients. However, the DRS-Construction subtest should be supplemented with additional visuoconstructional items to provide a thorough screen of cognitive functioning in PD. Although about three-quarters of nondemented PD patients did not appear to have any specific cognitive deficits on the DRS, the remaining patients were impaired on the Construction or Initiation/Perseveration subtests of the DRS. In summary, the DRS is a valid mental status screening test of cognitive functioning for individuals with PD.

Adult nutrient intake as a risk factor for Parkinson's disease.

BACKGROUND: This population-based case-control study evaluated nutrient intake as a risk factor for Parkinson's disease (PD) among people aged > or =50 years in metropolitan Detroit. METHODS: Cases (n = 126) were diagnosed between 1991 and 1995 and neurologist-confirmed. Controls (n = 432) were frequency-matched for sex, age (+/-5 years) and race. Using a standardized food frequency questionnaire, subjects reported the foods they ate within the past year. RESULTS: Estimating the association between PD and risk of being in the highest versus the lowest intake quartile, there were elevated odds ratios for total fat (OR 1.94, 95% confidence interval [CI] : 1.05-3.58), cholesterol (OR 2.11, 95% CI: 1.14-3.90), lutein (OR 2.52, 95% CI: 1.32-4.84) and iron (OR 1.88, 95% CI: 1.05-3.38). CONCLUSIONS: These results suggest an association of PD with high intake of total fat, saturated fats, cholesterol, lutein and iron.

The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living.

We assessed exposure to pesticides, farming, well water use, and rural living as risk factors for Parkinson's disease (PD) in a population-based case-control study consisting of men and women > or = 50 years of age who had primary medical care at Henry Ford Health System in metropolitan Detroit. Enrolled PD patients (n = 144) and control subjects (n = 464) were frequency-matched for age, race, and sex. When adjusted for these variables and smoking status, there was a significant association of occupational exposure to herbicides (odds ratio [OR], 4.10; 95% CI, 1.37, 12.24) and insecticides (OR, 3.55; 95% CI, 1.75, 7.18) with PD, but no relation was found with fungicide exposure. Farming as an occupation was significantly associated with PD (OR, 2.79; 95% CI, 1.03, 7.55), but there was no increased risk of the disease with rural or farm residence or well water use. The association of occupational exposure to herbicides or insecticides with PD remained after adjustment for farming. The association of farming with PD was maintained after adjustment for occupational herbicide exposure and was of borderline significance after adjustment for occupational insecticide exposure. These results suggest that PD is associated with occupational exposure to herbicides and insecticides and to farming and that the risk of farming cannot be accounted for by pesticide exposure alone.

Intra- and inter-rater agreement in the assessment of occupational exposure to metals.

BACKGROUND: Among the methods of retrospective occupational exposure assessment, expert review is considered the most accurate. Although expert review provides a more objective measure of exposure, depending on the exposure of interest it may still result in a significant degree of misclassification. METHODS: To evaluate the reliability in occupational metal exposure assessment by expert review, we analysed job history data from a case-control study of a neurological disease. First, one industrial hygienist (IH) did an initial exposure assessment of the metals copper, iron and lead, blinded to case-control status, for 608 subjects who had 3033 total jobs. We then compared exposure assessments from the original review with a second blinded review of 60 job histories (306 jobs) by the same IH (intra-rater) and of 64 job histories (361 jobs) by a different IH (inter-rater). RESULTS: The per cent agreements for the intra-IH comparisons were 89.6 for copper, 87.9 for iron and 94.6 for lead, whereas the inter-IH per cent agreements were 86.4 for copper, 81.1 for iron and 76.2 for lead. Based on the assumption that reliability is related to validity, we calculated an estimate of misclassification of metal exposure by one IH. Our exposure misclassification estimates show a sizable attenuation of the odds ratio, with the expected bias similar for copper and iron when using either intra- or inter-reliability results to estimate misclassification. CONCLUSION: Our results suggest that variation in the expert assessment of metal exposure is due mainly to the difficulties involved in transforming an occupational history into an estimate of exposure.

Occupational exposures to metals as risk factors for Parkinson's disease.

In a population-based case-control study, we investigated the potential role of occupational exposure to iron, copper, manganese, mercury, zinc, and lead as risk factors for Parkinson's disease (PD). Concurrently recruited, nondemented patients (n = 144) with idiopathic PD and controls (n = 464) consisting of men and women > or =50 years of age, frequency-matched for age (within 5 years), race, and sex were enrolled. All had primary medical care at Henry Ford Health System in urban/suburban metropolitan Detroit. Subjects were given an extensive risk-factor questionnaire detailing actual worksite conditions of all jobs held for more than 6 months from age 18 onward. An industrial hygienist, blinded to the case-control status of subjects, rated occupational exposure to each of the metals of interest. When adjusted for sex, race, age, and smoking status, we found in those with more than 20 years' exposure a significantly increased association with PD for copper (OR = 2.49, 95% CI = 1.06, 5.89) and manganese (OR = 10.61, 95% CI = 1.06, 105.83). For more than 20 years' exposure to combinations of lead-copper (OR = 5.24, 95% CI = 1.59, 17.21), lead-iron (OR = 2.83, 95% CI = 1.07, 7.50), and iron-copper (OR = 3.69, 95% CI = 1.40, 9.71), there was a greater association with PD than with any of these metals alone. These findings suggest that chronic exposure to these metals is associated with PD, and that they may act alone or together over time to help produce the disease.

