With ageing populations, the prevalence of age-related disorders such as dementia is on the rise. As there is currently no curable treatment for dementia, the vascular component of dementia is... Show moreWith ageing populations, the prevalence of age-related disorders such as dementia is on the rise. As there is currently no curable treatment for dementia, the vascular component of dementia is increasingly recognised as a key modifiable cause. This thesis aims to investigate biological pathways between risk factors of cardiometabolic disease and cognitive function, in a population of older adults at increased risk of cardiovascular disease (CVD). We hypothesise that changes in physiological functioning caused by (sub)clinical CVD are possible mediators within the pathway leading to cognitive dysfunction. In the first part of this thesis, we studied electrocardiogram-based intervals and serum cardiac biomarkers (such as troponin) in relation to cognitive function. In the second part of this thesis, we studied the interplay of body mass index and serum leptin, loss of body weight and body weight variability, as well as metabolomics-based health scores in relation to cognitive function. We found that various cardiometabolic risk factors are associated with worse cognitive function. The results of this thesis strongly suggest that subclinical changes in cardiometabolic health may exist before cognitive dysfunction becomes apparent. Treating these cardiometabolic risk factors may be of benefit to future cognitive health. Show less
Zonneveld, M.H.; Trompet, S.; Jukema, J.W.; Noordam, R. 2023
Prospective cohort studies have implied associations between blood levels of troponin T, troponin I, NT-proBNP, GDF15, dementia, and cognitive function, without providing evidence favoring... Show moreProspective cohort studies have implied associations between blood levels of troponin T, troponin I, NT-proBNP, GDF15, dementia, and cognitive function, without providing evidence favoring possible causality. We aimed to assess the causal associations of these cardiac blood biomarkers with dementia and cognition using two-sample Mendelian randomization (MR). Independent genetic instruments (p < 5e−7) for troponin T and I, N-terminal pro B-type natriuretic peptide (NT-proBNP) and growth-differentiation factor 15 (GDF15) were obtained from previously-performed genome-wide association studies of predominantly European ancestry. Summary statistics for gene-outcome associations in European-ancestry participants, for the two-sample MR analyses, were obtained for general cognitive performance (n = 257,842) and dementia (n = 111,326 clinically diagnosed and “proxy” AD cases, and 677,663 controls). Two-sample MR analyses were performed using inverse variance-weighted (IWV) analyses. Sensitivity analyses to evaluate horizontal pleiotropy included weighted median estimator, MR-Egger, and MR using cis-SNPs only. Using IVW, we did not find evidence for possible causal associations between genetically influenced cardiac biomarkers with cognition and dementia. For example, per standard deviation (SD) higher cardiac blood biomarker, the odds ratio for risk of dementia was 1.06 (95%CI 0.90; 1.21) for troponin T, 0.98 (95%CI 0.72; 1.23) for troponin I, 0.97 (95%CI 0.90; 1.06) for NT-proBNP and 1.07 (95%CI 0.93; 1.21) for GDF15. Sensitivity analyses showed higher GDF15 was significantly associated with higher dementia risk and worse cognitive function. We did not find strong evidence that cardiac biomarkers causally influence dementia risk. Future research should aim at elucidating the biological pathways through which cardiac blood biomarkers associate with dementia. Show less
Luo, J.; Cessie, S. le; Blauw, G.J.; Franceschi, C.; Noordam, R.; Heemst, D. van 2022
Observational studies have implied associations between multiple cytokines and cognitive decline, anti-inflammatory drugs however did not yield any protective effects on cognitive decline. We aimed... Show moreObservational studies have implied associations between multiple cytokines and cognitive decline, anti-inflammatory drugs however did not yield any protective effects on cognitive decline. We aimed to assess the associations of systemic inflammation, as measured by multiple cytokine and growth factor, with cognitive performance and brain atrophy using two-sample Mendelian randomization (MR). Independent genetic instruments (p < 5e - 8 and p < 5e - 6) for 41 systemic inflammatory markers were retrieved from a genome-wide association study conducted in 8293 Finnish participants. Summary statistics for gene-outcome associations