Community-based genetic study of Parkinson's disease in Estonia.

OBJECTIVE: To examine the genetic variability of Estonian Parkinson's disease (PD) patients using an ongoing epidemiological study in combination with a genetic analysis. METHODS: This study was a community-based genetic screening study of 189 PD patients, and 158 age- and sex-matched controls screened for potential mutations in 9 PD genes using next-generation sequencing and multiplex ligation-dependent probe amplification method. Different clinimetric scales and questionnaires were used to examine PD patients and assess clinical characteristics and severity of the disease. RESULTS: The overall frequency of pathogenic PD-causing variants was 1.1% (2/189), and any rare genetic variant was present in 21.2% (40/189) of the patients and in 8.2% (13/158) of the controls (P < .05). Variants of unknown significance accounted for 10.6% (20/189). Frequency of any GBA variant among PD patients was 10.1% (19/189) and in controls 3.8% (6/158). The frequency of any GBA variant in PD compared to controls was significantly higher (P = .035; OR 2.82; CI 95% 1.05-8.87). Burden of rare variants was not different between patients and controls. Also, a novel GBA pathogenic variant p.E10X was detected. CONCLUSION: Among different genetic variants identified in Estonian PD patients, GBA variants are the most common, while an overall pathogenic variant frequency was 1.1%.

Subacute administration of both methcathinone and manganese causes basal ganglia damage in mice resembling that in methcathinone abusers.

An irreversible extrapyramidal syndrome occurs in man after intravenous abuse of "homemade" methcathinone (ephedrone, Mcat) that is contaminated with manganese (Mn) and is accompanied by altered basal ganglia function. Both Mcat and Mn can cause alterations in nigrostriatal function but it remains unknown whether the effects of the 'homemade' drug seen in man are due to Mcat or to Mn or to a combination of both. To determine how toxicity occurs, we have investigated the effects of 4-week intraperitoneal administration of Mn (30 mg/kg t.i.d) and Mcat (100 mg/kg t.i.d.) given alone, on the nigrostriatal function in male C57BL6 mice. The effects were compared to those of the 'homemade' mixture which contained about 7 mg/kg of Mn and 100 mg/kg of Mcat. Motor function, nigral dopaminergic cell number and markers of pre- and postsynaptic dopaminergic neuronal integrity including SPECT analysis were assessed. All three treatments had similar effects on motor behavior and neuronal markers. All decreased motor activity and induced tyrosine hydroxylase positive cell loss in the substantia nigra. All reduced 123I-epidepride binding to D2 receptors in the striatum. Vesicular monoamine transporter 2 (VMAT2) binding was not altered by any drug treatment. However, Mcat treatment alone decreased levels of the dopamine transporter (DAT) and Mn alone reduced GAD immunoreactivity in the striatum. These data suggest that both Mcat and Mn alone could contribute to the neuronal damage caused by the 'homemade' mixture but that both produce additional changes that contribute to the extrapyramidal syndrome seen in man.

Relationship between the MDS-UPDRS and Quality of Life: A large multicenter study of 3206 patients.

BACKGROUND: The relationship between Health-Related Quality of Life (HRQoL) and MDS-UPDRS has not been fully studied so far. The aim of this study was to evaluate the relationship between all MDS-UPDRS components and HRQoL in a representative international cohort of PD patients. METHODS: We collected demographic and disease-related data as well as MDS-UPDRS and PDQ8 scales. Data were analyzed using correlations between PDQ8 and all MDS-UPDRS items, subsequently two hierarchical multiple regressions were performed, first between the scores of the MDS-UPDRS Parts and PDQ8 and second between individual items from those Parts demonstrating significant relationship to PDQ8 scores in the first regression. LASSO regression analyses were performed to evaluate the relationship between PDQ8 and all individual MDS-UPDRS items. RESULTS: A total of 3206 PD patients were included in the study. In the first regression analysis, PDQ8 was significantly related to MDS-UPDRS parts I and II, but not to III and IV. In the second regression model, significant contributions to PDQ8 were found for Part I items Fatigue, Pain, Depressed mood, Apathy; and Part II items Dressing, Doing hobbies, Freezing, Speech and Tremor. In the LASSO analysis, six Part I, seven Part II, three Part III and one Part IV items contributed to PDQ8 scores. The five items most significantly related to the model were Depressed mood, Dressing, Apathy, Pain and Fatigue. CONCLUSIONS: This is so far the largest study related to HRQoL issues in PD. Restrictions in activities of daily living and non-motor symptoms significantly contribute to HRQoL in PD.

