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Objectives: To determine whether alpha-synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD). Methods: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium provided REP1 genotypes and baseline and follow-up clinical data for cases. The primary outcome was time to death. Cox proportional hazards regression models were used to assess the association of REP1 genotypes with survival. Results: Twenty-one sites contributed data for 6,154 cases. There was no significant association between alpha-synuclein REP1 genotypes and survival in PD. However, there was a significant association between REP1 genotypes and age at onset of PD (hazard ratio: 1.06; 95% confidence interval: 1.01-1.10; P value = 0.01). Conclusions: In our large consortium study, alpha-synuclein REP1 genotypes were not associated with survival in PD. Further studies of alpha-synuclein's role in disease progression and long-term outcomes are needed. (C) 2014 International Parkinson and Movement Disorder Society

BackgroundVariants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. MethodsThe Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. ResultsHerein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. ConclusionsEstablishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. (c) 2013 International Parkinson and Movement Disorder Society (Less)

Incidence rates of Parkinson's disease are higher in men than in women at all ages, and these differences may be a result of the neuroprotective effects of estrogen on the nigrostriatal pathway. We investigated the association of common variants in 4 estrogen-related genes with Parkinson's disease. Tagging single-nucleotide polymorphisms in the CYP19A1, ESR1, ESR2, and PRDM2 genes were selected from the International Haplotype Map and genotyped in 1103 Parkinson's disease cases from the upper Midwest of the United States and in 1103 individually matched controls (654 unaffected siblings, and 449 unrelated controls from the same region). Of 137 informative single-nucleotide polymorphisms, 2 PRDM2 single-nucleotide polymorphisms were significantly associated with an increased risk of Parkinson's disease at the Bonferroni-corrected significance level of 0.0004 (rs2744690: OR, 1.54; SE(logOR), .109; 99.96% CI, 1.05-2.26; uncorrected P = .0001; rs2744687: OR, 1.53; SE(logOR), .113; 99.96% CI, 1.03-2.29, uncorrected P = .0002); the association was significant in the women-only stratum but not in the men-only stratum. An additional 6 single-nucleotide polymorphisms in PRDM2, 2 in ESR1, 1 in ESR2, and 1 in CYP19A1 had significant P values in the overall sample before Bonferroni correction. None of the single-nucleotide polymorphisms were significantly associated with age at onset of Parkinson's disease after Bonferroni correction. Our results confirm the association of PRDM2 variants with Parkinson's disease susceptibility, especially in women.

We studied the association of three personality traits related to neuroticism with the subsequent risk of Parkinson's disease (PD) using a historical cohort study. We included 7,216 subjects who resided within the 120-mile radius centered in Rochester, MN, at the time they completed the Minnesota Multiphasic Personality Inventory (MMPI) for research at the Mayo Clinic from 1962 to 1965. We considered three MMPI personality scales (pessimistic, anxious, and depressive traits). A total of 6,822 subjects (94.5%) were followed over four decades either actively or passively. During follow-up, 227 subjects developed parkinsonism (156 developed PD). An anxious personality was associated with an increased risk of PD [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.16-2.27]. A pessimistic personality trait was also associated with an increased risk of PD but only in men (HR = 1.92; 95% CI = 1.20-3.07). By contrast, a depressive trait was not associated with increased risk. Analyses combining scores from the three personality scales into a composite neuroticism score showed an association of neuroticism with PD (HR = 1.54; 95% CI = 1.10-2.16). The association with neuroticism remained significant even when the MMPI was administered early in life (ages 20-39 years). By contrast, none of the three personality traits was associated with the risk of non-PD types of parkinsonism grouped together. Our long-term historical cohort study suggests that an anxious personality trait may predict an increased risk of PD developing many years later.

We investigated the association of Bell's palsy (BP) with the subsequent risk of Parkinson's disease (PD) using a case-control study design. We matched 196 incident cases of PD in Olmsted County, MN, to 196 general population controls with same age (+/-1 year) and sex, and we reviewed the complete medical records of cases and controls in a medical records-linkage system to detect BP. Six of the 196 patients with PD and none of the 196 controls were diagnosed with BP before PD (exact binomial probability, P = 0.02). The median age at occurrence of BP was 49.5 years (range, 15-84 years) and the median time between BP and the onset of PD was 27.5 years (range, 2-54 years). The findings were similar using a standardized incidence ratio (SIR) approach, but were not statistically significant. This initial association between BP and PD awaits replication.

