Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia.

Importance: Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain. Objective: To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases. Design, Setting, and Participants: This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022. Exposures: Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations. Main Outcomes and Measures: The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses. Results: In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95% CI, 1.03-1.06; P = 1.9 × 10-14), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke. Conclusions: These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.

Social health and subsequent cognitive functioning in people aged 50 years and older: examining the mediating roles of depressive symptoms and inflammatory biomarkers in two European longitudinal studies.

BACKGROUND: Social health markers, including marital status, contact frequency, network size, and social support, have been shown to be associated with cognition. However, the mechanisms underlying these associations remain poorly understood. We investigated whether depressive symptoms and inflammation mediated associations between social health and subsequent cognition. METHODS: In the English Longitudinal Study of Ageing (ELSA), a nationally representative longitudinal study in England, UK, we sampled 7136 individuals aged 50 years or older living in private households without dementia at baseline or at the intermediate mediator assessment timepoint, who had recorded information on at least one social health marker and potential mediator. We used four-way decomposition to examine to what extent depressive symptoms, C-reactive protein, and fibrinogen mediated associations between social health and subsequent standardised cognition (verbal fluency and delayed and immediate recall), including cognitive change, with slopes derived from multilevel models (12-year slope). We examined whether findings were replicated in the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a population-based longitudinal study in Sweden, in a sample of 2604 individuals aged 60 years or older living at home or in institutions in Kungsholmen (central Stockholm) without dementia at baseline or at the intermediate mediator assessment timepoint (6-year slope). Social health exposures were assessed at baseline, potential mediators were assessed at an intermediate timepoint (wave 2 in ELSA and 6-year follow-up in SNAC-K); cognitive outcomes were assessed at a single timepoint (wave 3 in ELSA and 12-year follow-up in SNAC-K), and cognitive change (between waves 3 and 9 in ELSA and between 6-year and 12-year follow-ups in SNAC-K). FINDINGS: The study sample included 7136 participants from ELSA, of whom 3962 (55·5%) were women and 6934 (97·2%) were White; the mean baseline age was 63·8 years (SD 9·4). Replication analyses included 2604 participants from SNAC-K, of whom 1604 (61·6%) were women (SNAC-K did not collect ethnicity data); the mean baseline age was 72·3 years (SD 10·1). In ELSA, we found indirect effects via depressive symptoms of network size, positive support, and less negative support on subsequent verbal fluency, and of positive support on subsequent immediate recall (pure indirect effect [PIE] 0·002 [95% CI 0·001-0·003]). Depressive symptoms also partially mediated associations between less negative support and slower decline in immediate recall (PIE 0·001 [0·000-0·002]) and in delayed recall (PIE 0·001 [0·000-0·002]), and between positive support and slower decline in immediate recall (PIE 0·001 [0·000-0·001]). We did not observe mediation by inflammatory biomarkers. Findings of mediation by depressive symptoms in the association between positive support and verbal fluency and between positive support and change in immediate recall were replicated in SNAC-K. INTERPRETATION: The findings of this study provide new insights into mechanisms linking social health with cognition, suggesting that associations between interactional aspects of social health, especially social support, and cognition are partly underpinned by depressive symptoms. FUNDING: EU Joint Programme-Neurodegenerative Disease Research (JPND) and Alzheimer's Society. TRANSLATION: For the Swedish translation of the abstract see Supplementary Materials section.

Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics.

Importance: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear. Objective: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia. Design Setting and Participants: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022. Exposures: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke. Main outcomes and measures: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (ADmeta, n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses. Results: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of ADmeta (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and ADmeta, with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke. Conclusion: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.

