Multiple Gestation as a Risk Factor for SARS-CoV-2-Associated Adverse Maternal Outcome: Data From the COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS).

Introduction: Studies have shown that pregnant women with COVID-19 have a higher risk of intensive care unit admission and invasive mechanical ventilation support than non-pregnant women. Pregnancy-associated physiological changes in respiratory function may contribute to the elevated risk. Alteration in lung volumes and capacities are attributed to the mechanical impediment caused by the growing fetus. Multiple pregnancies may therefore compromise functional lung capacity earlier than singleton pregnancies and contribute to severe respiratory symptoms of COVID-19. Materials and Methods: A total of 5514 women with a symptomatic SARS-CoV-2 infection during pregnancy registered in the COVID-19 Related Obstetric and Neonatal Outcome Study were included. The COVID-19-related adverse maternal outcomes were compared in 165 multiple versus 5349 singleton pregnancies. Combined adverse maternal outcome was defined as presence of COVID-19-related hospitalization and/or pneumonia and/or oxygen administration and/or transfer to ICU and/or death. Multivariate logistic regression was used to estimate the odds ratios and 95% confidence intervals were calculated. Results: The frequency of dyspnea, likelihood of developing dyspnea in a defined pregnancy week and duration of the symptomatic phase of the COVID-19 infection did not differ between the two groups. On average, COVID-19-related combined adverse outcome occurred earlier during pregnancy in women expecting more than one child than in singleton pregnancies. The overall incidence of singular and combined COVID-19-associated adverse maternal outcomes was not significantly different between groups. However, regression analysis revealed that multiple gestation, preconceptional BMI > 30 kg/m 2 and gestational age correlated significantly with an increased risk of combined adverse maternal outcome. Conversely, maternal age and medically assisted reproduction were not significant risk factors for combined adverse maternal outcome. Conclusion: Our data show that multiple gestation alone is a risk factor for COVID-19-associated combined adverse maternal outcome. Moreover, severe courses of COVID-19 in women expecting more than one child are observed earlier in pregnancy than in singleton pregnancies.

Correction: Multiple Gestation as a Risk Factor for SARS-CoV-2-Associated Adverse Maternal Outcome: Data From the COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS).

[This corrects the article DOI: 10.1055/a-2196-6224.].

Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline: A Randomized Clinical Trial.

Importance: Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline. Objective: To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group. Design, Setting, and Participants: This 12-month randomized, double-masked, placebo-controlled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021. Interventions: One hundred participants were randomly assigned (1:1 ratio) to 12 months of dietary supplementation with either a spermidine-rich dietary supplement extracted from wheat germ (0.9 mg spermidine/d) or placebo (microcrystalline cellulose). Eighty-nine participants (89%) successfully completed the trial intervention. Main Outcomes and Measures: Primary outcome was change in memory performance from baseline to 12-month postintervention assessment (intention-to-treat analysis), operationalized by mnemonic discrimination performance assessed by the Mnemonic Similarity Task. Secondary outcomes included additional neuropsychological, behavioral, and physiological parameters. Safety was assessed in all participants and exploratory per-protocol, as well as subgroup, analyses were performed. Results: A total of 100 participants (51 in the spermidine group and 49 in the placebo group) were included in the analysis (mean [SD] age, 69 [5] years; 49 female participants [49%]). Over 12 months, no significant changes were observed in mnemonic discrimination performance (between-group difference, -0.03; 95% CI, -0.11 to 0.05; P = .47) and secondary outcomes. Exploratory analyses indicated possible beneficial effects of the intervention on inflammation and verbal memory. Adverse events were balanced between groups. Conclusions and Relevance: In this randomized clinical trial, longer-term spermidine supplementation in participants with subjective cognitive decline did not modify memory and biomarkers compared with placebo. Exploratory analyses indicated possible beneficial effects on verbal memory and inflammation that need to be validated in future studies at higher dosage. Trial Registration: ClinicalTrials.gov Identifier: NCT03094546.

Negative affective burden is associated with higher resting-state functional connectivity in subjective cognitive decline.

Subjective cognitive decline (SCD), as expressed by older adults, is associated with negative affect, which, in turn, is a likely risk factor for Alzheimer's Disease (AD). This study assessed the associations between negative affective burden, cognitive functioning, and functional connectivity in networks vulnerable to AD in the context of SCD. Older participants (60-90 years) with SCD (n = 51) and healthy controls (n = 50) were investigated in a cross-sectional study. Subclinical negative affective burden, quantified through a composite of self-reported negative affective factors, was related to cognitive functioning (self-perceived and objective) and functional connectivity. Seed-to-voxel analyses were carried out in default mode network (DMN) and salience network (SAL) nodes using resting-state functional magnetic resonance imaging. Greater negative affective burden was associated with lower self-perceived cognitive functioning and lower between-network functional connectivity of DMN and SAL nodes in the total sample. In addition, there was a significant moderation of SCD status. Greater negative affective burden related to higher functional connectivity within DMN (posterior cingulate-to-precuneus) and within SAL (anterior cingulate-to-insula) nodes in the SCD group, whereas in controls the inverse association was found. We show that negative affective burden is associated with functional brain alterations in older adults, regardless of SCD status. Specifically in the SCD phenotype, greater negative affective burden relates to higher functional connectivity within brain networks vulnerable to AD. Our findings imply that negative affective burden should be considered a potentially modifiable target for early intervention.

Severity of Subjective Cognitive Complaints and Worries in Older Adults Are Associated With Cerebral Amyloid-ß Load.

