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.

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.

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.

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.

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.

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.

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.

Determinants and Reference Ranges of Serum Immunoglobulins in Middle-Aged and Elderly Individuals: a Population-Based Study.

PURPOSE: In clinical practice, currently one reference range for serum immunoglobulin (Ig) A, G, and M is applied to all adults, although various factors may influence Ig serum levels. Population-based data on determinants of IgA, IgG, and IgM and recommendations for subgroup specific reference ranges are lacking. We aimed to provide an overview of determinants of IgA, IgG, and IgM in community-dwelling middle-aged and elderly individuals and explore determinants that influence Ig reference ranges. METHODS: Within the Rotterdam Study, we performed linear regression analyses for the association of demographic, lifestyle, and cardiovascular factors with serum IgA, IgG, and IgM. We furthermore calculated Ig reference ranges (based on percentiles), both overall and within relevant subgroups. RESULTS: We included 8768 participants (median age 62 years). IgA and IgG increased non-linearly with higher age (P < .0001 for both). Women had lower IgA (beta: - 0.24; 95% confidence interval [95% CI]: - 0.29; - 0.20) and IgG (beta: - 0.33; 95% CI: - 0.44; - 0.23), but higher IgM levels (beta: 0.08; 95% CI: 0.04;0.13) than men. Former and particularly current smoking were associated with lower IgA and IgG (betas between - 0.07 and - 1.03). Higher alcohol consumption was associated with lower IgG (beta for heavy drinking: - 0.70; 95% CI: - 0.91; - 0.48). Corticosteroid use was associated with lower IgG (beta: - 1.12; 95% CI: - 1.58; - 0.66). Associations with cardiovascular factors were heterogeneous and differed between sexes. CONCLUSION: Age, sex, smoking, alcohol consumption, corticosteroid use, and cardiovascular factors are determinants that should be considered when interpreting serum Ig levels in middle-aged and elderly individuals and may require adjusted reference ranges.

External validity of phase III trials on vaccines against SARS-CoV-2 to a middle-aged and elderly Western European population.

Initial results from various phase-III trials on vaccines against SARS-CoV-2 are promising. For proper translation of these results to clinical guidelines, it is essential to determine how well the general population is reflected in the study populations of these trials. This study was conducted among 7162 participants (age-range: 51-106 years; 58% women) from the Rotterdam Study. We quantified the proportion of participants that would be eligible for the nine ongoing phase-III trials. We further quantified the eligibility among participants at high risk to develop severe COVID-19. Since many trials were not explicit in their exclusion criterion with respect to 'acute' or 'unstable preexisting' diseases, we performed two analyses. First, we included all participants irrespective of this criterion. Second, we excluded persons with acute or 'unstable preexisting' diseases. 97% of 7162 participants was eligible for any trial with eligibility for separate trials ranging between 11-97%. For high-risk individuals the corresponding numbers were 96% for any trial with separate trials ranging from 5-96%. Importantly, considering persons ineligible due to 'acute' or 'unstable pre-existing' disease drastically dropped the eligibilities for all trials below 43% for the total population and below 36% for high-risk individuals. The eligibility for ongoing vaccine trials against SARS-CoV-2 can reduce by half depending on interpretation and application of a single unspecified exclusion criterion. This exclusion criterion in our study would especially affect the elderly and those with pre-existing morbidities. These findings thus indicate the difficulty as well as importance of developing clinical recommendations for vaccination and applying these to the appropriate target populations. This becomes especially paramount considering the fact that many countries worldwide have initiated their vaccination programs by first targeting the elderly and most vulnerable persons.

Season of birth and the risk of dementia in the population-based Rotterdam Study.