An inverse association between coffee and Parkinson's disease (PD) has been reported. However, it remains uncertain why some but not all coffee drinkers are less susceptible to PD. We considered the possibility of a pharmaco-genetic effect. In our study, we included 1,208 subjects (446 case-unaffected sibling pairs and 158 case-unrelated control pairs) recruited from an ongoing study of the molecular epidemiology of PD in the Upper Midwest (USA). We collected information on lifetime coffee drinking and we studied two genes: ADORA2A, which encodes the major receptor activity of caffeine in the brain (variants rs5751876 and rs3032740), and CYP1A2, which encodes the major rate-limiting step of caffeine metabolism (variants rs35694136 and rs762551). We did not observe significant associations of coffee drinking or of the genetic variants with PD susceptibility, either independently or jointly, in the sample overall and in most strata. Our study neither supports the hypothesis that coffee protects against PD nor provides evidence for a pharmacogenetic effect.

We investigated the association between number of children and Parkinson's disease (PD) in two independent studies. In a case-control study, we identified all subjects who developed PD in Olmsted County, MN, from 1976 through 1995, and matched them individually by age (+/-1 year) and sex to population controls (193 cases and 193 controls). The replication study was a population-based cohort study of 6,341 subjects from Rotterdam, the Netherlands (2,610 men). In the Olmsted County study, men who fathered at least one child had an increased risk of PD (unadjusted OR, 2.7; 95% CI, 1.2-6.1; P = 0.02), and the risk increased with increasing number of children. The findings in women were not significant. In the Rotterdam Study, the risk of PD increased significantly with increasing number of children in men (test for linear trend, unadjusted; P = 0.04), but not in women. The findings from both studies remained consistent in direction but reduced in magnitude of the association, and lost significance after simultaneous adjustment for education, cigarette smoking, alcohol consumption, and coffee consumption. The independent replication in two distinct populations and using different epidemiologic study designs may suggest a link between the number of children and PD restricted to men.

In an inception cohort of 196 Olmsted County, Minnesota, residents with Parkinson's disease (PD) first recognized in 1976 to 1995, we tested whether the increased risk of bone fractures is associated with concomitant dementia. Using the data resources of the Rochester Epidemiology Project, information about PD, dementia, other clinical risk factors for fracture and fracture events was obtained from review of complete inpatient and outpatient medical records spanning each subject's residence in the community. Compared to an equal number of age- and sex-matched non-PD referent subjects from the community, PD patients were at a 2.2-fold increased risk of fractures generally and a 3.2-fold greater risk of hip fractures specifically. Adjusting for age, the independent predictors of overall fracture risk in the PD subjects included female sex (hazard ratio [HR] 1.6; 95% confidence interval [CI], 1.1-2.3), dementia (HR, 1.6; 95% CI, 1.1-2.4) and chronic depression, which was associated with a reduced risk (HR, 0.4; 95% CI, 0.2-0.8). Hip fractures were predicted by dementia (HR, 2.2; 95% CI, 1.2-4.1). The increased fracture risk in patients with PD is not entirely explained by concomitant dementia, and additional study is needed to determine the relative contributions to fracture risk of falls versus bone loss in these patients.

The burden of comorbidity in Parkinson's disease (PD) remains unclear. All Olmsted County, Minnesota, residents with incident PD in 1976-1995 (n = 197) plus one age- and sex-matched non-PD referent subject per case were followed for all clinical diagnoses from 5 years before through 15 years after index (i.e., year of PD onset for each case and same year for the referent subject). Both members of a case-referent pair were censored at death or emigration of either member to ensure equivalent follow-up. Cases and referent subjects were compared for summary comorbidity (Charlson index) and for the likelihood of having one or more diagnoses within each International Classification of Diseases chapter/subchapter. Before index, the groups were similar for all comparisons. After index, cases had a higher likelihood of diagnoses within the chapters "Mental Disorders" and "Diseases of the Genitourinary System," and within the subchapters "Organic Psychotic Conditions," "Other Psychoses," "Neurotic/Personality/Other Nonpsychotic Disorders," "Hereditary/Degenerative Diseases of Central Nervous System," "Symptoms," "Other Diseases of Digestive System," "Other Diseases of Urinary System," "Diseases of Veins/Lymphatics/Other Circulatory System Diseases," "Fractures of Lower Limb," "Other Diseases of Skin/Subcutaneous Tissue," "Osteopathies/Chrondropathies/Acquired Musculoskeletal Deformities," and "Pneumonia and Influenza." The excess morbidity and mortality observed for persons with PD are consistent with recognized PD sequelae.

