Sex-differences in the association of social health and marital status with blood-based immune and neurodegeneration markers in a cohort of community-dwelling older adults.

BACKGROUND: The immune system has been proposed to play a role in the link between social health and all-cause dementia risk. We explored cross-sectional and longitudinal associations between social health, immune system balance and plasma neurodegeneration markers in community-dwelling older adults, and explored whether the balance between innate and adaptive immunity mediates associations between social health and both cognition and total brain volume. METHODS: Social health markers (social support, marital status, loneliness) were measured in the Rotterdam Study between 2002-2008. Immune system cell counts and balance were assessed repeatedly from 2002 to 2016 using white blood-cell-based indices and individual counts (granulocyte-to-lymphocyte ratio (GLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)). Plasma neurodegeneration biomarkers (amyloid-ß40, amyloid-ß42, total tau and neurofilament light chain) were measured once from blood samples collected between 2002-2008. Global cognitive function and total brain volume (MRI) were measured at the follow-up visit between 2009-2014. We used linear mixed models to study longitudinal associations and performed causal mediation analyses. RESULTS: In 8374 adults (mean age 65.7, 57 % female), never married participants (n = 394) had higher GLR, PLR and SII compared to married peers at baseline and during follow-up, indicating imbalance towards innate immunity. Being never married was associated with higher plasma amyloid-ß40, and being widowed or divorced with higher plasma total tau levels at baseline. Widowed or divorced males, but not females, had higher GLR, PLR and SII at baseline. Higher social support was associated with lower PLR in females, but higher PLR in males. Loneliness was not associated with any of the immune system balance ratios. Never married males had higher levels of all plasma neurodegeneration markers at baseline. Immune system balance did not mediate associations between social health and cognition or total brain volume, but does interact with marital status. CONCLUSION: This study indicates that marital status is associated with blood-based immune system markers toward innate immunity and higher levels of plasma neurodegeneration markers. This is particularly evident for never married or previously married male older adults compared to married or female peers.

NT-proBNP and changes in cognition and global brain structure: The Rotterdam Study.

OBJECTIVE: To investigate the association between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and changes in cognition and global brain structure. METHODS: In the Rotterdam Study, baseline NT-proBNP was assessed at baseline from 1997 to 2008. Between 1997 and 2016, participants without dementia or stroke at baseline (n = 9566) had repeated cognitive tests (every 3-6 years) for global cognitive function, executive cognitive function, fine manual dexterity, and memory. Magnetic resonance imaging of the brain was performed repeatedly at re-examination visits between 2005 and 2015 for 2607 participants to obtain brain volumes, focal brain lesions, and white matter microstructural integrity as measures of brain structure. RESULTS: Among 9566 participants (mean age 65.1 ± 9.8 years), 5444 (56.9%) were women, and repeated measures of cognition were performed during a median follow-up time of 5.5 (range 1.1-17.9) years, of whom 2607 participants completed at least one brain imaging scan. Higher levels of NT-proBNP were associated with a faster decline of scores in the global cognitive function (p value = 0.003) and the Word-Fluency test (p value = 0.003) but were not related to a steeper deterioration in brain volumes, global fractional anisotropy, and mean diffusivity, as indicators of white matter microstructural integrity, or focal brain lesions. CONCLUSIONS: Higher baseline NT-proBNP levels were associated with a faster decline in cognition; however, no association with global brain structure was found.

Subcortical brain structures and the risk of dementia in the Rotterdam Study.

INTRODUCTION: Volumetric and morphological changes in subcortical brain structures are present in persons with dementia, but it is unknown if these changes occur prior to diagnosis. METHODS: Between 2005 and 2016, 5522 Rotterdam Study participants (mean age: 64.4) underwent cerebral magnetic resonance imaging (MRI) and were followed for development of dementia until 2018. Volume and shape measures were obtained for seven subcortical structures. RESULTS: During 12 years of follow-up, 272 dementia cases occurred. Mean volumes of thalamus (hazard ratio [HR] per standard deviation [SD] decrease 1.94, 95% confidence interval [CI]: 1.55-2.43), amygdala (HR 1.66, 95% CI: 1.44-1.92), and hippocampus (HR 1.64, 95% CI: 1.43-1.88) were strongly associated with dementia risk. Associations for accumbens, pallidum, and caudate volumes were less pronounced. Shape analyses identified regional surface changes in the amygdala, limbic thalamus, and caudate. DISCUSSION: Structure of the amygdala, thalamus, hippocampus, and caudate is associated with risk of dementia in a large population-based cohort of older adults.

Determinants of social health trajectories during the COVID-19 pandemic in older adults: the Rotterdam Study.