Early-life environmental factors have been suggested in the pathophysiology of dementia. Season of birth has previously been used as a proxy for these external exposures. We investigated the link between season of birth and the risk of dementia and further explored underlying pathways by studying structural brain changes on MRI. From the Dutch, population-based Rotterdam Study, 12,964 participants born between 1887 and 1960 were followed between 1990 and 2018 for dementia. Cox regression was conducted to assess the association between season of birth and dementia. In addition, we distinguished between mild and cold winters. The association of season of birth with structural brain markers on MRI was examined in 5237 participants. The risk of dementia in participants born in winter and fall was higher than of those born in summer (hazard ratio (HR) 1.15 [95% confidence interval (CI) 1.01-1.31] for winter and HR 1.17 [95% CI 1.01-1.33] for fall), especially for Alzheimer's disease (HR 1.23 [1.06-1.43] for winter and HR 1.15 [95% CI 0.99-1.35] for fall). The risk was particularly increased for participants born in a cold winter. Except for slightly lower hippocampus in fall born participants (ß - 0.03; 95% CI - 0.06 to 0.00), we did not find associations with brain imaging markers. In conclusion, winter and fall births were associated with a higher incidence of dementia, especially of AD. We did not find evidence for structural brain changes as an underlying mechanism.

Hypothetical blood-pressure-lowering interventions and risk of stroke and dementia.

We aimed to study the effects of hypothetical interventions on systolic blood pressure (SBP) and smoking on risk of stroke and dementia using data from 15 years of follow-up in the Rotterdam Study. We used data from 4930 individuals, aged 55-80 years, with no prior history of stroke, dementia or cognitive impairment, followed for 15 years within the Rotterdam Study, a population-based cohort. We defined the following sustained interventions on SBP: (1) maintaining SBP below 120 mmHg, (2) maintaining SBP below 140 mmHg, (3) reducing SBP by 10% if above 140 mmHg, (4) reducing SBP by 20% if above 140 mmHg, and a combined intervention of quitting smoking with each of these SBP-lowering strategies. We considered incident stroke and incident dementia diagnoses as outcomes. We applied the parametric g-formula to adjust for baseline and time-varying confounding. The observed 15-year risk for stroke was 10.7%. Compared to no specified intervention (i.e., the "natural course"), all interventions that involved reducing SBP were associated with a stroke risk reduction of about 10% (e.g., reducing SBP by 20% if above 140 mmHg risk ratio: 0.89; 95% CI 0.76, 1). Jointly intervening on SBP and smoking status further decreased the risk of stroke (e.g., risk ratio: 0.83; 95% CI 0.71, 0.94). None of the specified interventions were associated with a substantive change in dementia risk. Our study suggests that a joint intervention on SBP and smoking cessation during later life may reduce stroke risk, while the potential for reducing dementia risk were not observed.

Design and overview of the Origins of Alzheimer's Disease Across the Life course (ORACLE) study.

Brain development and deterioration across the lifespan are integral to the etiology of late-life neurodegenerative disease. Factors that influence the health of the adult brain remain to be elucidated and include risk factors, protective factors, and factors related to cognitive and brain reserve. To address this knowledge gap we designed a life-course study on brain health, which received funding through the EU ERC Programme under the name Origins of Alzheimer's Disease Across the Life course (ORACLE) Study. The ORACLE Study is embedded within Generation R, a prospective population-based cohort study of children and their parents, and links this with the Rotterdam Study, a population-based study in middle-aged and elderly persons. The studies are based in Rotterdam, the Netherlands. Generation R focuses on child health from fetal life until adolescence with repeated in-person examinations, but has also included data collection on the children's parents. The ORACLE Study aims to extend the parental data collection in nearly 2000 parents with extensive measures on brain health, including neuroimaging, cognitive testing and motor testing. Additionally, questionnaires on migraine, depressive symptoms, sleep, and neurological family history were completed. These data allow for the investigation of longitudinal influences on adult brain health as well as intergenerational designs involving children and parents. As a secondary focus, the sampling is enriched by mothers (n = 356) that suffered from hypertensive disorders during pregnancy in order to study brain health in this high-risk population. This article provides an overview of the rationale and the design of the ORACLE Study.

Corticosteroids and Regional Variations in Thickness of the Human Cerebral Cortex across the Lifespan.

