Predictors of stress resilience in Parkinson's disease and associations with symptom progression.

People with Parkinson's disease (PD) are sensitive to effects of long-term stress, but might differ in stress resilience, i.e. the ability to maintain mental health despite adversity. It is unclear whether stress resilience in PD is predominantly determined by dopamine deficiency, psychosocial factors, or both. In PD animal models, chronic stressors accelerate disease progression, but evidence in humans is lacking. Our objectives were to (1) distinguish stressor-reactive from resilient PD patients, (2) identify resilience factors, and (3) compare symptom progression between stressor-reactive and resilient patients. We conducted a longitudinal survey in Personalized Parkinson Project participants (N = 350 PD). We used the COVID-19 pandemic as a model of a stressor, aligned in time for the entire cohort. COVID-19-related stressors, perceived stress, and PD symptoms were assessed at 11 timepoints (April-October 2020). Both pre-COVID and in-COVID clinical assessments were available. We quantified stressor-reactivity as the residual between actual and predicted perceived stress relative to COVID-19-related stressors, and modeled trajectories of stressor-reactivity across timepoints. We explored pre-COVID predictors of 6-month average stressor-reactivity, and tested whether stressor-reactivity was prospectively associated with one-year clinical progression rates. Latent class trajectory models distinguished patients with high (N = 123) or low (N = 227) stressor-reactivity. Pre-existing anxiety, rumination and non-motor symptom severity predicted high stressor-reactivity (risk factors), whereas quality of life, social support, positive appraisal style and cognitive abilities predicted low stressor-reactivity (resilience factors). PD-specific factors, e.g. disease duration, motor severity, and levodopa use, did not predict stressor-reactivity. The COVID-19 pandemic did not accelerate disease progression, but worsened depressive symptoms in stressor-reactive PD patients.

Trajectories of depression and anxiety during the COVID-19 pandemic in a population-based sample of middle-aged and older adults.

The COVID-19 pandemic and the related governmental restrictions have greatly impacted the lives of people worldwide and have been suggested to negatively impact mental health. We describe the trajectories of depressive and anxiety symptoms during the pandemic and their determinants in a large population-based sample of middle-aged and older adults. From April to June 2020, participants of the Rotterdam Study were asked to complete questionnaires including questions on depressive symptoms (Center of Epidemiological Studies Depression Scale, 10 item version) and anxiety symptoms (Hospital Anxiety and Depression Scale, anxiety subscale). We compared depressive and anxiety symptom scores to those before the pandemic and described its trajectories during the pandemic by demographic variables, chronic disease status and pre-pandemic clinically relevant depressive or anxiety symptoms. In total, 6241 participants responded to the questionnaires (mean age [standard deviation] 70.1 years [11.6]; 58% women). Participants more often reported clinically relevant depressive symptoms during than before the pandemic (19% vs. 12%, P < .001), which was similar for clinically relevant anxiety symptoms (17% vs. 12%, P < .001). During the pandemic, depressive symptoms persisted over time while anxiety symptoms improved. Depressive and anxiety symptoms were more common among women, persons living alone, with chronic diseases and with pre-pandemic clinically relevant symptoms, although the trajectories of these symptoms over time were broadly similar for the subgroups. Together, these results suggest that it is important to be aware of long-term depressive symptoms following the COVID-19 pandemic in the general population.

Risk factors, neuroimaging correlates and prognosis of the motoric cognitive risk syndrome: A population-based comparison with mild cognitive impairment.

BACKGROUND AND PURPOSE: This study was undertaken to compare risk factors, neuroimaging characteristics and prognosis between two clinical prodromes of dementia, namely, the motoric cognitive risk syndrome (MCRS) and mild cognitive impairment (MCI). METHODS: Between 2009 and 2015, dementia-free participants of the population-based Rotterdam Study were classified with a dementia prodrome if they had subjective cognitive complaints and scored >1 SD below the population mean of gait speed (MCRS) or >1.5 SD below the population mean of cognitive test scores (MCI). Using multinomial logistic regression models, we determined cross-sectional associations of risk factors and structural neuroimaging markers with MCRS and MCI, followed by subdistribution hazard models, to determine risk of incident dementia until 2016. RESULTS: Of 3025 included participants (mean age = 70.4 years, 54.7% women), 231 had MCRS (7.6%), 132 had MCI (4.4%), and 62 (2.0%) fulfilled criteria for both. Although many risk factors were shared, a higher body mass index predisposed to MCRS, whereas male sex and hypercholesterolemia were associated with MCI only. Gray matter volumes, hippocampal volumes, white matter hyperintensities, and structural white matter integrity were worse in both MCRS and MCI. During a mean follow-up of 3.9 years, 71 individuals developed dementia and 200 died. Five-year cumulative risk of dementia was 7.0% (2.5%-11.5%) for individuals with MCRS, versus 13.3% (5.8%-20.8%) with MCI and only 2.3% (1.5%-3.1%) in unaffected individuals. CONCLUSIONS: MCRS is associated with imaging markers of neurodegeneration and risk of dementia, even in the absence of MCI, highlighting the potential of motor function assessment in early risk stratification for dementia.