were obtained for cognitive performance (N=257,841) and for brain atrophy measures of cerebral cortical surface area and thickness (N=51,665) and hippocampal volume (N= 33,536). To rule out the heterogeneity in the cognitive performance, we additionally included three domains: the fluid intelligence score (N=108,818), prospective memory result (N=111,099), and reaction time (N=330,069). Main results were computed by inverse-variance weighting; sensitivity analyses taking pleiotropy and invalid instruments into account were performed by using weighted-median estimator, MR-Egger, and MR PRESSO. After correcting for multiple testing using false discovery rate, only genetically predicted (with p < 5e - 6 threshold) per-SD (standard deviation) higher IL-8 was associated with -0.103 (- 0.155, - 0.051, P-adjusted = 0.004) mm(3) smaller hippocampal volume and higher intelligence fluid score [beta: 0.103 SD (95% CI: 0.042, 0.165), P-adjusted =0.041]. Sensitivity analyses generally showed similar results, and no pleiotropic effect, heterogeneity, or possible reverse causation was detected. Our results suggested a possible causal association of high IL-8 levels with better cognitive performance but smaller hippocampal volume among the general healthy population, highlighting the complex role of inflammation in dementia-related phenotypes. Further research is needed to elucidate mechanisms underlying these associations. Show less
As the population is aging worldwide, and in spite of all preventive efforts, age-related diseases are increasingly prevalent, such as cardiovascular diseases and cognitive impairment. Different... Show moreAs the population is aging worldwide, and in spite of all preventive efforts, age-related diseases are increasingly prevalent, such as cardiovascular diseases and cognitive impairment. Different vascular risk factors, both the ‘traditional’ modifiable factors, such as hypertension or diabetes, and non-modifiable factors, such as age or gender, can lead to different kind of intertwined micro- and macrovascular diseases in various or multiple simultaneous organs. There is a growing need for knowledge regarding the interplay between different (co)morbidities, the relation of (co)morbidities with the various underlying pathophysiological mechanisms and treatment options of these (co)morbidities. Therefore, the aims of this thesis were to identify patients at high cardiovascular risk and to optimize treatment for these patients. We further unravelled the complexity of various interacting (poly) vascular diseases, ultimately leading to an increased risk of not only cognitive impairment, but also MACE including death. Identification of these patients and better understanding of the interplay and underlying mechanisms of these diseases is the first step towards preventive strategies. Treating these high risk patients can be a therapeutic challenge, but there is growing knowledge regarding both established and evolving therapies to optimize efficacy and efficiency. Show less
The aim of this thesis was to investigate cardiovascular determinants of neurocognitive functioning in old age, in particular cognitive dysfunction, depressive symptoms, and apathy. First, we found... Show moreThe aim of this thesis was to investigate cardiovascular determinants of neurocognitive functioning in old age, in particular cognitive dysfunction, depressive symptoms, and apathy. First, we found that the Geriatric Depression Scale(GDS)-3A, the apathy sub set of the GDS-15, moderately discriminates between presence and absence of apathy, and can be used in large study populations to investigate associations with apathy. Next, we demonstrated that higher levels of high sensitivity cardiac troponin T (hs-cTnT), a clinical cardiac biomarker, are related to accelerated cognitive decline, but not to apathy or depression.In the next chapters, we tested the hypothesis that in those older persons with more vascular brain damage, a lower rather than a higher blood pressure is related to worse neurocognitive function. Indeed, we found that only in those older persons with worse daily functioning and those with more cerebral small vessel disease, lower blood pressure was related to more symptoms of apathy. This pattern was not observed for depression or cognitive function.In conclusion, we found that cardiovascular risk factors are important for neurocognitive functioning in older persons. Moreover, we found that specific cardiovascular determinants, such as blood pressure and hs-cTnT, have different associations with apathy than with depression and cognitive function. Show less
