Fusion, 2021

https://hsrc.himmelfarb.gwu.edu/smhs_fusion/1013/thumbnail.jp

Trajectory Data Mining in Mouse Models of Stroke

Contains fulltext : 273912.pdf (Publisher’s version ) (Open Access)Radboud University, 04 oktober 2022Promotor : Kiliaan, A.J. Co-promotor : Wiesmann, M.167 p

Motoric cognitive risk: epidemiology of a walking speed-based syndrome to predict dementia

Dementia is a huge global health challenge without a cure. Identifying the early stages enables the implementation of risk-modifying interventions when they may be most effective. Slow gait speed and self-reported cognitive complaints are among the earliest findings reported in the preclinical stage of dementia. The Motoric Cognitive Risk (MCR) syndrome is a high-risk predementia state combining objective slow gait speed and subjective cognitive complaint in independent, dementia-free individuals. This thesis investigates the association between MCR and dementia using meta-analysis and several epidemiological approaches in a Scottish cohort of community-dwelling older adults. The first study presents a systematic review and meta-analysis of the prognostic ability of MCR. This review also outlined hypotheses regarding the underlying mechanisms of MCR, areas that are explored further in the final chapter of the thesis. It examined longitudinal cohort studies that compared an MCR group to a non-MCR group for any health outcome. A thorough search returned 705 records with 15 cohorts eligible for meta-analysis. The meta-analysis included only health outcomes reported from at least three cohorts and judged satisfactory by our clinical content experts. When a study reported an incompatible effect measure, I contacted authors to request data to allow for our own calculation, or I converted the effect measure where possible and appropriate. The meta-analysis found that participants with MCR were at an increased risk of cognitive impairment (adjusted Hazard Ratio [aHR] 1.76, 95% CI 1.49–2.08; I2 = 24.9%), dementia (aHR 2.12, 1.85–2.42; 33.1%), falls (adjusted relative risk 1.38, 1.15–1.66; 62.1%), and mortality (aHR 1.49, 1.16–1.91; 79.2%). There was considerable heterogeneity in how studies diagnosed MCR, cognitive impairment, and dementia. Our review of the underlying mechanisms of MCR suggested that interactions between MCR, poor brain health, falls, and increased mortality are likely due to a range of biological, psychological, and social mechanisms. A major strength of this systematic review and meta-analysis is the thoroughness of its methodology. The second study of the thesis described the prevalence of MCR and associated factors in the Lothian Birth Cohort 1936 (LBC1936). It was the first time MCR had been derived in a Scottish cohort, so it detailed how MCR was coded and implemented. This study also reported slow gait speed cut-offs for the first time in an older Scottish population. It also assessed the overlap of MCR with three other high-risk states of ageing - Mild Cognitive Impairment (MCI), Prefrailty, and Frailty, thus clarifying the degree of cross-over between these related states. MCR was derived in three waves of the cohort at mean ages of 76.3 years (n = 690), 79.3 years (n = 543) and 82 years (n = 425). MCR prevalence rate ranged from 5.3% to 5.7% across the three waves, a little lower than the global average. Factors associated with MCR in this cohort included age, socioeconomic status, and tests of executive function. There was partial overlap between individuals with MCR and MCI, indicating that these concepts, although derived using similar criteria, capture different cohorts of people. This supports the conceptualisation of MCR as complementary to MCI rather than an alternative. The study highlights the need to explore further the strong association between lower socioeconomic status in early and mid-life with MCR later in life. Building on a key finding from the second study of the thesis, the third study focused on socioeconomic status as a risk factor for MCR. This longitudinal observational study used logistic regression analysis adjusting for important demographic, lifestyle, and health covariates to explore the association between MCR at age 76 years, and years of education and occupational social class, categorised into manual versus non-manual occupations. The final