Subjective cognitive decline (SCD) is considered an early risk stage for dementia due to Alzheimer's disease (AD) and the development of pathological brain changes, such as the aggregation of amyloid-beta (amyloid-ß) plaques. This study evaluates the association between specific features of SCD and cerebral amyloid-ß load measured by positron emission tomography (PET) with 18F-florbetaben in 40 cognitively normal older individuals. Global amyloid-ß, as well as regional amyloid-ß load for the frontal, temporal, parietal, and cingulate cortex, was quantified. Specific features of SCD, such as subjective cognitive complaints and worry, were assessed using the 39-item Everyday Cognition Scales and the 16-item Penn State Worry Questionnaire. Spearman's rank partial correlation analyses, adjusted for age and apolipoprotein E ε4 status, were conducted to test the associations between specific features of SCD and cerebral amyloid-ß load. The severity of subjective cognitive complaints in everyday memory and organization was positively correlated with amyloid-ß load in the frontal cortex. In addition, the severity of subjective cognitive complaints in everyday planning was positively correlated with amyloid-ß load in the parietal cortex. Higher levels of worry were associated with higher amyloid-ß load in the frontal cortex. After correction of the PET data for partial volume effects, these associations were reduced to trend level. In conclusion, the severity of subjective cognitive complaints and the level of trait worry were positively associated with cortical amyloid-ß burden, particularly in the frontal and parietal cortex. Further studies are required to elucidate the direction of these associations in order to develop strategies to prevent amyloid deposition and cognitive decline.

Spermidine intake is associated with cortical thickness and hippocampal volume in older adults.

BACKGROUND: The natural polyamine spermidine, known to be important for cellular function, decreases during aging. Previous research has demonstrated beneficial impact of spermidine intake on memory functions in both animal models and humans, suggesting that spermidine may be a preventive approach to delay age-related cognitive decline and possibly even Alzheimer's disease (AD). However, the association of spermidine intake with brain health in humans is still unknown. In this study, we aimed to determine the association between dietary spermidine intake and structural brain measures in older individuals with subjective cognitive decline (SCD) and healthy controls (HC). METHODS: Dietary spermidine intake and adherence to Mediterranean Diet (MeDi) were assessed by a self-reported food frequency questionnaire in 90 older adults with SCD and 47 HC. Processing of structural MRI data yielded global brain volumes, hippocampal volume, mean and regional cortical thickness, and cortical thickness in a template encompassing AD-vulnerable regions. In exploratory analyses, the association between spermidine intake and structural brain measures was assessed using adjusted and unadjusted linear regression models. Additionally, we tested for differential associations as a function of group. Mediation analyses were performed to examine whether dietary spermidine intake mediates the associations between adherence to MeDi and structural brain measures. RESULTS: Higher spermidine intake was associated with larger hippocampal volume (standardized ߠ​= â€‹0.262, p â€‹= â€‹0.002), greater mean cortical thickness (standardized ߠ​= â€‹0.187, p â€‹= â€‹0.031), and greater cortical thickness in AD-vulnerable brain regions (standardized ߠ​= â€‹0.176, p â€‹= â€‹0.042), the parietal (standardized ߠ​= â€‹0.202, p â€‹= â€‹0.020), and temporal lobes (standardized ߠ​= â€‹0.217, p â€‹= â€‹0.012). No significant differential effect emerged between older adults with SCD and HC. Moreover, a substantial mediating effect of dietary spermidine intake on the associations between adherence to MeDi and structural brain measures was observed. CONCLUSION: Higher dietary spermidine intake was positively associated with several structural brain measures, irrespective of the presence of SCD, and substantially mediated the relationship of adherence to MeDi and structural brain measures. Our data suggest that higher spermidine intake might be a promising dietary approach to preserve brain health in older adults, a hypothesis currently tested in an interventional trial.

Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)-study protocol for a randomized controlled trial.

BACKGROUND: Given the global increase in the aging population and age-related diseases, the promotion of healthy aging is one of the most crucial public health issues. This trial aims to contribute to the establishment of effective approaches to promote cognitive and brain health in older individuals with subjective cognitive decline (SCD). Presence of SCD is known to increase the risk of objective cognitive decline and progression to dementia due to Alzheimer's disease. Therefore, it is our primary goal to determine whether spermidine supplementation has a positive impact on memory performance in this at-risk group, as compared with placebo. The secondary goal is to examine the effects of spermidine intake on other neuropsychological, behavioral, and physiological parameters. METHODS: The SmartAge trial is a monocentric, randomized, double-blind, placebo-controlled phase IIb trial. The study will investigate 12 months of intervention with spermidine-based nutritional supplementation (target intervention) compared with 12 months of placebo intake (control intervention). We plan to recruit 100 cognitively normal older individuals with SCD from memory clinics, neurologists and general practitioners in private practice, and the general population. Participants will be allocated to one of the two study arms using blockwise randomization stratified by age and sex with a 1:1 allocation ratio. The primary outcome is the change in memory performance between baseline and post-intervention visits (12 months after baseline). Secondary outcomes include the change in memory performance from baseline to follow-up assessment (18 months after baseline), as well as changes in neurocognitive, behavioral, and physiological parameters (including blood and neuroimaging biomarkers), assessed at baseline and post-intervention. DISCUSSION: The SmartAge trial aims to provide evidence of the impact of spermidine supplementation on memory performance in older individuals with SCD. In addition, we will identify possible neurophysiological mechanisms of action underlying the anticipated cognitive benefits. Overall, this trial will contribute to the establishment of nutrition intervention in the prevention of Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03094546 . Registered 29 March 2017-retrospectively registered. PROTOCOL VERSION: Based on EA1/250/16 version 1.5.