Najafabadi, A.H.Z.; Meer, P.B. van der; Boele, F.W.; Taphoorn, M.J.B.; Klein, M.; Peerdeman, S.M.; ... ; Dutch Meningioma Consortium 2021
BACKGROUND: Many intracranial meningioma patients have an impaired health-related quality of life (HRQoL) and neurocognitive functioning up to 4 yr after intervention.OBJECTIVE: To assess the long... Show moreBACKGROUND: Many intracranial meningioma patients have an impaired health-related quality of life (HRQoL) and neurocognitive functioning up to 4 yr after intervention.OBJECTIVE: To assess the long-term (>= 5 yr) disease burden of meningioma patients.METHODS: In this multicenter cross-sectional study, patients >= 5 yr after intervention (including active magnetic resonance imaging (MRI) surveillance) were included and assessed for HRQoL (Short-Form Health Survey 36), neurocognitive functioning (neuropsychological assessment), anxiety and depression (Hospital Anxiety and Depression Scale), and work productivity (Short Form-Health and Labour Questionnaire). Multivariable and propensity score regression analyses were used to compare patients and controls, and different treatment strategies corrected for possible confounders. Clinically relevant differences were reported.RESULTS: At amedian of 9 yr follow-up after intervention, meningioma patients (n = 190) reported more limitations due to physical (difference 12.5 points, P = .008) and emotional (13.3 points, P = .002) health problems compared with controls. Patients also had an increased risk to suffer from anxiety (odds ratio [OR]: 2.6, 95% CI: 1.2-5.7) and depression (OR: 3.7, 95% CI: 1.3-10.5). Neurocognitive deficits were found in 43% of patients. Although postoperative complications, radiotherapy, and reresection were associated with worse verbal memory, attention, and executive functioning when compared to patients resected once, the only clinically relevant association was between reresection and worse attention (-2.11, 95% CI: -3.52 to -0.07). Patients of working age less often had a paid job (48%) compared with the working-age Dutch population (72%) and reported more obstacles at work compared with controls.CONCLUSION: In the long term, a large proportion of meningioma patients have impaired HRQoL, neurocognitive deficits, and high levels of anxiety or depression. Patients treated with 1 resection have the best neurocognitive functioning. Show less
Objective: To determine the physical and mental health of very old people (aged 80+) with anaemia.Methods: Individual level meta-analysis from five cohorts of octogenarians (n = 2,392): LiLACS NZ... Show moreObjective: To determine the physical and mental health of very old people (aged 80+) with anaemia.Methods: Individual level meta-analysis from five cohorts of octogenarians (n = 2,392): LiLACS NZ Maori, LiLACS NZ non-Maori, Leiden 85-plus Study, Newcastle 85+ Study, and TOOTH. Mixed models of change in functional ability, cognitive function, depressive symptoms, and self-rated health over time were separately fitted for each cohort. We combined individual cohort estimates of differences according to the presence of anaemia at baseline, adjusting for age at entry, sex, and time elapsed. Combined estimates are presented as differences in standard deviation units (i.e. standardised mean differences-SMDs).Results: The combined prevalence of anaemia was 30.2%. Throughout follow-up, participants with anaemia, on average, had: worse functional ability (SMD -0.42 of a standard deviation across cohorts; CI -0.59, -0.25); worse cognitive scores (SMD -0.27; CI -0.39,-0.15); worse depression scores (SMD -0.20; CI -0.31, -0.08); and lower ratings of their own health (SMD -0.36; CI -0.47,-0.25). Differential rates of change observed were: larger declines in functional ability for those with anaemia (SMD -0.12 over five years; CI -0.21, -0.03) and smaller mean difference in depression scores over time between those with and without anaemia (SMD 0.18 over five years; CI 0.05, 0.30).Conclusion: Anaemia in the very old is a common condition associated with worse functional ability, cognitive function, depressive symptoms, and self-rated health, and a more rapid decline in functional ability over time. The question remains as to whether anaemia itself contributes to worse outcomes or is simply a marker of chronic diseases and nutrient deficiencies. Show less