We investigated the risk of cancer after the diagnosis of Parkinson's disease (PD) through a historical cohort study. We used the medical records-linkage system of the Rochester Epidemiology Project to identify all incident cases of PD in Olmsted County, Minnesota from 1976 through 1995. Patients with PD were matched by age (+/- 1 year) and gender to referent subjects from the same population. For 196 patients and 185 referent subjects, we ascertained the incidence of cancer through medical records abstraction between the date of diagnosis (or index date) and death, loss to follow-up, or end of study. The risk of cancer was higher among patients than in referent subjects (relative risk [RR] = 1.64; 95% confidence interval [CI] = 1.15-2.35; P = 0.007). The RR did not change noticeably after adjustment for smoking. The increased risk was significant for nonmelanoma skin cancer (RR = 1.76; 95% CI = 1.07-2.89; P = 0.03), but not for other more severe types of cancer; therefore, we cannot exclude the occurrence of a surveillance bias. Among PD patients, there was no relation between the risk of cancer and the cumulative dose of levodopa received or the use of other PD medications.

In one cross-sectional study of a community in northern Manhattan, women with essential tremor (ET) were more likely to have head tremor than were men. In that study, patients were seen at one point in time, rather than followed longitudinally. Head tremor often develops after arm tremor, and its appearance in patients with ET may therefore be a function of duration of follow-up. In a second epidemiological study utilizing the Rochester Epidemiology Project, in which ET subjects were followed from disease diagnosis to death, we determined whether there was an association between female gender and head tremor. We utilized the records-linkage system of the Rochester Epidemiology Project to identify ET cases. Records were reviewed and clinical data abstracted by a neurologist specializing in movement disorders. A second neurologist reviewed a subsample of records. There were 107 ET cases (69 women, 38 men) followed for 10.1 +/- 9.1 years from ET diagnosis to death. Head tremor was present in 37 (53.6%) women and 5 (13.2%) men (odds ratio [OR] = 7.6, 95% confidence interval [CI] = 2.7-21.9, P < 0.001). In a multivariate linear regression analysis, women remained at high risk for head tremor (OR = 6.5, 95% CI = 2.2-19.0, P = 0.001) independent of disease duration. We found in this longitudinal epidemiological study that women with ET were six times more likely to develop head tremor over the course of their illness than were men. The reason for the association between gender and head tremor, which has now been demonstrated in several studies, is not known, but it could reflect gender differences in the distribution of disease pathology within the brain.

We report on an evaluation of coding variants within the parkin gene to assess their frequency in a North American clinical series of 313 Parkinson's disease (PD) cases and 192 unrelated controls. We hypothesized that the carrier frequency of parkin coding mutations, exon deletions, or duplications may be greater in PD cases. However, point mutations and exonic deletions/duplications, reported previously as pathogenic in homozygous or compound heterozygous individuals, occurred in both cases and controls with similar frequencies (3.8% in cases, 3.1% in controls). Furthermore, only stratified subanalyses detected any genetic association between the V380L common coding polymorphism and PD. We discuss the implication of parkin mutations for Parkinson's disease from this population perspective.

