Cerebral Small Vessel Disease Progression Increases Risk of Incident Parkinsonism.

OBJECTIVE: Cerebral small vessel disease (SVD) is associated with motor impairments and parkinsonian signs cross-sectionally, however, there are little longitudinal data on whether SVD increases risk of incident parkinsonism itself. We investigated the relation between baseline SVD severity as well as SVD progression, and incident parkinsonism over a follow-up of 14 years. METHODS: This study included 503 participants with SVD, and without parkinsonism at baseline, from the RUN DMC prospective cohort study. Baseline inclusion was performed in 2006 and follow-up took place in 2011, 2015, and 2020, including magnetic resonance imaging (MRI) and motor assessments. Parkinsonism was diagnosed according to the UK Brain Bank criteria, and stratified into vascular parkinsonism (VaP) and idiopathic Parkinson's disease (IPD). Linear mixed-effect models were constructed to estimate individual rate changes of MRI-characteristics. RESULTS: Follow-up for incident parkinsonism was near-complete (99%). In total, 51 (10.2%) participants developed parkinsonism (33 VaP, 17 IPD, and 1 progressive supranuclear palsy). Patients with incident VaP had higher SVD burden compared with patients with IPD. Higher baseline white matter hyperintensities (hazard ratio [HR] = 1.46 per 1-SD increase, 95% confidence interval [CI] = 1.21-1.78), peak width of skeletonized mean diffusivity (HR = 1.66 per 1-SD increase, 95% CI = 1.34-2.05), and presence of lacunes (HR = 1.84, 95% CI = 0.99-3.42) were associated with increased risk of all-cause parkinsonism. Incident lacunes were associated with incident VaP (HR = 4.64, 95% CI = 1.32-16.32). INTERPRETATION: Both baseline SVD severity and SVD progression are independently associated with long-term parkinsonism. Our findings indicate a causal role of SVD in parkinsonism. Future studies are needed to examine the underlying pathophysiology of this relation. ANN NEUROL 2023;93:1130-1141.

Assessing the validity of a Parkinson's care evaluation: the PRIME-NL study.

INTRODUCTION: The PRIME-NL study prospectively evaluates a new integrated and personalized care model for people with parkinsonism, including Parkinson's disease, in a selected region (PRIME) in the Netherlands. We address the generalizability and sources of selection and confounding bias of the PRIME-NL study by examining baseline and 1-year compliance data. METHODS: First, we assessed regional baseline differences between the PRIME and the usual care (UC) region using healthcare claims data of almost all people with Parkinson's disease in the Netherlands (the source population). Second, we compared our questionnaire sample to the source population to determine generalizability. Third, we investigated sources of bias by comparing the PRIME and UC questionnaire sample on baseline characteristics and 1-year compliance. RESULTS: Baseline characteristics were similar in the PRIME (n = 1430) and UC (n = 26,250) source populations. The combined questionnaire sample (n = 920) was somewhat younger and had a slightly longer disease duration than the combined source population. Compared to the questionnaire sample in the PRIME region, the UC questionnaire sample was slightly younger, had better cognition, had a longer disease duration, had a higher educational attainment and consumed more alcohol. 1-year compliance of the questionnaire sample was higher in the UC region (96%) than in the PRIME region (92%). CONCLUSION: The generalizability of the PRIME-NL study seems to be good, yet we found evidence of some selection bias. This selection bias necessitates the use of advanced statistical methods for the final evaluation of PRIME-NL, such as inverse probability weighting or propensity score matching. The PRIME-NL study provides a unique window into the validity of a large-scale care evaluation for people with a chronic disease, in this case parkinsonism.

Caregiver burden in Parkinson's disease: a mixed-methods study.