OBJECTIVES: The coronavirus disease-2019 (COVID-19) pandemic and accompanying lockdown restrictions impacted social life significantly. We studied associations of sociodemographic factors, mental and social health markers, and brain structure with social health trajectories during the COVID-19 pandemic. DESIGN: Prospective longitudinal population-based cohort study. SETTING: Community-dwelling inhabitants of Rotterdam, the Netherlands. PARTICIPANTS: Repeated questionnaires including questions on social health were sent to Rotterdam Study participants from April 2020 onwards. Social health data at study baseline were available for 5017 participants (mean age: 68.7 ± 11.3; 56.9% women). MEASUREMENTS: Determinants were assessed in routine Rotterdam Study follow-up (1990-2020), including global brain volumes in a subset of participants (N = 1720). We applied linear mixed models and generalized estimating equations to quantify associations between determinants and trajectories of loneliness, perceived social isolation and social connectedness over three time points from April 22nd to July 31st 2020. RESULTS: Loneliness prevalence was 27.9% in April 2020 versus 12.6% prepandemic. Social isolation (baseline mean 4.7 ± 2.4) and loneliness scores (baseline mean 4.9 ± 1.5) decreased over time, whereas social connectedness trajectories remained stable. Depressive symptoms, female sex, prepandemic loneliness, living alone, and not owning a pet were independently associated with lower social connectedness and higher social isolation and loneliness at COVID-19 baseline, but recovery of social health was similar for all determinants. Larger intracranial volume was associated with higher social connectedness. CONCLUSIONS: Despite baseline differences for specific determinants, older adults showed similar recovery of loneliness and social isolation alongside stable social connectedness over time during the pandemic. Social health is multidimensional, especially during a global health crisis.

The network of psychosocial health in middle-aged and older adults during the first COVID-19 lockdown.

PURPOSE: Psychosocial health problems, such as social isolation, loneliness, depression and anxiety, have gained attention during the COVID-19 pandemic and are commonly co-occurring. We investigated the network of psychosocial health constructs during the COVID-19 pandemic. METHODS: This study included 4553 participants (mean age: 68.6 ± 11.2 years, 56% women) from the prospective Rotterdam Study, who filled out a questionnaire between April and July 2020, the time of the first COVID-19 wave in the Netherlands. Psychosocial health constructs included were depressive symptoms (Center for Epidemiological Studies Depression scale), anxiety symptoms (Hospital Anxiety and Depression scale), loneliness (University of California, Los Angeles loneliness scale), social connectedness (five items) and pandemic-related worry (five items). We estimated mixed graphical models to assess the network of items of these constructs and whether age and sex affected the network structure. RESULTS: Within the network of psychosocial constructs, a higher depressive symptoms score was particularly associated with items of loneliness and social connectedness, whereas overall anxiety was particularly associated with items of pandemic-related worry. Between people from different sex and age, the network structure significantly altered. CONCLUSION: This study demonstrates that within the same network of psychosocial health constructs, depressive symptom score is particularly associated with loneliness and social connectedness, whereas anxiety symptom score is associated with pandemic-related worry during the first COVID-19 lockdown. Our results support that psychosocial constructs should be considered in conjunction with one another in prevention and treatment efforts in clinical care, and that these efforts need to be tailored to specific demographic groups.

Hemodynamic and serum cardiac markers and risk of cognitive impairment and dementia.

INTRODUCTION: Cardiac function is a key player in maintaining energy homeostasis in the brain. Heart failure is closely related to higher risk of neurocognitive disorders. Recent evidence shows that this relationship might not be limited to patients with advanced heart failure, and even suboptimal cardiac functioning is associated with accelerated brain aging. Hence, hemodynamic and serum cardiac markers may provide valuable information about the risk of dementia. METHODS: We provide an overview on the link between cardiac markers and cognitive function by a systematic search in five databases. Furthermore, we discuss the pathophysiological aspects of this link and highlight the pertinent clinical and public health implications. RESULTS: Increasing evidence supports the associations of hemodynamic and serum cardiac markers with accelerated cognitive decline. DISCUSSION: Hemodynamic and serum cardiac markers are closely linked with risk of cognitive impairment. This highlights the significance of the heart-brain connection in reducing the burden of dementia.

Where is VALDO? VAscular Lesions Detection and segmentatiOn challenge at MICCAI 2021.

