Lower serum ferritin levels are associated with worse cognitive performance in aging.

OBJECTIVES: Iron is important for neurogenesis, synaptic development, and neurotransmitter synthesis. Serum ferritin (SF) is a reliable marker for assessing iron stores. Therefore, we evaluated the cognitive function associated with SF levels. We also assessed brain iron content using R2* Magnetic Resonance Imaging (MRI) and its association with SF levels. DESIGN: Data from three cross-sectional observational studies were used. Aging Imageomics (n = 1030) was conducted on aged subjects. Health Imageomics (n = 971) and IR0NMET (n = 175) were conducted in middle-aged subjects. SETTING AND PARTICIPANTS: Participants were enrolled at Dr. Josep Trueta University Hospital facilities. The three cohorts included a total of 2176 subjects (mean age, 52 years; 48% men). MEASUREMENTS: SF levels were measured by standard laboratory methods. Total Digits Span (TDS), and Phonemic Verbal Fluency (PVF) were used to assess executive function. Language function was assessed by semantic verbal fluency (SVF), attention by the Symbol Digit Modalities Test, and memory by the Memory Binding Tests - Total Free Recall and Total Delayed Free Recall. MRI was used to assess the iron content of the brain by R2*. RESULTS: In subjects aged 65 years or older, SF levels were associated with increased TDS (ß = 0.003, p = 0.02), PVF (ß = 0.004, p = 0.01), and SVF (ß = 0.004, p = 0.002) scores. After stratification by sex, these findings were significant only in men, where SF was associated with increased TDS (ß = 0.003, p = 0.01), PVF (ß = 0.004, p = 0.03), and SVF (ß = 0.004, p = 0.009) scores. In middle-aged subjects, SF was also associated with increased SVF scores (ß = 0.005, p = 0.011). Lastly, in men, SF levels were negatively associated with R2*, a surrogate marker of brain iron content, in both the left frontal inferior opercular area (r = -0.41, p = 0.005) and the right frontal inferior opercular area (r = -0.44, p = 0.002). CONCLUSIONS: SF is significantly and positively associated with cognition. In older people with low SF levels, iron supplementation may be a promising therapy to improve cognition.

Multimorbidity patterns and disability and healthcare use in Europe: do the associations change with the regional socioeconomic status?

Multimorbidity, the concurrence of several chronic conditions, is a rising concern that increases the years lived with disability and poses a burden on healthcare systems. Little is known on how it interacts with socioeconomic deprivation, previously associated with poor health-related outcomes. We aimed to characterize the association between multimorbidity and these outcomes and how this relationship may change with socioeconomic development of regions. 55,915 individuals interviewed in 2017 were drawn from the Survey of Health, Ageing and Retirement in Europe, a population-based study. A Latent Class Analysis was conducted to fit multimorbidity patterns based on 16 self-reported conditions. Physical limitation, quality-of-life and healthcare utilization outcomes were regressed on those patterns adjusting for additional covariates. Those analyses were then extended to assess whether such associations varied with the region socioeconomic status. We identified six different patterns, labelled according to their more predominant chronic conditions. After the "healthy" class, the "metabolic" and the "osteoarticular" classes had the best outcomes involving limitations and the lowest healthcare utilization. The "neuro-affective-ulcer" and the "several conditions" classes yielded the highest probabilities of physical limitation, whereas the "cardiovascular" group had the highest probability of hospitalization. The association of multimorbidity over physical limitations appeared to be stronger when living in a deprived region, especially for metabolic and osteoarticular conditions, whereas no major effect differences were found for healthcare use. Multimorbidity groups do differentiate in terms of limitation and healthcare utilization. Such differences are exacerbated with socioeconomic inequities between regions even within Europe.

Gut microbiota links to serum ferritin and cognition.

