Angus Macleod

Monoamine oxidase type B inhibitors in early Parkinson's disease: meta-analysis of 17 randomised trials involving 3525 patients

Abstract Objective To quantify more reliably the benefits and risks of monoamine oxidase type B inhibitors (MAOBIs) in early Parkinsons 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 Parkinsons 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 Parkinsons 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.

Mortality in Parkinson's disease: A systematic review and meta-analysis

This study was undertaken to perform a systematic review and meta‐analysis of studies of mortality in Parkinsons 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. Parkinsons 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.

Motor complications in an incident Parkinson’s disease cohort

Levodopa treatment in Parkinsons disease (PD) causes motor fluctuations and dyskinesias, but few data describe their development or severity in unselected incident cohorts.

Medium-term prognosis of an incident cohort of parkinsonian patients compared to controls

Background The best data on prognosis comes from population-based incident cohorts but few such cohorts exist for Parkinsons disease and atypical parkinsonism. Methods The PINE study is a prospective follow-up study of an incident cohort of people with degenerative or vascular parkinsonism and age-sex matched controls. Participants have annual follow-up from diagnosis until death with review of primary/secondary care records and linkage to the UK death register. Data are collected on survival, disability (dependency on others for activities of daily living) and institutionalization. Research criteria are used to guide the clinical diagnosis, which is updated annually. We compared all-cause mortality, disability and institutionalization in patients (subdivided by diagnosis) and controls, adjusted for important confounders. Results 323 incident parkinsonian patients (199 Parkinsons disease, 124 atypical parkinsonism, mean age at diagnosis 75yrs) and 262 controls (mean age 75yrs) had 1349 and 1334 person-years follow-up respectively (maximum follow-up 10 years). All outcomes were worse in parkinsonian patients than controls, especially in atypical parkinsonism (adjusted mortality hazards ratios Parkinsons disease 2.49, 95%CI 1.72–3.58, atypical parkinsonism, 6.85, 95%CI 4.78–9.81). Median survival times for Parkinsons disease and atypical parkinsonism were 7.8 and 2.7 years respectively but were very age-dependent. At three years the rates of death or dependency were controls 21%, Parkinsons disease 46%, atypical parkinsonism 96% whilst overall institutionalization rates were 5%, 15% and 55% respectively. Conclusion The prognosis of Parkinsons disease and atypical parkinsonism in this unselected incident cohort was significantly worse than previously reported. This has important implications for patient management.

Predictors of functional dependency in Parkinson’s disease

Functional dependency, the need for help in basic activities of daily living, is an important patient‐oriented outcome. We aimed to describe the development of dependency in Parkinsons disease (PD) and identify independent prognostic factors for this outcome.

Early weight loss in parkinsonism predicts poor outcomes: Evidence from an incident cohort study.

Objective: To compare weight change over time in patients with Parkinson disease (PD), those with atypical parkinsonism, and matched controls; to identify baseline factors that influence weight loss in parkinsonism; and to examine whether it predicts poor outcome. Methods: We analyzed data from the Parkinsonism Incidence in North-East Scotland (PINE) study, an incident, population-based prospective cohort of parkinsonian patients and age- and sex-matched controls with annual follow-up. Mixed-model analysis described weight change in patients with PD, those with atypical parkinsonism, and controls. Baseline determinants of sustained clinically significant weight loss (>5% loss from baseline) and associations between early sustained weight loss and death, dementia, and dependency in parkinsonism were studied with Cox regression. Results: A total of 515 participants (240 controls, 187 with PD, 88 with atypical parkinsonism) were followed up for a median of 5 years. At diagnosis, atypical parkinsonian patients had lower body weights than patients with PD, who were lighter than controls. Patients with PD lost weight more rapidly than controls, and weight loss was most rapid in atypical parkinsonism. After multivariable adjustment for potential confounders, only age was independently associated with sustained clinically significant weight loss (hazard ratio [HR] for 10-year age increase 1.83, 95% confidence interval [CI] 1.44–2.32). Weight loss occurring within 1 year of diagnosis was independently associated with increased risk of dependency (HR 2.11, 95% CI 1.00–4.42), dementia (HR 3.23, 95% CI 1.40–7.44), and death (HR 2.23, 95% CI 1.46–3.41). Conclusion: Weight loss occurs in early parkinsonism and is greater in atypical parkinsonism than in PD. Early weight loss in parkinsonism has prognostic significance, and targeted dietary interventions to prevent it may improve long-term outcomes.

