Serum immunoglobulins and biomarkers of dementia: a population-based study.

BACKGROUND: Inflammation plays a key role in the development of dementia, but its link to early biomarkers, particularly those in plasma or neuroimaging, remains elusive. This study aimed to investigate the association between serum immunoglobulins and biomarkers of dementia. METHODS: Between 1997 and 2009, serum immunoglobulins (IgA, IgG and IgM) were measured in dementia-free participants of the population-based Rotterdam Study. A random subset of participants had assessment of biomarkers in plasma (total tau (t-tau), neurofilament light chain (NfL), amyloid-ß40 (Aß-40), amyloid-ß42 (Aß-42), while another subset of participants underwent neuroimaging to quantify brain volume, white matter structural integrity and markers of cerebral small vessel disease. Linear regression models were constructed to determine cross-sectional associations between IgA, IgG, IgM and biomarkers of dementia, with adjustment for potential confounders. Multiple testing correction was applied using the false discovery rate. As a sensitivity analysis, we re-ran the models for participants within the reference range of immunoglobulins, excluding those using immunomodulating drugs, and conducted a stratified analysis by APOE-ε4 carriership and sex. RESULTS: Of 8,768 participants with serum immunoglobulins, 3,455 participants (65.8 years [interquartile range (IQR): 61.5-72.0], 57.2% female) had plasma biomarkers available and 3,139 participants (57.4 years [IQR: 52.7-60.7], 54.4% female) had neuroimaging data. Overall, no associations between serum immunoglobulins and biomarkers of dementia remained significant after correction for multiple testing. However, several suggestive associations were noted: higher serum IgA levels concurred with lower plasma levels of Aß-42 (standardized adjusted mean difference: -0.015 [95% confidence interval (CI): -0.029--0.002], p = 2.8 × 10-2), and a lower total brain volume, mainly driven by less gray matter (-0.027 [-0.046--0.008], p = 6.0 × 10-3) and more white matter hyperintensities (0.047 [0.016 - 0.077], p = 3.0 × 10-3). In sensitivity analyses, higher IgM was linked to lower t-tau, Aß-40, and Aß-42, but also a loss of white matter microstructural integrity. Stratified analyses indicate that these associations potentially differ between carriers and non-carriers of the APOE-ε4 allele and men and women. CONCLUSIONS: While associations between serum immunoglobulins and early markers of dementia could not be established in this population-based sample, it may be valuable to consider factors such as APOE-ε4 allele carriership and sex in future investigations.

The Association of Serum Immunoglobulins with Risk of Cardiovascular Disease and Mortality: the Rotterdam Study.

PURPOSE: Inflammation is implicated in cardiovascular disease (CVD), but the association of total serum immunoglobulin (Ig) A, G, and M with CVD across the whole spectrum of atherosclerosis in community-dwelling elderly is unknown. METHODS: This study was embedded in the Rotterdam Study, an ongoing population-based cohort study. We performed Cox regression for the associations of Igs with incident atherosclerotic CVD (ACVD; composite of myocardial infarction, revascularization, and stroke), cardiovascular mortality, and all-cause mortality, and multinomial logistic regression for the association between Igs and coronary artery calcification (CAC) scores. We adjusted for age, sex, lifestyle, and cardiovascular risk factors and presented results per standard deviation increase. RESULTS: We included 8767 participants (median age 62.2 years, 57% women). Higher IgG was associated with an increased ACVD risk (hazard ratio [HR]: 1.08; 95% confidence interval [95% CI]: 1.01-1.15). Higher IgA and IgG were associated with an increased cardiovascular mortality risk, mainly within Ig reference ranges, and with an increased all-cause mortality risk, although less marked. Higher IgA was associated with severe atherosclerosis, i.e., CAC score > 400 (odds ratio: 1.29; 95% CI: 1.03-1.62), while for higher IgG a trend was seen with severe atherosclerosis. CONCLUSION: In middle-aged and older individuals from the general population, higher serum IgA and IgG, but not IgM, are associated with CVD, cardiovascular mortality, and severe atherosclerosis, particularly within Ig reference ranges and independent of serum C-reactive protein. Future studies are needed to elucidate potential causality of the reported associations.

The association of serum immunoglobulins with cognition and dementia: the Rotterdam Study.