Comparability of different methods of retrospective exposure assessment of metals in manufacturing industries.

Many occupational case-control studies have relied on either self-report or exposure assessment based on job titles linked to a job exposure matrix (JEM) as opposed to the generally considered more accurate, but labor intensive, method of expert review of job histories. Our study examined the comparability of these different methods in assessing occupational exposure to the metals copper (Cu), lead (Pb), and iron (Fe) in manufacturing industries. Subjects were older people from a case-control study of a neurologic disease, and consisted of 188 individuals (72% male, 85% white) who had worked an average of 22.4 years in the manufacturing industry. An industrial hygienist review (IHR) of occupational history data from a comprehensive questionnaire was used as the reference method. The percent agreement (%A), sensitivity (SE), and specificity (SP) for direct self-report of metal exposures were: Cu, %A = 94.6, SE = 83.6, SP = 96.1; Pb, %A = 91.9, SE = 72.5, SP = 93.5; and Fe, %A = 82.7, SE = 64.5, SP = 88.1. Using the National Institute for Occupational Safety and Health (NIOSH) JEM, we analyzed the jobs of 115 of the 188 study subjects who had all their jobs listed in the JEM. Exposure assessment based on the NIOSH JEM compared with the IHR resulted in greater misclassification relative to direct self-report: Cu, %A = 81.5, SE = 21.2, SP = 89.2; Pb, %A = 86.0, SE = 0.0, SP = 92.6; and Fe, %A = 69.2, SE = 15.5, SP = 86.4. For all three study metals, combining the information from both direct self-report and the JEM did not improve upon the results compared with direct self-report alone. Due to the complex nature of metal exposure assessment, we suggest using an expert review of job histories whenever possible to minimize potential misclassification.

Impaired set-shifting in Parkinson's disease: new evidence from a lexical decision task.

On a lexical decision (LD) task, participants quickly decide whether a target letter string is a word. When a target word (e.g., CARROT) is preceded by a category cue (e.g., VEGETABLE), participants respond more quickly than when the target is preceded by a semantically neutral cue (e.g., BLANK). Previously, Spicer, Brown, and Gorell (1994) reported that patients with PD, when tested with a variation of Neely's (1977) LD task, showed hyperpriming. That is, patients with PD exhibited a larger difference in reaction time between the neutral cue and category prime conditions than did controls. The present study found little evidence that PD hyperpriming was explained by difficulties accessing semantic information. Rather, hyperpriming appeared to be related to a general tendency among a subgroup of patients with PD to perseverate.

Increased iron-related MRI contrast in the substantia nigra in Parkinson's disease.

Elevated iron levels in the substantia nigra (SN) of the brain in Parkinson's disease (PD) may mediate lipid peroxidative reactions, promoting SN neuronal death. To assess SN iron accumulation in living PD patients and its relation to motor performance, we measured, in 13 nondemented PD patients and 10 normal control subjects, simple reaction time (SRT) and simple movement time (SMT), followed by head MRI in a 3-tesla system. We measured T2 and T2* in the right and left SN of all subjects and calculated R2', the relaxation rate due to local magnetic field in-homogeneities, from these values. Asymmetries of 1/T2 (R2), 1/T2* (R2*), or R2' versus asymmetries of SRT and SMT were assessed in eight PD subjects who had not taken anti-PD medication(s) for 12 hours. The average of right and left SN values for R2 was lower, and R2* and R2' were higher, in PD patients than in controls (R2, p = 0.046; R2*, p = 0.001; R2', p < 0.001). R2' best predicted group differences. The asymmetry of SRT performance was highly correlated with asymmetries of SN R2* (0.91; p = 0.001) and R2' (0.72; p = 0.03). These results strongly suggest that the increases in iron levels seen postmortem in the SN in PD are reflected in increased iron-related MRI contrast at 3 tesla in living PD patients. Correlations with motor performance in PD suggest that the clinical severity of PD may be related to SN iron accumulation.

Preliminary observations of transverse relaxation rates obtained at 3 tesla from the substantia nigra of adult normal human brain.

The transverse relaxation rates R2 and R2* were measured at 3 T in the substantia nigra of the midbrain of adult normal human controls. The relaxation rate arising from magnetic inhomogeneities, R2', was calculated from the relationship R2* = R2 + R2'. No significant differences were found for any parameters between left and right side substantia nigra regions, however, a significant inverse correlation was found between R2 and R2' (r = 0.70, p = 0.035). Water diffusion, in the presence of paramagnetic metal ions, may play a role in determining the relative contributions to reversible and irreversible transverse relaxation and may explain the inverse correlation demonstrated here.