Healthy lifestyle in older adults and life expectancy with and without heart failure.

Several lifestyle factors have been linked to risk for heart failure (HF) and premature mortality. The aim of this study was to estimate the impact of a healthy lifestyle on life expectancy with and without HF among men and women from a general population. This study was performed among 6113 participants (mean age 65.8 ± 9.7 years; 58.9% women) from the Rotterdam Study, a large prospective population-based cohort study. A continuous lifestyle score was created based on five lifestyle factors: smoking status, alcohol consumption, diet quality, physical activity and weight status (assessed 1995-2008). The lifestyle score was categorized into three levels: unhealthy (reference), intermediate and healthy. Gompertz regression and multistate life tables were used to estimate the effects of lifestyle on life expectancy with and without HF in men and women separately at ages 45, 65 and 85 years (follow-up until 2016). During an average follow-up of 11.3 years, 699 incident HF events and 2146 deaths occurred. At the age of 45 years, men in the healthy lifestyle category had a 4.4 (95% CI: 4.1-4.7) years longer total life expectancy than men in the unhealthy lifestyle category, and a 4.8 (95% CI: 4.4-5.1) years longer life expectancy free of HF. Among women, the difference in total life-expectancy at the age of 45 years was 3.4 (95% CI: 3.2-3.5) years and was 3.4 (95% CI: 3.3-3.6) years longer for life expectancy without HF. This effect persisted also at older ages. An overall healthy lifestyle can have a positive impact on total life expectancy and life expectancy free of HF.

Peripheral Immune Cell Numbers and C-Reactive Protein in Parkinson's Disease: Results from a Population-Based Study.

BACKGROUND: The immune system is known to be involved in Parkinson's disease (PD) pathogenesis, but the temporal relationship between peripheral immune responses and PD remains unknown. OBJECTIVE: We determined the association between peripheral immune cell numbers, C-reactive protein (CRP), and prevalent as well as incident PD. METHODS: This study was embedded in the population-based setting of the Rotterdam Study. We repeatedly measured peripheral immune cell numbers (differential leukocyte count and platelet count, granulocyte-to-lymphocyte ratio [GLR], platelet-to-lymphocyte ratio [PLR], and adapted systemic immune-inflammation index [adapted SII]) and CRP between 1990 and 2016. Participants were continuously followed-up for PD until 2018. We estimated the association of the markers with prevalent and incident PD using logistic regression models and joint models, respectively. Models were adjusted for age, sex, smoking, body mass index, and medication use. Odds ratios (OR) and hazard ratios (HR) are shown per doubling of the marker. RESULTS: A total of 12,642 participants were included in this study. The mean age (standard deviation) was 65.1 (9.8) years and 57.5%were women. Participants with a higher lymphocyte count were less likely to have prevalent PD (adjusted OR: 0.34, 95%CI 0.17-0.68). Participants with a higher GLR, PLR, and adapted SII were more likely to have prevalent PD, but these effects were explained by the lymphocyte count. The peripheral immune cell numbers and CRP were not significantly associated with the risk of incident PD. CONCLUSION: We found participants with a higher lymphocyte count to be less likely to have prevalent PD, but we did not find an association between peripheral immune cell numbers nor CRP and the risk of incident PD.

Diet Quality and Risk of Parkinson's Disease: The Rotterdam Study.