Iron is required for the replication and growth of almost all bacterial species and in the production of myelin and neurotransmitters. Increasing clinical studies evidence that the gut microbiota plays a critical role in iron metabolism and cognition. However, the understanding of the complex iron-microbiome-cognition crosstalk remains elusive. In a recent study in the Aging Imageomics cohort (n = 1,030), we identified a positive association of serum ferritin (SF) with executive function (EF) as inferred from the semantic verbal fluency (SVF,) the total digit span (TDS) and the phonemic verbal fluency tests (PVF). Here, we explored the potential mechanisms by analyzing the gut microbiome and plasma metabolome using shotgun metagenomics and HPLC-ESI-MS/MS, respectively. Different bacterial species belonging to the Proteobacteria phylum (Klebsiella pneumoniae, Klebsiella michiganensis, Unclassified Escherichia) were negatively associated both with SF and executive function. At the functional level, an enrichment of microbial pathways involved in phenylalanine, arginine, and proline metabolism was identified. Consistently, phenylacetylglutamine, a metabolite derived from microbial catabolism of phenylalanine, was negatively associated with SF, EF, and semantic memory. Other metabolites such as ureidobutyric acid and 19,20-DiHDPA, a DHA-derived oxylipin, were also consistently and negatively associated with SF, EF, and semantic memory, while plasma eicosapentaenoic acid was positively associated. The associations of SF with cognition could be mediated by the gut microbiome through microbial-derived metabolites.

Influence of Social Determinants of Health on the Quality of Life of Older Adults in Europe: A Sex Analysis.

Introduction: The global aging population poses challenges for society such as health inequalities among older persons and between genders. Objectives: To determine how Social Determinants of Health (SDH) influence the quality of life (QoL) of individuals over 50 years old in various European countries, taking a gender perspective in a longitudinal study. Materials and methods: Sample of 11,493 individuals from 13 European countries from Waves 5 (2013), 6 (2015), and 7 (2017) of the SHARE study. Instruments: CASP-12 (QoL), EURO-D (depression), SDH: gender, age, educational level, socioeconomic status, ethnicity, place of residence, and European region. Sociodemographic and clinical variables. Statistical analysis: Bivariate and multivariate mixed linear models. Results: The bivariate analysis showed higher economic hardship and lower education in women compared to men. The CASP-12 score was higher in men than in women. In the multivariate analysis, the variables associated with lower QoL scores among men and women from Wave 5 to Wave 7 were: (ß:-0.196, 95% CI: -0.345; -0.047) vs (ß:0.038, 95% CI: -0.122; 0.197); economic hardship; and the European region between South and North (ß: 2.709, 95% CI: 2.403; 3.015) vs men (ß: 2.224, 95% CI: 1.896; 2.551). Conclusions: The main SDH associated with poorer QoL were female gender, advanced age, economic hardship, educational level, and geographic location within Europe. Depression in women and in Southern Europe were associated with a decrease in QoL scores.

Association of depression phenotypes and antidepressant treatment with mortality due to cancer and other causes: a community-based cohort study.

Objective: This study aimed to assess the association of somatic depressive symptoms (SDS), cognitive/emotional depressive symptoms (C-EDS), and antidepressant treatment on mortality due to cancer and other causes in a community cohort. Methods: A community-based sample recruited in 1995, 2000, and 2005 aged between 35 and 75 years was examined in two waves and followed for a median of 6.7 years. SDS and C-EDS phenotypes were assessed using the Patient Health Questionnaire-9. Medication used by participants was collected. Deaths and their causes were registered during follow-up. Cox proportional hazard models stratified by sex were performed to determine the association between depressive phenotypes and mortality. Results: The cohort consisted of 5,646 individuals (53.9% women) with a mean age of 64 years (SD = 11.89). During the follow-up, 392 deaths were recorded, of which 27.8% were due to cancer. C-EDS phenotype was associated with an increased risk of cancer mortality in both men (HR = 2.23; 95% CI = 1.11-4.44) and women (HR = 3.69; 95% CI = 1.69-8.09), and SDS was significantly associated with non-cancer mortality in men (HR = 2.16; 95 CI % = 1.46-3.18). Selective serotonin reuptake inhibitors (SSRIs) were significantly associated with both cancer (HR = 2.78; 95% CI = 1.10-6.98) and non-cancer mortality (HR = 2.94; 95% CI = 1.76-4.90) only in the male population. Conclusion: C-EDS phenotype was related to an increased risk of cancer mortality at 6 years. In addition, the use of SSRIs in the male population was associated with cancer and all-cause mortality.

