Survival in Parkinson's disease. Relation with motor and non-motor features

BackgroundSurvival in patients with Parkinson's disease is reduced as compared to the general population. We aimed to identify motor and non-motor features that predict mortality in Parkinson's disease.MethodsA broad range of motor and non-motor features were assessed in a hospital-based cohort of 414 patients with Parkinson's disease, who underwent five annual follow-up examinations including vital status assessment. Multivariable Cox's proportional hazards regression analysis was used to evaluate the association between baseline characteristics and mortality risk. Stepwise regression with backward elimination was carried out to determine the best model to predict mortality in Parkinson's disease.ResultsAfter a mean follow-up period of 4.3 years, 49 (11.8%) patients had died. In the stepwise regression model, predictors of mortality in Parkinson's disease were higher age, male sex, cognitive impairment, higher postural instability gait disorder score, and the presence of psychotic symptoms.ConclusionsHigher age, male sex, cognitive impairment, higher postural instability gait disorder score, and the presence of psychotic symptoms are independent predictors of decreased survival in Parkinson's disease. Mortality in Parkinson's disease thus seems to be affected mainly by non-dopaminergic and non-motor features.     

Smoking and age-at-onset of both motor and non-motor symptoms in Parkinson's disease

IntroductionSeveral evidence suggest that smoking may decrease the risk of Parkinson's disease and is associated with an older age-at-onset of motor signs. The relation between smoking and age-at-onset of non-motor symptoms has never been analyzed. Objective of the study is to evaluate whether smoking habit and pack-years of smoking are associated with a delay of age-at-onset of motor signs, and of some non-motor symptoms.MethodsThe study population consisted of 262 consecutive parkinsonian patients. Information on relevant demographic/clinical data focused on motor signs, REM sleep behavior disorder, constipation, depression, and hyposmia. Patients were stratified according to smoking habit (ever-versus never-smoker) and number of pack-years of smoking was computed. Repeatability of data on age-at-onset was checked 6 months after the initial interview in a randomly recruited subsample.ResultsSmoking habit and number of pack-years smoked were associated with an older in age-at-onset of motor signs, REM sleep behavior disorder and depression. By contrast, smoking did not affect age-at-onset of hyposmia and constipation.Conclusioninformation from this study confirms that smoking may be associated with an older age-at-onset of motor signs, and that a similar effect can be observed on some non-motor symptoms like REM sleep behavior and depression.     

MRI biomarkers of motor and non-motor symptoms in Parkinson's disease

Parkinson's disease is a heterogeneous disorder with both motor and non-motor symptoms that contribute to functional impairment. To develop effective, disease modifying treatments for these symptoms, biomarkers are necessary to detect neuropathological changes early in the disease course and monitor changes over time. Advances in MRI scan sequences and analytical techniques present numerous promising metrics to detect changes within the nigrostriatal system, implicated in the cardinal motor symptoms of the disease, and detect broader dysfunction involved in the non-motor symptoms, such as cognitive impairment. There is emerging evidence that iron sensitive, neuromelanin sensitive, diffusion sensitive, and resting state functional magnetic imaging measures can capture changes within the nigrostriatal system. Iron, neuromelanin, and diffusion sensitive measures demonstrate high specificity and sensitivity in distinguishing Parkinson's disease relative to controls, with inconsistent results differentiating Parkinson's disease relative to atypical parkinsonian disorders. They may also serve as useful monitoring biomarkers, with each possibly detecting different aspects of the disease course (early nigrosome changes versus broader substantia nigra changes). Investigations of non-motor symptoms, such as cognitive impairment, require careful consideration of the nature of cognitive deficits to characterize regional and network specific impairment. While the early, executive dysfunction observed is consistent with nigrostriatal degeneration, the memory and visuospatial impairments, the harbingers of a dementia process reflect dopaminergic independent dysfunction involving broader regions of the brain.     