The Mediterranean diet has been associated with the risk of Parkinson's disease (PD), but limited research has been performed on other dietary patterns. We studied the relationship between overall diet quality and PD risk in the general population. We included 9414 participants from the Rotterdam Study, a prospective population-based study in the Netherlands. Diet was defined using a Dutch diet quality score, a Mediterranean diet score and data-driven dietary patterns constructed with principal component analysis (PCA). During an average follow-up of 14.1 years, PD was diagnosed in 129 participants. We identified a 'Prudent', 'Unhealthy' and 'Traditional Dutch' pattern from the PCA. We found a possible association between the Mediterranean diet (Hazard ratio (HR) per standard deviation (SD) 0.89 (95% confidence interval (CI) 0.74-1.07)), the 'Prudent' pattern (HR per SD 0.81 (95% CI 0.61-1.08)) and the risk of PD. However, no associations with PD risk were found for the Dutch diet quality score (HR per SD 0.93 (95% CI 0.77-1.12)), the 'Unhealthy' pattern (HR per SD 1.05 (95% CI 0.85-1.29)) or the 'Traditional Dutch' pattern (HR per SD 0.90 (95% CI 0.69-1.17)). In conclusion, our results corroborate previous findings of a possible protective effect of the Mediterranean diet. Further research is warranted to study the effect of other dietary patterns on PD risk.

Probing the Pre-diagnostic Phase of Parkinson's Disease in Population-Based Studies.

Parkinson's disease covers a wide spectrum of symptoms, ranging from early non-motor symptoms to the characteristic bradykinesia, tremor and rigidity. Although differences in the symptomatology of Parkinson's disease are increasingly recognized, there is still a lack of insight into the heterogeneity of the pre-diagnostic phase of Parkinson's disease. In this perspective, we highlight three aspects regarding the role of population-based studies in providing new insights into the heterogeneity of pre-diagnostic Parkinson's disease. First we describe several specific advantages of population-based cohort studies, including the design which overcomes some common biases, the broad data collection and the high external validity. Second, we draw a parallel with the field of Alzheimer's disease to provide future directions to uncover the heterogeneity of pre-diagnostic Parkinson's disease. Finally, we anticipate on the emergence of prevention and disease-modification trials and the potential role of population-based studies herein. In the coming years, bridging gaps between study designs will be essential to make vital advances in elucidating the heterogeneity of pre-diagnostic Parkinson's disease.

Long-term trajectories of decline in cognition and daily functioning before and after stroke.

OBJECTIVE: Although knowledge on poststroke cognitive and functional decline is increasing, little is known about the possible decline of these functions before stroke. We determined the long-term trajectories of cognition and daily functioning before and after stroke. METHODS: Between 1990 and 2016, we repeatedly assessed cognition (Mini-Mental State Examination (MMSE), 15-Word Learning, Letter-Digit Substitution, Stroop, Verbal Fluency, Purdue Pegboard) and basic and instrumental activities of daily living (BADL and IADL) in 14 712 participants within the population-based Rotterdam Study. Incident stroke was assessed through continuous monitoring of medical records until 2018. We matched participants with incident stroke to stroke-free participants (1:3) based on sex and birth year. Trajectories of cognition and daily functioning of patients who had a stroke 10 years before and 10 years after stroke and the corresponding trajectories of stroke-free individuals were constructed using adjusted linear mixed effects models. RESULTS: During a mean follow-up of 12.5±6.8 years, a total of 1662 participants suffered a first-ever stroke. Patients who had a stroke deviated from stroke-free controls up to 10 years before stroke diagnosis in cognition and daily functioning. Significant deviations before stroke were seen in scores of MMSE (6.4 years), Stroop (5.7 years), Purdue Pegboard (3.8 years) and BADL and IADL (2.2 and 3.0 years, respectively). CONCLUSION: Patients who had a stroke have steeper declines in cognition and daily functioning up to 10 years before their first-ever stroke compared with stroke-free individuals. Our findings suggest that accumulating intracerebral pathology already has a clinical impact before stroke.

Consultation Recording: What Is the Added Value for Patients Aged 50 Years and Over? A Systematic Review.

This systematic review aimed to provide medical professionals with insight into beneficial and harmful effects of consultation recording for patients aged 50 years and over. This insight could enable medical professionals to decide on whether or not to promote consultation recording in their practice. The systematic literature search was performed in six databases; additional relevant articles were sought using the snowball method. Studies were included that investigated the value of consultation recording for patients aged 50 years and over. The selected studies were analyzed on affective cognitive outcomes, behavioral outcomes, and health outcomes. Twenty-five studies of both qualitative and quantitative design were included. Consultation recordings mainly improved patient satisfaction, recall, fulfillment of information needs, and decision-making. Both positive and negative effects were reported on anxiety. The recordings did not distinctly affect functional outcomes or quality of life. In conclusion, consultation recording positively influenced patients' affective cognitive and behavioral outcomes, and the negative effects of consultation recording were minor. Because of the positive effects of consultation replay, we recommend that doctors promote consultation recording among their patients of 50 years and over. However, more studies are necessary among older patients because this patient population is underrepresented in the current literature.

