Background: The association of age with coronary plaque dynamics is not well characterized by coronary computed tomography angiography (CCTA).Methods: From a multinational registry of patients who... Show moreBackground: The association of age with coronary plaque dynamics is not well characterized by coronary computed tomography angiography (CCTA).Methods: From a multinational registry of patients who underwent serial CCTA, 1153 subjects (61 +/- 5 years old, 61.1% male) were analyzed. Annualized volume changes of total, fibrous, fibrofatty, necrotic core, and dense calcification plaque components of the whole heart were compared by age quartile groups. Clinical events, a composite of all-cause death, acute coronary syndrome, and any revascularization after 30 days of the initial CCTA, were also analyzed. Random forest analysis was used to define the relative importance of age on plaque progression.Results: With a 3.3-years' median interval between the two CCTA, the median annual volume changes of total plaque in each age quartile group was 7.8, 10.5, 10.8, and 12.1 mm(3)/year and for dense calcification, 2.5, 4.6, 5.4, and 7.1 mm(3)/year, both of which demonstrated a tendency to increase by age (p-for-trend = 0.001 and < 0.001, respectively). However, this tendency was not observed in any other plaque components. The annual volume changes of total plaque and dense calcification were also significantly different in the propensity score-matched lowest age quartile group versus the other age groups as was the composite clinical event (log-rank p = 0.003). In random forest analysis, age had comparable importance in the total plaque volume progression as other traditional factors.Conclusions: The rate of whole-heart plaque progression and dense calcification increases depending on age. Age is a significant factor in plaque growth, the importance of which is comparable to other traditional risk factors. Show less
Background Aging is a multifactorial process that affects multiple tissues and is characterized by changes in homeostasis over time, leading to increased morbidity. Whole blood gene expression... Show moreBackground Aging is a multifactorial process that affects multiple tissues and is characterized by changes in homeostasis over time, leading to increased morbidity. Whole blood gene expression signatures have been associated with aging and have been used to gain information on its biological mechanisms, which are still not fully understood. However, blood is composed of many cell types whose proportions in blood vary with age. As a result, previously observed associations between gene expression levels and aging might be driven by cell type composition rather than intracellular aging mechanisms. To overcome this, previous aging studies already accounted for major cell types, but the possibility that the reported associations are false positives driven by less prevalent cell subtypes remains. Results Here, we compared the regression model from our previous work to an extended model that corrects for 33 additional white blood cell subtypes. Both models were applied to whole blood gene expression data from 3165 individuals belonging to the general population (age range of 18-81 years). We evaluated that the new model is a better fit for the data and it identified fewer genes associated with aging (625, compared to the 2808 of the initial model; P <= 2.5x10(-6)). Moreover, 511 genes (similar to 18% of the 2808 genes identified by the initial model) were found using both models, indicating that the other previously reported genes could be proxies for less abundant cell types. In particular, functional enrichment of the genes identified by the new model highlighted pathways and GO terms specifically associated with platelet activity. Conclusions We conclude that gene expression analyses in blood strongly benefit from correction for both common and rare blood cell types, and recommend using blood-cell count estimates as standard covariates when studying whole blood gene expression. Show less
Jung, Y.J.; Viviano, R.P.; Rooden, S. van; Grond, J. van der; Rombouts, S.A.R.B.; Damoiseaux, J.S. 2021
Background: White matter hyperintensities (WMH) show a robust relationship with arterial pressure as well as objective and subjective cognitive functioning. In addition, APOE epsilon 4 carriership... Show moreBackground: White matter hyperintensities (WMH) show a robust relationship with arterial pressure as well as objective and subjective cognitive functioning. In addition, APOE epsilon 4 carriership may influence how arterial pressure affects cognitive functioning.Objective: To determine the role of region-specific WMH burden and APOE epsilon 4 carriership on the relationship between mean arterial pressure (MAP) and cognitive function as well as subjective cognitive decline (SCD).Methods: The sample consisted of 87 cognitively unimpaired middle-aged to older adults aged 50-85. We measured WMH volume for the whole brain, anterior thalamic radiation (ATR), forceps minor, and superior longitudinal fasciculus (SLF). We