Diagnostic challenge of Creutzfeldt-Jakob disease in a patient with multimorbidity: a case-report.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive and ultimately fatal neurodegenerative condition caused by prions. The clinical symptoms of CJD vary with its subtype, and may include dementia, visual hallucinations, myoclonus, ataxia, (extra)pyramidal signs and akinetic mutism. In the early course of disease however, several clinical symptoms of CJD may mimic those of co-existing morbidities. CASE PRESENTATION: We report a male in his 60s with a history of situs inversus totalis and Churg Strauss syndrome, who presented with speech fluency disturbances, neuropsychiatric symptoms and allodynia, a few months after becoming a widower. Initially presumed a bereavement disorder along with a flare-up of Churg Strauss, his symptoms gradually worsened with apraxia, myoclonic jerks and eventually, akinetic mutism. MRI revealed hyperintensities at the caudate nucleus and thalami, while the cerebrospinal fluid was positive for the 14-3-3 protein and the real-time quick test, making the diagnosis of CJD highly probable. This case illustrates the complexities that may arise in diagnosing CJD when pre-existing multimorbidity may cloud the clinical presentation. We also discuss the potential mechanisms underlying the co-occurrence of three rare conditions (situs inversus totalis, Churg Strauss syndrome, CJD) in one patient, taking into consideration the possibility of coincidence as well as common underlying factors. CONCLUSIONS: The diagnosis of CJD may be easily missed when its clinical symptoms are obscured by those of pre-existing (rare) multimorbidity. This case highlights that when the multimorbidity has neurological manifestations, an extensive evaluation remains crucial to establish the diagnosis, minimize the risk of prion-transmission and provide appropriate guidance to patients and their caregivers.

Social Health and Change in Cognitive Capability among Older Adults: Findings from Four European Longitudinal Studies.

INTRODUCTION: In this study, we examine whether social health markers measured at baseline are associated with differences in cognitive capability and the rate of cognitive decline over an 11-to-18-year period among older adults and compare results across studies. METHODS: We applied an integrated data analysis approach to 16,858 participants (mean age 65 years; 56% female) from the National Survey for Health and Development (NSHD), the English Longitudinal Study of Aging (ELSA), the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), and the Rotterdam Study. We used multilevel models to examine social health in relation to cognitive capability and the rate of cognitive decline. RESULTS: Pooled estimates show distinct relationships between markers of social health and cognitive domains, e.g., a large network size (≥6 people vs. none) was associated with higher executive function (0.17 standard deviation [SD] [95% CI: 0.00, 0.34], I2 = 27%) but not with memory (0.08 SD [95% CI: -0.02, 0.18], I2 = 19%). We also observed pooled associations between being married or cohabiting, having a large network size, and participating in social activities with slower decline in cognitive capability. However, estimates were close to zero, e.g., 0.01 SD/year (95% CI: 0.01, 0.02) I2 = 19% for marital status and executive function. There were clear study-specific differences: results for average processing speed were the most homogenous, and results for average memory were the most heterogeneous. CONCLUSION: Overall, markers of good social health have a positive association with cognitive capability. However, we found differential associations between specific markers of social health and cognitive domains and differences between studies. These findings highlight the importance of examining between-study differences and considering the context specificity of findings in developing and deploying interventions.

Unraveling Neuro-Proteogenomic Landscape and Therapeutic Implications for Human Behaviors and Psychiatric Disorders.

Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioral traits and the disease etiology of neuropsychiatric disorders. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-related proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-related traits such as sleeping, smoking, feelings, alcohol intake, mental health, and psychiatric disorders. Integrating with established drug information, we validated 13 out of 13 matched combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets. This consortium effort provides a large-scale proteogenomic resource for biomedical research on human behaviors and other neuro-related phenotypes.

Projections of costs and quality adjusted life years lost due to dementia from 2020 to 2050: A population-based microsimulation study.

INTRODUCTION: Efficient healthcare planning requires reliable projections of the future increase in costs and quality-adjusted life years (QALYs) lost due to dementia. METHODS: We used the microsimulation model MISCAN-Dementia to simulate life histories and dementia occurrence using population-based Rotterdam Study data and nationwide birth cohort demographics. We estimated costs and QALYs lost in the Netherlands from 2020 to 2050, incorporating literature estimates of cost and utility for patients and caregivers by dementia severity and care setting. RESULTS: Societal costs and QALYs lost due to dementia are estimated to double between 2020 and 2050. Costs are incurred predominantly through institutional (34%), formal home (31%), and informal home care (20%). Lost QALYs are mostly due to shortened life expectancy (67%) and, to a lesser extent, quality of life with severe dementia (14%). DISCUSSION: To limit healthcare costs and quality of life losses due to dementia, interventions are needed that slow symptom progression and reduce care dependency.