BACKGROUND: Providing informal care for a person with Parkinson's disease (PD) can be a demanding process affecting several dimensions of a caregiver's life and potentially causing caregiver burden. Despite the emerging literature on caregiver burden in people with PD, little is known about the inter-relationship between quantitative and qualitative findings. Filling this knowledge gap will provide a more holistic approach to develop and design innovations aiming at reducing or even preventing caregiver burden. This study aimed to characterize the determinants of caregiver burden among informal caregivers of persons with PD, in order to facilitate the development of tailored interventions that reduce caregiver burden. METHODS: We conducted a cross-sectional study in The Netherlands using a sequential mixed methods approach, entailing a quantitative study of 504 persons with PD and their informal caregivers as well as a qualitative study in a representative subsample of 17 informal caregivers. The quantitative study included a standardized questionnaire of caregiver burden (Zarit Burden Inventory) and patient-related (Beck Depression Inventory, State-Trait Anxiety Inventory, Acceptance of Illness Scale, MDS-Unified Parkinson's Disease Rating Scale part II on motor functions in daily life, Self-assessment Parkinson's Disease Disability Score), caregiver-related (Brief Coping Orientation to Problems Experience Inventory, Caregiver Activation Measurement, Multidimensional Scale of Perceived Social Support) and interpersonal determinants (sociodemographic variables including among others gender, age, education, marital status and working status). The qualitative study consisted of semi-structured interviews. Multivariable regression and thematic analysis were used to analyse quantitative and qualitative data, respectively. RESULTS: A total of 337 caregivers were women (66.9%), and the majority of people with PD were men (N = 321, 63.7%). The mean age of persons with PD was 69.9 (standard deviation [SD] 8.1) years, and the mean disease duration was 7.2 (SD 5.2) years. A total of 366 (72.6%) persons with PD had no active employment. The mean age of informal caregivers was 67.5 (SD 9.2) years. Most informal caregivers were female (66.9%), had no active employment (65.9%) and were the spouse of the person with PD (90.7%). The mean Zarit Burden Inventory score was 15.9 (SD 11.7). The quantitative study showed that a lack of active employment of the person affected by PD was associated with a higher caregiver burden. The qualitative study revealed cognitive decline and psychological or emotional deficits of the person with PD as additional patient-related determinants of higher caregiver burden. The following caregiver-related and interpersonal determinants were associated with higher caregiver burden: low social support (quantitative study), concerns about the future (qualitative study), the caregiving-induced requirement of restrictions in everyday life (qualitative study), changes in the relationship with the person with PD (qualitative study) and a problem-focused or avoidant coping style (both studies). Integration of both data strands revealed that qualitative findings expanded quantitative findings by (1) distinguishing between the impact of the relationship with the person with PD and the relationship with others on perceived social support, (2) revealing the impact of non-motor symptoms next to motor symptoms and (3) revealing the following additional factors impacting caregiver burden: concern about the future, perceived restrictions and limitations in performing daily activities due to the disease, and negative feelings and emotional well-being. Qualitative findings were discordant with the quantitative finding demonstrating that problem-focused was associated with a higher caregiver burden. Factor analyses showed three sub-dimensions of the Zarit Burden Inventory: (i) role intensity and resource strain, (2) social restriction and anger and (3) self-criticism. Quantitative analysis showed that avoidant coping was a determinant for all three subscales, whereas problem-solved coping and perceived social support were significant predictors on two subscales, role intensity and resource strain and self-criticism. CONCLUSIONS: The burden experienced by informal caregivers of persons with PD is determined by a complex interplay of patient-related, caregiver-related and interpersonal characteristics. Our study highlights the utility of a mixed-methods approach to unravel the multidimensional burden experienced by informal caregivers of persons with chronic disease. We also offer starting points for the development of a tailored supportive approach for caregivers.

Lipopolysaccharide-binding protein and future Parkinson's disease risk: a European prospective cohort.

INTRODUCTION: Lipopolysaccharide (LPS) is the outer membrane component of Gram-negative bacteria. LPS-binding protein (LBP) is an acute-phase reactant that mediates immune responses triggered by LPS and has been used as a blood marker for LPS. LBP has recently been indicated to be associated with Parkinson's disease (PD) in small-scale retrospective case-control studies. We aimed to investigate the association between LBP blood levels with PD risk in a nested case-control study within a large European prospective cohort. METHODS: A total of 352 incident PD cases (55% males) were identified and one control per case was selected, matched by age at recruitment, sex and study center. LBP levels in plasma collected at recruitment, which was on average 7.8 years before diagnosis of the cases, were analyzed by enzyme linked immunosorbent assay. Odds ratios (ORs) were estimated for one unit increase of the natural log of LBP levels and PD incidence by conditional logistic regression. RESULTS: Plasma LBP levels were higher in prospective PD cases compared to controls (median (interquartile range) 26.9 (18.1-41.0) vs. 24.7 (16.6-38.4) µg/ml). The OR for PD incidence per one unit increase of log LBP was elevated (1.46, 95% CI 0.98-2.19). This association was more pronounced among women (OR 2.68, 95% CI 1.40-5.13) and overweight/obese subjects (OR 1.54, 95% CI 1.09-2.18). CONCLUSION: The findings suggest that higher plasma LBP levels may be associated with an increased risk of PD and may thus pinpoint to a potential role of endotoxemia in the pathogenesis of PD, particularly in women and overweight/obese individuals.