Imaging markers of cerebral small vessel disease provide valuable information on brain health, but their manual assessment is time-consuming and hampered by substantial intra- and interrater variability. Automated rating may benefit biomedical research, as well as clinical assessment, but diagnostic reliability of existing algorithms is unknown. Here, we present the results of the VAscular Lesions DetectiOn and Segmentation (Where is VALDO?) challenge that was run as a satellite event at the international conference on Medical Image Computing and Computer Aided Intervention (MICCAI) 2021. This challenge aimed to promote the development of methods for automated detection and segmentation of small and sparse imaging markers of cerebral small vessel disease, namely enlarged perivascular spaces (EPVS) (Task 1), cerebral microbleeds (Task 2) and lacunes of presumed vascular origin (Task 3) while leveraging weak and noisy labels. Overall, 12 teams participated in the challenge proposing solutions for one or more tasks (4 for Task 1-EPVS, 9 for Task 2-Microbleeds and 6 for Task 3-Lacunes). Multi-cohort data was used in both training and evaluation. Results showed a large variability in performance both across teams and across tasks, with promising results notably for Task 1-EPVS and Task 2-Microbleeds and not practically useful results yet for Task 3-Lacunes. It also highlighted the performance inconsistency across cases that may deter use at an individual level, while still proving useful at a population level.

Psychosocial health modifies associations between HPA-axis function and brain structure in older age.

BACKGROUND: Dysregulation of the negative feedback loop of the hypothalamic-pituitary-adrenal (HPA) axis may have damaging effects on the brain, potentially under influence of psychosocial health factors. We studied associations between functioning of the negative feedback loop of HPA-axis, measured with a very low-dose dexamethasone suppression test (DST), and brain structure in middle-aged and older adults, and whether these associations were modified by psychosocial health. METHODS: From 2006 to 2008, 1259 participants (mean age 57.6 ± 6.4, 59.6 % female) of the population-based Rotterdam Study completed a very low-dose DST (0.25 mg) and underwent magnetic resonance imaging (MRI) of the brain. Self-reported psychosocial health (depressive symptoms, loneliness, marital status, perceived social support) were assessed in the same time period. Multivariable linear and logistic regression were used to study cross-sectional associations between cortisol response and brain volumetrics, cerebral small vessel disease markers and white matter structural integrity. To assess the effect of psychosocial health on these associations, analyses were further stratified for psychosocial health markers. RESULTS: Cortisol response was not associated with markers of global brain structure in the overall study sample. However, in participants with clinically relevant depressive symptoms, a diminished cortisol response was associated with smaller white matter volume (mean difference: - 1.00 mL, 95 %CI = - 1.89;- 0.10) and smaller white matter hyperintensity volume (mean difference: - 0.03 mL (log), 95 %CI = - 0.05;0.00). In participants with low/moderate perceived social support compared to those with high social support, a diminished cortisol response was associated with larger gray matter volume (mean difference: 0.70 mL, 95 %CI = 0.01;1.39) and higher fractional anisotropy (standardized mean difference 0.03, 95 %CI = 0.00;0.06). CONCLUSION: Diminished function of the HPA-axis is differently associated with brain structure in community-dwelling middle-aged and older adults with clinically relevant depressive symptoms or suboptimal social support, but not in adults without depressive symptoms or with optimal social support.

Social Health Is Associated With Tract-Specific Brain White Matter Microstructure in Community-Dwelling Older Adults.

Background: Poor social health has been linked to a risk of neuropsychiatric disorders. Neuroimaging studies have shown associations between social health and global white matter microstructural integrity. We aimed to identify which white matter tracts are involved in these associations. Methods: Social health markers (loneliness, perceived social support, and partnership status) and white matter microstructural integrity of 15 white matter tracts (identified with probabilistic tractography after diffusion magnetic resonance imaging) were collected for 3352 participants (mean age 58.4 years, 54.9% female) from 2002 to 2008 in the Rotterdam Study. Cross-sectional associations were studied using multivariable linear regression. Results: Loneliness was associated with higher mean diffusivity (MD) in the superior thalamic radiation and the parahippocampal part of the cingulum (standardized mean difference for both tracts: 0.21, 95% CI, 0.09 to 0.34). Better perceived social support was associated with lower MD in the forceps minor (standardized mean difference per point increase in social support: -0.06, 95% CI, -0.09 to -0.03), inferior fronto-occipital fasciculus, and uncinate fasciculus. In male participants, better perceived social support was associated with lower MD in the forceps minor, and not having a partner was associated with lower fractional anisotropy in the forceps minor. Loneliness was associated with higher MD in the superior thalamic radiation in female participants only. Conclusions: Social health was associated with tract-specific white matter microstructure. Loneliness was associated with lower integrity of limbic and sensorimotor tracts, whereas better perceived social support was associated with higher integrity of association and commissural tracts, indicating that social health domains involve distinct neural pathways of the brain.

Social Health Is Associated With Structural Brain Changes in Older Adults: The Rotterdam Study.