Genetic mechanisms of 184 neuro-related proteins in human plasma.

Understanding the genetic basis of neuro-related proteins is essential for dissecting the disease etiology of neuropsychiatric disorders and other complex traits and diseases. Here, the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,500 individuals for 184 neuro-reiated proteins in human plasma. The analysis identified 117 cis-regulatory protein quantitative trait loci (cis-pQTL) and 166 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. Mendelian randomization analyses revealed multiple proteins showing potential causal effects on neuro-reiated traits as well as complex diseases such as hypertension, high cholesterol, immune-related disorders, and psychiatric disorders. Integrating with established drug information, we validated 13 combinations of protein targets and diseases or side effects with available drugs, while suggesting hundreds of re-purposing and new therapeutic targets for diseases and comorbidities. This consortium effort provides a large-scale proteogenomic resource for biomedical research.

Genome-wide profiling of circulatory microRNAs associated with cognition and dementia.

INTRODUCTION: MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Their role in the pathophysiology of dementia and potential as biomarkers remains undetermined. METHODS: We conducted a single- (one-by-one) and multi-marker (joint) analysis to identify well-expressed circulating miRNAs in plasma (total = 591) associated with general cognition and incident dementia, for 1615 participants of the population-based Rotterdam Study. RESULTS: During single-marker analysis, 47 miRNAs were nominally (P ≤ .05) associated with cognition and 18 miRNAs were nominally associated with incident dementia, after adjustment for potential confounders. Three miRNAs were common between cognition and dementia (miR-4539, miR-372-3p, and miR-566), with multi-marker analysis revealing another common miRNA (miR-7106-5p). In silico analysis of these four common miRNAs led to several putative target genes expressed in the brain, highlighting the mitogen-activated protein kinase signaling pathway. DISCUSSION: We provide population-based evidence on the relationship between circulatory miRNAs with cognition and dementia, including four common miRNAs that may elucidate downstream mechanisms. HIGHLIGHTS: MicroRNAs (miRNAs) are involved in the (dys)function of the central nervous system. Four circulating miRNAs in plasma are associated with cognition and incident dementia. Several predicted target genes of these four miRNAs are expressed in the brain. These four miRNAs may be linked to pathways underlying dementia. Although miRNAs are promising biomarkers, experimental validation remains essential.

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.

Time spent in physical activity, sedentary behavior, and sleep: Associations with self-rated sleep quality in middle-aged and older adults.

OBJECTIVES: We examined the associations of estimated allocations of time spent in physical activity, sedentary behavior and sleep with self-rated sleep quality. METHODS: Between 2011 and 2016, 1918 participants (mean age 71 ± 9 years, 51% women) from the population-based Rotterdam Study were included. Durations of light physical activity, moderate-to-vigorous physical activity, sedentary behavior, and sleep were assessed by accelerometry, self-rated sleep quality with the Pittsburgh Sleep Quality Index. Associations were assessed with compositional isotemporal substitution analyses. RESULTS: Spending 30 minutes more in sedentary behavior (adjusted mean difference in PSQI score: 0.21, 95% confidence interval [0.15; 0.28] or in light physical activity (adjusted mean difference in PSQI score: 0.25 [0.03; 0.46], and 30 minutes less in sleep, was associated with poorer sleep quality. CONCLUSIONS: Our findings suggest reducing sedentary behavior and increasing sleep duration might be a potential intervention target to improve sleep quality in this population of middle-aged and older adults.

Sex steroids and sex steroid-binding globulin levels amongst middle-aged and elderly men and women from general population.