examined whether WMH burden mediated the relationship between MAP and cognition (i.e., TMT-A score for processing speed; Stroop performance for executive function) as well as SCD (i.e., Frequency of Forgetting (FoF)), and whether APOE epsilon 4 carriership moderated that mediation.Results: WMH burden within SLF mediated the effect of MAP on Stroop performance. Both whole brain and ATR WMH burden mediated the effect of MAP on FoF score. In the MAP-WMH-Stroop relationship, the mediation effect of SLFWMH and the effect of MAP on SLF WMH were significant only in APOE epsilon 4 carriers. In the MAP-WMH-FoF relationship, the effect of MAP on whole brain WMH burden was significant only in epsilon 4 carriers.Conclusion: WMH burden and APOE genotype explain the link between blood pressure and cognitive function and may enable a more accurate assessment of the effect of high blood pressure on cognitive decline and risk for dementia. Show less
Giacconi, R.; Maggi, F.; Macera, L.; Spezia, P.G.; Pistello, M.; Provinciali, M.; ... ; Malavolta, M. 2020
Torquetenovirus (TTV) viremia has been associated with increased mortality risk in the elderly population. This work aims to investigate TTV viremia as a potential biomarker of immunosenescence. We... Show moreTorquetenovirus (TTV) viremia has been associated with increased mortality risk in the elderly population. This work aims to investigate TTV viremia as a potential biomarker of immunosenescence. We compared levels of circulating TTV in 1813 participants of the MARK-AGE project, including human models of delayed (offspring of centenarians [GO]) and premature (Down syndrome [DS]) immunosenescence. The TTV load was positively associated with age, cytomegalovirus (CMV) antibody levels, and the Cu/Zn ratio and negatively associated with platelets, total cholesterol, and total IgM. TTV viremia was highest in DS and lowest in GO, with intermediate levels in the SGO (spouses of GO) and RASIG (Randomly Recruited Age-Stratified Individuals From The General Population) populations. In the RASIG population, TTV DNA loads showed a slight negative association with CD3+T-cells and CD4+T-cells. Finally, males with >= 4log TTV copies/mL had a higher risk of having a CD4/CD8 ratio<1 than those with lower viremia (odds ratio [OR] = 2.85, 95% confidence interval [CI]: 1.06-7.62), as well as reduced CD3+ and CD4+T-cells compared to males with lower replication rates (<4log), even after adjusting for CMV infection. In summary, differences in immune system preservation are reflected in the models of delayed and premature immunosenescence, displaying the best and worst control over TTV replication, respectively. In the general population, TTV loads were negatively associated with CD4+ cell counts, with an increased predisposition for an inverted CD4/CD8 ratio for individuals with TTV loads >= 4log copies/mL, thus promoting an immune risk phenotype. Show less
My research projects include the investigation of effects of different environmental factors on sleep and the circadian clock in the course of aging (such as light levels, exercise, diet and... Show moreMy research projects include the investigation of effects of different environmental factors on sleep and the circadian clock in the course of aging (such as light levels, exercise, diet and pharmacological substances including caffeine and diazepam). Investigating thebeneficial or adverse effects in the course of aging provides significant insights that could accelerate, hinder or ameliorate parts of the aging process allowing for a healthier and longer life span.Chronic consupmtion of high-caloric diet, eventually leading to obesity, alters the sleep homeostasis as well as the sleep architecture denoting a potentially enhanced aging phenotype.In addition to dietary preferences, light levels particularly at night significantly affect sleep and the sleep electroencephalogram across a wide age span, impactingthe sleep regulatory system as well as the brain integrity.Factors that induce beneficial effects include exercise and caffeine intake. Long-term exercise was able to lead to a younger brain phenotype across all ages while caffeine generally ameliorated sleep health. Show less
Montfort, S.J.T. van; Slooter, A.J.C.; Kant, I.M.J.; Leur, R.R. van der; Spies, C.; Bresser, J. de; ... ; Dellen, E. van 2020