model included 671 participants. Results show that lower socioeconomic status as defined by non-manual versus manual occupation (and not years of education) is associated with a greater than three-fold risk of having MCR later in life (adjusted odds ratio 3.55, 95% CI 1.46–8.74; p = 0.005). Putting this study in context with the literature is difficult as there is a paucity of work focussing on socioeconomic status as a risk factor for MCR. However, having a low socioeconomic status is a widely accepted predictor of ill health generally, and dementia more specifically. Therefore, it is no surprise that it was strongly associated with MCR, which is a high-risk state for dementia. This study highlights a novel risk factor for MCR and offers a hypothesis on underlying mechanisms but concludes by recommending further work to unravel the relationship between lower socioeconomic status and MCR. The fourth study shifted temporarily to focus on identifying dementia in LBC1936, an essential piece of work to allow for the later study of MCR as a predictor of dementia. Previously, the LBC1936 cohort lacked a clinically diagnosed dementia outcome. Our study introduced a novel approach to identifying dementia in cohort studies and reported for the first time the incidence and prevalence of all-cause dementia and its subtypes in the LBC1936. We comprehensively evaluated all participants' electronic health records to identify any indications of cognitive impairment. In addition, we performed in-person clinician assessments whenever a participant's cognition was in doubt. Clinical dementia specialists from Old Age Psychiatry, Neurology, and Geriatrics agreed on a diagnosis of probable dementia, possible dementia, or the absence of dementia, and determined the subtype whenever possible. Of the 865 LBC1936 participants included, 118 (13.6%) had dementia by an average age of approximately 86 years. Dementia was more common with increasing age and in women, and the most common type of dementia was due to Alzheimer disease (49.2%). Self-reported dementia diagnoses were positive in only 17.8% of clinically identified dementia diagnoses. This illustrates the importance of a robust clinical dementia diagnosis instead of relying on self-reported diagnoses. Our work will enable researchers to explore the extensive LBC936 data accumulated over a 16-year period for signals that differentiate participants currently living with dementia from those who are not. This includes my newly derived MCR measure, which brings us to the final study of the thesis. The fifth and final study provided a time-to-event analysis with MCR as the predictor variable and dementia as the outcome of interest. It also explored the various trajectories of participants diagnosed with MCR. It classified a total of 680 community-dwelling participants (mean [SD] age 76.3 [0.8] years) free from dementia into non-MCR or MCR groups. It used Cox proportional hazards methods and competing risk regression to evaluate the risk of developing all-cause dementia in the years following MCR diagnosis. The final model adjusted for potential confounders. Results show that, after 10 years of follow-up, 79 of 680 (11.6%) participants developed dementia. The presence of MCR increased the risk of dementia (aHR 2.34 [1.14 to 4.78, p=0.020]) in this Scottish cohort to a similar extent as in other populations. Individuals with MCR follow similar trajectories to the related predementia syndrome, MCI. This study reinforces that MCR could potentially identify a target group for early interventions of modifiable risk factors for dementia. However, it illustrates the heterogeneous nature of MCR progression and highlights that not all older adults with MCR will follow a similar path. This thesis explores the predementia syndrome MCR through meta-analysis and several epidemiological approaches in the Lothian Birth Cohort 1936. The findings represent a significant advancement in our understanding of MCR prevalence, risk factors, predictive ability, and trajectories. Since there are no effective treatments for dementia, prevention is paramount. By improving our understanding of this high-risk predementia state, this thesis brings us closer to the ultimate goal of intervening early in the lifecourse to reduce the number of people living with dementia