We correlated the clinical features with pathological findings in an autopsy series of cases of incident parkinsonism. We used the medical records-linkage system of the Rochester Epidemiology Project to identify all incident cases of parkinsonism in Olmsted County, MN, for the years 1976 to 1990. Medical histories were abstracted in a standardized manner. Included in this study were those incident cases who died and underwent autopsy. Brain sections were studied with routine histology and special stainings. A neuropathologist blinded to any clinical information assigned cases to neuropathological categories. We found 364 incident cases of parkinsonism of which 235 were deceased at the time of this study; there were 39 autopsied brains available for analysis (17% of deceased cases). Of the 16 patients diagnosed pathologically with Lewy body disease, documentation indicated that 8 had an early dementia, 3 had prominent dysautonomia, and 2 had prominent ataxia. Of the 7 patients diagnosed pathologically with progressive supranuclear palsy, 4 had no documentation of supranuclear gaze palsy, and 3 had no documentation of early falls. Of the 3 patients diagnosed pathologically with multiple system atrophy, none had prominent ataxia or dysautonomia documented. Of the 5 patients with vascular disease at pathology, none had been given the clinical diagnosis of vascular parkinsonism. Of the 8 cases given the clinical diagnosis of drug-induced parkinsonism, 6 were found to have basal ganglia pathology. The autopsied cases in this study were not representative of all patients with parkinsonism, because atypical cases are more likely to come to autopsy than typical ones. Despite this selection bias, the retrospective data collection, and the small sample size, we made several observations that illustrate the difficulty in achieving an accurate antemortem diagnosis of parkinsonism.

We investigated the association of Parkinson's disease (PD) with two estrogen receptor gene polymorphisms. In a sample of 319 unrelated PD cases and 196 control subjects including both men and women, we observed no association of PD with the estrogen receptor genotypes derived from XbaI and PvuII digests. Analyses restricted to women or to cases and controls of European origin yielded similar findings. Further analyses stratified by age at examination or by family history did not show associations. While exogenous and endogenous estrogen may modify the risk of PD in women, the two estrogen receptor gene polymorphisms considered here do not seem to contribute to PD susceptibility.

We studied the association of Parkinson's disease (PD) with type of menopause (natural or surgical), age at menopause, and postmenopausal estrogen replacement therapy using a case-control design. We used the medical records-linkage system of the Rochester Epidemiology Project to identify 72 women who developed PD in Olmsted County, MN, during the twenty years 1976-1995. Each incident case was matched by age (+/- 1 year) to a general population control subject. We collected exposure data through review of the complete medical records of cases and control subjects in the system. PD cases had undergone hysterectomy (with or without unilateral oophorectomy) significantly more often than control subjects (odds ratio [OR] = 3.36; 95% confidence interval [CI] = 1.05-10.77). In addition, PD cases had experienced early menopause (< or = 46 years) more commonly than control subjects (OR = 2.18; 95% CI = 0.88-5.39). Finally, PD cases had used estrogens orally or parenterally for at least 6 months after menopause less frequently (8%) than control subjects (14%; OR = 0.47; 95% CI = 0.12-1.85). However, the findings for early menopause and estrogen replacement therapy were not statistically significant. Despite the limited sample size of this exploratory study, we hypothesize that there is an increased risk of PD in conditions causing an early reduction in endogenous estrogen. This hypothesis needs to be confirmed in a larger study.

We investigated the association of Parkinson's disease (PD) with two genes encoding liver-detoxifying enzymes, debrisoquine 4-hydroxylase (CYP2D6) and N-acetyltransferase 2 (NAT2), and with one gene related to Alzheimer's disease, apolipoprotein E (APOE). In a sample of 139 unrelated PD cases and 113 control subjects, the NAT2 M3 allele was associated with PD (odds ratio = 7.9; 95% confidence interval = 1.7-36.3). Case-control analyses for CYP2D6, APOE, and NAT2 M1 or M2 did not show a significant association. However, the age at onset of PD was significantly earlier in cases with the APOE epsilon2/epsilon3 genotype than in cases with the epsilon3/epsilon3 genotype.

We studied the association between preceding psychiatric disorders and Parkinson's disease (PD) using a case-control design. We used the medical records-linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, Minnesota, during the years 1976-1995. Each case was matched by age (+/-1 yr) and sex to a general population control. We reviewed the complete medical records of cases and control subjects to detect preceding psychiatric disorders. The frequency of psychiatric disorders was higher in cases than in control subjects; the odds ratio was 2.2 for anxiety disorders (95% confidence interval [95% CI] = 1.4-3.4; p = 0.0003), 1.9 for depressive disorders (95% CI = 1.1-3.2; p = 0.02), and 2.4 for both anxiety disorders and depressive disorders occurring in the same individual (95% CI = 1.2-4.8; p = 0.02). When we restricted analyses to disorders present 5 years or more before the onset of motor symptoms of PD, the association with depressive disorders lost statistical significance. However, the association with anxiety disorders remained significant for disorders present 5, 10, or 20 years before onset of motor symptoms. Our results suggest that anxiety disorders and depressive disorders are associated with PD and that the causative process or the risk factors underlying PD are present many years before the appearance of motor symptoms.

