Motor Functioning and Parkinson’s Disease: Insights from the general population

Motor functioning strongly impacts the ability to maintain functional independence, in particular among the elderly. The detrimental influence of motor impairments on functional independence is painfully noticeable in individuals with neurodegenerative movement disorders, in particular in those with the most widely recognized among these disorders: Parkinson’s Disease (PD). As the number of elderly individuals is expected to grow due to ageing of populations worldwide, there is now a growing sense of urgency to unravel determinants of motor functioning and PD. This thesis provides novel insight on determinants of motor functioning and PD. Intriguingly, deterioration of motor functioning begins well before individuals are clinically diagnosed with PD, as a result of accumulating pathology in the brain, in the ‘prediagnostic’ phase of the disease. This thesis describes the identification of risk factors (both genetic and non-genetic) and prodromal features of PD, which adds to our understanding of the prediagnostic phase of PD. Furthermore, this thesis examines modalities to identify individuals at high risk of PD. Progressive motor impairments may also occur in the prediagnostic phase of other neurodegenerative diseases than PD, including those that are primarily characterized by dementia. Motor impairments are often accompanied by cognitive deficits across neurodegenerative diseases, typically adding to the loss of functional independence. This thesis seeks to fill the gap on knowledge on overlap of cognitive and motor impairments in the prediagnostic phase of neurodegenerative diseases and on overlap in their lifetime risk by presenting observational data from the general population. Taken together, these observations add to our understanding of determinants of motor impairments, which has implications not only for PD but also for other neurodegenerative diseases. This thesis concludes by placing its main observations in a broader clinical context, pointing out methodological considerations that merit attention in the interpretation of these observations, and offering directions for future research

Predicting Parkinson disease in the community using a nonmotor risk score

At present, there are no validated methods to identify persons who are at increased risk for Parkinson Disease (PD) from the general population. We investigated the clinical usefulness of a recently proposed non-motor risk score for PD (the PREDICT-PD risk score) in the population-based Rotterdam Study. At baseline (1990), we constructed a weighted risk score based on 10 early nonmotor features and risk factors in 6492 persons free of parkinsonism and dementia. We followed these persons for up to 20 years (median 16.1 years) for the onset of PD until 2011. We studied the association between the PREDICT-PD risk score and incident PD using competing risk regression models with adjustment for age and sex. In addition, we assessed whether the PREDICT-PD risk score improved discrimination (C-statistics) and risk classification (net reclassification improvement) of incident PD beyond age and sex. During follow-up, 110 persons were diagnosed with incident PD. The PREDICT-PD risk score was associated with incident PD (hazard ratio [HR] = 1.30; 95 % confidence interval [1.06; 1.59]) and yielded a small, non-significant improvement in overall discrimination (ΔC-statistic = 0.018[−0.005; 0.041]) and risk classification (net reclassification improvement = 0.172[−0.017; 0.360]) of incident PD. In conclusion, the PREDICT-PD risk score only slightly improves long-term prediction of PD in the community

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

From trials to clinical practice: Temporal trends in the coverage of specialized allied health services for Parkinson's disease

Background and purpose: To determine how the coverage of specialized allied health services for patients with Parkinson's disease (PD) has developed in the Netherlands since the publication of trials that demonstrated cost-effectiveness. Methods: We used healthcare expenditure-based data on all insured individuals in the Netherlands to determine the annual proportion of patients with PD who received either specialized or generic allied health services (physiotherapy, occupational therapy, speech–language therapy) in 2 calendar years separated by a 5-year interval (2012 and 2017). Specialized allied health services were delivered through the ParkinsonNet approach, which encompassed professional training and concentration of care among specifically trained professionals. Results: Between 2012 and 2017, there was an increase in the number of patients with any physiotherapy (from 17,843 [62% of all patients with PD that year] to 22,282 [68%]), speech–language therapy (from 2171 [8%] to 3378 [10%]), and occupational therapy (from 2813 [10%] to 5939 [18%]). Among therapy-requiring patients, the percentage who were treated by a specialized therapist rose substantially for physiotherapy (from 36% in 2012 to 62% in 2017; χ2 = 2460.2; p < 0.001), speech–language therapy (from 59% to 85%; χ2 = 445.4; p < 0.001), and occupational therapy (from 61% to 77%; χ2 = 231.6; p < 0.001). By contrast, the number of patients with generic therapists did not change meaningfully. By 2017, specialized care delivery had extended to regions that had been poorly covered in 2012, essentially achieving nationwide coverage. Conclusions: Following the publication of positive trials, specialized allied healthcare delivery was successfully scaled for patients with PD in the Netherlands, potentially serving as a template for other healthcare innovations for patients with PD elsewhere

Quantitative gait, cognitive decline, and incident dementia: The Rotterdam Study

Introduction: Poor gait has recently emerged as a potential prodromal feature of cognitive decline and dementia. We assessed to what extent various aspects of poor gait are independently associated with cognitive decline and incident dementia. Methods: We leveraged detailed quantitative gait (GAITRite™) and cognitive assessments in 4258 dementia-free participants (median age 67 years, 55% women) of the population-based Rotterdam Study (baseline 2009–2013). We summarized 30 gait parameters into seven mutually independent gait domains and a Global Gait score. Participants underwent follow-up cognitive assessments between 2014 and 2016 and were followed up for incident dementia until 2016 (median 4 years). Results: Three independent gait domains (Base of Support, Pace, and Rhythm) and Global Gait were associated with cognitive decline. Two independent gait domains (Pace and Variability) and Global Gait were associated with incident dementia. Associations of gait with cognitive decline and incident dementia were only present in individuals who had been cognitively unimpaired at baseline. Discussion: Poor performance on several independent gait domains precedes cognitive decline and incident dementia

Clopidogrel use is associated with an increased prevalence of cerebral microbleeds in a stroke-free population: the Rotterdam study.