BACKGROUND: Chronic inflammation is involved in the pathophysiology of dementia, but the association of serum immunoglobulins with dementia has been understudied and longitudinal data are currently lacking. We investigated the association of serum immunoglobulin (Ig) A, G, and M with cognition and dementia in a population-based cohort. METHODS: This study was embedded in the Rotterdam Study. Participants with information on serum immunoglobulin levels, measured between 1997 and 2009, were followed for incident dementia until 2016. Assessment of cognitive function and dementia was performed according to validated tests and clinical criteria respectively. We studied the association between serum immunoglobulins with prevalent and incident dementia using logistic regression and Cox proportional hazards regression analyses respectively. We performed linear regression analyses to quantify the cross-sectional association of serum immunoglobulins with global cognition as well as separate cognitive tests. Analyses were adjusted for age, sex, lifestyle, and cardiovascular factors. RESULTS: We included 8768 participants (median age of 62.2 years, 57% women, median follow-up 10.7 years). Overall, none of the immunoglobulins was associated with prevalent or incident dementia. Higher IgG levels were associated with lower scores of global cognition (adjusted standardized mean difference - 0.04; 95% confidence interval:- 0.06; - 0.02) and separate cognitive tests. CONCLUSION: In middle-aged and older individuals from the general population, serum Igs were not associated with prevalent or incident dementia, which may imply that serum Igs are not involved in the pathophysiology of dementia. Although higher IgG levels were associated with worse cognitive function, studies with longitudinal data should exclude reverse causation.

Serum Immunoglobulins, Pneumonia Risk, and Lung Function in Middle-Aged and Older Individuals: A Population-Based Cohort Study.

Introduction: Immunoglobulins (Igs) play a pivotal role in host defense and prevention of pneumonia. Aging influences serum Ig levels, but the association between Igs and pneumonia in community-dwelling older individuals remains unknown. We evaluated the association of serum IgA, IgG, and IgM with pneumonia and lung function in middle-aged and older individuals. Methods: We performed Cox and negative binomial regression analyses for the association of Igs with incident pneumonia and pneumonia-related mortality, and recurrent pneumonia respectively. We performed logistic regression analyses for the association between Igs and lung function values. Associations were adjusted for age, sex, smoking, comorbidities, and serum C-reactive protein. Results: We included 8,766 participants (median age 62.2 years, 57% women, median follow-up 9.8 years). Higher IgA (hazard ratio [HR]: 1.15; 95% confidence interval [95% CI]: 1.00-1.32) and IgG (HR: 1.13; 95% CI: 1.06-1.19) were associated with an increased pneumonia risk. Higher IgG was associated with an increased risk of pneumonia-related mortality (HR: 1.08; 95% CI: 1.01-1.16) and recurrent pneumonia (incidence rate ratio: 1.04; 95% CI: 1.00-1.09). Higher IgA and IgG were also associated with lower forced expiratory volume in one second (FEV1), lower forced vital capacity (FVC), and an increased odds of preserved ratio impaired spirometry (PRISm, i.e. FEV1 <80% and FEV1/FVC ratio ≥70%). No association was seen with an obstructive spirometry pattern. Discussion: Higher serum IgA and IgG levels were associated with pneumonia, pneumonia-related mortality, and PRISm in middle-aged and older individuals from the general population. Future studies should validate our findings and elucidate underlying pathophysiology.

The role of serum testosterone and dehydroepiandrosterone sulfate in kidney function and clinical outcomes in chronic kidney disease: a systematic review and meta-analysis.

Objective/design: Testosterone might mediate sex differences in kidney function and chronic kidney disease (CKD). However, few studies analyzing the association between testosterone and kidney function showed conflicting results. Therefore, we performed a systematic review and meta-analysis. Methods: Six electronic databases were searched from inception to March 4, 2020, for studies that investigated the association of (i) testosterone status with kidney function in the general population or (ii) testosterone status with clinical outcomes (kidney function decline, kidney failure, cardiovascular (CV) events, and cardiovascular and all-cause mortality) in CKD patients. We used random and fixed-effect models to obtain pooled effect estimates with 95% confidence intervals (CIs). Results: No randomized-controlled trials that met the inclusion criteria were identified. One study was conducted in the general population and reported an increased risk of incident CKD with low vs normal testosterone (hazard ratio (HR): 1.38, 95% CI: 1.05;1.80). Seven studies were conducted in men with CKD and included testosterone as determinant, of which six could be meta-analyzed. Low testosterone was associated with an increased risk of all-cause mortality and CV events (pooled HR: 1.98, 95% CI: 1.36;2.89; pooled HR of 2.40, 95% CI: 1.22;4.71, respectively). Two studies showed an increased risk of all-cause mortality with decreased dehydroepiandrosterone sulfate (DHEAS) in men with CKD; results regarding CV events were conflicting. Conclusions: Although literature is scarce, evidence suggests that lower testosterone may increase CKD risk in the general population and risk of all-cause mortality and CV events in men with CKD. Whether testosterone supplementation could prevent these potential detrimental outcomes should be determined in future intervention studies.