Adipose tissue coregulates cognitive function.

Obesity is associated with cognitive decline. Recent observations in mice propose an adipose tissue (AT)-brain axis. We identified 188 genes from RNA sequencing of AT in three cohorts that were associated with performance in different cognitive domains. These genes were mostly involved in synaptic function, phosphatidylinositol metabolism, the complement cascade, anti-inflammatory signaling, and vitamin metabolism. These findings were translated into the plasma metabolome. The circulating blood expression levels of most of these genes were also associated with several cognitive domains in a cohort of 816 participants. Targeted misexpression of candidate gene ortholog in the Drosophila fat body significantly altered flies memory and learning. Among them, down-regulation of the neurotransmitter release cycle-associated gene SLC18A2 improved cognitive abilities in Drosophila and in mice. Up-regulation of RIMS1 in Drosophila fat body enhanced cognitive abilities. Current results show previously unidentified connections between AT transcriptome and brain function in humans, providing unprecedented diagnostic/therapeutic targets in AT.

A 14-Year Longitudinal Analysis of Healthcare Expenditure on Dementia and Related Factors (DEMENCOST Study).

BACKGROUND: The large number of dementia cases produces a great pressure on health and social care services, which requires efficient planning to meet the needs of patients through infrastructure, equipment, and financial, technical, and personal resources adjusted to their demands. Dementia analysis requires studies with a very precise patient characterization of both the disease and comorbidities present, and long-term follow-up of patients in clinical aspects and patterns of resource utilization and costs generated. OBJECTIVE: To describe and quantify direct healthcare expenditure and its evolution from three years before and up to ten years after the diagnosis of dementia, compared to a matched group without dementia. METHODS: Retrospective cohort design with follow-up from 6 to 14 years. We studied 996 people with dementia (PwD) and 2,998 controls matched for age, sex, and comorbidity. This paper adopts the provider's perspective as the perspective of analysis and refers to the costs actually incurred in providing the services. Aggregate costs and components per patient per year were calculated and modelled. RESULTS: Total health expenditure increases in PwD from the year of diagnosis and in each of the following 7 years, but not thereafter. Health status and mortality are factors explaining the evolution of direct costs. Dementia alone is not a statistically significant factor in explaining differences between groups. CONCLUSION: The incremental direct cost of dementia may not be as high or as long as studies with relatively short follow-up suggest. Dementia would have an impact on increasing disease burden and mortality.

Plasma acylcarnitines and gut-derived aromatic amino acids as sex-specific hub metabolites of the human aging metabolome.

Aging biology entails a cell/tissue deregulated metabolism that affects all levels of biological organization. Therefore, the application of "omic" techniques that are closer to phenotype, such as metabolomics, to the study of the aging process should be a turning point in the definition of cellular processes involved. The main objective of the present study was to describe the changes in plasma metabolome associated with biological aging and the role of sex in the metabolic regulation during aging. A high-throughput untargeted metabolomic analysis was applied in plasma samples to detect hub metabolites and biomarkers of aging incorporating a sex/gender perspective. A cohort of 1030 healthy human adults (45.9% females, and 54.1% males) from 50 to 98 years of age was used. Results were validated using two independent cohorts (1: n = 146, 53% females, 30-100 years old; 2: n = 68, 70% females, 19-107 years old). Metabolites related to lipid and aromatic amino acid (AAA) metabolisms arose as the main metabolic pathways affected by age, with a high influence of sex. Globally, we describe changes in bioenergetic pathways that point to a decrease in mitochondrial ß-oxidation and an accumulation of unsaturated fatty acids and acylcarnitines that could be responsible for the increment of oxidative damage and inflammation characteristic of this physiological process. Furthermore, we describe for the first time the importance of gut-derived AAA catabolites in the aging process describing novel biomarkers that could contribute to better understand this physiological process but also age-related diseases.