Specialized Versus Generic Allied Health Therapy and the Risk of Parkinson's Disease Complications.

BACKGROUND: Specialized versus generic physiotherapy (PT) reduces Parkinson's disease (PD)-related complications. It is unclear (1) whether other specialized allied heath disciplines, including occupational therapy (OT) and speech and language therapy (S<), also reduce complications; (2) whether there is a synergistic effect among multiple specialized disciplines; and (3) whether each allied health discipline prevents specific complications. OBJECTIVES: To longitudinally assessed whether the level of expertise (specialized vs. generic training) of PT, OT, and S< was associated with the incidence rate of PD-related complications. METHODS: We used claims data of all insured persons with PD in the Netherlands between January 1, 2010, and December 31, 2018. ParkinsonNet-trained therapists were classified as specialized, and other therapists as generic. We used mixed-effects Poisson regression models to estimate rate ratios adjusting for sociodemographic and clinical characteristics. RESULTS: The population of 51,464 persons with PD (mean age, 72.4 years; standard deviation 9.8) sustained 10,525 PD-related complications during follow-up (median 3.3 years). Specialized PT was associated with fewer complications (incidence rate ratio [IRR] of specialized versus generic = 0.79; 95% confidence interval, [0.74-0.83]; P < 0.0001), as was specialized OT (IRR = 0.88 [0.77-0.99]; P = 0.03). We found a trend of an association between specialized S< and a lower rate of PD-related complications (IRR = 0.88 [0.74-1.04]; P = 0.18). The inverse association of specialized OT persisted in the stratum, which also received specialized PT (IRR = 0.62 [0.42-0.90]; P = 0.001). The strongest inverse association of PT was seen with orthopedic injuries (IRR = 0.78 [0.73-0.82]; P < 0.0001) and of S< with pneumonia (IRR = 0.70 [0.53-0.93]; P = 0.03). CONCLUSIONS: These findings support a wider introduction of specialized allied health therapy expertise in PD care and conceivably for other medical conditions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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.

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.

Rationale and design to evaluate the PRIME Parkinson care model: a prospective observational evaluation of proactive, integrated and patient-centred Parkinson care in The Netherlands (PRIME-NL).

BACKGROUND: Culminating evidence shows that current care does not optimally meet the needs of persons with parkinsonism, their carers and healthcare professionals. Recently, a new model of care was developed to address the limitations of usual care: Proactive and Integrated Management and Empowerment in Parkinson's Disease (PRIME Parkinson). From 2021 onwards, PRIME Parkinson care will replace usual care in a well-defined region in The Netherlands. The utility of PRIME Parkinson care will be evaluated on a single primary endpoint (parkinsonism-related complications), which reflects the health of people with parkinsonism. Furthermore, several secondary endpoints will be measured for four dimensions: health, patient and carer experience, healthcare professional experience, and cost of healthcare. The reference will be usual care, which will be continued in other regions in The Netherlands. METHODS: This is a prospective observational study which will run from January 1, 2020 until December 31, 2023. Before the new model of care will replace the usual care in the PRIME Parkinson care region all baseline assessments will take place. Outcomes will be informed by two data sources. We will use healthcare claims-based data to evaluate the primary endpoint, and costs of healthcare, in all persons with parkinsonism receiving PRIME Parkinson care (estimated number: 2,000) and all persons with parkinsonism receiving usual care in the other parts of The Netherlands (estimated number: 48,000). We will also evaluate secondary endpoints by performing annual questionnaire-based assessments. These assessments will be administered to a subsample across both regions (estimated numbers: 1,200 persons with parkinsonism, 600 carers and 250 healthcare professionals). DISCUSSION: This prospective cohort study will evaluate the utility of a novel integrated model of care for persons with parkinsonism in The Netherlands. We anticipate that the results of this study will also provide insight for the delivery of care to persons with parkinsonism in other regions and may inform the design of a similar model for other chronic health conditions.

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.

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.

Home-based monitoring of falls using wearable sensors in Parkinson's disease.