Single-photon emission computed tomography (SPECT) imaging with the dopamine transporter ligand, [123I] beta-CIT (2beta-carboxymethoxy-3beta-[4-iodophenyl] tropane), has been proposed as a means of measuring Parkinson's disease (PD) progression. To be useful in this role, however, [123I] beta-CIT imaging should not be influenced by the medications used to treat PD, including the dopamine agonist drugs such as pergolide. We assessed the effect of adjunctive pergolide administration on [123I] beta-CIT uptake in 12 patients with PD, who were being treated with levodopa, initiating pergolide therapy for motor fluctuations. Patients underwent [123I] beta-CIT imaging at baseline, subsequently while on pergolide therapy (6 weeks), and again 4 weeks after pergolide wash-out. Uptake in the striatum was averaged for the two sides and expressed as (striatum - occipital)/occipital, with similar calculations for putamen and caudate. Consistent with PD, the patients' mean striatal and putamen uptake ratios at baseline were significantly less (p

Nine patients with advanced levodopa-responsive Parkinson's disease were enrolled in a double-blind, placebo-controlled crossover trial of intranasal apomorphine as rescue therapy for parkinsonian off-states. Patients were assigned in random order to each of four possible combinations of apomorphine, trimethobenzamide antiemetic, and their matched placebos and received detailed in-office motor scoring during each of the four study periods. Patients also completed diaries describing the effectiveness of the nasal spray for reversing off-states. A statistically significant reduction in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score was seen following active apomorphine during in-office evaluation visits but not following placebo nasal spray. Patient diaries revealed that active apomorphine had a latency to onset of 11 minutes and a duration of 50 minutes. Significant nausea from apomorphine spray was seen in only one patient whereas nasal irritation was disabling in three and mild in two. We conclude that intranasal apomorphine is an effective rescue agent for parkinsonian off-states although nasal irritation is a limiting factor.

Using unpublished data from five completed prevalence surveys of Parkinson's disease (PD), we investigated case ascertainment uncertainties that potentially have a direct effect on prevalence. These uncertainties arise from the choice of diagnostic criteria, the choice of screening method, and the amount of information lost because of nonresponse. The surveys were conducted in Argentina, India, China, Italy, and the Netherlands. Our analyses consisted of simple comparisons of prevalence results, positive predictive values (a screening measure), and nonresponse percentages. We found that (a) prevalence comparisons between surveys have diminished value if the surveys used different diagnostic criteria for PD; (b) screening performance may be affected adversely if symptom questions are answered by one family member for the entire family living together rather than by each family member individually; and (c) nonresponse from refusal or unavailability does not necessarily lead to bias, but special caution may be appropriate with prevalence results pertaining to elderly women.

We report the first family with adult onset cervical dystonia in which monozygotic twins and multiple family members are affected. In this family, the disease exhibits an autosomal dominant inheritance pattern, and all affected members have only cervical dystonia. Five members have definite cervical dystonia, and five others have possible cervical dystonia. Although identical genotypically, the twins demonstrate some phenotypic variation. Despite long follow-up, no family members have shown progression from focal to generalized dystonia. This family may prove valuable in identifying a gene locus for cervical dystonia and hence determine whether a single gene locus exists for hereditable focal dystonia and generalized dystonia.

In three survivors of central pontine myelinolysis, dystonia (in two patients) and rest tremor (in one) were sequelae. The onset of these movements occurred 3 weeks to 5 months after the initial presentation with central pontine myelinolysis. Magnetic resonance imaging revealed basal ganglia lesions suggestive of extra-pontine myelinolysis in all three patients. We propose that the movement disorders seen in our cases are clinical correlates of extra-pontine myelinolysis.

Tyrosine hydroxylase (TH) is a theoretical candidate gene determining susceptibility to Parkinson's disease (PD), and an association between one allele of a polymorphism at the TH locus and sporadic PD has been reported. We investigated TH polymorphism in 44 patients with sporadic PD, 48 patients with familial PD and 89 of their unaffected relatives, and 50 control subjects. No evidence of allelic association was detected in either familial or sporadic PD, and linkage analysis excluded the TH locus, or a closely linked gene, as a major determinant of familial PD.