CIGARETTE SMOKING, ALCOHOL CONSUMPTION AND CAFFEINE INTAKE IN PD AND PD SUBTYPES: A COMMUNITY–BASED, INCIDENT COHORT WITH MATCHED CONTROLS

Background Previous studies have demonstrated negative associations between cigarette smoking, alcohol consumption and caffeine intake and Parkinsons disease (PD), but most data come from unrepresentative cohorts (1). One previous study suggested different associations with these exposures in different PD phenotypes (2). There are no data describing change in these exposures after diagnosis: a differential change between cases and controls would introduce bias to prevalence-based case-control studies. Methods We recruited a community-based, inception cohort of PD and matched controls and gathered data about previous duration and intensity of cigarette smoking and alcohol and caffeine intake with face-to-face questionnaires. We calculated odds ratios and adjusted odds ratios using logistic regression analysis to examine the associations between these exposures and PD and the tremor-dominant and postural instability and gait difficulty (PIGD) subtypes. We also assessed the change in exposures after recruitment in patients and controls with a linear mixed model. Results 201 patients with PD and 249 controls were analysed. Moderate and high cumulative levels of smoking, OR 0.42 (0.24–0.74) and 0.48 (0.28–0.82) respectively; high alcohol intake, OR 0.27 (0.13–0.56); and moderate and high caffeine consumption, ORs 0.48 (0.28–0.82) and 0.39 (0.22–0.68) respectively; were statistically significant negative associations with PD. There were statistically significant inverse trends between rising levels of consumption for each exposure and PD (P<0.001 for smoking, P=0.003 for alcohol and P<0.001 for caffeine). A similar pattern of associations with these exposures was seen in the PIGD and tremor-dominant patients as in the whole PD group. Smoking and alcohol consumption declined after diagnosis, but not at different rates between patients and controls. Conclusions Our study therefore provides further evidence for dose-dependent negative associations between these exposures and PD in a truly-representative inception cohort. We found no evidence of different associations with the tremor-dominant and PIGD PD subtypes. The lack of a differential reduction in exposure is important for interpretation of prevalent studies.

Age-related selection bias in Parkinson's disease research: are we recruiting the right participants?

OBJECTIVE To describe, and explore heterogeneity in, age at onset/diagnosis in Parkinsons disease (PD) and compare mean age at onset/diagnosis in incidence studies with that in general PD research studies. METHODS We systematically reviewed studies of PD incidence. We meta-analysed mean age at onset/diagnosis and age-stratum-specific incidence rates. We compared age-specific incidence rates in screening studies in the elderly with whole-population studies. We collated mean ages at onset/diagnosis in clinical studies of PD in five journals July-December 2016. RESULTS In 17 studies reporting sufficient data to pool, mean age at onset/diagnosis was 69.6 years (95% CI 68.2-71.1), but heterogeneity was high (I2 = 96%). In ten of these studies reporting age at diagnosis specifically, the pooled mean age at diagnosis was slightly higher (71.6 [95% CI 70.6-72.6]) with lower, but still high, heterogeneity (I2 = 84%). In twelve whole-population studies reporting age-specific incidence rates, these peaked in age 70-79 (pooled incidence rate per 100,000 = 93.8 [95% CI 80.3-107.4]). Heterogeneity increased with each increase in age stratum (0% in youngest to 88% in oldest age stratum). Pooled age-specific incidence rates in five population-based screening studies of older age groups were several-fold higher than in whole-population studies. The mean of the reported mean ages at onset/diagnosis in recently published research studies was 60.8 (SD 5.6). CONCLUSION The mean age of onset/diagnosis PD is about 70, although this may be an underestimate due to under-diagnosis in the elderly. Many published studies use age-unrepresentative subjects: the effect of this selection bias deserves further study.

Development and validation of prognostic survival models in newly diagnosed Parkinson’s disease

The objective of this study was to develop valid prognostic models to predict mortality, dependency, and “death or dependency” for use in newly diagnosed Parkinsons disease (PD).

Association of glucocerebrosidase polymorphisms and mutations with dementia in incident Parkinson's disease

Both polymorphisms and mutations in glucocerebrosidase (GBA) may influence the development of dementia in patients with Parkinsons disease.