A B S T R AC T :This study was undertaken to perform a systematic review and meta-analysis of studies of mortality in Parkinson's disease (PD) and to investigate which factors were associated with mortality. We conducted comprehensive searches of studies reporting a ratio of mortality in PD versus controls, descriptive survival measures, or factors predicting survival; assessed study quality; and extracted relevant data. Descriptive analysis, meta-analysis, and meta-regression were performed as appropriate. Eighty-eight studies were included in the review with variable study methods and quality. Almost all studies reported increased mortality in PD (vs. controls), with mortality ratios ranging from 0.9 to 3.8, with major between-study heterogeneity. Inception cohorts were more consistent with a pooled mortality ratio of approximately 1.5. Inception cohorts, measurements at longer follow-up duration, and older study recruitment year were associated with lower mortality ratios, but these findings were not robust in sensitivity analyses. Within studies, mortality ratios increased over time. No robust evidence was found that mortality has decreased after the introduction of levodopa (L-dopa). On average, PD survival reduced by approximately 5% every year of follow-up, although there was significant heterogeneity. In post-mortem studies, mean duration until death ranged from 6.9 to 14.3 years. Increasing age and presence of dementia were most commonly associated with increased mortality. Parkinson's disease is associated with increased mortality, but major heterogeneity is seen in estimates of mortality, which is probably explained by variable methodology and patient selection. Individual-patient-data meta-analysis of high-quality inception studies with long-term follow-up would be the optimal way to investigate the factors influencing mortality.

Objective To quantify more reliably the benefits and risks of monoamine oxidase type B inhibitors (MAOBIs) in early Parkinson's disease. Data sources Searches of the Cochrane Library, Medline, Embase, PubMed, and Web of Science for years 1966-2003, plus major journals in the field, abstract books, and proceedings of meetings, for randomised trials comparing MAOBIs with placebo or levodopa. Data extraction Available data on mortality, motor complications, side effects, treatment compliance, and clinician rated disability (for example, unified Parkinson's disease rating scale) were extracted from 17 trials and combined using standard meta-analytic methods. Results No significant difference in mortality existed between patients on MAOBIs and control patients (odds ratio 1.13, 95% confidence interval 0.94 to 1.34; P = 0.2). Patients randomised to MAOBIs had significantly better total scores, motor scores, and activities of daily living scores on the unified Parkinson's disease rating scale at three months compared with patients taking placebo; they were also less likely to need additional levodopa (0.57, 0.48 to 0.67; P < 0.00001) or to develop motor fluctuations (0.75, 0.59 to 0.95; P = 0.02). No difference existed between the two groups in the incidence of side effects or withdrawal of patients. Conclusions MAOBIs reduce disability, the need for levodopa, and the incidence of motor fluctuations, without substantial side effects or increased mortality. However, because few trials have compared MAOBIs with other antiparkinsonian drugs, uncertainty remains about the relative benefits and risks of MAOBIs. Further large, long term comparative trials that include patient rated quality of life measures are needed.

word count: 249Article word count: 3412 Running title: Motor complications in PD Conflicts of Interest:We declare we have no conflicts of interest. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Page 1 of 52 European Journal of Neurology MethodsWe gathered demographic, clinical, treatment, smoking, caffeine, and alcohol data from 183 people with PD from the PINE study, a community-based, incident cohort. With Kaplan-Meier survival analysis and Cox regression modelling we assessed the development, and severity, of dyskinesias and motor fluctuations and which factors independently influenced their onset. ResultsAfter mean follow-up of 59 months, 39 patients (21.3%) developed motor fluctuations and 52 .51]) were independently associated with dyskinesias. In exploratory analyses, moderate caffeine exposure was associated with fewer motor fluctuations, longer symptom duration with more dyskinesias, and tremor at diagnosis with higher rates of both complications. ConclusionsIn this community-based incident PD cohort, severe dyskinesias were rare. Cumulative levodopa dose was the strongest predictor of both dyskinesias and motor fluctuations. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1-3 A previous review of studies of motor complications estimated that the risk of developing motor fluctuations and dyskinesias were both about 40% after levodopa treatment for 4-6 years. 4 However, most previous studies have been based on unrepresentative samples, with attendant selection biases, such as cohorts from specialist clinics or clinical trials in which younger patients with fewer co-morbidities than the general PD population are often over-represented. 5,6 Only two representative, community-based incidence studies have examined the development of motor complications over time, both of which were small, only reported dyskinesias 7,8 and one was retrospective. Page 2 of 52 European Journal of Neurology 8Several risk factors for the development of dyskinesias have been identified, including: younger age at diagnosis, female sex, higher levodopa dose, longer duration of levodopa therapy, and lower body weight, [8][9][10][11][12][13][14] but most data come from non-incident or hospital-based studies. By contrast, few predictors of motor fluctuations have been identified but dose and duration on levodopa therapy are most commonly reported. 12,[15][16][17][18] In addition, nicotine, caffeine and alcohol may protect against the development of PD 19 and there is some inconsistent clinical trial data to suggest caffeine and another adenosine A2A antagonist, may reduce dyskinesia risk. 20,21We therefore aimed to (i) describe the development of dyskinesias and motor flu...

GBA variants are of great clinical relevance for the development of dementia in Parkinson's disease, especially due to the relatively higher frequency of these alleles compared with other risk alleles.

Background Common genetic variance in apolipoprotein E (APOE), β‐glucocerebrosidase (GBA), microtubule‐associated protein tau (MAPT), and α‐synuclein (SNCA) has been linked to cognitive decline in Parkinson's disease (PD), although studies have yielded mixed results. Objectives To evaluate the effect of genetic variants in APOE, GBA, MAPT, and SNCA on cognitive decline and risk of dementia in a pooled analysis of six longitudinal, non‐selective, population‐based cohorts of newly diagnosed PD patients. Methods 1002 PD patients, followed for up to 10 years (median 7.2 years), were genotyped for at least one of APOE‐ε4, GBA mutations, MAPT H1/H2, or SNCA rs356219. We evaluated the effect of genotype on the rate of cognitive decline (Mini‐Mental State Examanation, MMSE) using linear mixed models and the development of dementia (diagnosed using standardized criteria) using Cox regression; multiple comparisons were accounted for using Benjamini−Hochberg corrections. Results Carriers of APOE‐ε4 (n = 281, 29.7%) and GBA mutations (n = 100, 10.3%) had faster cognitive decline and were at higher risk of progression to dementia (APOE‐ε4, HR 3.57, P < 0.001; GBA mutations, HR 1.76, P = 0.001) than non‐carriers. The risk of cognitive decline and dementia (HR 5.19, P < 0.001) was further increased in carriers of both risk genotypes (n = 23). No significant effects were observed for MAPT or SNCA rs356219. Conclusions GBA and APOE genotyping could improve the prediction of cognitive decline in PD, which is important to inform the clinical trial selection and potentially to enable personalized treatment © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society