Proton therapy offers an attractive alternative to conventional photon-based radiotherapy in low grade glioma patients, delivering radiotherapy with equivalent efficacy to the tumour with less... Show moreProton therapy offers an attractive alternative to conventional photon-based radiotherapy in low grade glioma patients, delivering radiotherapy with equivalent efficacy to the tumour with less radiation exposure to the brain. In the Netherlands, patients with favourable prognosis based on tumour and patient characteristics can be offered proton therapy. Radiation-induced neurocognitive function decline is a major concern in these long surviving patients. Although level 1 evidence of superior clinical outcome with proton therapy is lacking, the Dutch National Health Care Institute concluded that there is scientific evidence to assume that proton therapy can have clinical benefit by reducing radiation-induced brain damage. Based on this decision, proton therapy is standard insured care for selected low grade glioma patients. Patients with other intracranial tumours can also qualify for proton therapy, based on the same criteria. In this paper, the evidence and considerations that led to this decision are summarised. Additionally, the eligibility criteria for proton therapy and the steps taken to obtain high-quality data on treatment outcome are discussed. (C) 2020 The Author(s). Published by Elsevier B.V. Show less
Wouters, H.; Hilmer, S.N.; Twisk, J.; Teichert, M.; Meer, H.G. van der; Hout, H.P.J. van; Taxis, K. 2020
Objectives: Anticholinergic/antimuscarinic and sedative medications (eg, benzodiazepines) have been found to be associated with poorer cognitive and physical function and mobility impairment in... Show moreObjectives: Anticholinergic/antimuscarinic and sedative medications (eg, benzodiazepines) have been found to be associated with poorer cognitive and physical function and mobility impairment in older age. However, previous studies were mostly conducted among community-dwelling older individuals and had often a cross-sectional design. Accordingly, our aim was to examine longitudinal associations between cumulative exposure to anticholinergic and sedative medications and cognitive and physical function among residents from aged care homes.Design: Longitudinal study.Setting and Participants: A total of 4624 residents of Dutch aged care homes of whom data were collected between June 2005 and April 2014.Methods: Outcome measures were collected with the Long-Term Care Facilities assessment from the international Residential Assessment Instrument (interRAI-LTCF) and included the Cognitive Performance Scale, the Activities of Daily Living (ADL) Hierarchy scale, a timed 4-meter walk test, distance walked, hours of physical activity, and days being outside. Cumulative exposure to anticholinergic and sedative medications was calculated with the Drug Burden Index (DBI), a linear additive pharmacological dose-response model. Associations were examined with linear mixed models to take the potential dependence of observations into account (ie, data were collected at repeated assessment occasions of residents who were clustered in aged care homes). Analyses were adjusted for sex, age, dementia, comorbidity (neurological, psychiatric, cardiovascular, oncological, and pulmonary), fractures, depressive symptoms, and medications excluded from the DBI.Results: We observed significant longitudinal associations between a higher DBI and poorer ADLs, fewer hours of physical activity, and fewer days being outside. We found no significant longitudinal association between a higher DBI and poorer cognitive function.Conclusions and Implications: Over time, cumulative exposure to anticholinergic and sedative medications is associated with poorer physical but not cognitive function in aged care residents. Careful monitoring of aged care residents with high cumulative anticholinergic and sedative medication exposure is needed. (C) 2020 Published by Elsevier Inc. on behalf of AMDA - The Society for Post-Acute and Long-Term Care Medicine. Show less
Background Age-related decline in muscle strength, dynapenia, is linked to serious adverse health outcomes. Evidence on the determinants of muscle strength decline in the oldest old is lacking.... Show moreBackground Age-related decline in muscle strength, dynapenia, is linked to serious adverse health outcomes. Evidence on the determinants of muscle strength decline in the oldest old is lacking. Aims To identify clinical variables associated with handgrip strength and its change over a 4-year period in an oldest old cohort. Methods We included 555 participants from the Leiden 85-plus Study, a prospective population-based study of 85-year-old inhabitants of Leiden, the Netherlands. Handgrip strength was assessed at age 85 and 89 years. Anthropometry, mental status, functional performance, and