INTRODUCTION: Falling is among the most serious clinical problems in Parkinson's disease (PD). We used body-worn sensors (falls detector worn as a necklace) to quantify the hazard ratio of falls in PD patients in real life. METHODS: We matched all 2063 elderly individuals with self-reported PD to 2063 elderly individuals without PD based on age, gender, comorbidity, and living conditions. We analyzed fall events collected at home via a wearable sensor. Fall events were collected either automatically using the wearable falls detector or were registered by a button push on the same device. We extracted fall events from a 2.5-year window, with an average follow-up of 1.1 years. All falls included were confirmed immediately by a subsequent telephone call. The outcomes evaluated were (1) incidence rate of any fall, (2) incidence rate of a new fall after enrollment (ie, hazard ratio), and (3) 1-year cumulative incidence of falling. RESULTS: The incidence rate of any fall was higher among self-reported PD patients than controls (2.1 vs. 0.7 falls/person, respectively; P < .0001). The incidence rate of a new fall after enrollment (ie, hazard ratio) was 1.8 times higher for self-reported PD patients than controls (95% confidence interval, 1.6-2.0). CONCLUSION: Having PD nearly doubles the incidence of falling in real life. These findings highlight PD as a prime "falling disease." The results also point to the feasibility of using body-worn sensors to monitor falls in daily life. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Sleep and risk of parkinsonism and Parkinson's disease: a population-based study.

Sleep disturbances may signal presence of prodromal parkinsonism, including Parkinson's disease. Whether general sleep quality or duration in otherwise healthy subjects is related to the risk of parkinsonism remains unclear. We hypothesized that both worse self-reported sleep quality and duration, as well as a longitudinal deterioration in these measures, are associated with the risk of parkinsonism, including Parkinson's disease. In the prospective population-based Rotterdam Study, we assessed sleep quality and duration with the Pittsburgh Sleep Quality Index in 7726 subjects (mean age 65 years, 57% female) between 2002 and 2008, and again in 5450 subjects between 2009 and 2014. Participants were followed until 2015 for a diagnosis of parkinsonism and Parkinson's disease. Outcomes were assessed using multiple modalities: interviews, physical examination, and continuous monitoring of pharmacy records and medical records of general practitioners. We used Cox regression to associate sleep, and changes in sleep over time, with incident parkinsonism and Parkinson's disease, adjusting for age, sex, education and smoking status. Over 64 855 person-years in 13 years of follow-up (mean: 8.4 years), 75 participants developed parkinsonism, of whom 47 developed Parkinson's disease. We showed that within the first 2 years of follow-up, worse sleep quality {hazard ratio (HR) 2.38 per standard deviation increase [95% confidence interval (CI 0.91-6.23)]} and shorter sleep duration [HR 0.61 per standard deviation increase (95% CI 0.31-1.21)] related to a higher risk of parkinsonism. Associations of worse sleep quality [HR 3.86 (95% CI 1.19-12.47)] and shorter sleep duration [HR 0.48 (95% CI 0.23-0.99)] with Parkinson's disease were more pronounced, and statistically significant, compared to parkinsonism. This increased risk disappeared with longer follow-up duration. Worsening of sleep quality [HR 1.76 per standard deviation increase (95% CI 1.12-2.78)], as well as shortening of sleep duration [HR 1.72 per standard deviation decrease (95% CI 1.08-2.72)], were related to Parkinson's disease risk in the subsequent 6 years. Therefore, we argue that in the general population, deterioration of sleep quality and duration are markers of the prodromal phase of parkinsonism, including Parkinson's disease.

Lifetime risk of common neurological diseases in the elderly population.

