Cognitive and physical performance correlates of low iron status

Dissertação de mestrado em Ciências da SaúdeIron deficiency is the most prevalent nutrient deficiency affecting all age groups worldwide. Deleterious alterations on cognition, psychological morbidity and physical performance have been observed in several reports; however, the main body of literature focuses on infants, children, adolescents or women of childbearing age. These groups are considered to be at high risk due to physiologic conditions. Nonetheless, several pathological conditions are also risk factors for iron deficiency, with many of them highly prevalent in older individuals. In a growing older society, considering that older individuals are at greater risk of cognitive decline, neuropsychological morbidity, decrements in physical performance and impaired functional ability, the study of the factors influencing these outcomes are of utmost importance. Still, despite of all the evidence pointing for a role of iron deficiency in cognition, mood and physical functional ability, there is a worrying small amount of research in older individuals. In this work, by first using a cross-sectional analysis, we investigated the association of low iron status with cognitive performance, neuropsychological morbidity and physical functional ability in a cohort of older individuals (n=151). Next, using a quasi-experimental study design (n=12, intervention; n=10, non-intervention), namely intervention via an iron-fortified fruit–based dessert, we addressed if low dosage iron fortification of foods is feasible and effective in altering (and/or correcting for) the effects of low iron status. In order to reduce the number of multiple comparisons, principal component analysis of cognitive, psychological, physical variables and iron biomarkers was performed and the obtained dimensions used for analysis. We observed that the storage [body iron, soluble serum transferrin receptor (sTFR), ratio of sTFR to the logarithmic value of ferritin (sTFR – Log(FT)) index and ferritin (FT)] and erythropoiesis [red cells blood Count (RBC), hemoglobin and hematocrit] dimensions were significant predictors of the memory dimension [selective reminding test (SRT) - consistent long term retrieval (CLTR), - long term storage (LTS) and - delayed recall (DR) and the Consortium to establish a registry for Alzheimer's disease (CERAD) (total hits and DR)], along with the interaction of storage and nutritional status. The geriatric depression scale (GDS) score was predicted by the transport [serum iron (Fe) and transferrin saturation (TF sat.)], transport saturation [transferrin (TF) and total iron binding capacity (TIBC)] and erythropoiesis dimensions. The functional tiredness (mobility-, lower limb- and upperlimb-tiredness) dimension was predicted by the storage, transport, red cells composition [mean corpuscular volume (MCV), mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC) and red cell distribution width (RDW)] and erythropoiesis dimensions. After 12 weeks (+/- 2 weeks) of intervention, the daily consumption of an iron fortified dessert was associated with an improvement of the total and sub-scores of performance-oriented mobility assessment, along with hand grip strength and lower limb tiredness. Our observations indicate that lower iron status is associated with poorer memory ability, depressive mood and functional tiredness from activities of daily living. Furthermore, results indicate that the physical negative effects of low iron status seem to be recovered by iron supplementation, highlighting the importance of prevention. Identification of molecular bases of the associations here reported is paramount and further research is needed.A deficiência de ferro é o deficit nutricional mais prevalente em todo o mundo, afetando todas as faixas etárias. Vários estudos têm demonstrado um impacto negativo da deficiência de ferro sobre a cognição, a morbidade psicológica e desempenho físico; no entanto, os referidos estudos debruçam-se essencialmente em crianças, adolescentes ou mulheres em idade fértil, nos quais várias condições fisiológicas concorrem para que estes grupos sejam considerados de alto risco. No entanto não devemos descurar, igualmente, que várias condições patológicas são fatores de risco para deficiência de ferro, sendo muitas delas altamente prevalentes em idosos. Numa sociedade cada vez mais envelhecida, e onde os indivíduos mais velhos apresentam risco acrescido de declínio cognitivo, morbidade neuropsicologia, decréscimos no desempenho físico e capacidade funcional comprometida, o estudo dos fatores que influenciam estas consequências do envelhecimento são de extrema importância. Apesar de todas as evidências apontarem para um papel da deficiência de ferro na cognição, humor e capacidade física funcional, a investigação em idosos é escassa. Neste trabalho, utilizando uma análise transversal, investigámos as associações de baixos níveis de ferro com o desempenho cognitivo, a morbidade neuropsicológica e a capacidade funcional física em idosos. Através de um estudo quasi-experimental, investigamos, ainda, se a fortificação de alimentos com pequenas doses de ferro é viável e eficaz para melhorar a capacidade cognitiva, o humor e a condição física. Com o objetivo de reduzir o número de comparações múltiplas foi realizada a análise dos componentes principais das variáveis cognitivas, psicológicas, físicas e dos biomarcadores de ferro e os componentes obtidos utilizados para análise estatística. Observou-se que os componentes armazenamento [ferro corporal, receptor solúvel da transferrina (sTFR), indice do rácio do sTFR para a transformação logarítmica da ferritina (sTFR – Log(FT)) e ferritina (FT)] e eritropoiese [eritrócitos (RBC), hemoglobina e hematócrito], bem como a interação do componente armazenamento com estado nutricional, foram preditores significativos do componente memória [teste de memoria selectiva (SRT) – evocação da memória a longo prazo (CLTR), - armazenamento na memória a longo prazo (LTS) e – evocação tardia (DR); e o Consórcio para estabelecer um registro para a doença de Alzheimer (CERAD) (total de respostas certas e DR)]. O valor da escala de depressão geriátrica (GDS) foi previsto pelos componentes transporte [ferro sérico (Fe) e saturação da transferrina (TF sat.)], saturação do transporte [transferrina (TF) e capacidade total de ligação do ferro (TIBC)] e da eritropoiese. Os componentes armazenamento, transporte, composição células vermelhas [volume corpuscular médio (MCV), hemoglobina corpuscular média (MCH), concentração de hemoglobina corpuscular média (MCHC) e a anisocitose (RDW)] e eritropoiese foram preditores significativos do componente obtido para o cansaço associado às atividades funcionais diárias. Observámos, ainda, que após 12 semanas (+ / - 2 semanas), o consumo diário de uma sobremesa fortificada em ferro se associa a uma melhoria no total e subtotais de avaliação da mobilidade orientada para o desempenho, juntamente com força de preensão manual e menor cansaço dos membros inferiores. Estes resultados indicam que os níveis de ferro estão associados a menor memória, a humor depressivo e a cansaço funcional nas atividades da vida diária. Além disso, os resultados sugerem que os efeitos negativos de baixo nível de ferro a nível físico melhoram com a suplementação de ferro, destacando a importância da prevenção do declínio nos níveis de ferro. Importa no futuro a confirmação destes resultados em estudos de base populacional, assim como a identificação das bases moleculares que lhes estão subjacentes