BACKGROUND: Social health markers have been linked to the development of dementia. We hypothesize that social health affects brain structure and consequently influences cognitive function. We aim to elucidate the cross-sectional and longitudinal associations between social health markers and structural brain changes in older adults in the general population. METHODS: Social health markers (loneliness, perceived social support, marital status) were assessed in the Rotterdam Study from 2002 to 2008. Magnetic resonance imaging of the brain was performed repeatedly between 2005 and 2015 for 3737 participants to obtain brain volumetrics, cerebral small vessel disease markers, and white matter microstructural integrity as measures of brain structure. Cross-sectional associations between social health and brain structure were studied using multivariable linear and logistic regression models. Longitudinal associations between baseline social health and changes in brain structure were examined using linear mixed models and generalized estimating equations. RESULTS: Loneliness was associated with smaller white matter volume at baseline (mean difference = -4.63 mL, 95% CI = -8.46 to -0.81). Better perceived social support was associated with larger total brain volume and gray matter volume at baseline and a less steep decrease in total brain volume over time. Better social support was associated with higher global fractional anisotropy and lower mean diffusivity at baseline. Participants who had never been married had a smaller total brain volume (mean difference = -8.27 mL, 95% CI = -13.16 to -3.39) at baseline than married peers. CONCLUSIONS: Social health is associated with brain structure. Better perceived social support at baseline was associated with better brain structure over time.

Recognition of social health: A conceptual framework in the context of dementia research.

Objective: The recognition of dementia as a multifactorial disorder encourages the exploration of new pathways to understand its origins. Social health might play a role in cognitive decline and dementia, but conceptual clarity is lacking and this hinders investigation of associations and mechanisms. The objective is to develop a conceptual framework for social health to advance conceptual clarity in future studies. Process: We use the following steps: underpinning for concept advancement, concept advancement by the development of a conceptual model, and exploration of its potential feasibility. An iterative consensus-based process was used within the international multidisciplinary SHARED project. Conceptual framework: Underpinning of the concept drew from a synthesis of theoretical, conceptual and epidemiological work, and resulted in a definition of social health as wellbeing that relies on capacities both of the individual and the social environment. Consequently, domains in the conceptual framework are on both the individual (e.g., social participation) and the social environmental levels (e.g., social network). We hypothesize that social health acts as a driver for use of cognitive reserve which can then slow cognitive impairment or maintain cognitive functioning. The feasibility of the conceptual framework is demonstrated in its practical use in identifying and structuring of social health markers within the SHARED project. Discussion: The conceptual framework provides guidance for future research and facilitates identification of modifiable risk and protective factors, which may in turn shape new avenues for preventive interventions. We highlight the paradigm of social health in dementia as a priority for dementia research.

Mapping the multicausality of Alzheimer's disease through group model building.

Alzheimer's disease (AD) is a complex, multicausal disorder involving several spatiotemporal scales and scientific domains. While many studies focus on specific parts of this system, the complexity of AD is rarely studied as a whole. In this work, we apply systems thinking to map out known causal mechanisms and risk factors ranging from intracellular to psychosocial scales in sporadic AD. We report on the first systemic causal loop diagram (CLD) for AD, which is the result of an interdisciplinary group model building (GMB) process. The GMB was based on the input of experts from multiple domains and all proposed mechanisms were supported by scientific literature. The CLD elucidates interaction and feedback mechanisms that contribute to cognitive decline from midlife onward as described by the experts. As an immediate outcome, we observed several non-trivial reinforcing feedback loops involving factors at multiple spatial scales, which are rarely considered within the same theoretical framework. We also observed high centrality for modifiable risk factors such as social relationships and physical activity, which suggests they may be promising leverage points for interventions. This illustrates how a CLD from an interdisciplinary GMB process may lead to novel insights into complex disorders. Furthermore, the CLD is the first step in the development of a computational model for simulating the effects of risk factors on AD.

Impaired Cardiac Function and Cognitive Brain Aging.

It is well established that patients with heart failure are at a greater risk for dementia. Recent evidence suggests that the heart-brain link goes beyond advanced heart failure, and even suboptimal cardiac function is associated with brain structural and functional changes leading to cognitive impairment. In this review, we address several pathophysiological mechanisms underlying this association, including hemodynamic stress and cerebral hypoperfusion, neuroinflammation, cardiac arrhythmias, and hypercoagulation. The close link between cardiac function and brain health has numerous clinical and public health implications. Cardiac dysfunction and cognitive impairment are both common in older adults. However, in our current clinical practice, these medical conditions are generally evaluated and treated in isolation. Emerging evidence on the significance of the heart-brain link calls for comprehensive cardiovascular risk assessment in patients with cognitive impairment and a neurocognitive workup in patients with impaired cardiac function. A multidisciplinary approach by cardiologists, neurologists, and geriatricians would benefit the diagnostic process and disease management and ultimately improve the quality of life for patients with cardiac and cognitive dysfunction.