Differences in MDS-UPDRS Scores Based on Hoehn and Yahr Stage and Disease Duration.

BACKGROUND: The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a newly developed tool to assess Parkinson's disease (PD). Changes in scores on the scale over the course of PD, including increasing disease duration and Hoehn and Yahr (HY) stages, have not been described. The objectives of this study were to analyze MDS-UPDRS scores on Parts I through IV and their differences based on HY stage and disease duration in a large cohort of patients with PD. METHODS: For this cross-sectional study, demographic data and MDS-UPDRS scores were collected, including HY stage. Subscores on MDS-UPDRS Parts I through IV were analyzed using 1-way analyses of variance for each HY stage and in 5-year increments of disease duration. Part III (motor assessment) scores were analyzed separately for on and off states. RESULTS: The mean age of the 3206 patients was 65.8 ± 10.6 years, 53.3% were men, the mean disease duration was 11.5 ± 4.6 years, and the median HY stage was 2 (range, 0-5); 2156 patients were examined in an on state and 987 were examined in an off state. Scores for all MDS-UPDRS parts increased significantly through HY stages 1 through 5, with an average increase of 3.8, 7.7, 14.6, and 2.0 points consecutively for parts I through IV, respectively. For the 5-year increments of disease duration, MDS-UPDRS subscores increased by an average of 1.6, 3.3, 4.2, and 1.4 points consecutively for parts I through IV, respectively. This increase was significant only during the first 15 years of disease for all 4 parts, including part III scores evaluated in both on and off states. CONCLUSIONS: MDS-UPDRS scores for all 4 parts increase significantly with every HY stage and also with 5-year increments of disease duration in the first 15 years of the disease.

Nonmotor Features in Parkinson's Disease: What Are the Most Important Associated Factors?

Introduction. The purpose of this study was to demonstrate the frequency and severity of nonmotor symptoms and their correlations with a wide range of demographic and clinical factors in a large cohort of patients with Parkinson's disease (PD). Methods. 268 PD patients were assessed using the validated Movement Disorders Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Beck Depression Inventory (BDI), Parkinson's Disease Questionnaire (PDQ-39), the Hoehn and Yahr scale (HY), the Schwab and England Activities of Daily Living (SE-ADL) Scale, and the Minimental State Examination (MMSE). Results. Nonmotor symptoms had a strong positive relationship with depression and lower quality of life. Also, age, duration and severity of PD, cognitive impairment, daily dose, and duration of levodopa treatment correlated with the burden of nonmotor symptoms. Patients with postural instability and gait disorder (PIGD) dominance or with the presence of motor complications had higher MDS-UPDRS Part I scores expressing the load of nonmotor features, compared to participants with other disease subtypes or without motor complications. Conclusions. Though the severity of individual nonmotor symptoms was generally rated by PD patients as "mild" or less, we found a significant cumulative effect of nonmotor symptoms on patients' mood, daily activities, and quality of life.

Health-related quality of life in Parkinson's disease: a cross-sectional study focusing on non-motor symptoms.

BACKGROUND: The objective of this study was to investigate factors affecting health-related quality of life (HRQoL) among Estonian persons with Parkinson's disease (PD). METHODS: 268 persons with PD were evaluated using: the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS); the Hoehn and Yahr scale (HY); the Schwab and England Activities of Daily Living scale (SE-ADL); the Beck Depression Inventory (BDI); the Mini Mental State Examination (MMSE); the Parkinson's Disease Questionnaire (PDQ-39). Additional questions on clinical and socio-demographic variables were asked during a semi-structured interview. Predictors of HRQoL were tested using multiple regression analysis. RESULTS: The main predictors of low HRQoL were depression and motor and non-motor aspects of daily living. 59.9 % of the variation in the PDQ-39 summary index (SI) score was explained by the predictive variables identified in this study. None of the socio-demographic variables (age, gender, urban/rural living, marital status, living alone/with others, education level) were significant predictors of HRQoL. Prevalence of non-motor Parkinson's symptoms were high (99.6 %); cognitive impairment, sleep and urinary problems were the most common. All non-motor symptoms correlated significantly with low HRQoL, except the features of impulse control disorders (ICDs). CONCLUSIONS: Depression and motor and non-motor daily living experiences were found to be significant and independent factors of low HRQoL in persons with PD. Depression was the strongest determinant of low HRQoL. Our results highlight the importance of recognition and management of non-motor symptoms, as these features had more impact on patients' HRQoL than clinically assessed motor symptoms.