BACKGROUND AND AIMS: Availability of age- and sex-specific reference values for sex steroids and sex steroid-binding globulin (SHBG) levels allows for appropriate interpretation of research findings and their clinical applications. We report the sex-specific distribution and reference levels of sex steroids, including total estradiol, total testosterone and (calculated) free androgen index (cFAI), SHBG and other androgens dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS) and androstenedione across age. METHODS: Using data from 3291 participants from the prospective population-based Rotterdam Study (2006-2008), we visualised the distribution of sex steroids and SHBG levels by calculating and depicting the 5th, 25th, 50th, 75th and 95th percentiles per year and per age-year across 5-year age bands to provide reference value ranges in men and women. Total estradiol and SHBG were measured using automated immunoassay and androgens using liquid chromatography-mass spectrometry (LC-MS/MS). RESULT: Mean age was 56.8 (range 45.6-79.9) years in men and 56.9 (range 45.7-79.9) years in women. Amongst men, total estradiol and SHBG showed an increasing trend from 45 years onwards. In women, total estradiol and SHBG showed a decreasing trend from 45 years until the age of 60. From 60 years onwards, SHBG showed an increasing trend. For total testosterone, a clear declining trend was observed amongst men but not women. Other androgens showed a similar decreasing trend in both sexes from 45 years onwards. DISCUSSION AND CONCLUSION: Our study underlines sex-specific trends in sex steroids and SHBG levels with ageing. This warrants taking into account sex- and age-specific reference values for sex steroids and SHBG when investigating their impact on health outcomes to prevent controversial results and allow for their appropriate clinical application.

Genetic evidence for the most common risk factors for chronic axonal polyneuropathy in the general population.

BACKGROUND AND PURPOSE: Chronic axonal polyneuropathy is a common disease, but the etiology remains only partially understood. Previous etiologic studies have identified clinical risk factors, but genetic evidence supporting causality between these factors and polyneuropathy are largely lacking. In this study, we investigate whether there is a genetic association of clinically established important risk factors (diabetes, body mass index [BMI], vitamin B12 levels, and alcohol intake) with chronic axonal polyneuropathy. METHODS: This study was performed within the population-based Rotterdam Study and included 1565 participants (median age = 73.6 years, interquartile range = 64.6-78.8, 53.5% female), of whom 215 participants (13.7%) had polyneuropathy. Polygenic scores (PGSs) for diabetes, BMI, vitamin B12 levels, and alcohol intake were calculated at multiple significance thresholds based on published genome-wide association studies. RESULTS: Higher PGSs of diabetes, BMI, and alcohol intake were associated with higher prevalence of chronic axonal polyneuropathy, whereas higher PGS of vitamin B12 levels was associated with lower prevalence of polyneuropathy. These effects were most pronounced for PGSs with lenient significance thresholds for diabetes and BMI (odds ratio [OR]diabetes, p < 1.0  = 1.21, 95% confidence interval [CI] = 1.05-1.39 and ORBMI, p < 1.0  = 1.21, 95% CI = 1.04-1.41) and for the strictest significance thresholds for vitamin B12 level and alcohol intake (OR vitamin B12, p < 5e-6  = 0.79, 95% CI = 0.68-0.92 and ORalcohol, p < 5e-8  = 1.17, 95% CI = 1.02-1.35). We did not find an association between different PGSs and sural sensory nerve action potential amplitude, nor between individual lead variants of PGSp < 5e-8 and polyneuropathy. CONCLUSIONS: This study provides evidence for polygenic associations of diabetes, BMI, vitamin B12 level, and alcohol intake with chronic axonal polyneuropathy. This supports the hypothesis of causal associations between well-known clinical risk factors and polyneuropathy.

Risk factors, neuroimaging correlates and prognosis of the motoric cognitive risk syndrome: A population-based comparison with mild cognitive impairment.