OBJECTIVE: To quantify the burden of common neurological disease in older adults in terms of lifetime risks, including their co-occurrence and preventive potential, within a competing risk framework. METHODS: Within the prospective population-based Rotterdam Study, we studied lifetime risk of dementia, stroke and parkinsonism between 1990 and 2016. Among 12 102 individuals (57.7% women) aged ≥45 years free from these diseases at baseline, we studied co-occurrence, and quantified the combined, and disease-specific remaining lifetime risk of these diseases at various ages for men and women separately. We also projected effects on lifetime risk of hypothetical preventive strategies that delay disease onset by 1, 2 and 3 years, respectively. RESULTS: During follow-up of up to 26 years (156 088 person-years of follow-up), 1489 individuals were diagnosed with dementia, 1285 with stroke and 263 with parkinsonism. Of these individuals, 438 (14.6%) were diagnosed with multiple diseases. Women were almost twice as likely as men to be diagnosed with both stroke and dementia during their lifetime. The lifetime risk for any of these diseases at age 45 was 48.2% (95% CI 47.1% to 51.5%) in women and 36.2% (35.1% to 39.3%) in men. This difference was driven by a higher risk of dementia as the first manifesting disease in women than in men (25.9% vs 13.7%; p<0.001), while this was similar for stroke (19.0%vs18.9% in men) and parkinsonism (3.3% vs 3.6% in men). Preventive strategies that delay disease onset with 1 to 3 years could theoretically reduce lifetime risk for developing any of these diseases by 20%-50%. CONCLUSION: One in two women and one in three men will develop dementia, stroke or parkinsonism during their life. These findings strengthen the call for prioritising the focus on preventive interventions at population level which could substantially reduce the burden of common neurological diseases in the ageing population.

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.

Kidney function, gait pattern and fall in the general population: a cohort study.

Background: Gait disturbance is proposed as a mechanism for higher risk of fall in kidney disease patients. We investigated the association of kidney function with gait pattern in the general population and tested whether the association between impaired kidney function and fall is more pronounced in subjects with lower gait function. Methods: We included 1430 participants (mean age: 60 years) from the Rotterdam Study. Kidney function was assessed using estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). We assessed global gait, gait velocity and seven independent gait domains: Rhythm, Phases, Variability, Pace, Tandem, Turning and Base of Support. Regression models adjusted for cardiometabolic and neurological factors were used. We evaluated whether participants with impaired kidney function and impaired gait fell more in the previous year. Results: The study population had a median (interquartile range) ACR of 3.6 (2.5-6.2) mg/g and mean ± SD eGFR of 87.6 ± 15 mL/min/1.73 m2. Higher ACR and lower eGFR were associated with lower global gait score [per doubling of ACR: -0.10, 95% confidence interval (CI): -0.14 to -0.06, and per SD eGFR:-0.09, 95% CI: -0.14 to -0.03] and slower gait speed (ACR: -1.44 cm/s, CI: -2.12 to -0.76; eGFR: -1.55 cm/s, CI: -2.43 to -0.67). Worse kidney function was associated with lower scores in Variability domain. The association between impaired kidney function and history of fall was present only in participants with lower gait scores [odds ratio (95% CI): ACR: 1.34 (1.09-1.65); eGFR: 1.58 (1.07-2.33)]. Conclusions: We observed a graded association between lower kidney function and impaired gait suggesting that individuals with decreased kidney function, even at an early stage, need to be evaluated for gait abnormalities and might benefit from fall prevention programmes.

Trajectories of prediagnostic functioning in Parkinson's disease.

SEE BREEN AND LANG DOI101093/AWW321 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: At the time of clinical diagnosis, patients with Parkinson's disease already have a wide range of motor and non-motor features that affect their daily functioning. However, the temporal sequence of occurrence of these features remains largely unknown. We studied trajectories of daily functioning and motor and non-motor features in the 23 years preceding Parkinson's disease diagnosis by performing a nested case-control study within the prospective Rotterdam study. Between 1990 and 2013, we repeatedly performed standardized assessments of daily functioning (Stanford Health Assessment Questionnaire, Lawton Instrumental Activities of Daily Living Scale), potential prediagnostic motor (hypo- and bradykinesia, tremor, rigidity, postural imbalance, postural abnormalities) and non-motor features of Parkinson's disease, including cognition (Mini-Mental State Examination, Stroop Test, Letter-Digit-Substitution Test, Word Fluency Test), mood (Center for Epidemiological Studies-Depression Scale, Hamilton Anxiety and Depression Scale), and autonomic function (blood pressure, laxative use). In addition, the cohort was followed-up for the onset of clinical Parkinson's disease using several overlapping modalities, including repeated in-person examinations, as well as complete access to medical records and specialist letters of study participants. During follow-up, 109 individuals were diagnosed with Parkinson's disease, and each case was matched to 10 controls based on age and sex (total n = 1199). Subsequently, we compared prediagnostic trajectories of daily functioning and other features between Parkinson's disease cases and controls. From 7 years before diagnosis onwards, prediagnostic Parkinson's disease cases more commonly had problems in instrumental activities of daily functioning, and more frequently showed signs of movement poverty and slowness, tremor and subtle cognitive deficits. In the past 5 years, Parkinson's disease cases developed additional motor features (postural imbalance, rigidity, and postural abnormalities) and increasingly reported problems in basic daily activities. Parkinson's disease cases also increasingly reported anxiety symptoms, depressive symptoms, and use of laxatives throughout study follow-up, although differences with controls only became statistically significant in the last years before diagnosis. In conclusion, in patients with prediagnostic Parkinson's disease, impairments in instrumental daily activities, which require both motor and non-motor skills, pre-date difficulties in more physically oriented daily activities.media-1vid110.1093/brain/aww291_video_abstractaww291_video_abstract.