The significance of motor (A)symmetry in Parkinson's disease

This study was undertaken to evaluate whether the predominant motor distribution pattern (ie, symmetric or asymmetric) observed in patients with Parkinson's disease (PD) contributes independently to disease severity and progression. We further examine whether this pattern is stable over time, and whether a potential change in pattern affects the course of the disease. We used data from the longitudinal PROPARK study (N > 400) to examine the association of the predominant motor distribution pattern with motor, cognitive, depressive, psychotic, and autonomic symptoms, and with excessive daytime sleepiness. We found that a symmetrical distribution of motor features was associated with poorer performance on nearly all domains, but that this was entirely explained by confounding, in particular by higher age and longer disease duration. We also found that greater asymmetry was associated with younger age, younger age at onset, and shorter disease duration. We further observed a clear tendency to develop a more symmetric distribution pattern as the disease advanced. Conversion to a symmetric pattern was associated with more severe disease, but this conversion did not contribute independently to the less favorable disease course. With increasing age and disease duration comes a clear tendency to develop a more symmetric distribution of motor features in PD. Although this change in distribution pattern is associated with more severe disease as compared with nonconvertors, this pattern change did not contribute independently to the less favorable course. We discuss these findings in light of the evidence from the literature. © 2014 International Parkinson and Movement Disorder Society     

The association between non-motor symptoms in Parkinson's disease and age at onset

Objective

Age at onset is likely to be related to a wide range of problems in Parkinson's disease (PD), including cardinal motor features, motor complications and non-motor symptoms (NMS). This study investigated the effect of the age at onset on NMS.

Methods

Two hundred and thirty patients were examined and classified into one of three groups based on age at onset: early onset PD (EOPD) group (<45 years), middle-age onset group (45–64 years) and old-age onset group (≥65 years). The trends relating to NMS were compared across the three groups. The EOPD and old-age onset groups were separately studied to determine their association to the appearance of non-motor features using logistic regression analysis.

Results

There were upward trends in the occurrence of dribbling (P = 0.009; all P values are stated for trend), impaired taste/smelling (P = 0.016), constipation (P = 0.006), urinary urgency (P = 0.002), nocturia (P = 0.018), hallucinations (P = 0.016) and acting out during dreams (P = 0.011) with the increase of age at onset. Older age at onset is an independent risk factor for dementia (OR = 8.42, CI 3.16–22.44), dribbling (OR = 4.14, CI 1.93–8.87), impaired taste/smelling (OR = 2.23, CI 1.20–4.13), constipation (OR = 3.42, CI 1.88–6.24), incomplete bowel emptying (OR = 2.23, CI 1.19–4.20), urinary urgency (OR = 2.58 CI 1.46–4.57), nocturia (OR = 2.65, CI 1.49–4.71), hallucinations (OR = 5.32, CI 1.78–15.97), dizziness (OR = 3.03, CI 1.59–5.79), falling (OR = 3.60, CI 1.67–7.77), insomnia (OR = 2.29, CI 1.28–4.11), intense vivid dreaming (OR = 2.10, CI 1.21–3.66) and acting out during dreams (OR = 2.23, CI 1.24–4.01).

Conclusions

PD patients with different ages at onset present clinically different symptoms in terms of NMS. Old-age onset PD is characterized by more olfactory and sensory symptoms, autonomic symptoms, sleep disorders, dementia and psychosis compared to EOPD.     

Effects of socioeconomic status on mortality after Parkinson's disease: A nationwide population-based matched cohort study in Korean populations

IntroductionTo evaluate the mortality rate and impact of SES on mortality in PD using a nationwide cohort in Korea.MethodsWe selected patients diagnosed with PD (ICD-10 code: G20) and registration code for PD (V124) in the program for rare intractable diseases between 2004 and 2015. After that, atypical parkinsonism was excluded. A matched cohort of individuals without PD were enrolled by randomly matching patients by sex, age, and year of diagnosis to the PD group with a ratio of 1:9. Cox proportional hazard models were used to identify the effects of SES on mortality using Hazard Ratios and 95% confidence intervals.ResultsIn total, 26,570 participants were enrolled. The mortality rate was 30.37% in PD cohort and 16.69% in the comparison cohort. According to income level, PD patients in low-middle group revealed significantly decreased HRs of 0.704 (95% CI, 0.533–0.930) compared to those in the lowest group. The medical aid group showed an increased mortality rate (HR = 1.552, 95% CI, 1.191–2.021) compared to the national health insurance group. In the subgroup analyses, medical aid was associated with mortality only in PD with female (HR = 1.740, 95% CI, 1.242–2.438) or aged 60–79 years (HR = 1.434, 95% CI 1.005–2.045). There was no significant difference in mortality rate according to residential area in PD.ConclusionsIn Korea, individual level low SES including income level and insurance type were significantly associated with increased mortality, whereas regional level SES (residential area) was not related with mortality on PD.     