Determinants and Clinical Implications of Thyroid Peroxidase Antibodies in Middle-Aged and Elderly Individuals: The Rotterdam Study.

Background: Thyroid peroxidase antibodies (TPO-Abs) play an important role in autoimmune thyroid disease, but are also prevalent in healthy individuals. However, it is unclear what determinants may influence the occurrence of TPO-Abs in healthy individuals and how TPO-Abs may affect health outcomes in these individuals. We aimed to identify determinants of TPO-Abs in a large, prospective population-based cohort of middle-aged and elderly individuals and to subsequently assess the association between TPO-Abs and risk of overall and cause-specific mortality. Methods: We performed binomial and multinomial logistic regression analyses to obtain odds ratios (ORs) and 95% confidence intervals [95% CIs] for the association of potential determinants based on previous literature with TPO-Ab positivity (>35 kU/L), TPO-Ab detectability (>5 kU/L), and TPO-Ab categories. Cox proportional hazards regression analyses were performed to obtain hazard ratios (HRs) and CIs for the association between TPO-Abs and mortality risk. Results: In 9685 participants (57% women, median baseline age 63.3 years, median follow-up time 10.1 years), we identified female sex (OR = 2.47 [CI 2.13-2.86]) and current smoking (OR = 3.10 [CI 2.66-3.62]) as determinants of TPO-Ab positivity and TPO-Ab detectability, respectively. Higher age (OR = 0.98 [CI 0.97-0.98]) and all categories of alcohol consumption (ORs ranging from 0.71-0.78) were associated with lower odds of TPO-Ab detectability. TPO-Ab detectability was associated with a higher risk of overall (HR = 1.09 [CI 1.01-1.17]), cancer-related (HR = 1.18 [CI 1.01-1.38]), and cardiovascular mortality (HR = 1.21 [CI 1.01-1.45]). Interestingly, this was more prominent in men compared with women (HR for cardiovascular mortality 1.50 vs. 0.99, respectively). Conclusions: In community-dwelling middle-aged and elderly individuals, female sex and current smoking are the most important determinants associated with TPO-Ab levels in the detectable and positive range, whereas alcohol consumption is associated with lower odds of TPO-Abs. The clinical importance of detectable TPO-Ab levels is illustrated by the association with an increased mortality risk, mainly in men. Our results warrant further exploration of the clinical applicability of detectable TPO-Ab levels, potentially as a marker for low-grade inflammation. The Rotterdam Study has been entered into the Netherlands National Trial Register (NTR; www.trialregister.nl) and into the WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/) under shared catalogue number NTR6831.

Determinants of Serum Immunoglobulin Levels: A Systematic Review and Meta-Analysis.

Background: An up-to-date overview of determinants of serum immunoglobulins in adults is pivotal for clinical practice and research, but currently lacking. We therefore performed a systematic review and meta-analysis to identify determinants of serum immunoglobulin levels. Methods: Embase, Web of Science, Medline, Cochrane, and Google Scholar were searched from inception to July 11th, 2019 for articles reporting on determinants of serum immunoglobulin A, G or M (IgA, IgG or IgM) in adult humans. Random and fixed effect models were applied to obtain pooled mean differences (MDs) and 95% confidence intervals (CIs) for the association of age and sex with serum immunoglobulins. Results: We retrieved 117 articles reporting on determinants of serum immunoglobulins, of which 28 could be meta-analyzed. Older compared to younger individuals had higher IgA (MD: 0.38; CI: 0.18 - 0.58), but lower IgM levels (MD: -0.40; 95%: -0.66 - -0.14). Men had higher IgA (MD: 0.22; CI: 0.03 - 0.42), but lower IgM levels (MD: -0.21; CI: -0.32 - -0.10) than women. Age and sex did not influence IgG. Caucasian ethnicity was associated with lower IgA, IgG, and IgM. Smoking and corticosteroid use were associated with lower IgG. Positive associations were reported of probiotics with IgG, alcohol with IgA, hypertension with IgA and IgG, and acute psychological stress with IgA, IgG, and IgM. Conclusions: Older age and male sex are associated with higher IgA, but lower IgM, and urge investigation of age- and sex-specific reference ranges of immunoglobulins. Other identified determinants were ethnicity, diet, lifestyle and cardio-metabolic factors.

The association of autoimmune thyroid disease (AITD) with psoriatic disease: a prospective cohort study, systematic review and meta-analysis.

