Unveiling the molecular landscape of cognitive aging: insights from polygenic risk scores, DNA methylation, and gene expression.

BACKGROUND: Aging represents a significant risk factor for the occurrence of cerebral small vessel disease, associated with white matter (WM) lesions, and to age-related cognitive alterations, though the precise mechanisms remain largely unknown. This study aimed to investigate the impact of polygenic risk scores (PRS) for WM integrity, together with age-related DNA methylation, and gene expression alterations, on cognitive aging in a cross-sectional healthy aging cohort. The PRSs were calculated using genome-wide association study (GWAS) summary statistics for magnetic resonance imaging (MRI) markers of WM integrity, including WM hyperintensities, fractional anisotropy (FA), and mean diffusivity (MD). These scores were utilized to predict age-related cognitive changes and evaluate their correlation with structural brain changes, which distinguish individuals with higher and lower cognitive scores. To reduce the dimensionality of the data and identify age-related DNA methylation and transcriptomic alterations, Sparse Partial Least Squares-Discriminant Analysis (sPLS-DA) was used. Subsequently, a canonical correlation algorithm was used to integrate the three types of omics data (PRS, DNA methylation, and gene expression data) and identify an individual "omics" signature that distinguishes subjects with varying cognitive profiles. RESULTS: We found a positive association between MD-PRS and long-term memory, as well as a correlation between MD-PRS and structural brain changes, effectively discriminating between individuals with lower and higher memory scores. Furthermore, we observed an enrichment of polygenic signals in genes related to both vascular and non-vascular factors. Age-related alterations in DNA methylation and gene expression indicated dysregulation of critical molecular features and signaling pathways involved in aging and lifespan regulation. The integration of multi-omics data underscored the involvement of synaptic dysfunction, axonal degeneration, microtubule organization, and glycosylation in the process of cognitive aging. CONCLUSIONS: These findings provide valuable insights into the biological mechanisms underlying the association between WM coherence and cognitive aging. Additionally, they highlight how age-associated DNA methylation and gene expression changes contribute to cognitive aging.

Larger dlPFC and vmPFC grey matter volumes are associated with high adherence to the Mediterranean diet: A cross-sectional study in older adults.

Dietary self-control is associated with inter-individual differences in neuroanatomy. Yet, whether such inter-individual differences are also associated with healthier dietary patterns is yet to be determined. In this cross-sectional study, a total of 100 northern Portuguese older community-dwellers were assessed with regards to i) the adherence to a healthy dietary eating pattern - the Mediterranean diet (MedDiet), and ii) grey matter density (GMD) of brain regions associated with valuation and dietary self-regulation, the ventromedial (vmPFC) and dorsolateral prefrontal cortex (dlPFC), through voxel-based morphometry. Healthy food choices were ascertained through the Mediterranean Diet Adherence Screener (MEDAS) where higher scores indicated greater adherence to the MedDiet. Voxel-based morphometry showed that greater grey matter density in the dlPFC and vmPFC associated with a higher adherence to the MedDiet. These results replicate previous links between dietary decision-making measured under laboratory conditions and the neuroanatomy of the brain's valuation and self-control system. Importantly, they shed new light on the potential relevance of inter-individual differences in the neuroanatomy of these two brain regions for adhering to healthier dietary patterns in everyday life.

Perceived stress modulates the activity between the amygdala and the cortex.

The significant link between stress and psychiatric disorders has prompted research on stress's impact on the brain. Interestingly, previous studies on healthy subjects have demonstrated an association between perceived stress and amygdala volume, although the mechanisms by which perceived stress can affect brain function remain unknown. To better understand what this association entails at a functional level, herein, we explore the association of perceived stress, measured by the PSS10 questionnaire, with disseminated functional connectivity between brain areas. Using resting-state fMRI from 252 healthy subjects spanning a broad age range, we performed both a seed-based amygdala connectivity analysis (static connectivity, with spatial resolution but no temporal definition) and a whole-brain data-driven approach to detect altered patterns of phase interactions between brain areas (dynamic connectivity with spatiotemporal information). Results show that increased perceived stress is directly associated with increased amygdala connectivity with frontal cortical regions, which is driven by a reduced occurrence of an activity pattern where the signals in the amygdala and the hippocampus evolve in opposite directions with respect to the rest of the brain. Overall, these results not only reinforce the pathological effect of in-phase synchronicity between subcortical and cortical brain areas but also demonstrate the protective effect of counterbalanced (i.e., phase-shifted) activity between brain subsystems, which are otherwise missed with correlation-based functional connectivity analysis.