Motor and non-motor features of Parkinson's disease that predict persistent drug-induced Parkinsonism

BackgroundDrug-induced Parkinsonism is common, causes significant morbidity, and can be clinically indistinguishable from idiopathic Parkinson's disease. Additionally, drug-induced Parkinsonism may, in some cases, represent “unmasking” of incipient Parkinson's disease. Clinical features or tests that distinguish degenerative from pharmacologic Parkinsonism are needed.MethodsWe performed a retrospective case-control study of 97 drug-induced Parkinsonism subjects and 97 age-matched patients with Parkinson's disease. We compared the frequency of subjective motor and non-motor complaints, objective motor findings (Unified Parkinson's Disease Rating Scale Part III) and, where available, objective olfactory tests. We also performed a nested case-control study wherein we compared these same features between drug-induced Parkinsonism patients based on whether or not they recovered after changing the offending agent.ResultsNon-motor symptoms including constipation and sexual dysfunction were more common in Parkinson's disease than in drug-induced Parkinsonism. While total motor scores were similar between groups, Postural Instability-Gait Difficulty scores were also higher in Parkinson's disease. Features that were significantly different or showed a trend towards significance in both comparisons included subjective loss of facial expression, dream-enactment behavior, autonomic complaints and Postural Instability-Gait Difficulty scores. Hyposmia was more common in Parkinson's disease and was strongly predictive of persistent drug-induced Parkinsonism after therapy change (odds ratio 30.3, 95% confidence interval: 1.5–500, p = 0.03).ConclusionsA constellation of motor and non-motor features may differentiate unmasked Parkinson's disease from drug-induced Parkinsonism. In particular, olfactory testing may offer a simple and inexpensive method to help predict outcomes in drug-induced Parkinsonism and, potentially, identify a cohort of pre-motor Parkinson's disease.     

Prevalence of non motor features in a cohort of Parkinson's disease patients

Background

There is a lack of awareness among physicians of the considerable disability caused by non-motor symptoms (NMS) in PD. The aim of this work is to estimate the prevalence of NMS in a series of patients with Parkinson's disease (PD).

Materials and methods

We studied 112 patients with Parkinson's disease. Motor symptoms were scored on the Unified Parkinson's Disease Rating Scale (UPDRS) part III and the Hoehn and Yahr (HY) Scale. Other symptoms were quantified with the Non-Motor Symptom Questionnaire and Scale (NMSQuest and NMSS) as well as Minimental State Examination (MNSE).

Results

Analysis of the data from the NMSS showed that mood/cognition was the most commonly affected domain (prevalence rate = 87.5%), followed by sleep disturbance/fatigue second (78.6%). However, all other non-motor symptoms scored highly: gastrointestinal and urinary (76.8% for both), sexual dysfunction (73%), cardiovascular (70.5%) with significantly higher percentage in predominantly akinetic/rigid patients. Perceptual problems/hallucinations (9.9%) were infrequent in this population. Dementia was recorded in 22.3% of patients, most of them having a mild degree of dementia. UPDRS scores were correlated with total scores in both NMSQuest and NMSS.

Conclusions

Mood/cognition, sleep disorders, GIT, and sexual disorders were common non motor manifestations in this population of PD patients.     

Subcutaneous apomorphine and non-motor symptoms in Parkinson's disease

Non-motor symptoms (NMS) are now recognized to occur across all stages of Parkinson's disease (PD) and as a result there has been an increasing focus on their diagnosis, quantification and effective management. While in some subjects, NMS may be present before diagnosis, in advanced PD, NMS can contribute to hospitalization, severe disability and a shortened life expectancy. Strategies for continuous drug delivery have been reported to have a beneficial effect on NMS in PD and while the efficacy of apomorphine on motor function in PD has been confirmed in a number of studies, in addition to its possible anti-dyskinetic effect, a number of reports have also outlined the possible beneficial effect of apomorphine on NMS. This review sets out to examine the efficacy of apomorphine in non-motor aspects of PD, including its effect on neuropsychiatric and gastrointestinal symptoms, sleep (including restless legs syndrome), urinary dysfunction, pain and impulse control disorders. The analysis takes into consideration case reports, and open-label and comparative case–control studies published to date. Results of this review suggest that although data on the effect of apomorphine on NMS in PD patients are limited there is a strong suggestion of a beneficial effect that warrants further investigation in double-blind studies.     