OBJECTIVE: Autoimmune thyroid disease (AITD) and psoriatic disease share auto-immunological components. Few studies have investigated the link between both, yielding inconclusive results. DESIGN: We assessed the association of AITD with psoriatic disease in a prospective cohort study and performed a systematic review and meta-analysis. METHODS: 8214 participants of the Rotterdam Study (RS) with thyroid peroxidase antibodies (TPO-Abs), thyroid-stimulating hormone (TSH) and/or free thyroxine (FT4) measurements and information on psoriatic disease were included. We performed logistic and Cox regression analyses and a systematic literature search in several electronic databases on AITD and psoriatic disease. We pooled odds ratios (ORs) of included studies using the Mantel-Haenszel method, while adding RS data on prevalent psoriatic disease. RESULTS: Within the RS, we found no association between TPO-Ab positivity and psoriatic disease. There was a positive trend between TSH and prevalent psoriatic disease, and between FT4 and incident psoriatic disease, although not significant. Out of 1850 articles identified, seven were included in the systematic review and four in the meta-analysis. The risk of psoriatic disease (pooled OR) was 1.71 (confidence interval (CI): 1.27-2.31) for TPO-Ab positivity, 1.25 (CI: 1.14-1.37) for AITD and 1.34 (CI: 1.16-1.54) respectively, and 1.17 (CI: 1.03-1.32) for hypothyroidism and hyperthyroidism. CONCLUSIONS: Our meta-analysis suggests that TPO-Ab positivity, hypothyroidism and hyperthyroidism might be associated with prevalent psoriatic disease. However, there are only few studies with large heterogeneity regarding psoriatic disease definition and indication of publication bias. Additional prospective data are needed to assess the association of AITD with incident psoriatic disease.

Thyroid Function and Cancer Risk: The Rotterdam Study.

CONTEXT: In vitro and in vivo experiments have assigned both oncosuppressive and oncogenic properties to thyroid hormones. Population-based studies have found inconclusive results. OBJECTIVE: We aimed to prospectively assess the relation between thyroid function and incident cancer in a population-based setting. DESIGN, SETTING, AND PARTICIPANTS: The current study is a prospective population-based cohort study including 10 318 participants for whom baseline measurements of free T4 (FT4) and/or TSH were available. MAIN OUTCOME MEASURES: Cox proportional hazards models were used to assess hazard ratios (HRs) of any solid non-skin cancer, as well as lung, breast, prostate, and gastrointestinal cancer specifically. RESULTS: Higher FT4 levels were associated with a higher risk of any solid cancer (HR, 1.42; 95% confidence interval [CI], 1.12-1.79), lung cancer (HR, 2.33; 95% CI, 1.39-3.92) and breast (HR, 1.77; 95% CI, 1.10-2.84) cancer. The risk estimates were similar after exclusion of thyroid-altering medication, but the association lost significance for breast cancer. Compared with the lowest FT4 tertile, the highest tertile was associated with a 1.13-fold increased risk of any solid, 1.79-fold increased risk of lung, and 1.14-fold increased risk of breast cancer (P for trend <.05 for all). For TSH levels we found no associations with cancer risk. There was no differential effect of sex or age on the association between thyroid function and cancer risk. CONCLUSIONS: Higher FT4 levels are significantly associated with an increased risk of any solid, lung, and breast cancer. Further research should elucidate the underlying pathophysiological mechanisms.

PP068. Evaluation of cardiovascular health in previously preeclamptic women.

INTRODUCTION: Women with a history of preeclampsia have an increased risk of developing cardiovascular disease (CVD) later in life. Classical risk scores are not suitable as risk estimates of CVD in this young population. Recent recommendations from the American Heart Association are aimed to improve cardiovascular health (CVH). OBJECTIVES: Examining CVH by Health Life Check (HLC) (http://mylifecheck.heart.org/) in previously severe preeclamptic women is part of our cardiovascular risk follow-up program. Final score is a scale from 1 to 10, where 10 represents ideal CVH. RESULTS: Since 2011 HLC is offered to all women in this program. So far, 213 women were included, 148 (70%) underwent a CVH assessment by performing HLC between three months and one year after delivery. The overall HLC score was 7.4 (median; range: 0.8-10.0) at 3.6 months after the delivery. Only 2 out of 148 women (1.4%) had an ideal score. HLC score was 7.1 (median; range: 0.8-10.0) for 48 women who had a HLC score within 6 months after delivery versus 8.2 (median; range: 2.6-9.8) in the second half of the first year after delivery. CONCLUSION: These are the first data on CVH in women after severe preeclampsia. Only 1.4% of these women had an ideal score. Active counselling of these women could be the reason of the improved score over time. We showed that CVH as assessed by HLC is an excellent tool for cardiovascular risk management in this specific group of women.