INTERNACIONALIZAÇÃO BANCÁRIA BRASILEIRA: ESTUDO DE CASO DO BANCO ITAÚ

Este estudo tem como objetivo avaliar as estratégias adotadas por um dos três maiores bancos brasileiros, o Banco Itaú, para ingressar no mercado varejo no exterior. Para alcançar o objetivo proposto, foi feita uma revisão bibliográfica da literatura sobre as principais abordagens teóricas de internacionalização de empresas. Esta revisão se apoiou, principalmente, no paradigma eclético proposto por Dunning (1993, 1998 e 2000) e na Teoria da Escola de Uppsala (Johanson; Vahlne, 1977; 1990). Como apoio às teorias, esta pesquisa revisou trabalhos com foco na internacionalização de bancos de varejo, publicados em periódicos nacionais e do exterior. Para a análise das estratégias de internacionalização, individual e comparativa entre os bancos, assim como para identificar os modos de entrada escolhidos pelos bancos, foi desenvolvida uma pesquisa com objetivos exploratórios, abordagem qualitativa e coleta de dados secundários. Os resultados das análises apontaram que a internacionalização do Itaú pode ser analisada pelo paradigma eclético e que foi sequencial, de certa forma como proposto por Uppsala. E com a intenção de se tornar um grande player global, mas, no momento, com forte atuação na America Latina por intermédio de aquisições

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.Financial support was provided by FEDER funds through the Operational Programme Competitiveness Factors-COMPETE and National Funds through FCT-Foundation for Science and Technology under the project POCI-01-0145-FEDER-007038, by the project NORTE-01-0145-FEDER-000013 [supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 (P2020) Partnership Agreement, through the European Regional Development Fund (FEDER)], by POCI-01-0145-FEDER-016428 [supported by the Operational Programme Competitiveness and Internationalization (COMPETE 2020) and the Regional Operational Program of Lisbon and National Funding through Portuguese Foundation for Science and Technology (FCT, Portugal)], and by the Portuguese North Regional Operational Programme [ON.2 – O Novo Norte, under the National Strategic Reference Framework (QREN), through FEDER]. The work was also developed under the scope of the projects SwitchBox (European Commission, FP7; contract HEALTH-F2-2010-259772) and TEMPO-Better mental health during aging based on temporal prediction of individual brain aging trajectories (Fundação Calouste Gulbenkian; Contract grant number P-139977). LA, TC, RM, PSM, and CP-N were supported by FCT PhD scholarships [SFRH/BD/101398/2014 to LA; SFRH/BD/90078/2012 to TC; PDE/BDE/113604/2015 from the PhD-iHES Programme to RM; PDE/BDE/113601/2015 to PSM; PD/BD/106050/2015 from the Inter-University Doctoral Programme in Aging and Chronic Disease (PhDOC) to CP-N] and AC by a scholarship from the project NORTE-08-5639-FSE-000041 (NORTE 2020; UMINHO/BD/51/2017). NCS was a recipient of a Research Assistantship by the through the FCT Investigator Programme 200∞ Ciência.info:eu-repo/semantics/publishedVersio