DPP9 as a Potential Novel Mediator in Gastrointestinal Virus Infection.

Dipeptidyl peptidase 9 (DPP9) is a member of the dipeptidyl peptidase IV family. Inhibition of DPP9 has recently been shown to activate the nucleotide-binding domain leucine-rich repeat 1 (NLRP1) inflammasome. NLRP1 is known to bind nucleic acids with high affinity and directly interact with double stranded RNA, which plays a key role in viral replication. DPP9 has also recently emerged as a key gene related to lung-inflammation in critical SARS-CoV-2 infection. Importantly, DPP9 activity is strongly dependent on the oxidative status. Here, we explored the potential role of DPP9 in the gastrointestinal tract. We performed transcriptomics analyses of colon (microarray, n = 37) and jejunal (RNA sequencing, n = 31) biopsies from two independent cohorts as well as plasma metabolomics analyses in two independent cohorts (n = 37 and n = 795). The expression of DPP9 in the jejunum, colon, and blood was significantly associated with circulating biomarkers of oxidative stress (uric acid, bilirubin). It was also associated positively with the expression of transcription factors (NRF-2) and genes (SOD, CAT, GPX) encoding for antioxidant enzymes, but negatively with that of genes (XDH, NOX) and transcription factors (NF-KB) involved in ROS-generating enzymes. Gene co-expression patterns associated with DPP9 identified several genes participating in antiviral pathways in both tissues. Notably, DPP9 expression in the colon and plasma was strongly positively associated with several circulating nucleotide catabolites (hypoxanthine, uric acid, 3-ureidopropionic acid) with important roles in the generation of ROS and viral infection, as well as other metabolites related to oxidative stress (Resolvin D1, glutamate-containing dipeptides). Gene-drug enrichment analyses identified artenimol, puromycin, anisomycin, 3-phenyllactic acid, and linezolid as the most promising drugs targeting these DPP9-associated genes. We have identified a novel potential pathogenic mechanism of viral infection in the digestive tract and promising existing drugs that can be repositioned against viral infection.

Control of Therapeutic Levels of Anticoagulation and Associated Factors: A Prospective Cohort Study.

Maintaining therapeutic levels of anticoagulation is essential to avoid health complications in people who take vitamin K antagonists. This study aimed to analyze the influence of people's characteristics and the presence of changes in their lives in the control of therapeutic levels of anticoagulation. A longitudinal multicenter study with a 1-year follow-up of a cohort of 199 people receiving anticoagulant therapy was performed. The effect of biological, clinical, social, lifestyle, and changes in life on the international normalized ratio (INR) was analyzed. During the follow-up, 46.7% of participants presented good INR control. At baseline, a diagnosis of atrial fibrillation (P = .00), the lack of comorbidities (P = .03), absence of depression (P = .04), and not following a pharmacological treatment with hypoglycemia drugs (P = .01) were associated with good INR control. During the follow-up, the variable of making changes to the usual diet was associated with poor INR control (P = .05). In the binary multiple regression model, factors associated with poor control were taking hypoglycemia drugs (P = .02) and the presence of depression (P = .04), and only the diagnosis of atrial fibrillation was associated with good control (P = .03). People with a diagnosis of atrial fibrillation had good INR control. Having comorbidities, suffering depression, taking hypoglycemia drugs, and making changes to the diet have a negative effect on INR control.

Longitudinal effect of dementia carers' sense of coherence on burden.