Delirium, the clinical expression of acute encephalopathy, is a common neuropsychiatric syndrome that is related to poor outcomes, such as long-term cognitive impairment. Disturbances of functional... Show moreDelirium, the clinical expression of acute encephalopathy, is a common neuropsychiatric syndrome that is related to poor outcomes, such as long-term cognitive impairment. Disturbances of functional brain networks are hypothesized to predispose for delirium. The aim of this study in non-delirious elderly individuals was to investigate whether predisposing risk factors for delirium are associated with fMRI network characteristics that have been observed during delirium. As predisposing risk factors, we studied age, alcohol misuse, cognitive impairment, depression, functional impairment, history of transient ischemic attack or stroke, and physical status. In this multicenter study, we included 554 subjects and analyzed resting-state fMRI data from 222 elderly subjects (63% male, age range: 65-85 year) after rigorous motion correction. Functional network characteristics were analyzed and based on the minimum spanning tree (MST). Global functional connectivity strength, network efficiency (MST diameter) and network integration (MST leaf fraction) were analyzed, as these measures were altered during delirium in previous studies. Linear regression analyses were used to investigate the relation between predisposing delirium risk factors and delirium-related fMRI characteristics, adjusted for confounding and multiple testing. Predisposing risk factors for delirium were not associated with delirium-related fMRI network characteristics. Older age within our elderly cohort was related to global functional connectivity strength (beta = 0.182, p < 0.05), but in the opposite direction than hypothesized. Delirium-related functional network impairments can therefore not be considered as the common mechanism for predisposition for delirium. Show less
Overbeek, C.L.; Kolk, A.; Groot, J.H. de; Witte, P.B. de; Gademan, M.G.J.; Nelissen, R.G.H.H.; Nagels, J. 2019
Middle-aged individuals cocontract with adductor muscles during abduction. This may be crucial for counteracting deltoid forces, depressing the humerus and ensuring free passage of subacromial... Show moreMiddle-aged individuals cocontract with adductor muscles during abduction. This may be crucial for counteracting deltoid forces, depressing the humerus and ensuring free passage of subacromial tissues underneath the acromion during abduction. We questioned whether adductor co-contraction is always present, or develops during ageing, in which case it may explain the age-related character of common shoulder conditions such as Subacromial Pain Syndrome. In a cross-sectional analysis with electromyography (EMG), activation patterns of the latissimus dorsi, teres major, pectoralis major and deltoid muscle were assessed during isometric force tasks in 60 asymptomatic individuals between 21 and 60 years old. Cocontraction was expressed as the degree of antagonistic activation relative to the same muscle's degree of agonistic activation, resulting in an activation ratio between -1 and 1, where lower values indicate more cocontraction. Using linear regression analyses, we found age-related decreases in the activation ratio of the latissimus dorsi (regression estimate: -0.004, 95% CI: -0.007 to 0.0, p-value: 0.042) and teres major (regression estimate: -0.013, 95% CI: -0.019 to -0.008, p-value: < 0.001). In contrast to young individuals, middle-aged individuals showed a high degree of adductor cocontraction during abduction. This may indicate that during ageing, alterations in activation patterns are required for preserving pain-free shoulder function. Show less
Schipper, L.J. de; Hafkemeijer, A.; Bouts, M.J.R.J.; Grond, J. van der; Marinus, J.; Henselmans, J.M.L.; Hilten, J.J. van 2019
The subject of this Thesis is the role of the immune system in age-related eye diseases, such as glaucoma. Glaucoma is a disease that afflicts nearly 70 million people worldwide. Little is known... Show moreThe subject of this Thesis is the role of the immune system in age-related eye diseases, such as glaucoma. Glaucoma is a disease that afflicts nearly 70 million people worldwide. Little is known about the origins of the disease, which damages the retina and optic nerve and can lead to blindness. One of the biggest risk factors for glaucoma is elevated eye pressure. Our study found that glaucoma may in fact be an autoimmune disorder. We found that the body’s own T cells are responsible for the progressive retinal degeneration seen in glaucoma. Furthermore these T cells appear to be primed to attack retinal neurons as the result of previous interactions with bacteria that normally live in our body. This opens a new approach to prevent and treat glaucoma. Currently most treatments focus on lowering eye pressure. However, in many patients, the disease worsens even after intraocular pressure returns to normal. We showed that when we blocked these autoreactive T cells in the eye, not only does it diminish the loss of retinal ganglion cells and axons, but it also preserves retinal function. Show less