biochemical variables were obtained at baselines. Significant univariates were included into multivariable regression models to extract the final predictive variables. Results Handgrip strength for men and women at age 85 years was 30.6 kg (SD 8.2) and 18.7 kg (SD, 5.5), respectively. In the cross-sectional analysis, body height and weight were positively associated with handgrip strength in both genders. Higher functional performance was associated with stronger handgrip strength in women. Mean absolute handgrip strength decline over 4 years was greater for men than women (- 6.1 kg (SD, 5.2) vs. - 3.4 kg (SD, 4.1),p < 0.001). Men with better baseline cognitive functioning had smaller decline in handgrip strength. Conclusions This study further strengthens evidence linking functional and cognitive performances to muscle strength in the oldest old. Future research is needed to ascertain causality and determine if these markers represent potential targets for intervention. Show less
Background The prevalence of impaired cognitive functioning in older patients with end stage kidney disease (ESKD) is high. We aim to describe patterns of memory, executive function or psychomotor... Show moreBackground The prevalence of impaired cognitive functioning in older patients with end stage kidney disease (ESKD) is high. We aim to describe patterns of memory, executive function or psychomotor speed and to identify nephrologic, geriatric and neuroradiologic characteristics associated with cognitive impairment in older patients approaching ESKD who have not yet started with renal replacement therapy (RRT). Methods The COPE-study (Cognitive Decline in Older Patients with ESRD) is a prospective cohort study including 157 participants aged 65 years and older approaching ESKD (eGFR <= 20 ml/min/1.73 m(2)) prior to starting with RRT. In addition to routinely collected clinical parameters related to ESKD, such as vascular disease burden and parameters of metabolic disturbance, patients received a full geriatric assessment, including extensive neuropsychological testing. In a subgroup of patients (n = 93) a brain MRI was performed. Results The median age was 75.3 years. Compared to the normative data of neuropsychological testing participants memory performance was in the 24th percentile, executive function in the 18th percentile and psychomotor speed in the 20th percentile. Independent associated characteristics of impairment in memory, executive and psychomotor speed were high age, low educational level and low functional status (all p-values < 0.003). A history of vascular disease (p = 0.007) and more white matter hyperintensities on brain MRI (p = 0.013) were associated with a lower psychomotor speed. Conclusion Older patients approaching ESKD have a high prevalence of impaired memory, executive function and psychomotor speed. The patterns of cognitive impairment and brain changes on MRI are suggestive of vascular cognitive impairment. These findings could be of potentially added value in the decision-making process concerning patients with ESKD. Show less
BackgroundChronic kidney disease (CKD) has been identified as a significant direct marker for cognitive decline, but controversy exists regarding the magnitude of the association of kidney function... Show moreBackgroundChronic kidney disease (CKD) has been identified as a significant direct marker for cognitive decline, but controversy exists regarding the magnitude of the association of kidney function with cognitive decline across the different CKD stages. Therefore, the aim of this study was to investigate the association of kidney function with cognitive decline in older patients at high risk of cardiovascular disease, using data from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).MethodsData of 5796 patients of PROSPER were used. Strata were made according to clinical stages of CKD based on estimated glomerular filtration rate; <30ml/min/1.73m(2) (stage 4), 30-45ml/min/1.73m(2) (stage 3b), 45-60ml/min/1.73m(2) (stage 3a) and >= 60ml/min/1.73m(2) (stage 1-2). Cognitive function and functional status was assessed at six different time points and means were compared at baseline and over time, adjusted for multiple prespecified variables. Stratified analyses for history of vascular disease were executed.ResultsMean age was 75.3years and 48.3% participants were male. Mean follow-up was 3.2years. For all cognitive function tests CKD stage 4 compared to the other stages had the worst outcome at baseline and a trend for faster cognitive decline over time. When comparing stage 4 versus stage 1-2 over time