Association of amygdala size with stress perception: Findings of a transversal study across the lifespan.

Daily routines are getting increasingly stressful. Interestingly, associations between stress perception and amygdala volume, a brain region implicated in emotional behaviour, have been observed in both younger and older adults. Life stress, on the other hand, has become pervasive and is no longer restricted to a specific age group or life stage. As a result, it is vital to consider stress as a continuum across the lifespan. In this study, we investigated the relationship between perceived stress and amygdala size in 272 healthy participants with a broad age range. Participants were submitted to a structural magnetic resonance imaging (MRI) to extract amygdala volume, and the Perceived Stress Scale (PSS) scores were used as the independent variable in volumetric regressions. We found that perceived stress is positively associated with the right amygdala volume throughout life.

Applicability and validation of the Reaction to Tests Scale (RTT) in a sample of Portuguese medical students.

BACKGROUND: Test anxiety is a crucial factor in determining academic outcomes, and it may lead to poor cognitive performance, academic underachievement, and psychological distress, interfering specifically with their ability to think and perform during tests. The main objective of this study was to explore the applicability and psychometric properties of a Portuguese version of the Reactions to Tests scale (RTT) in a sample of medical students. METHOD: A sample of 672 medical students completed the RTT. The sample was randomly split in half to allow for independent Exploratory Factor Analysis (EFA) and to test the best fit model-Confirmatory Factor Analysis (CFA). CFA was used to test both the first-order factor structure (four subscales) and second-order factor structure, in which the four subscales relate to a general factor, Test Anxiety. The internal consistency of the RTT was assessed through Cronbach's alpha, Composite reliability (CR) and Average Variance Extracted (AVE) for the total scale and each of the four subscales. Convergent validity was evaluated through the correlation between RTT and the State-Trait Anxiety Inventory (STAI-Y).To explore the comparability of measured attributes across subgroups of respondents, measurement invariance was also studied. RESULTS: Results from exploratory and confirmatory factor analyses showed acceptable fits for the Portuguese RTT version. Concerning internal consistency, results indicate that RTT was found to be reliable to measure test anxiety in this sample. Convergent validity of the RTT with both state and trait anxiety STAI-Y's subscales was also shown. Moreover, multigroup analyses showed metric invariance across gender and curriculum phase. CONCLUSION: Our results suggest that the RTT scale is a valid and reliable instrument for the measurement of test anxiety among Portuguese Medical Students.

The Association of Metabolic Dysfunction and Mood Across Lifespan Interacts With the Default Mode Network Functional Connectivity.

Background: Numerous studies suggest a relationship between depression and metabolic syndrome, which is likely influenced by age. Interestingly, functional imaging analysis has shown an association between functional connectivity in the default mode network (DMN-FC) and components of metabolic syndrome, which is explored in this study. Methods: From a larger longitudinal cohort study on healthy aging, 943 individuals were extensively characterized for mood and cognition. Among these, 120 individuals who were selected for displaying extreme cognitive performance within the normal range (good and poor performers) were further studied. Here, in a cross-sectional design, using confirmatory factor analysis (CFA), the association between metabolic dysfunction and depressive mood as a function of age and its relationship with DMN-FC was studied. Results: Metabolic dysfunction was modeled as a second-order latent variable using CFA. First-order latent variables were obesity, glucose dysmetabolism, lipids imbalance, and blood pressure. Using multiple linear regression models, this study observed that metabolic dysfunction, glucose dysmetabolism, and lipids imbalance were linearly associated with depressive mood, and the association with obesity was U-shaped. The association of metabolic dysfunction, obesity, and glucose dysmetabolism with depressive mood is positive for the younger individuals in our sample and vanishes with aging. The FC of the right superior temporal gyrus with the DMN correlated with both obesity and depressive mood. In participants with higher obesity scores, FC increased with higher GDS scores, while in those with lower GDS scores, FC decreased. Age and blood pressure were associated with a more complex pattern of association between FC of the right supramarginal gyrus and GDS score. Conclusion: The association of metabolic dysfunction with depressive mood is influenced by age and relates with differential patterns of DMN-FC. The combination of the effects of age, mood, and metabolic dysfunction is likely to explain the heterogeneity of DMN-FC, which deserves further investigation with larger and longitudinal studies.

Iron Status is Associated with Mood, Cognition, and Functional Ability in Older Adults: A Cross-Sectional Study.