Importance of motor vs. non-motor symptoms for health-related quality of life in early Parkinson's disease

BackgroundThe relative impact of motor- and non-motor symptoms on health-related quality of life in early Parkinson's disease is poorly documented.Methods188 patients with incident Parkinson's disease from a population-based study were examined at the time of diagnosis, before initiation of dopaminergic treatment, with follow-up of 166 patients three years later. Health-related quality of life was assessed by the 36-item Short-form Health Survey (SF-36). Motor and non-motor variables were derived from the Unified Parkinson's disease rating scale and other established scales.ResultsMultiple regression analyses showed that the non-motor symptoms strongest associated with reduced SF-36 scores at diagnosis and three years later were depression, fatigue and sensory complaints. The motor symptoms most related to impaired SF-36 scores were problems with gait and activities of daily living that cover personal needs. The variance of SF-36 mental summary scores was much better explained by non-motor vs. motor symptoms, both at baseline (R² = 0.384 vs. 0.095) and 3 years later (R² = 0.441 vs. 0.195). Also SF-36 physical summary scores were better explained by non-motor vs. motor symptoms with R² = 0.372 vs. 0.322 at baseline and R² = 0.468 vs. 0.315 after 3 years.ConclusionIn early PD, including the phase before dopaminergic treatment is initiated, non-motor symptoms are more important for reduced health-related quality of life than motor symptoms. Fatigue, depression, sensory complaints and gait disturbances emerge as the most relevant symptoms and should be given corresponding attention in the management of patients with early PD.     

Validation of a non-motor fluctuations questionnaire in Parkinson's disease

IntroductionNon-motor fluctuations (NMF) in Parkinson's disease (PD) remain poorly recognized but have a high impact on patients’ quality of life. The lack of assessment tools limits our understanding of NMF, compromising appropriate management. Our objective was to validate a hetero-questionnaire for NMF in PD patients at different stages of the disease: without treatment, without motor fluctuations, with motor fluctuations.MethodsWe included patients in 15 centers in France. Our questionnaire, NMF-Park, resulted from previous studies, allowing us to identify the more pertinent NMF for evaluation. Patients reported the presence (yes or no) of 22 selected NMF, and their link with dopaminergic medications. The assessment was repeated at one and two years to study the progression of NMF. We performed a metrological validation of our questionnaire.ResultsWe included 255 patients (42 without treatment, 88 without motor fluctuations and 125 with motor fluctuations). After metrological validation, three dimensions of NMF were found: dysautonomic; cognitive; psychiatric. The sensory/pain dimension described in the literature was not statistically confirmed by our study.DiscussionOur questionnaire was validated according to clinimetric standards, for different stages of PD. It was clinically coherent with three homogeneous dimensions. It highlighted a link between fatigue, visual accommodation disorder, and cognitive fluctuations; and the integration of sensory/pain fluctuations as part of dysautonomic fluctuations. It focused exclusively on NMF, which is interesting considering the described differences between non-motor and motor fluctuations.ConclusionOur study validated a hetero-questionnaire of diagnosis for NMF for different stages of PD.     