Inflammatory markers and the risk of dementia and Alzheimer's disease: A meta-analysis.

INTRODUCTION: Inflammatory markers are often elevated in patients with dementia, including Alzheimer's disease (AD). However, it remains unclear whether inflammatory markers are associated with the risk of developing dementia. METHODS: We searched PubMed, Embase, and Cochrane library for prospective population-based studies reporting associations between inflammatory markers and all-cause dementia or AD. We used random effects meta-analyses to obtain pooled hazard ratios (HRs) and 95% confidence intervals of inflammatory markers (highest vs. lowest quantile) for all-cause dementia and AD. RESULTS: Fifteen articles from 13 studies in six countries reported data that could be meta-analyzed. C-reactive protein (HR = 1.37 [1.05; 1.78]), interleukin-6 (HR = 1.40 [1.13; 1.73]), α1-antichymotrypsin (HR = 1.54 [1.14; 2.80]), lipoprotein-associated phospholipase A2 activity (HR = 1.40 [1.03; 1.90]), and fibrinogen were each associated with all-cause dementia, but neither was significantly associated with AD. DISCUSSION: Several inflammatory markers are associated with an increased risk of all-cause dementia; however, these markers are not specific for AD. Whether inflammatory markers closely involved in AD pathology are associated with the risk of AD remains to be elucidated.

Cerebral small vessel disease and the risk of dementia: A systematic review and meta-analysis of population-based evidence.

INTRODUCTION: Cerebral small vessel disease is increasingly linked to dementia. METHODS: We systematically searched Medline, Embase, and Cochrane databases for prospective population-based studies addressing associations of white matter hyperintensities, covert brain infarcts (i.e., clinically silent infarcts), and cerebral microbleeds with risk of all-dementia or Alzheimer's disease and performed meta-analyses. RESULTS: We identified 11 studies on white matter hyperintensities, covert brain infarcts, or cerebral microbleeds with risk of all-dementia or Alzheimer's disease. Pooled analyses showed an association of white matter hyperintensity volume and a borderline association of covert brain infarcts with risk of all-dementia (hazard ratio: 1.39 [95% confidence interval: 1.00; 1.94], N = 3913, and 1.47 [95% confidence interval: 0.97; 2.22], N = 8296). Microbleeds were not statistically significantly associated with an increased risk of all-dementia (hazard ratio: 1.25 [95% confidence interval: 0.66; 2.38], N = 8739). DISCUSSION: White matter hyperintensities are associated with an increased risk of all-dementia and Alzheimer's disease in the general population. However, studies are warranted to further determine the role of markers of cerebral small vessel disease in dementia.

Coronary heart disease, heart failure, and the risk of dementia: A systematic review and meta-analysis.

INTRODUCTION: Cardiovascular risk factors are closely linked with dementia risk, but whether heart disease predisposes to dementia is uncertain. METHODS: We systematically reviewed the literature and meta-analyzed risk estimates from longitudinal studies reporting the association of coronary heart disease (CHD) or heart failure (HF) with risk of dementia. RESULTS: We identified 16 studies (1,309,483 individuals) regarding CHD, and seven studies (1,958,702 individuals) about HF. A history of CHD was associated with a 27% increased risk of dementia (pooled relative risk [RR] [95% confidence interval, CI]: 1.27 [1.07-1.50]), albeit with considerable heterogeneity across studies (I2 = 80%). HF was associated with 60% increased dementia risk (pooled RR 1.60 [1.19-2.13]) with moderate heterogeneity (I2 = 59%). Among prospective population-based cohorts, pooled estimates were similar (for CHD, RR 1.26 [1.06-1.49], nine studies; and HF, RR 1.80 [1.41-2.31], four studies) and highly consistent (I2 = 0%). CONCLUSION: CHD and HF are associated with an increased risk of dementia.