Thoracale epidurale anesthesie (TEA), ook wel ruggenprik genoemd, zorgt voor een uitstekende pijnstilling rondom operaties en wordt als zodanig veelvuldig toegepast binnen de cardiothoracale... Show moreThoracale epidurale anesthesie (TEA), ook wel ruggenprik genoemd, zorgt voor een uitstekende pijnstilling rondom operaties en wordt als zodanig veelvuldig toegepast binnen de cardiothoracale chirurgie. TEA heeft echter ook effecten op het hart en de bloedsomloop. Hoewel in fysiologische studies is aangetoond dat thoracale epidurale anesthesie gunstige effecten heeft op het hart, heeft zich dit in grote klinische studies niet vertaald in een betere uitkomst. Dit proefschrift beschrijft de anatomie en fysiologie van het hart tijdens TEA bij patiënten die een long ingreep ondergaan. Het doel van dit proefschrift is het bepalen van de bijwerkingen van TEA op het hart en de bloedsomloop waarbij deze effecten van TEA zowel tijdens rust als gedurende omstandigheden van stress (zoals tijdens operatie of inspanning) onderzocht werden. De resultaten van dit proefschrift tonen aan dat TEA de functie van de rechter hartkamer vermindert. Dit proefschrift toont ook aan dat de toename van de linker- en rechter kamerfunctie tijdens inspanning nauwelijks wordt beïnvloed door TEA. Leeftijd lijkt geen duidelijke invloed te hebben op de bijwerkingen van TEA. Het is nog niet duidelijk in hoeverre deze resultaten klinisch relevant zijn. Echter, de resultaten uit dit proefschrift zouden kunnen helpen bij het maken van weloverwogen besluiten rond het gebruik van TEA bij cardiothoracale chirurgie. Show less
Structural brain markers are studied extensively in the field of neurodegeneration, but are thought to occur rather late in the process. Functional measures such as functional connectivity are... Show moreStructural brain markers are studied extensively in the field of neurodegeneration, but are thought to occur rather late in the process. Functional measures such as functional connectivity are gaining interest as potentially more subtle markers of neurodegeneration. However, brain structure and function are also affected by ‘normal’ brain ageing. More information is needed on how functional connectivity relates to aging, particularly in the absence of overt neurodegenerative disease. We investigated the association of age with resting-state functional connectivity in 2878 non-demented persons between 50 and 95 years of age (54.1% women) from the population-based Rotterdam Study. We obtained nine well-known resting state networks using data-driven methodology. Within the anterior default mode network, ventral attention network, and sensorimotor network, functional connectivity was significantly lower with older age. In contrast, functional connectivity was higher with older age within the visual network. Between resting state networks, we found patterns of both increases and decreases in connectivity in approximate equal proportions. Our results reinforce the notion that the aging brain undergoes a reorganization process, and serves as a solid basis for exploring functional connectivity as a preclinical marker of neurodegenerative disease. Show less
The main objective of this thesis was to investigate the serotonergic and cholinergic neurotransmitter systems, and the way these are altered in older age and Alzheimer’s disease. For that purpose,... Show moreThe main objective of this thesis was to investigate the serotonergic and cholinergic neurotransmitter systems, and the way these are altered in older age and Alzheimer’s disease. For that purpose, the neuroimaging technique resting state fMRI (RS-fMRI) was used to measure whole brain functional connectivity with and without pharmacological stimulation. The first part of the thesis concerns two pharmacological RS-fMRI studies that were executed in young adults. Pharmacological challenge effects of two selective serotonin reuptake inhibitors (sertraline and citalopram) and a cholinesterase inhibitor (galantamine) on brain connectivity were examined to gain more insight into the underlying neurotransmitter systems and the mechanisms of drug action in the central nervous system. The second part of this thesis was aimed at discovering changes in brain connectivity and serotonergic and cholinergic system functioning in aging and Alzheimer’s disease, by comparing brain network connections and the pharmacological response of this measure between young and older adults and patients with Alzheimer’s disease. Show less
In this thesis the risk factors of venous thrombosis will be discussed in the general and particularly the elderly population. The goal of this thesis is to provide insights on risk factors of... Show moreIn this thesis the risk factors of venous thrombosis will be discussed in the general and particularly the elderly population. The goal of this thesis is to provide insights on risk factors of thrombosis in the elderly population, in order to advance our basic understanding of physiological age-related changes that increase the risk of venous thrombosis and which may ultimately lead to improved personalized interventions. In this chapter firstly background information will be provided on risk factors for venous thrombosis, focussing specifically on age as a risk factor. Secondly, the role of veins and venous valves in the development of venous thrombosis will be discussed and thirdly, global assays as a potential tool to identify patients at high risk for venous thrombosis will be considered. The study populations used in this thesis will discussed, and an outline of this thesis will be provided. Show less
Koini, M.; Duering, M.; Gesierich, B.G.; Rombouts, S.A.R.B.; Ropele, S.; Wagner, F.; ... ; Schmidt, R. 2018