Characterizing motor and non-motor aspects of early-morning off periods in Parkinson's disease: An international multicenter study

IntroductionThe characteristic off periods that develop over time in subjects with Parkinson's disease (PD) on chronic levodopa therapy are usually considered to be motor complications but more recently the important contribution of non-motor off and non-motor fluctuations has also been acknowledged. Early-morning off (EMO) periods in PD patients are known to be a cause of significant disability, in addition to having a negative impact on quality of life. Yet EMOs are poorly defined, particularly in relation to non-motor symptoms (NMS).MethodsThis European, multicentre, observational study was undertaken to characterize the range and patterns of NMS that occur during EMO periods in a consecutive series of PD patients.ResultsThe results demonstrate that EMO periods are common and occur in 59.7% of subjects across all disease stages in line with other reports. However, importantly, in 88.0% of those, EMOs were found to be associated with NMS. The predominant NMS associated with EMO were urinary urgency, anxiety, dribbling of saliva, pain, low mood, limb paresthesia and dizziness. The patterns of dopaminergic treatment being taken by patients in this study suggested that a prolonged-release or continuous drug delivery strategy can alleviate some NMS associated with EMO.ConclusionsIn light of these findings it is suggested that greater awareness, recognition and appropriate treatment of EMO and NMS could improve the overall 24-h management of PD. An EMO-specific scale/questionnaire which captures both motor and NMS associated with EMO over the off time period is warranted.     

Risk of Parkinson's disease in patients with hypothyroidism: A nationwide population-based cohort study

IntroductionHypothyroidism has been implicated in many other disease conditions, including neurodegenerative diseases. Parkinson's disease (PD) is one of the most common neurodegenerative diseases. The purpose of this study was to investigate the risk of PD in patients with hypothyroidism.MethodsA total of 4725 patients with hypothyroidism and 4725 controls (without hypothyroidism) matched by age, gender, index year, and Charlson Comorbidity Index (CCI) score were enrolled between 2000 and 2012. Patients were then followed until the end of 2013 using Taiwan's National Health Insurance Research Database, at which time participants who developed PD were identified. Cox regression analysis was used to calculate the hazard ratio (HR) with a 95% confidence interval (CI) of PD incidence rate between patients with hypothyroidism and unaffected controls.ResultsPatients with hypothyroidism had a significantly increased risk of PD compared with unaffected controls (2.00 versus 1.10 per 1,000 person-years, HR: 1.77, 95% CI: 1.13–2.76) after adjusting for age, gender, CCI score, physical comorbidities (brain injury, cerebrovascular disease, hypertension, dyslipidemia, and diabetes mellitus), and duration of levothyroxine use. Also, older age (≥50 vs. <50 - HR:14.83), higher CCI score (CCI score 1–2 & ≥3 vs. 0 - HR: 1.66–1.74), and specific comorbidities (brain injury (HR: 1.78) and cerebrovascular disease (HR: 2.46)) significantly increased the risk of PD after adjusting for the variables mentioned above.ConclusionsPatients with hypothyroidism have an increased risk of developing PD. Other prospective studies that take into account genetic vulnerability and environmental exposures are warranted to confirm their relationship.     

The effect of Origanum majorana tea on motor and non-motor symptoms in patients with idiopathic Parkinson's disease: A randomized controlled pilot study

AimsThe effect of Origanum majorana tea consumption on motor and non-motor symptoms was investigated in patients with idiopathic Parkinson's disease, measured by validated tools.MethodsSixty patients with idiopathic Parkinson's disease and under conventional medication were enrolled voluntarily in the study. All participants were randomized on double-blind to placebo or Origanum majorana. Clinical assessment with validated tools (UPDRSIII, NMSS, and BDI) was done before Origanum majorana or placebo consumption (Day 0) and at the end of the experiment (Day 30).ResultsThe treatment groups were similar at baseline on demographic and clinical variables. During the course of study, nine participants withdrew for reasons of noncompliance and inability to follow-up. Fifty-one participants completed the study. Upon completion of 30 days of treatment, Origanum majorana tea consumption did not decrease the UPDRSIII score ([UPDRSIII^] D0 = 18.76 ± 8.58, D30 = 16.52 ± 7.96, p = 0.069) at the p value was 0.07. However, a statistically significant improvement was noted in NMSS and BDI scores (p < 0.0001 and p < 0.0001, respectively). Assessment of the UPDRSIII, NMSS and BDI scores of the patients did not reflect any improvement with placebo. No side effect was detected during the study^.ConclusionThese findings show improvement of depressive and non-motor signs in patients with Parkinson's disease in the group that consumed Origanum majorana tea in combination with conventional therapy. Improvement of motor signs may need an extended treatment period. However, more research with a large number of participants and lasting longer than 1 month is needed to argue these findings.