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.This work has been funded by National funds, through the Foundation for Science and Technology (FCT)-project UIDB/50026/2020 and UIDP/50026/2020; and by the projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), by the Fundacao Calouste Gulbenkian (Portugal) (contract grant number: P-139977; project "Better Mental Health during Ageing based on Temporal Prediction of Individual Brain Ageing Trajectories (TEMPO)") and by the European Commission (FP7): "SwitchBox" (Contract HEALTH-F2-2010-259772). C.P.-N was supported by the Portuguese Science Foundation (FCT) doctoral scholarship PD/BD/106050/2015 via the Inter-University PhD Programme in Ageing and Chronic Diseases, T.C.C. was a recipient of a doctoral fellowship from the Portuguese Foundation for Science and Technology (FCT; SFRH/BD/90078/2012), L.A. was a recipient of a doctoral fellowship from the Portuguese Foundation for Science and Technology (FCT; SFRH/BD/101398/2014), P.S.M. was supported by the FCT fellowship grant with the reference PDE/BDE/113601/2015 from the PhDiHES program, N.C.S. was a recipient of a research assistantship by the through the FCT Investigator Programme 200 infinity Ciencia

Effector memory CD4+ T cells are associated with cognitive performance in a senior population

Objective: Immunosenescence and cognitive decline are common markers of the aging process. Taking into consideration the heterogeneity observed in aging processes and the recently described link between lymphocytes and cognition, we herein explored the possibility of an association between alterations in lymphocytic populations and cognitive performance. Methods: In a cohort of cognitively healthy adults (n = 114), previously characterized by diverse neurocognitive/psychological performance patterns, detailed peripheral blood immunophenotyping of both the innate and adaptive immune systems was performed by flow cytometry. Results: Better cognitive performance was associated with lower numbers of effector memory CD4(+) T cells and higher numbers of naive CD8(+) T cells and B cells. Furthermore, effector memory CD4(+) T cells were found to be predictors of general and executive function and memory, even when factors known to influence cognitive performance in older individuals (e.g., age, sex, education, and mood) were taken into account. Conclusions: This is the first study in humans associating specific phenotypes of the immune system with distinct cognitive performance in healthy aging.This work was funded by the European Commission (FP7): "SwitchBox" (Contract HEALTH-F2-2010-259772) and co-financed by the Portuguese North Regional Operational Program (ON.2-O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER)

Longitudinal measurement invariance of memory performance and executive functioning in healthy aging

In this work, we examined the longitudinal measurement invariance of a battery composed of distinct cognitive parameters. A sample of 86 individuals (53.5% females; mean age = 65.73), representative of the Portuguese older population, with respect to sex, age and level of education was assessed twice over an average of two years. By means of a confirmatory factor analysis approach, we tested whether a two-factor solution [corresponding to measures of memory performance (MEM) and executive functioning (EXEC)] was reliable over time. Nested models of longitudinal invariance demonstrated the existence of partial strong invariance over time. In other words, this indicates that there is an equivalence of the factorial structure and factor loadings for all items; this was also observed for the item intercepts for all the items, except for one of the items from the EXEC dimension. Stability coefficients revealed high associations between the dimensions over time and that, whereas there was a significant decline of the MEM across time, this was not observed for the EXEC dimension. These findings reveal that changes in MEM and EXEC scores can be attributed to true changes on these constructs, enabling the use of this battery as a reliable method to study cognitive aging.PSM (ref: PDE/BDE/113601/2015 - PhD-iHES program), TCC (ref: SFRH/BD/90078/2012), LA (SFRH/BD/101398/2014) and CPN (ref: PD/BD/106050/2015 - PhDOC program) were supported by FCT fellowship grants. The work has been developed under the scope of the projects NORTE-01-0145-FEDER-000013 supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 (P2020) Partnership Agreement, through the European Regional Development Fund (FEDER) and POCI-01-0145-FEDER-016428 supported by the Operational Programme Competitiveness and Internationalization (COMPETE 2020) and the Regional Operational Program of Lisbon and National Funding through Portuguese Foundation for Science and Technology (FCT, Portugal); and, by the Portuguese North Regional Operational Programme (ON.2 - O Novo Norte), under the National Strategic Reference Framework (QREN), through FEDER, the Fundação Calouste Gulbenkian (Portugal) (contract grant number: P-139977; project "TEMPO - Better mental health during ageing based on temporal prediction of individual brain ageing trajectories") and SwitchBox-FP7-HEALTH-2010-grant 259772-2info:eu-repo/semantics/publishedVersio