Exposures to life stressors accumulate across the lifespan, with possible impact on brain health. Little is known, however, about the mechanisms mediating age-related changes in brain structure. We use a lifespan sample of participants (n = 21 251; 4-97 years) to investigate the relationship between the thickness of cerebral cortex and the expression of the glucocorticoid- and the mineralocorticoid-receptor genes (NR3C1 and NR3C2, respectively), obtained from the Allen Human Brain Atlas. In all participants, cortical thickness correlated negatively with the expression of both NR3C1 and NR3C2 across 34 cortical regions. The magnitude of this correlation varied across the lifespan. From childhood through early adulthood, the profile similarity (between NR3C1/NR3C2 expression and thickness) increased with age. Conversely, both profile similarities decreased with age in late life. These variations do not reflect age-related changes in NR3C1 and NR3C2 expression, as observed in 5 databases of gene expression in the human cerebral cortex (502 donors). Based on the co-expression of NR3C1 (and NR3C2) with genes specific to neural cell types, we determine the potential involvement of microglia, astrocytes, and CA1 pyramidal cells in mediating the relationship between corticosteroid exposure and cortical thickness. Therefore, corticosteroids may influence brain structure to a variable degree throughout life.

Dietary protein intake and all-cause and cause-specific mortality: results from the Rotterdam Study and a meta-analysis of prospective cohort studies.

Evidence for associations between long-term protein intake with mortality is not consistent. We aimed to examine associations of dietary protein from different sources with all-cause and cause-specific mortality. We followed 7786 participants from three sub-cohorts of the Rotterdam Study, a population-based cohort in the Netherlands. Dietary data were collected using food-frequency questionnaires at baseline (1989-1993, 2000-2001, 2006-2008). Deaths were followed until 2018. Associations were examined using Cox regression. Additionally, we performed a highest versus lowest meta-analysis and a dose-response meta-analysis to summarize results from the Rotterdam Study and previous prospective cohorts. During a median follow-up of 13.0 years, 3589 deaths were documented in the Rotterdam Study. In this cohort, after multivariable adjustment, higher total protein intake was associated with higher all-cause mortality [e.g. highest versus lowest quartile of total protein intake as percentage of energy (Q4 versus Q1), HR = 1.12 (1.01, 1.25)]; mainly explained by higher animal protein intake and CVD mortality [Q4 versus Q1, CVD mortality: 1.28 (1.03, 1.60)]. The association of animal protein intake and CVD was mainly contributed to by protein from meat and dairy. Total plant protein intake was not associated with all-cause or cause-specific mortality, mainly explained by null associations for protein from grains and potatoes; but higher intake of protein from legumes, nuts, vegetables, and fruits was associated with lower risk of all-cause and cause-specific mortality. Findings for total and animal protein intake were corroborated in a meta-analysis of eleven prospective cohort studies including the Rotterdam Study (total 64,306 deaths among 350,452 participants): higher total protein intake was associated with higher all-cause mortality [pooled RR for highest versus lowest quantile 1.05 (1.01, 1.10)]; and for dose-response per 5 energy percent (E%) increment, 1.02 (1.004, 1.04); again mainly driven by an association between animal protein and CVD mortality [highest versus lowest, 1.09 (1.01, 1.18); per 5 E% increment, 1.05 (1.02, 1.09)]. Furthermore, in the meta-analysis a higher plant protein intake was associated with lower all-cause and CVD mortality [e.g. for all-cause mortality, highest versus lowest, 0.93 (0.87, 0.99); per 5 E% increment, 0.87 (0.78, 0.98), for CVD mortality, highest versus lowest 0.86 (0.73, 1.00)]. Evidence from prospective cohort studies to date suggests that total protein intake is positively associated with all-cause mortality, mainly driven by a harmful association of animal protein with CVD mortality. Plant protein intake is inversely associated with all-cause and CVD mortality. Our findings support current dietary recommendations to increase intake of plant protein in place of animal protein.Clinical trial registry number and website NTR6831, https://www.trialregister.nl/trial/6645.

Discrimination of degrees of auditory performance from the digits-in-noise test based on hearing status.