BACKGROUND: A sense of coherence (SOC) could help us better understand why there are individuals who cope better than others in similar situations. The study aimed to assess the effect of SOC on the course of burden reports in relatives of persons with dementia. METHODS: This was a prospective cohort study of 156 dementia carers. The SOC was assessed by the Orientation to Life Questionnaire (OLQ-13), burden by Burden Interview, and personal and contextual characteristics were collected via ad hoc questions. The main dementia symptoms, including functional difficulties (Disability Assessment for Dementia), neuropsychiatric symptoms (Neuropsychiatric Inventory), and cognitive impairment (Mini-Mental State Examination), were also assessed. A general linear model was adjusted to determine the effect of SOC and other covariates on burden throughout the follow-up. Burden differences between baseline and 12 and 24 months were analysed, and the baseline OLQ-13 score was grouped by quartiles. RESULTS: The global burden reported increased after 24 months (F = 9.98; df = 2; p < 0.001), but not equally for all carers; daughters reported the greatest increase. SOC, functional disability, and neuropsychiatric disorders showed a significant effect on burden, but time did not. Carers with higher SOC at baseline tend to remain with lower burden levels, whereas carers with low SOC reported higher burden at each visit. CONCLUSIONS: This study reports evidence of the effect of SOC on burden at baseline, 12 and 24 months of follow-up. Burden scores differ by carers' SOC; those with higher SOC showed lower burden levels, whereas the low-SOC group reported a greater burden at each visit.

Presence of Blastocystis in gut microbiota is associated with cognitive traits and decreased executive function.

Growing evidence implicates the gut microbiome in cognition. Blastocystis is a common gut single-cell eukaryote parasite frequently detected in humans but its potential involvement in human pathophysiology has been poorly characterized. Here we describe how the presence of Blastocystis in the gut microbiome was associated with deficits in executive function and altered gut bacterial composition in a discovery (n = 114) and replication cohorts (n = 942). We also found that Blastocystis was linked to bacterial functions related to aromatic amino acids metabolism and folate-mediated pyrimidine and one-carbon metabolism. Blastocystis-associated shifts in bacterial functionality translated into the circulating metabolome. Finally, we evaluated the effects of microbiota transplantation. Donor's Blastocystis subtypes led to altered recipient's mice cognitive function and prefrontal cortex gene expression. In summary, Blastocystis warrant further consideration as a novel actor in the gut microbiome-brain axis.

Microbiota alterations in proline metabolism impact depression.

The microbiota-gut-brain axis has emerged as a novel target in depression, a disorder with low treatment efficacy. However, the field is dominated by underpowered studies focusing on major depression not addressing microbiome functionality, compositional nature, or confounding factors. We applied a multi-omics approach combining pre-clinical models with three human cohorts including patients with mild depression. Microbial functions and metabolites converging onto glutamate/GABA metabolism, particularly proline, were linked to depression. High proline consumption was the dietary factor with the strongest impact on depression. Whole-brain dynamics revealed rich club network disruptions associated with depression and circulating proline. Proline supplementation in mice exacerbated depression along with microbial translocation. Human microbiota transplantation induced an emotionally impaired phenotype in mice and alterations in GABA-, proline-, and extracellular matrix-related prefrontal cortex genes. RNAi-mediated knockdown of proline and GABA transporters in Drosophila and mono-association with L. plantarum, a high GABA producer, conferred protection against depression-like states. Targeting the microbiome and dietary proline may open new windows for efficient depression treatment.

The effect of external stimulation on functional networks in the aging healthy human brain.

Understanding the brain changes occurring during aging can provide new insights for developing treatments that alleviate or reverse cognitive decline. Neurostimulation techniques have emerged as potential treatments for brain disorders and to improve cognitive functions. Nevertheless, given the ethical restrictions of neurostimulation approaches, in silico perturbation protocols based on causal whole-brain models are fundamental to gaining a mechanistic understanding of brain dynamics. Furthermore, this strategy could serve to identify neurophysiological biomarkers differentiating between age groups through an exhaustive exploration of the global effect of all possible local perturbations. Here, we used a resting-state fMRI dataset divided into middle-aged (N =310, <65 years) and older adults (N =310, $\geq $65) to characterize brain states in each group as a probabilistic metastable substate (PMS) space. We showed that the older group exhibited a reduced capability to access a metastable substate that overlaps with the rich club. Then, we fitted the PMS to a whole-brain model and applied in silico stimulations in each node to force transitions from the brain states of the older- to the middle-aged group. We found that the precuneus was the best stimulation target. Overall, these findings could have important implications for designing neurostimulation interventions for reversing the effects of aging on whole-brain dynamics.

Caudovirales bacteriophages are associated with improved executive function and memory in flies, mice, and humans.

