Treatment in early Parkinson's disease: the Norwegian ParkWest study.

OBJECTIVES: There are limited data on treatment effect in early and drug-naïve Parkinson's disease (PD) outside of clinical trials. We sought to review the treatment effects on motor symptoms in early, unselected PD patients. METHODS: We included 183 drug-naïve patients from a longitudinal cohort (The Norwegian ParkWest study). At the time of diagnosis, motor symptoms were assessed and rated. Treatment was unrestricted, aimed at treating each patient optimally. Patients were reassessed after 12 months, and then grouped according to treatment: No dopaminergic treatment (NDT), dopamine agonists (DA) or levodopa. All strategies could be combined with monoamine oxidase B inhibitors. RESULTS: In general, the chosen treatment was coherent with current practice. During follow-up, patients given NDT (n = 40) had unaltered clinical motor symptoms, as opposed to improvement in the DA- and levodopa-treated patients (n = 140). The overall improvement in these two groups was fairly similar, but axial symptoms did not improve in levodopa-treated patients as opposed to the younger DA-treated patients. CONCLUSIONS: Twelve months after the diagnosis, motor symptoms in approximately one-fifth of PD patients remained clinically stable. Tremor, bradykinesia and rigidity improved in the dopaminergic-treated patients. Axial symptoms were more treatment resistant, and the different symptomatic effects found between treatment strategies may be age related.

Parkinson disease: associated disorders in the Norwegian population based incident ParkWest study.

Parkinson's disease (PD) may be associated with a number of different diseases due to common risk factors or overlapping symptomatology. We have asked for possible associated disorders in a Norwegian population of incident PD patients and controls, the Norwegian ParkWest study. The patients were diagnosed according to the Gelb criteria. 212 incident PD patients and 175 age and gender matched controls were included. PD patients and controls were asked for information on earlier medical history and family history. PD patients had a higher frequency of self-reported symptoms of depression (p = 0.003) and anxiety disorders (p = 0.004) before baseline. They tended to have a higher frequency of diabetes (p = 0.09) and had a higher frequency of prior stroke or TIA (p = 0.004).

Autonomic symptoms and dopaminergic treatment in de novo Parkinson's disease.

OBJECTIVES: Autonomic symptoms are present in early stages of Parkinson's disease (PD), but evidence on how they are influenced by dopaminergic treatment remains unclear. The aim of this study was to investigate the impact of dopaminergic treatment on autonomic symptoms in early PD in a population-based cohort. METHODS: A total of 171 drug-naive patients with PD were investigated at diagnosis and 12 months later. Orthostatic blood pressure was measured, and autonomic symptoms were assessed by a preliminary version of the Movement Disorders Society-sponsored new version of the Unified Parkinson's Disease Rating Scale (range 0-4). RESULTS: In the 82% using dopaminergic treatment after 1 year, constipation and orthostatic blood pressure drop increased. There was a tendency towards increased orthostatic dizziness and urinary dysfunction. Dysphagia scores were reduced, and this was associated with higher levodopa-equivalent daily dose. CONCLUSIONS: Dopaminergic treatment during the first year after initiation seems to have only a minor impact on autonomic symptoms in early PD. It may increase constipation and orthostatic dizziness, while dysphagia can improve. Autonomic symptoms remained mild after 1 year of dopaminergic treatment.

Differential effect of environmental risk factors on postural instability gait difficulties and tremor dominant Parkinson's disease.

Both environmental and genetic factors contribute to the development of Parkinson's disease (PD). We have examined environmental risk factors in a Norwegian population of incident PD patients and controls, the Norwegian ParkWest study. All five neurological wards in the study area of Western Norway participated in the study. A 4-step diagnostic procedure was used to establish a representative cohort of patients with incident PD at a high level of diagnostic accuracy. 212 incident PD patients and 175 age- and gender-matched controls were included. PD patients and controls were asked for information on occupation, education, exposure to pesticides, tobacco, alcohol, and caffeine. Agricultural work was associated with a higher risk of PD (OR 1.75 (1.03-3.0) P = 0.009). There were no differences as to other occupations. Smoking (OR 0.63 (0.42-0.95) P = 0.016) and alcohol use (OR 0.55 P = 0.008) were associated with a lower risk for PD. Interestingly, this inverse association was only seen in postural instability gait difficulties (PIGD) PD (P = 0.046 for smoking, P = 0.07 for alcohol consumption), and not in tremor dominant (TD) PD which was similar to controls. Consumption of coffee was lower in PD patients (3.3 ± 1.8 cups per day vs. 3.8 ± 2.0 in controls P = 0.02). In the regression model including intake of alcohol, coffee, and smoke, only coffee (P = 0.007) and alcohol intake (P = 0.021) remained significant whereas smoking was no longer significant. Thus, it seems as though only coffee intake reduces the risk of PD in general while associations to alcohol and smoking differ between PIGD and TD-PD patients.

The role of APOE alleles in incident Parkinson's disease. The Norwegian ParkWest Study.

OBJECTIVES: Apolipoprotein E (APOE) gene alleles have been associated with various neurodegenerative disorders. However, there have been conflicting reports on associations between APOE alleles and Parkinson's disease (PD) and age at onset in PD. There exist no data on APOE alleles in an unselected cohort of patients with incident PD. PATIENTS AND METHODS: To determine the role of APOE alleles in PD and age of onset in PD at time of diagnosis, 203 patients with incident PD and 187 healthy control subjects from Western and Southern Norway were investigated according to their APOE allele status. RESULTS: No association was observed between any APOE alleles and susceptibility to PD or age at onset in PD. CONCLUSION: In our cohort of unselected, incident PD patients APOE alleles do not seem to play a role for development of PD. Prospective, long-term follow-up may still reveal associations between APOE alleles and clinical and neuropsychological progression in PD.

Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease.

OBJECTIVE: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of Parkinson disease (PD). Several dominantly inherited pathogenic substitutions have been identified in different domains of the Lrrk2 protein. Herein, we characterize the clinical and genetic features associated with Lrrk2 p.R1441C. METHODS: We identified 33 affected and 15 unaffected LRRK2 c.4321C>T (p.R1441C) mutation carriers through an international consortium originating from three continents. The age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis. RESULTS: The clinical presentation of Lrrk2 p.R1441C carriers was similar to sporadic PD and Lrrk2 p.G2019S parkinsonism. The mean age at onset for parkinsonism was 60 years, range 30-79 years; fewer than 20% of the patients had symptoms before the age 50 years, while by 75 years >90% of them had developed symptoms. Haplotype analysis suggests four independent founders for the p.R1441C mutation. CONCLUSIONS: The distribution in age at onset and clinical features in Lrrk2 p.R1441C patients are similar to idiopathic and Lrrk2 p.G2019S parkinsonism. Several independent founders of the p.R1441C substitution suggest this site is prone to recurrent mutagenesis.

alpha-Synuclein and Parkinson disease susceptibility.

BACKGROUND: Mutations in the alpha-synuclein (SNCA) gene have been shown to be responsible for a rare familial form of Parkinson disease (PD). Furthermore, polymorphic variants in multiple regions of the gene have been associated with susceptibility to idiopathic PD in different populations. OBJECTIVE: To evaluate and to confirm the role of SNCA variants in PD pathogenesis. METHODS: We included 667 subjects (397 cases with idiopathic PD and 270 healthy, ethnically matched controls) of Northern Central and Southeastern European origin. We analyzed genotypes at 14 markers spanning the SNCA locus and its major haplotype blocks and conducted a haplotype analysis for four promoter markers including the microsatellite marker Rep1. RESULTS: The three single nucleotide polymorphisms (SNPs) of the promoter region (rs2583988, rs2619364, rs2619363) and a SNP in the 3'UTR (rs356165) of the SNCA gene showed the greatest evidence for an association with PD (p or= 0.74, r (2) >or= 0.29). The promoter haplotype "261-T-G-T" (Rep1-rs2583988-rs2619364-rs2619363) was associated with disease (p = 0.032). The most significant association with PD was generated by excluding Rep1 (p = 0.008). This association remained significant when analyzing the Serbian patients separately and was of borderline significance for the German patients. CONCLUSIONS: Our findings confirm that genetic variability within the SNCA locus is associated with susceptibility to idiopathic Parkinson disease (PD). We found evidence for disease association with single nucleotide polymorphisms at both the 5' and the 3' end of the gene with pairwise linkage disequilibrium between them. The association was independent of the Rep1 status, and one major SNCA promoter haplotype class seems to be associated with PD susceptibility.

LRRK2 and Parkinson's disease in Norway.

OBJECTIVES: Mutations in the LRRK2 gene have been associated with both familial and sporadic late-onset Parkinson's disease. A large number of mutations in this gene have been identified; however, for many of these variants, the pathogenicity and relative frequency are unknown. Herein, we investigate the frequency of a number of recently identified LRRK2 mutations in Norway. METHODS: We genotyped eight putatively pathogenic LRRK2 mutations (R793M, R1067Q, I1371V, IVS31+3 A>G, M1869T, R1941H, T2356I and G2385R) in a series of 433 patients with Parkinson's disease and 587 controls from Norway. An intronic polymorphism previously reported to be associated with disease susceptibility was also examined (rs10506151). RESULTS: The Lrrk2 R793M substitution was found in two healthy individuals. No other LRRK2 mutations were identified in the Norwegian population, and furthermore no association was observed between rs10506151 and Parkinson's disease (P = 0.41). CONCLUSIONS: LRRK2 mutations other than the Lrrk2 G2019S mutation are rare in Norway. Our results indicate that the Lrrk2 R793M substitution is most likely a rare polymorphism.

The influence of cerebrovascular risk factors on incident dementia in patients with Parkinson's disease.

OBJECTIVE: To examine if risk factors for cerebrovascular disease would increase the risk for dementia in patients with Parkinson's disease (PD). METHODS: Non-demented patients were recruited from an epidemiological study of PD in the county of Rogaland, Norway. PD and dementia were diagnosed according to strict diagnostic criteria. Established cerebrovascular risk factors were recorded at baseline, and their influence on incident dementia was assessed 4 years later using logistic regression analysis. RESULTS: A total of 171 non-demented PD patients constituted the at-risk population. Seventy-two (55%) had at least one cerebrovascular risk factor. A total of 130 subjects (96% of survivors) completed the follow-up examination. Forty-three (33%) new cases of dementia were found. Twenty-five of the 72 (35%) patients with and 18 of the 58 (31%) subjects without any risk factor developed dementia (ns). A significant association with dementia was found for a diagnosis of heart failure in the univariate analyses. However, in the logistic regression analysis none of the cerebrovascular risk factors were significantly associated with incident dementia. CONCLUSIONS: In this large and representative cohort of patients with PD cerebrovascular risk factors were not associated with incident dementia, indicating that the disease-related degenerative brain changes are the main causes of dementia in PD.