Several conditions are risk factors for iron deficiency (ID), some of which are highly prevalent in older individuals. Despite the amount of evidence pointing for a role of ID in cognition, mood and physical functional ability, the research addressing these associations in older individuals is still scarce. In the present study, 162 older community-dwelling individuals (29.53% classified as ID) were enrolled in a cross-sectional analysis and characterized regarding cognition, mood, functional ability, general nutritional intake and iron status. Assessment of iron status was performed using several blood biomarkers. Storage and erythropoiesis dimensions were positively associated with memory, along with an interaction (moderator effect) between iron storage and nutritional status. A more depressed mood was negatively associated with (iron) transport, transport saturation and erythropoiesis dimensions, and functional tiredness was positively associated with the erythropoiesis dimension. These observations indicate that lower iron status is associated with depressive mood, functional tiredness and poorer memory ability, with the latter moderated by nutritional status. These findings suggest that using iron as a continuous variable may be useful in finding associations with iron homeostasis, eventually missed when iron levels are considered within the usual classification groups.

Higher Adherence to the Mediterranean Diet Is Associated With Preserved White Matter Integrity and Altered Structural Connectivity.

The Mediterranean diet (MedDiet) has been associated with cognitive performance. Yet, controlled trials have yielded contradictory results. To tackle this controversy, a comprehensive multimodal analysis of the association of the MedDiet with cognitive performance and brain structure in normative aging is still necessary. Here, community dwellers ≥50 years from a cohort study on normative aging (n = 76) underwent a (i) magnetic resonance imaging session with two acquisitions: structural and diffusion-weighted imaging (DWI); (ii) neuropsychological battery of tests focusing on memory and executive functioning; and (iii) dietary assessment through the Mediterranean Diet Assessment Screener (MEDAS, score range: 0-14, scores ≥10 indicate high adherence to the Mediterranean diet) 18 months prior to the brain imaging and neuropsychological assessment. We found that high adherence to the MedDiet (MEDAS ≥10) was associated with higher values of fractional anisotropy and lower diffusivity values in the brain white matter. Similarly, high adherence to the MedDiet was associated with higher structural connectivity between left hemisphere brain regions. Specifically, the amygdala, lingual, olfactory, middle occipital gyrus, and calcarine areas. No association was found between high adherence to the MedDiet and total brain volumes or hypointensities. Higher adherence to the MedDiet was positively associated with executive functioning scores. These results suggest that high adherence to the MedDiet positively associates with brain health, specifically with executive function scores and white matter integrity of bundles related to the processing and integration of taste, reward, and decision making. These findings seem to support the view that the MedDiet should be part of recommendations to promote a healthy brain.

The moderator effect of age in the association between mood and adiposity in the elderly is specific for the subcutaneous adipose compartment: An MRI study.

The positive association between obesity and depressive mood in young- and middle-age individuals is a phenomenon with major clinical implications in public health. Interestingly, the trend of this association in older individuals is not clear, given the conflicting results of multiple studies. Since aging is accompanied by changes in body fat distribution, we questioned whether age is a modulator of such association. This study explores the role of age in the association between mood and general (body mass index [BMI]) and abdominal adiposity (waist circumference [WC]) in older adults characterizing the different abdominal adipose tissue compartments (subcutaneous adipose tissue [SAT] and visceral adipose tissue [VAT]) with magnetic resonance imaging (MRI) techniques. METHODS: One hundred twenty aged community-dwelling individuals (≥50 y of age) were assessed regarding depressive mood (Geriatric Depression Scale) and adiposity (BMI and WC). From these, 96 were assessed for SAT and VAT using MRI. RESULTS: Using multiple linear regression models, depressive mood was positively associated with BMI, WC, and VAT. Age was a significant moderator of the association between depressive mood and BMI, WC, and SAT: positive in younger participants and null or negative in older participants. On the other hand, higher VAT was significantly associated with a more depressive mood, independently of age. CONCLUSIONS: This study identifies age as a relevant moderator in the association between depressive mood and adiposity in the elderlies. Furthermore, the body fat compartment analysis revealed that the effect of age is specific for the SAT, suggesting its protective role in depressive mood.

25-OH Vitamin D Levels and Cognitive Performance: Longitudinal Assessment in a Healthy Aging Cohort.