Growing evidence implicates the gut microbiome in cognition. Viruses, the most abundant life entities on the planet, are a commonly overlooked component of the gut virome, dominated by the Caudovirales and Microviridae bacteriophages. Here, we show in a discovery (n = 114) and a validation cohort (n = 942) that subjects with increased Caudovirales and Siphoviridae levels in the gut microbiome had better performance in executive processes and verbal memory. Conversely, increased Microviridae levels were linked to a greater impairment in executive abilities. Microbiota transplantation from human donors with increased specific Caudovirales (>90% from the Siphoviridae family) levels led to increased scores in the novel object recognition test in mice and up-regulated memory-promoting immediate early genes in the prefrontal cortex. Supplementation of the Drosophila diet with the 936 group of lactococcal Siphoviridae bacteriophages resulted in increased memory scores and upregulation of memory-involved brain genes. Thus, bacteriophages warrant consideration as novel actors in the microbiome-brain axis.

Gender analysis of the frequency and course of depressive disorders and relationship with personality traits in general population: A prospective cohort study.

BACKGROUND: We aimed to determine the prevalence and course of subthreshold depressive symptomatology (sDS) and probable major depressive episode (MDE) and to examine their association with personality traits among men and women. METHODS: A community-based sample aged 35 years or older was examined in two waves (median follow-up of 6.9 years). The Patient Health Questionnaire-9 (PHQ-9) was used to assess sDS and MDE. The 10-item version of the Big Five Inventory was used to assess personality traits. Prevalence was assessed at baseline (n = 5,557) and incidence and persistence-recurrence rates were computed at follow up (n = 3,102). Logistic regression models were adjusted to explore the association of personality traits with prevalence and course of depressive disorders. RESULTS: The prevalence of sDS and MDE was 14.04% (95% CI = 17.04-19.08) and 8.54 (95% CI=7.82-9.31), the incidence was 14.30 per 1,000 person-years (95% CI=12.49-16.31) and 4.34 per 1,000 person-years (95% CI=3.46-5.36), and the persistence-recurrence was 35.04 per 1,000 person-years (95% CI=29.00-41.96) and 28.8 per 1,000 person-years (95% CI=20.49-38.14). The gender gap was higher for MDE. Personality traits were differentially associated with the prevalence and course of depressive disorders between men and women. LIMITATIONS: Because this study used questionnaires to assess depressive disorders and personality traits, information bias could not be ruled out. CONCLUSIONS: The gender gap was higher for the prevalence and course of the probable MDE. There were more personality traits related with the course of the sDS and they had a major role in the course of the probable MDE in women.

Multimorbidity patterns and their related characteristics in European older adults: A longitudinal perspective.

BACKGROUND: The concurrence of several chronic conditions is a rising concern that poses a serious burden on ageing populations. Analysing how these conditions appear together and how they change through time may provide useful information to design successful multimorbidity-management programs. OBJECTIVE: To identify multimorbidity patterns and their related characteristics from a longitudinal perspective. SUBJECTS: 25,931 older adults aged 50+ drawn from the Survey of Health, Ageing and Retirement in Europe (SHARE), a population-based longitudinal European study. METHODS: A sex-stratified Latent Transition Analysis was conducted to fit latent classes based on 15 self-reported chronic conditions across three time points. Health-related and socioeconomic variables were assessed as covariates of those patterns. RESULTS: We identified 4 time-constant latent classes for each sex. A "severely impaired" class (with a weighted prevalence percentage of 7.24% for females and 3.30% for males at the first time point), a "metabolic" class (26.15% and 23.82%) and a "healthy" class (50.92% and 54.32%). The fourth class was named "osteoarticular" for females (15.70%) and "articular-COPD-ulcer" for males (18.56%). Age, smoke, material deprivation and a high body mass index were associated with worse health patterns, whereas education, being employed and physical activity were related to less multimorbid classes. Few class changes were detected when modelling transitions. CONCLUSIONS: We reported information of multimorbidity classes and their characteristics that may help to develop targeted health strategies. Within a time window of four years, the identified latent classes were consistent between time points.