BACKGROUND AND PURPOSE: This study was undertaken to compare risk factors, neuroimaging characteristics and prognosis between two clinical prodromes of dementia, namely, the motoric cognitive risk syndrome (MCRS) and mild cognitive impairment (MCI). METHODS: Between 2009 and 2015, dementia-free participants of the population-based Rotterdam Study were classified with a dementia prodrome if they had subjective cognitive complaints and scored >1 SD below the population mean of gait speed (MCRS) or >1.5 SD below the population mean of cognitive test scores (MCI). Using multinomial logistic regression models, we determined cross-sectional associations of risk factors and structural neuroimaging markers with MCRS and MCI, followed by subdistribution hazard models, to determine risk of incident dementia until 2016. RESULTS: Of 3025 included participants (mean age = 70.4 years, 54.7% women), 231 had MCRS (7.6%), 132 had MCI (4.4%), and 62 (2.0%) fulfilled criteria for both. Although many risk factors were shared, a higher body mass index predisposed to MCRS, whereas male sex and hypercholesterolemia were associated with MCI only. Gray matter volumes, hippocampal volumes, white matter hyperintensities, and structural white matter integrity were worse in both MCRS and MCI. During a mean follow-up of 3.9 years, 71 individuals developed dementia and 200 died. Five-year cumulative risk of dementia was 7.0% (2.5%-11.5%) for individuals with MCRS, versus 13.3% (5.8%-20.8%) with MCI and only 2.3% (1.5%-3.1%) in unaffected individuals. CONCLUSIONS: MCRS is associated with imaging markers of neurodegeneration and risk of dementia, even in the absence of MCI, highlighting the potential of motor function assessment in early risk stratification for dementia.

Long-term association of pregnancy and maternal brain structure: the Rotterdam Study.

The peripartum period is the highest risk interval for the onset or exacerbation of psychiatric illness in women's lives. Notably, pregnancy and childbirth have been associated with short-term structural and functional changes in the maternal human brain. Yet the long-term effects of pregnancy on maternal brain structure remain unknown. We investigated a large population-based cohort to examine the association between parity and brain structure. In total, 2,835 women (mean age 65.2 years; all free from dementia, stroke, and cortical brain infarcts) from the Rotterdam Study underwent magnetic resonance imaging (1.5 T) between 2005 and 2015. Associations of parity with global and lobar brain tissue volumes, white matter microstructure, and markers of vascular brain disease were examined using regression models. We found that parity was associated with a larger global gray matter volume (ß = 0.14, 95% CI = 0.09-0.19), a finding that persisted following adjustment for sociodemographic factors. A non-significant dose-dependent relationship was observed between a higher number of childbirths and larger gray matter volume. The gray matter volume association with parity was globally proportional across lobes. No associations were found regarding white matter volume or integrity, nor with markers of cerebral small vessel disease. The current findings suggest that pregnancy and childbirth are associated with robust long-term changes in brain structure involving a larger global gray matter volume that persists for decades. Future studies are warranted to further investigate the mechanism and physiological relevance of these differences in brain morphology.

Adiponectin, Leptin, and Resistin and the Risk of Dementia.

BACKGROUND: Adipokines are hormones secreted by adipose tissue with roles in energy homeostasis and regulation of metabolism. Their dysregulation is suggested to contribute to the increased risk of dementia seen with midlife obesity, but longitudinal studies investigating this are scarce. We determined the association between plasma levels of adiponectin, leptin, and resistin with the risk of dementia. METHODS: We performed a case-cohort study embedded in the prospective, population-based Rotterdam Study. Plasma levels of the adiponectin, leptin, and resistin were measured at baseline (1997-1999) in a random subcohort of 945 participants without dementia, and additionally in 177 participants, who were diagnosed with dementia during follow-up (until January 1, 2018). RESULTS: Higher levels of leptin and resistin were associated with a decreased risk of dementia (adjusted hazard ratio [95% confidence interval] per SD increase of log-transformed values: 0.85 [0.72-1.00] for leptin; 0.82 [0.71-0.95] for resistin). The association of leptin with dementia was further modified by body mass index and by APOE ε4 carrier status. Adiponectin levels were not associated with the risk of dementia. CONCLUSIONS: These findings support the hypothesis that adipokines have a role in the pathophysiology of dementia. Future studies are warranted to confirm the findings and to explore the underlying mechanisms.

Vascular risk factors as predictors of epilepsy in older age: The Framingham Heart Study.