the estimates (95% CI) were 2.23 (0.60-3.85; p=0.009) for the Stroop-Colour-Word test, -0.33 (-0.66-0.001; p=0.051) for the Letter-Digit-Coding test, 0.08 (-0.06-0.21; p=0.275) for the Picture-Word-Learning test with immediate recall and-0.07 (-0.02-0.05; p=0.509) for delayed recall. This association was most present in patients with a history of vascular disease. No differences were found in functional status.ConclusionIn older people with vascular burden, only severe kidney disease (CKD stage 4), but not mild to modest kidney disease (CKD stage 3a and b), seem to be associated with cognitive impairment at baseline and cognitive decline over time. The association of severe kidney failure with cognitive impairment and decline over time was more outspoken in patients with a history of vascular disease, possibly due to a higher probability of polyvascular damage, in both kidney and brain, in patients with proven cardiovascular disease. Show less
Background Cognitive and motor-performance decline with age and the process is accelerated by decline in general health. In this study, we aimed to estimate the effects of COPD and HB levels on... Show moreBackground Cognitive and motor-performance decline with age and the process is accelerated by decline in general health. In this study, we aimed to estimate the effects of COPD and HB levels on cognitive and motor performance in the general older population and assess potential interaction. Methods The English Longitudinal Study of Aging is a population-based cohort study including measurements of lung-function and HB levels together with cognitive and motor performance testing. Data were collected from 5709 participants including three measurement time over eight years. COPD was defined using lung-function-parameters and clinical symptoms. HB was assessed continuously and low HB was defined using clinical anemia cutoffs. Linear mixed-effects regression models were used to quantify the associations of COPD and HB with outcome measures, both individually and in combination. Results Participants with both low HB and COPD demonstrated worse motor performance compared to individuals with only one exposure, resulting in up to 1 s (95%CI, 0.04-1.8) longer time needed to complete the five times sit to stand task than what would be expected based on purely additive effects. Additionally in individuals with COPD, the time to complete the motor-performance task per unit decrease in continuous HB levels was longer than in participants without COPD after full adjustment for confounding (up to 1.38 s/unit HB level, 95% CI: 0.65-2.11). Conclusion In persons with COPD low HB levels may contribute to low motor-performance in a supra additive fashion. Further studies should re-evaluate whether earlier treatment of lower HB in these individuals might be beneficial. Show less
Many common disorders, including depression, dementia and obesity are for a large part heritable. Despite the fact that genome-wide association studies (GWAS) have contributed substantially to... Show moreMany common disorders, including depression, dementia and obesity are for a large part heritable. Despite the fact that genome-wide association studies (GWAS) have contributed substantially to unraveling the genetic architecture of these polygenetic disorders, a large amount of ‘missing heritability’ remains. A possible explanation is that GWAS, aside single-nucleotide polymorphisms cannot assess the contribution of other important genetic polymorphisms, especially tandem repeats. Tandem repeats constitute 3% of the human genome. Nine hereditary neurodegenerative diseases, known as polyglutamine diseases, including Huntington disease (HD), are the most prevalent disorders associated with tandem repeat variations. These diseases are caused by an elongated cytosine-adenine-guanine (CAG) repeat sequence in the respective polyglutamine disease-associated gene (PDAG). In this dissertation, we provide ample evidence that CAG repeat variations within the ‘normal’ range in PDAGs can affect various aspects of disease, including the age of onset in HD, cognitive function, depression and body mass index. Finally, we found a relatively large prevalence of intermediate and pathological PDAG alleles in the general population. Therefore, we provided support for the role of repetitive DNA polymorphisms in elucidating the ‘missing heritability’ of polygenetic disorders and emphasized the necessity to include these variations in future genetic research. Show less
Djurovic, M.; Pereira, A.M.; Smit, J.W.A.; Vasovic, O.; Damjanovic, S.; Jemuovic, Z.; ... ; Petakov, M. 2018