Orthostatic Hypotension: A Prodromal Marker of Parkinson's Disease?

BACKGROUND: Orthostatic hypotension is common in patients with Parkinson's disease (PD). However, it remains unknown whether orthostatic hypotension is a marker of prodromal PD or more advanced disease. The objectives of this study were to assess whether orthostatic hypotension is a prodromal marker of PD in the general population. METHODS: This study was embedded in the Rotterdam Study, a large prospective population-based cohort in the Netherlands. We measured orthostatic hypotension in 6910 participants. First, we determined the relation between prevalent PD and orthostatic hypotension using logistic regression. Second, we followed PD-free participants for the occurrence of PD until 2016 and studied the association between orthostatic hypotension and the risk of PD using Cox proportional hazards models. All models were adjusted for age and sex. RESULTS: At baseline, the mean age ± standard deviation of the study population was 69.0 ± 8.8 years, and 59.1% were women. Orthostatic hypotension was present in 1245 participants (19.8%), and 62 participants (1.0%) had PD at the time of orthostatic hypotension measurement. Participants with PD were significantly more likely to have orthostatic hypotension (odds ratio, 1.88; 95% confidence interval, 1.09-3.24). During a median (interquartile range) follow-up of 16.1 years (8.5-22.7 years), 122 participants were diagnosed with incident PD. Orthostatic hypotension at baseline was not associated with an increased risk of PD (hazard ratio, 0.97; 95% confidence interval, 0.59-1.58). CONCLUSIONS: Our study suggests that orthostatic hypotension is common in patients with PD, but that orthostatic hypotension is not associated with an increased risk of PD and thus is not a prodromal marker of PD in the general population. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Ethical Considerations in Screening for Rapid Eye Movement Sleep Behavior Disorder in the General Population.

Clinical studies have shown that up to 90% of patients with idiopathic rapid eye movement sleep behavior disorder (RBD) will eventually be diagnosed with a clinical α-synucleinopathy. Because of this high conversion rate, screening for RBD is often performed to identify eligible participants for studies aimed at elucidating the prodromal phase of α-synucleinopathies. However, screening for RBD, especially in the general population, raises many ethical dilemmas. In light of the existing ethical literature and our experience in establishing a screening approach for RBD in the Rotterdam Study, we discuss ethical dilemmas when screening for RBD in population-based studies. We conclude that informing study participants about the reason for invitation and the possible trajectory that lies ahead when participating is essential. However, participants should not be troubled unnecessarily by giving them detailed information about possible diagnoses or associated disease risks. © 2020 International Parkinson and Movement Disorder Society.

Life expectancy of parkinsonism patients in the general population.

INTRODUCTION: Detailed data on the life expectancy of patients with parkinsonism from the general population are largely lacking. This study aimed to determine the absolute life expectancy of patients newly-diagnosed with parkinsonism. METHODS: This study was part of the Rotterdam Study, an ongoing, population-based cohort study in the Netherlands. We included 12,789 participants of 50 years and older, free of parkinsonism. Patients diagnosed with parkinsonism were matched to controls on sex, birth year, dementia status, cancer status, and coronary heart disease status. We used Gompertz regression and lifetables to estimate the remaining life expectancy per year of age. RESULTS: The mean age of our study population was 65.0 (SD 9.7) years and 57.6% were women. During an average follow-up of 12 years, 297 participants were diagnosed with parkinsonism. The mean age at parkinsonism diagnosis was 78.6 (SD 8.1) years. Once diagnosed with parkinsonism, the life expectancy was lower than matched controls across a wide age range. At 65 years, the life expectancy of patients with parkinsonism was reduced with 6.7 [95% CI: 2.4;10.7] years compared to controls. At 85, the difference in life expectancy was 1.2 [95% CI: -2.2;4.5] years compared to controls. CONCLUSION: Patients diagnosed with parkinsonism have a reduced life expectancy compared to their peers in the general population. The absolute life expectancy is mainly reduced if parkinsonism is diagnosed before the age of 70.

Quantitative Gait Impairments in Patients With Stroke or Transient Ischemic Attack: A Population-Based Approach.