Background: Declining serum levels of 25-hydroxyvitamin D [25(OH)D, a biomarker of vitamin D status] with aging is a well-recognized phenomenon. However, scarce information is available on the relation between 25(OH)D levels and cognitive performance over time in older individuals. Our purpose was to evaluate, longitudinally, the association of 25(OH)D with cognitive function in a healthy older adults' cohort. Methods: Sixty-four individuals over 55 years-old with no cognitive impairment, clustered as healthy "Poor" and "Good" cognitive performers, were followed for an average of 18 months. Seasonal-adjusted 25(OH)D serum levels (measured by high-performance liquid chromatography-tandem mass spectrometry) were related, longitudinally, with cognitive (memory and general/executive) composite scores. Results: Overall seasonal-adjusted median serum 25(OH)D level was of 47 nmol/l [interquartile range (IQR), 38-60 nmol/l]. A negative correlation between baseline 25(OH)D and the general/executive composite score was found in the "Poor" cognitive performers (r s = -0.52, p = 0.006), an association lost after adjusting 25(OH)D levels for the season. No effect was found in both groups between seasonal-adjusted 25(OH)D levels and the variation of both memory and general/executive composites during follow-up when adjusted for age, gender and education level. Conclusion: In this healthy older population with no cognitive impairment, lower serum levels of 25(OH)D were not longitudinally associated with poorer cognitive scores.

Poor Sleep Quality Associates With Decreased Functional and Structural Brain Connectivity in Normative Aging: A MRI Multimodal Approach.

Sleep is a ubiquitous phenomenon, essential to the organism homeostasis. Notwithstanding, there has been an increasing concern with its disruption, not only within the context of pathological conditions, such as neurologic and psychiatric diseases, but also in health. In fact, sleep complaints are becoming particularly common, especially in middle-aged and older adults, which may suggest an underlying susceptibility to sleep quality loss and/or its consequences. Thus, a whole-brain modeling approach to study the shifts in the system can cast broader light on sleep quality mechanisms and its associated morbidities. Following this line, we sought to determine the association between the standard self-reported measure of sleep quality, the Pittsburgh Sleep Quality Index (PSQI) and brain correlates in a normative aging cohort. To this purpose, 86 participants (age range 52-87 years) provided information regarding sociodemographic parameters, subjective sleep quality and associated psychological variables. A multimodal magnetic resonance imaging (MRI) approach was used, with whole-brain functional and structural connectomes being derived from resting-state functional connectivity (FC) and probabilistic white matter tractography (structural connectivity, SC). Brain regional volumes and white matter properties associations were also explored. Results show that poor sleep quality was associated with a decrease in FC and SC of distinct networks, overlapping in right superior temporal pole, left middle temporal and left inferior occipital regions. Age displayed important associations with volumetric changes in the cerebellum cortex and white matter, thalamus, hippocampus, right putamen, left supramarginal and left lingual regions. Overall, results suggest that not only the PSQI global score may act as a proxy of changes in FC/SC in middle-aged and older individuals, but also that the age-related regional volumetric changes may be associated to an adjustment of brain connectivity. These findings may also represent a step further in the comprehension of the role of sleep disturbance in disease, since the networks found share regions that have been shown to be affected in pathologies, such as depression and Alzheimer's disease.

Discriminant power of socio-demographic characteristics and mood in distinguishing cognitive performance clusters in older individuals: a cross-sectional analysis.

OBJECTIVES: Identification of predictors of cognitive trajectories has been a matter of concern on aging research. For this reason, it is of relevance to infer cognitive profiles based on rapid screening variables in order to determine which individuals will be more predisposed to cognitive decline. METHOD: In this work, a linear discriminant analysis (LDA) was conducted with socio-demographic variables and mood status as predictors of cognitive profiles, computed in a previous sample, based on different cognitive dimensions. Data were randomly split in two samples. Both samples were representative of the Portuguese population in terms of gender, age and education. The LDA was performed with one sample (n = 506, mean age 65.7 ± 8.98 years) and tested in the second sample (n = 548, mean age 68.5 ± 9.3 years). RESULTS: With these variables, we were able to achieve an overall hit rate of 65.9%, which corresponds to a significant increment in comparison to classification by chance. CONCLUSION: Although not ideal, this model may serve as a relevant tool to identify cognitive profiles based on a rapid screening when few variables are available.

When New Technology is an Answer for Old Problems: The Use of Videoconferencing in Cognitive Aging Assessment.