Demographic differences in referral rates to neurologists of patients with suspected Parkinson's disease: implications for case-control study design.

Although patients with Parkinson's disease (PD) are often treated by neurologists, most are first diagnosed by a primary care physician. Epidemiologic studies which use PD cases from only neurology clinics may be subject to referral bias due to differential case selection in the referral process. To study this methodological issue, a historical cohort study of all outpatients with PD diagnosed by a non-neurologist from January 1, 1988 to June 1, 1992 at the Henry Ford Health System was conducted. This health system has specialty and primary care outpatient clinics located at the main facility in Detroit, Mich. and throughout the metropolitan area. The analysis included those who had at least one outpatient visit during the follow-up period from January 1, 1988 to June 30, 1993 (n = 588), of whom 183 (31.1%) were referred to a neurologist. The univariate analysis resulted in crude risk ratios for referral of 2.14 [95% confidence interval (CI) = 1.56-2.93] for age less than 70, 2.11 (95% CI = 1.57-2.84) for male sex, 1.64 (95% CI = 1.17-2.32) for nonwhite race, 2.48 (95% CI = 1.77-3.47) for private health insurance, 1.79 (95% CI = 1.32-2.43) for being married, 1.44 (95% CI = 1.08-1.92) for 10 or more health care visits per year and 2.27 (95% CI = 1.66-3.11) for having the initial visit for PD at the main Detroit clinic. In a Cox proportional hazards model which included all study variables, race and marital status were no longer statistically significant (p < 0.05), and no risk estimates were greater than 2.0. In summary, patients referred to neurologists in this study were more likely younger, male, to have private health insurance, frequent users of health care and to use hospital-based clinics for their primary health care. We suggest that future case-control studies of PD avoid potential referral bias by not using a study population comprised solely of patients referred to a neurology clinic or design studies which can estimate the potential effect of this bias.

Parkinson's disease and its comorbid disorders: an analysis of Michigan mortality data, 1970 to 1990.

Using data from death certificates, we compared underlying causes of death for two populations of Michigan decedents: (1) persons 40 years of age and older for whom Parkinson's disease (PD) was listed as a contributing cause of death and who died in the years 1970 through 1989, and (2) all persons in Michigan over 40 years of age who died in 1970, 1980, or 1990. PD decedents were approximately 1.5 times more likely to die from cerebrovascular disease and three to four times more likely to die from pneumonia/influenza, but they had just 29% of the expected number of deaths due to cancer. These associations were maintained irrespective of gender or race. PD decedents had diabetes mellitus and heart diseases as frequently as decedents in the general population, but liver diseases were less frequent among PD decedents. These trends held throughout the 21-year study period. When we stratified cancers by whether they are known to be (1) highly related, (2) moderately related, or (3) weakly related or unrelated to smoking, there were still 2.5 times fewer cancers unrelated or weakly related to smoking among PD decedents than among decedents in the general population. We believe that the greater frequency of cerebrovascular disease in PD decedents may be due to a detection bias, since PD patients are more likely to be seen by neurologists, who are more apt to diagnose and document diseases of the nervous system. Pneumonia/influenza is more common among PD patients because of their relative immobility near the end of life.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of relative brain iron concentrations using T2-weighted and T2*-weighted MRI at 3 Tesla.

In this paper a new method is presented for the relative assessment of brain iron concentrations based on the evaluation of T2 and T2*-weighted images. A multiecho sequence is employed for rapid measurement of T2 and T2*, enabling calculation of the line broadening effect (T2'). Several groups have failed to show a correlation between T2 and brain iron content. However, quantification of T2', and the associated relaxation rate R2', may provide a more specific relative measure of brain iron concentration. This may find application in the study of brain diseases, which cause associated changes in brain iron levels. A new method of field inhomogeneity correction is presented that allows the separation of global and local field inhomogeneities, leading to more accurate T2* measurements and hence, T2' values. The combination of T2*, and T2-weighted MRI methods enables the differentiation of Parkinson's disease patients from normal age-matched controls based on differences in iron content within the substantia nigra.

Lexical decision in Parkinson disease: lack of evidence for generalized bradyphrenia.

Twenty-two nondemented patients with idiopathic Parkinson disease (PD) and 22 controls completed a lexical decision task for which the expected relationship between primes and targets was manipulated. Both reaction times and movement times were measured. PD subjects were as effective as controls in utilizing the priming cues to reduce their reaction times compared with a neutral condition. This facilitation occurred even at the shortest stimulus onset asynchrony employed (300 ms), and was observed in a condition requiring a shift of attention, suggesting that PD patients experience no general cognitive slowing and no difficulty efficiently shifting attention to a specified semantic category. The degree of facilitation was significantly greater in the PD group in several comparisons, indicating hyperpriming. Finally, expectancy primes facilitated movement times in the PD group only. Although the results do not support the existence of generalized bradyphrenia in nondemented Parkinson disease, the hyperpriming effect and correlational analyses involving vocabulary scores and choice reaction time do raise the possibility of a subtle semantic processing deficit or an impairment of strategic decision-making in PD.