Mineralocorticoids and sodium in chronic kidney disease - regulation and cardiovascular implications

Chronic kidney disease is common and associated with an elevated cardiovascular risk, as well as the long-term risk of renal failure. At present, therapeutic approaches to managing chronic kidney disease (CKD) do not fully reverse these risks. This has led to study of the determinants of pathological outcomes in these patients, with the hope of further therapeutic interventions to reduce these risks. Mineralocorticoids, predominantly aldosterone, are produced by the adrenal cortex and have a vital role in maintaining sodium status and blood pressure. However, high levels of aldosterone in humans are known to produce an adverse phenotype of hypertension and a disproportionately elevated cardiovascular risk. Furthermore, in animal models of renal failure, elevated aldosterone levels stimulate renal damage, in the presence of a high sodium milieu. These laboratory findings have been translated to provide a basis for several short-term follow-up clinical trials looking at the impact of non-genomic non-natriuretic doses of mineralocorticoid receptor inhibition in patients with chronic kidney disease. These studies have shown a reduction in proteinuria, often independent of decline in blood pressure. However, there is a paucity of baseline physiological data relating to the normal regulation of mineralocorticoid synthesis and action in chronic kidney disease. The response of the adrenal cortex to renal failure is not understood. Is mineralocorticoid synthesis regulated in the usual way? Are the stimulators of mineralocorticoid production and release affected by uraemia? Is dietary sodium intake associated with steroid status and adverse outcomes in humans? The hypothesis of this thesis was that the renin-angiotensin-aldosterone system is inappropriately activated in patients with chronic kidney disease. Secondly, that high levels of mineralocorticoids are associated with adverse end-organ damage including proteinuria excretion, left ventricular hypertrophy, endothelial dysfunction, elevated pulse wave velocity and markers of renal fibrosis. Furthermore, that these deleterious effects are associated with sodium status and that an elevated dietary sodium intake is independently associated with increased renal and cardiovascular risk. In order to test these hypotheses, 70 patients with CKD and 30 patients with essential hypertension (EH) were recruited and underwent detailed clinical and biochemical phenotyping. This included 24 hour urinary steroid metabolite analysis, plasma renin and aldosterone measurement, cardiac magnetic resonance imaging, carotid-femoral pulse wave velocity and assessment of endothelial function. 20 It was shown that levels of the main mineralocorticoids (MC) (aldosterone and deoxycorticosterone) are not elevated in patients with CKD, as compared with patients with essential hypertension (EH). However, the determinants of levels of MC excretion differed between the two conditions. In CKD, excretion of MC metabolites was directly proportional to excretion of urinary sodium. A high urinary sodium (a marker of dietary sodium intake) was associated with a higher excretion of tetrahydroaldosterone (THALDO - the main aldosterone metabolite). In patients with EH, no relationship was seen between urinary steroid excretion and urinary sodium excretion. This is a novel relationship between the kidney and adrenal gland which questions the conventional wisdom that the adrenal cortex is unaffected by uraemia and prompts further study into the regulation of steroid synthesis in CKD. Furthermore, it was shown for the first time that 24h excretion of tetrahydrodeoxycorticosterone (THDOC) is an independent predictor of left ventricular mass index and that THALDO is an independent predictor of proteinuria excretion – demonstrating a relationship between mineralocorticoids and two of the main predictors of mortality in CKD. An interaction between sodium, MCs and these two features was also demonstrated. No association between levels of mineralocorticoids and vascular function was seen. Urinary 24 hour excretion of sodium was significantly associated with endothelial dysfunction in patients with CKD and pulse wave velocity in patients with essential hypertension. Retrospective data analysis further confirmed an association between a high dietary sodium intake and adverse outcomes. In a study of 498 patients with CKD and a median follow-up of 7 years, an elevated 24h urinary sodium to creatinine ratio was shown to be associated with an increased risk of death. There was however no independent association with renal progression or requirement for renal replacement therapy. This is the first time that sodium intake has been clearly linked to adverse outcomes in patients with CKD. Lastly, laboratory work demonstrated that steroid stimulation (aldosterone or cortisol) of human proximal tubular cells resulted in increased collagen 1 gene expression, but only in the context of a high sodium environment. Collagen 1 is deposited in renal interstitial fibrosis. This effect was inhibited by MR blockade, further expanding on the potential role 21 of steroids in the progression of CKD and again confirming the relationship between salt and steroids. In conclusion, in this thesis it has been demonstrated that production of MCs in patients with CKD is closely associated with urinary sodium excretion (a surrogate for dietary sodium intake). This relationship is novel and not seen in patients with essential hypertension. It suggests that the response of the adrenal cortex in the context of uraemia is altered. Moreover, levels of mineralocorticoids are independently associated with left ventricular mass index and proteinuria excretion, both significant predictors of mortality, in patients with CKD. Dietary sodium intake has been shown to be an independent predictor of mortality and laboratory studies have demonstrated that mineralocorticoid receptor binding in a high sodium environment is associated with collagen 1 gene upreguation. These findings have important implications for the role of adequate renin-angiotensin-aldosterone blockade in patients with CKD and suggest that the addition of a mineralocorticoid receptor blocker and dietary sodium restriction should be advocated