People living with cognitive impairment and dementia require regular screening of their symptomatology and needs. Brief cognitive screening is crucial for assessing these conditions. Such screening can give health professionals a snapshot of the patient's cognitive abilities and help in their monitoring and adaptation. An appropriate administration of brief cognitive screening using telemedicine technology, such as videoconference, can improve access to care and treatment planning. Moreover, the burden that rural and underserved communities often suffer because of limited access to specialty mental health services is also of concern. Herein, in this review, we describe the existing and relevant research regarding the administration of neuropsychological instruments via videoconferencing, and suggest methodological improvements for further studies. To date, only a handful of scientific studies have been published documenting the feasibility and acceptability of videoconferencing among older people and health professionals. Varying in their assessment tools, the studies demonstrate the reliability of cognitive testing and clinical diagnosis of dementia via videoconferencing, as noted by the associations between results of several cognitive tests using it as compared to face-to-face interviews. Further research is required to replicate findings and bring new solutions for their adaptation to a wide range of individuals, health professionals, areas of practice and settings.

Assessing Cognitive Function in Older Adults Using a Videoconference Approach.

BACKGROUND: The use of communication technologies is an emerging trend in healthcare and research. Despite efficient, reliable and accurate neuropsychological batteries to evaluate cognitive performance in-person, more diverse and less expensive and time consuming solutions are needed. Here we conducted a pilot study to determine the applicability of a videoconference (VC, Skype®) approach to assess cognitive function in older adults, using The Telephone Interview for Cognitive Status-Modified - Portuguese version (TICSM-PT). METHODS: After inclusion and exclusion criteria, 69 individuals (mean age=74.90±9.46years), selected from registries of local health centers and assisted-living facilities, were assessed on cognitive performance using videoconference, telephone and in-person approaches. FINDINGS: The videoconference administration method yielded comparable results to the traditional application. Correlation analyses showed high associations between the testing modalities: TICSM-PT VC and TICSM-PT telephone (r=0.885), TICSM-PT VC and MMSE face-to-face (r=0.801). Using the previously validated threshold for cognitive impairment on the TICSM-PT telephone, TICSM-PT VC administration presented a sensitivity of 87.8% and a specificity of 84.6%. INTERPRETATION: Findings indicate for the range of settings where videoconference approaches can be used, and for their applicability and acceptability, providing an alternative to current cognitive assessment methods. Continued validation studies and adaptation of neuropsychological instruments is warranted.

Applicability of the Telephone Interview for Cognitive Status (Modified) in a community sample with low education level: association with an extensive neuropsychological battery.

OBJECTIVE: To explore the applicability of a Portuguese (PT) version of the Telephone Interview for Cognitive Status (TICS), with a delayed recall item [modified (M)], here termed TICSM-PT, against an extensive (in-person) battery of neuropsychological instruments, in a sample of older individuals with low educational level and without clinically manifest/diagnosed cognitive impairment. METHODS: Following translation/back-translation and pilot testing in 33 community dwellers, 142 community dwellers aged 52 to 84 years (mean = 67.45, SD = 7.91) were selected from local health care centres for the study (convenience sampling; stratified age and gender). Cronbach's alpha was used to assess internal consistency, and convergent validity was evaluated through the correlation between TICSM-PT and the Mini Mental State Examination (MMSE), as well as with a comprehensive battery of cognitive instruments. Divergent/discriminant validity was assessed through a battery of psychological instruments. The receiver operating curve was determined for TICSM-PT to classify participants with and without possible indication of cognitive impairment. RESULTS: TICSM-PT showed a satisfactory internal consistency (Cronbach's alpha = 0.705), convergent validity and discriminant validity. TICSM-PT presented a positive association with the global cognitive measures Mini Mental State Examination and the Montreal Cognitive Assessment, and also with most neuropsychological parameters. Receiver operating curve curves presented a sensitivity of 90.6% and specificity of 73.7%. The area under the curve statistic yielded a threshold score equal or below 13.5 for cognitive impairment. CONCLUSION: TICSM-PT is a practical tool for rapid cognitive assessment among older individuals with low educational background.

The role of sex and sex-related hormones in cognition, mood and well-being in older men and women.

Alterations in hormone levels during aging impact on cognition and mood. Serum concentration levels of testosterone (TT), estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEAS) and prolactin (PRL) were assessed in 120 community-dwellers (51+ years of age, males and females), in a cross-sectional approach. Performance clusters based on executive functioning (GENEXEC), memory (MEM), mood and well-being were obtained. In males, higher PRL levels associated with worse cognitive performance, lower well-being, and higher scores in depression scales, and lower E2 with poorer cognition and higher depressive mood. DHEAS positively associated with GENEXEC and MEM. Nutritional status significantly associated with PRL (positively) and with DHEAS (negatively). Findings indicate that besides the more exhaustively studied E2 and TT, variations in the levels of sex-related hormones such as PRL, FSH, LH and DHEAS are of interest for the mental health aging profile particularly in men.