OBJECTIVE: Stroke is the most common cause of epilepsy in older age. Subclinical cerebrovascular disease is believed to underlie some of the 30%-50% of late-onset epilepsy without a known cause (Li et al. Epilepsia. 1997;38:1216; Cleary et al. Lancet. 2004;363:1184). We studied the role of modifiable vascular risk factors in predicting subsequent epilepsy among participants ages 45 or older in the Framingham Heart Study (FHS), a longitudinal, community-based study. METHODS: Participants of the Offspring Cohort who attended FHS exam 5 (1991-1995) were included who were at least 45-years-old at that time, had available vascular risk factor data, and epilepsy follow-up (n = 2986, mean age 58, 48% male). Adjudication of epilepsy cases included review of medical charts to exclude seizure mimics and acute symptomatic seizures. The vascular risk factors studied included hypertension, diabetes mellitus, smoking, and hyperlipidemia. The role of the Framingham Stroke Risk Profile score was also investigated. Cox proportional hazards regression models were used for the analyses. RESULTS: Fifty-five incident epilepsy cases were identified during a mean of 19 years of follow-up. Hypertension was associated with a near 2-fold risk (hazard ratio [HR]: 1.93, 95% confidence interval [CI]: 1.10-3.37, p = .022) of developing epilepsy, even after adjustment for prevalent and interim stroke. In secondary analysis, excluding patients with normal blood pressure who were receiving anti-HTN (anti-hypertensive) treatment (n = 2613, 50 incident epilepsy cases) the association was (HR: 2.44, 95% CI: 1.36-4.35, p = .003). SIGNIFICANCE: Our results offer further evidence that hypertension, a potentially modifiable and highly prevalent vascular risk factor in the general population, increases 2- to 2.5-fold the risk of developing late-onset epilepsy.

Trajectories and Determinants of Physical Activity during COVID-19 Pandemic: A Population-Based Study of Middle-Aged and Elderly Individuals in The Netherlands.

Physical inactivity is a major public health problem, and there are concerns this might have increased during the COVID-19 pandemic. We aimed to identify distinct trajectories of physical activity over a 6-week period after the first restrictive measures and to explore determinants of these trajectories in a population-based cohort of middle-aged and elderly in the Netherlands (n = 5777). We observed that at least 59% of participants did not meet the World Health Organization recommendations for physical activity. Using latent class trajectory analyses over three time points, we identified five distinct trajectories, including four steady trajectories at different levels (very low, low, medium and high) and one increasing trajectory. Using multinomial logistic regression analyses, we observed that, compared to the 'steadily high' trajectory, participants in the 'steadily very low' trajectory were more often older, lower educated, reporting poorer physical health, more depressive symptoms, consuming a less healthy diet, smoking, and lower alcohol use, and were less often retired. A similar pattern of determinants was seen for those in the increasing trajectory, albeit with smaller effect sizes. Concluding, we observed low levels of physical activity that generally remained during the pandemic. The determinants we described can help identify groups that require additional preventive interventions.

Age at Natural Menopause and Blood Pressure Traits: Mendelian Randomization Study.

Observational studies suggest that early onset of menopause is associated with increased risk of hypertension. Whether this association is causal or due to residual confounding and/or reverse causation remains undetermined. We aimed to evaluate the observational and causal association between age at natural menopause (ANM) and blood pressure traits in Caucasian women. A cross-sectional and one-sample Mendelian randomization (MR) study was conducted in 4451 postmenopausal women from the CoLaus and Rotterdam studies. Regression models were built with observational data to study the associations of ANM with systolic and diastolic blood pressure (SBP/DBP) and hypertension. One-sample MR analysis was performed by calculating a genetic risk score of 54 ANM-related variants, previously identified in a genome-wide association study (GWAS) on ANM. In the two-sample MR analysis we used the estimates from the ANM-GWAS and association estimates from 168,575 women of the UK Biobank to evaluate ANM-related variants and their causal association with SBP and DBP. Pooled analysis from both cohorts showed that a one-year delay in menopause onset was associated with 2% (95% CI 0; 4) increased odds of having hypertension, and that early menopause was associated with lower DBP (ß = -1.31, 95% CI -2.43; -0.18). While one-sample MR did not show a causal association between ANM and blood pressure traits, the two-sample MR showed a positive causal association of ANM with SBP; the last was driven by genes related to DNA damage repair. The present study does not support the hypothesis that early onset of menopause is associated with higher blood pressure. Our results suggest different ANM-related genetic pathways could differently impact blood pressure.