BACKGROUND AND PURPOSE: Gait is a complex process involving various cortical and subcortical brain regions. An acute stroke or transient ischemic attack (TIA) may disrupt white and gray matter integrity and, therefore, affect gait in patients without evident neurological signs. We determined whether patients with stroke and TIA experience subtle changes in global gait and several independent gait domains. METHODS: In the population-based Rotterdam Study, 4456 participants (median age, 65 years; 55% women) underwent detailed quantitative gait assessment (GAITRite) between 2009 and 2016. We summarized 30 gait parameters into a global gait score and 7 mutually independent gait domains. First, we assessed the association between prior stroke or TIA and global and domain-specific gait using linear regression models adjusted for age, sex, vascular risk factors, and cognition. Subsequently, we repeated the analysis stratified by the presence of different neurological symptoms in a subgroup of participants with ischemic stroke after study entry. RESULTS: Compared with participants without prior stroke, patients with stroke had a worse global gait (SD, -0.49 [95% CI, -0.64 to -0.34]), especially in the gait domains Pace, Phases, and Turning. The detrimental effect of stroke on gait was amplified in participants with worse cognition. No gait differences were found between participants with and without prior TIA. Ischemic stroke patients without lower limb weakness, loss of coordination, or visuospatial problems still had a worse gait compared with participants without stroke. Stratification by different stroke symptoms showed that different gait domains were affected in each group. CONCLUSIONS: Prior stroke without neurological signs that affect gait is still associated with gait difficulties compared with individuals without stroke. Our study suggests that stroke not only has a direct impact on gait through neurological impairments but also includes an indirect effect possibly through disruption of gray and white matter integrity and accelerated neurodegeneration.

The Possible Impact of Aortic Stiffness on Quality of Late Life: An Exploratory Study.

PURPOSE: Aortic stiffness (AS) is associated with cardiovascular events and all-cause mortality in the older population. AS might also influence the health-related quality of life (HRQOL) as a result of the negative effects of AS on cognitive and physical morbidity. We aimed to investigate the possible association between AS and HRQOL in people aged 75 years and over. PATIENTS AND METHODS: This cross-sectional study was part of the SCOPE study, an international multicenter cohort observational study. The indicators for AS were aortic pulse wave velocity (aPWV) and central pulse pressure (cPP). HRQOL was assessed using the EQ-5D index and the EQ-5D visual analog scale (VAS). ANCOVA and multivariate regression models were used to investigate possible associations. RESULTS: We included 280 Dutch participants of the SCOPE study. Median age was 79 years (IQR 76-83) and 42.1% were women. Participants reporting any problem on the EQ-5D index (n=214) had higher values of aPWV (12.6 vs 12.2 m/s, p = 0.024) than participants not experiencing any problem (n=66) and comparable values of cPP (44.4 vs 42.0 mmHg, p = 0.119). Estimates only slightly changed after adjustments. No association was found between indicators of AS and EQ-5D VAS. CONCLUSION: Aortic stiffness was associated with impaired quality of late life. This association could be mediated by subclinical vascular pathology affecting mental and physical health.

Unraveling the Association Between Gait and Mortality-One Step at a Time.

BACKGROUND: Slowness of walking is one of the very first signs of aging and is considered a marker for overall health that is strongly associated with mortality risk. In this study, we sought to disentangle the clinical drivers of the association between gait and mortality. METHODS: We included 4,490 participants of the Rotterdam Study who underwent a gait assessment between 2009 and 2015 and were followed-up for mortality until 2018. Gait was assessed with an electronic walkway and summarized into the domains Rhythm, Phases, Variability, Pace, Tandem, Turning, and Base of Support. Cox models adjusted for age, sex, and height were built and consecutively adjusted for six categories of health indicators (lifestyle, musculoskeletal, cardiovascular, pulmonary, metabolic, and neurological). Analyses were repeated in comorbidity-free individuals. RESULTS: Multiple gait domains were associated with an increased risk of mortality, including Pace (hazard ratio (HR) per SD worse gait, adjusted for other domains: 1.34 [1.19-1.50]), Rhythm (HR: 1.12 [1.02-1.23]) and Phases (HR: 1.12 [1.03-1.21]). Similarly, a 0.1 m/s decrease in gait speed was associated with a 1.21 (1.15-1.27) times higher hazard of mortality (HR fully adjusted: 1.14 [1.08-1.20]). In a comorbidity-free subsample, the HR per 0.1 m/s decrease in gait speed was 1.25 (1.09-1.44). Cause-specific mortality analyses revealed an association between gait speed and multiple causes of death. CONCLUSIONS: Several gait domains were associated with mortality risk, including Pace which primarily represents gait speed. The association between gait speed and mortality persisted after an extensive adjustment for covariates, suggesting that gait is a marker for overall health.