Although clopidogrel reduces the incidence of atherothrombotic events, its use is associated with an increased risk of major bleeding. Cerebral microbleeds (CMBs) are indicative of subclinical microangiopathy in the brain and may prelude symptomatic intracerebral hemorrhage. We examined the association between use of clopidogrel and CMBs in persons without a history of stroke. We performed a cross-sectional analysis using data from the Rotterdam Study, a prospective population-based cohort of persons aged 45 years and older. Among 4408 stroke-free individuals who underwent brain magnetic resonance imaging for the detection of CMBs, we identified 121 ever-users and 4287 never-users of clopidogrel before magnetic resonance imaging. We used multiple logistic regression to analyze the association between clopidogrel and CMBs with adjustment for age, sex, cardiovascular risk factors, and common cardiovascular medication. Users of clopidogrel had a higher prevalence of CMBs (odd ratio 1.55, 95% CI 1.01 to 2.37) than nonusers and more often had a high number (> 4) of CMBs (odds ratio 3.19, 95% CI 1.52 to 6.72). Clopidogrel use was associated with a significantly higher prevalence of deep or infratentorial CMBs (odd ratio 1.90, 95% CI 1.05 to 3.45). Among clopidogrel users, we were unable to demonstrate differences in the prevalence of CMBs by indication of prescription, history of coronary heart disease, or common genetic variants in CYP2C19. In stroke-free individuals, clopidogrel use was associated with a higher prevalence and higher number of CMBs. Whether this association is causal requires confirmation in prospective studies, especially given the small number of participants taking clopidogrel and the possibil

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

Parkinson Matters

Recent epidemiological observations have drawn attention to the rapid rise in the burden caused by Parkinson's disease over the past years, emphasizing that Parkinson's disease is a matter of serious concern for our future generations. A recent report by Public Health England corroborates this message, by providing new insight on trends in deaths associated with neurological diseases in England between 2001 to 2014. The report indicates that mortality associated with Parkinson's disease and related disorders increased substantially between 2001 and 2014. This trend is partially explained by increased longevity in the population. However, it is possible that changes in exposure to risk factors, recent improvements in multidisciplinary care (leading to prolonged survival), and improved diagnostic awareness or improved registration also influenced the observed trend. Furthermore, patients with Parkinson's disease and related disorders were found to die at an advanced age, and the majority die in a care home or hospital, despite a preponderant preference for many patients and their families to spend their last days at home. To combat these concerning observations, future efforts should be focused on providing resources for vulnerable elderly Parkinson patients, avoiding unplanned hospital admissions and out-of-home deaths as much as possible. Possible solutions include a community-based network of specifically trained allied health therapists, personal case managers for Parkinson patients, dedicated Parkinson nursing homes, and improved centralised support services from university clinics to regional community hospitals aimed at facilitating optimal wide-scale care delivery

Gait patterns associated with thyroid function: The Rotterdam Study

Gait is an important health indicator and poor gait is strongly associated with disability and risk of falls. Thyroid dysfunction is suggested as a potential determinant of gait deterioration, but this has not been explored in a population-based study. We therefore investigated the association of thyroid function with gait patterns in 2645 participants from the Rotterdam Study with data available on TSH (thyroid-stimulating hormone), FT4 (free thyroxine) and gait, without known thyroid disease or dementia. The primary outcome was Global gait (standardized Z-score), while secondary outcomes included gait domains (Rhythm, Variability, Phases, Pace, Base of support, Tandem, Turning) and velocity. Gait was assessed by electronic walkway. Multivariable regression models revealed an inverted U-shaped association of TSH (p < 0.001), but no association of FT4 concentrations with Global gait (p = 0.2). TSH levels were positively associated with Base of support (p = 0.01) and followed an inverted U-shaped curve with Tandem (p = 0.002) and velocity (p = 0.02). Clinical and subclinical hypothyroidism were associated with worse Global gait than euthyroidism (β =-0.61; CI =-1.03,-0.18; p = 0.004 and β =-0.13; CI =-0.26,-0.00; p = 0.04, respectively). In euthyroid participants, higher thyroid function was associated with worse gait patterns. In conclusion, both low and high thyroid function are associated with alterations in Global gait, Tandem, Base of support and velocity

Trajectories of Cognitive and Motor Function Between Ages 45 and 90 Years: A Population-Based Study

BACKGROUND: To establish trajectories of cognitive and motor function, and to determine the sequence of change across individual tests in community-dwelling individuals aged 45-90 years. METHOD: Between 1997 and 2016, we repeatedly assessed cognitive function with 5 tests in 9514 participants aged 45-90 years from the population-based Rotterdam Study. Between 1999 and 2016, we measured motor function with 3 tests in 8297 participants. All participants were free from dementia, stroke, and parkinsonism. We assessed overall and education-specific cognitive and motor trajectories using linear mixed models with age as time scale. Next, we determined the sequence of change across individual tests. RESULTS: The number of assessments per participant ranged between 1 and 6 (mean interval, years [SD]: 5.1 [1.4]) for cognitive function, and 1 and 4 (5.4 [1.4]) for motor function. Cognitive and motor trajectories declined linearly between ages 45 and 65 years, followed by steeper declines after ages 65-70 years. Lower educated participants had lower cognitive function at age 45 years (baseline), and declined faster on most cognitive, but not on motor tests than higher educated participants. Up to a 25-year age difference between the fastest and slowest declining test scores was observed. CONCLUSIONS: On a population-level, cognitive and motor function decline similarly. Compared to higher educated individuals, lower educated individuals had lower cognitive f