OBJECTIVE: To discriminate among degrees of auditory performance of the Digits-in-Noise (DIN) test. DESIGN: We performed Pearson's correlations and age- and sex-adjusted linear regression models to examine the correlation between pure-tone average (PTA) from pure-tone audiometric tests and speech recognition thresholds (SRT) from the DIN test. Then, optimal SRT cut-points by PTA-defined hearing status (0-25 dB HL [normal], 26-40 dB HL [mild hearing loss], 41-50 dB HL [moderate hearing loss]) were compared across three methods: Youden, Nearest, and Liu. SRT-defined categories of auditory performance were compared to PTA-defined hearing categories to examine the convergence of similar categories. Study Sample: 3422 Rotterdam Study participants aged 51-98 years between 2011 and 2014. RESULTS: The correlation between SRT and PTA was 0.65 (95% Confidence Interval: 0.63, 0.67) in the overall sample. The variability of SRT explained by PTA after age and sex adjustment was 54%. Optimal cut-points for the overall sample across the three methods were: ≤ -5.55 dB SNR (normal); > -5.55 to ≤ -3.80 dB SNR (insufficient performance); > -3.80 dB SNR (poor performance). When comparing the SRT- or PTA-defined categories, 59.8% had concordant hearing categories and 40.2% had discordant hearing categories. CONCLUSIONS: Discrimination of degrees of auditory performance may add greater utility of the DIN test.

Association of migraine with calcification in major vessel beds: The Rotterdam Study.

BACKGROUND: To explore the role of large-artery atherosclerosis in migraine, we investigated the association between migraine and arterial calcification in different intracranial and extracranial vessels. METHODS: 1856 participants were included, mean age (standard deviation) 67.4 (5.8) years, from the population-based Rotterdam Study cohort. Migraine was assessed by validated questionnaire and vascular calcification was assessed by computed tomography (expressed in Agatston score for the coronary arteries and volume in mm3 for the aortic arch, intracranial, and extracranial carotid arteries). Per vessel, the association of migraine with calcification was investigated by linear regression, adjusted for age, sex, cardiovascular risk factors, and calcification in other vessels. RESULTS: Of the participants, 279 (15%) were identified as persons with lifetime migraine. In multivariable adjusted models, migraine was associated with smaller intracranial carotid artery calcification volume (difference in log-transformed calcification volume in persons with migraine compared to persons without migraine: -0.19[-0.29, -0.08]). While subjects with migraine also showed a lower calcification burden in the remaining arterial beds, those associations did not reach statistical significance. CONCLUSIONS: Persons with migraine, compared to those without, had less arterial calcification in the intracranial carotid artery, but not in other arterial beds. Future studies are needed to confirm these findings.

Animal foods and postmenopausal breast cancer risk: a prospective cohort study.

The role of diet on breast cancer risk is not well elucidated but animal food sources may play a role through, for example, the pathway of the insulin-like growth factor 1 system or cholesterol metabolism. The aim of this study was to evaluate the association between animal foods and the risk of postmenopausal breast cancer. This study was embedded in the Rotterdam Study, a population-based prospective cohort study of subjects aged 55 years and over (61 % female). Dietary intake of different animal foods was assessed at baseline using a validated FFQ and adjusted for energy intake using the residual method. We performed Cox proportional hazards modelling to analyse the association between the intake of the different food sources and breast cancer risk after adjustment for socio-demographic, lifestyle and metabolic factors. During a median follow-up of 17 years, we identified 199 cases of breast cancer (6·2 %) among 3209 women. After adjustment for multiple confounders, no consistent association was found between the intake of red meat intake, poultry, fish or dairy products and breast cancer risk. However, we found that egg intake was significantly associated with a higher risk of breast cancer (hazard ratioQ4 v. Q1: 1·83; 95 % CI 1·20, 2·79; Ptrend=0·01). In conclusion, this study found that dietary egg intake but no other animal foods was associated with a higher risk of postmenopausal breast cancer. Further research on the potential mechanisms underlying this association is warranted.