Prevention and Management of Frailty

It is important to prevent and manage the frailty of the elderly because their muscle strength and physical activity decrease in old age, making them prone to falling, depression, and social isolation. In the end, they need to be admitted to a hospital or a nursing home. When successful aging fails and motor ability declines due to illness, malnutrition, or reduced activity, frailty eventually occurs. Once frailty occurs, people with frailty do not have the power to exercise or the power to move. The functions of the heart and muscles are deteriorated more rapidly when they are not used. Consequently, frailty goes through a vicious cycle. As one’s physical fitness is deteriorated, the person has less power to exercise, poorer cognitive functions, and inferior nutrition intake. Consequently, the whole body of the person deteriorates. Therefore, in addition to observational studies to identify risk factors for preventing aging, various intervention studies have been conducted to develop exercise programs and apply them to communities, hospitals, and nursing homes for helping the elderly maintain healthy lives. Until now, most aging studies have focused on physical frailty. However, social frailty and cognitive frailty affect senile health negatively just as much as physical frailty. Nevertheless, little is known about social frailty and cognitive frailty. This special issue includes original experimental studies, reviews, systematic reviews, and meta-analysis studies on the prevention of senescence (physical senescence, cognitive senescence, social senescence), high-risk group detection, differentiation, and intervention

Proceedings Virtual Imaging Trials in Medicine 2024

This submission comprises the proceedings of the 1st Virtual Imaging Trials in Medicine conference, organized by Duke University on April 22-24, 2024. The listed authors serve as the program directors for this conference. The VITM conference is a pioneering summit uniting experts from academia, industry and government in the fields of medical imaging and therapy to explore the transformative potential of in silico virtual trials and digital twins in revolutionizing healthcare. The proceedings are categorized by the respective days of the conference: Monday presentations, Tuesday presentations, Wednesday presentations, followed by the abstracts for the posters presented on Monday and Tuesday

BIOMECHANICS AND BIOCHEMISTRY OF THE AORTA IN CHRONIC AORTIC DISSECTION

Chronic aortic dissection (AD) is defined as being one in which there is a tear which originates in aortic wall and has been present for more than 30 days. Chronic AD tends to be associated with a weakened aortic wall. Eventually the degenerated, weakened aortic wall may rupture. Although tensile or biaxial testing techniques have previously been used in vitro for biomechanical testing of AD tissues at the macro-scale, little is known about how localised changes in aortic structure and biomechanics contribute to progression of chronic AD. To find a way to address this challenge, the nanoindentation technique and ball indentation tests were used to investigate localised mechanical properties and time-dependent deformation behaviour respectively, of human aortic tissue samples from chronic AD patients. Using ovine aortic tissue as a model, the utility of the nanoindentation technique and ball indentation methods were validated and optimised. The data were correlated with conventional uniaxial indentation testing. Further, the mechanical properties and biochemical composition (collagen, elastin and GAG) were correlated across the entire aortic length. The human tissue work characterised the biomechanics, biochemistry, and histology of the dissection flap (FP), true lumen outer wall (TL) and false lumen outer wall (FL) in chronic dissection. These micromechanical properties and biochemical properties were compared with clinical data (interval of index event to operation (IIEO) and aortic growth rate). The main outcome of this thesis was the demonstration of how structural properties of dissection tissues within the aortic wall alter with time. FP and TL are stiffer with the arrangement of elastin fibres being highly compact, long, and aligned, whereas the FL was more compliant with localised loss of elastic fibres and increased elastin fragmentation that correlated with IIEO. Overall, the findings of this thesis suggest that indications for surgery in chronic AD, which are currently based on aortic size, may be independent of features such as aetiology, aortic dimensions, and anatomical segment

Racemases and epimerases operating through a 1,1-proton transfer mechanism:Reactivity, mechanism and inhibition

Racemases and epimerases catalyse changes in the stereochemical configurations of chiral centres and are of interest as model enzymes and as biotechnological tools. They also occupy pivotal positions within metabolic pathways and, hence, many of them are important drug targets. This review summarises the catalytic mechanisms of PLP-dependent, enolase family and cofactor-independent racemases and epimerases operating by a deprotonation/reprotonation (1,1-proton transfer) mechanism and methods for measuring their catalytic activity. Strategies for inhibiting these enzymes are reviewed, as are specific examples of inhibitors. Rational design of inhibitors based on substrates has been extensively explored but there is considerable scope for development of transition-state mimics and covalent inhibitors and for the identification of inhibitors by high-throughput, fragment and virtual screening approaches. The increasing availability of enzyme structures obtained using X-ray crystallography will facilitate development of inhibitors by rational design and fragment screening, whilst protein models will facilitate development of transition-state mimics