COVID-19 collaborative screening: an action-research project for large scale contact tracing in Northern Portugal

In late November 2020, when Europe reached the highest 14-day incidence of COVID-19 cases, the resource-intensive and time-consuming traditional contact tracing performed by Public Health was challenged. In this context, innovative approaches were necessary to guarantee a timely interruption of disease transmission. “COVID-19 Collaborative Screening” Project was developed as a faster solution, not only because the contact tracing process is simpler for the operator, but mainly because it is possible to quickly scale up the number of operators involved. It was designed to interrupt family and social transmission chains, in a partnership with the Local Public Health Services – allowing these services to dedicate to scenarios of more complex risk assessment, using the traditional contact tracing. To perform contact tracing, this method involves Public Servants, Armed Forces and Medical Dentists. The Project also promotes participatory citizenship, by delegating to the citizen the responsibility of registering his/hers contacts with high-risk exposure in an online form, in contrast to the traditional contact tracing method which is more health professional-dependent. Until the end of January 2021, the Project has trained eight teams, enrolling a total of 213 professionals, and was implemented in eight Health Regions (with an estimated population of 1,346,150 inhabitants). The Project was successful at facing the delays in case interview and contact tracing. The strategy implemented by ColabCOVID is assembled as a sustainable, reproducible and scalable platform and is ready to be re-implemented to face the emergence of more contagious variants, as well as an eventual forthcoming health threat

Asymmetrical subcortical plasticity entails cognitive progression in older individuals

Structural brain asymmetries have been associated with cognition. However, it is not known to what extent neuropsychological parameters and structural laterality covary with aging. Seventy-five subjects drawn from a larger normal aging cohort were evaluated in terms of MRI and neuropsychological parameters at two moments (M1 and M2), 18 months apart. In this time frame, asymmetry as measured by structural laterality index (ΔLI) was stable regarding both direction and magnitude in all areas. However, a significantly higher dispersion for this variation was observed in subcortical over cortical areas. Subjects with extreme increase in rightward lateralization of the caudate revealed increased M1 to M2 Stroop interference scores, but also a worsening of general cognition (MMSE). In contrast, subjects showing extreme increase in leftward lateralization of the thalamus presented higher increase in Stroop interference scores. In conclusion, while a decline in cognitive function was observed in the entire sample, regional brain asymmetries were relatively stable. Neuropsychological trajectories were associated with laterality changes in subcortical regions.This work was supported by the project NORTE‐01‐0145‐FEDER‐000013 through the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER), and funded by the European Commission (FP7) “SwitchBox ‐ Maintaining health in old age through homeostasis” (Contract HEALTH‐F2‐2010‐259772), and co‐financed by the Portuguese North Regional Operational Program (ON.2 – O Novo Norte), under the National Strategic Reference Framework (QREN), through FEDER, and by the Fundação Calouste Gulbenkian (Portugal) (Contract grant number: P‐139977; project “TEMPO ‐ Better mental health during ageing based on temporal prediction of individual brain ageing trajectories”) and by “PANINI ‐ Physical Activity and Nutrition INfluences In ageing” (European Commission (Horizon 2020), Contract GA 675003). Individual authors were supported under: "SwitchBox" to PM and NCS; Fundação para a Ciência e a Tecnologia (FCT) grants SFRH/BD/52291/2013 to ME and PD/BD/106050/2015 to CPN via Inter‐University Doctoral Programme in Ageing and Chronic Disease (PhDOC), PDE/BDE/113601/2015 to PSM and PDE/BDE/113604/2015 to RM via PhD Program in Health Sciences (Applied) (Phd‐iHES), SFRH/BD/90078/2012 to TCC, SFRH/BD/101398/2014 to LA and SFRH/BPD/80118/2011 do HLAinfo:eu-repo/semantics/publishedVersio

Reduced hedonic valuation of rewards and unaffected cognitive regulation in chronic stress

Cognition can influence choices by modulation of decision-making processes. This cognitive regulation is defined as processing information, applying knowledge, and changing preferences to consciously modulate decisions. While cognitive regulation of emotions has been extensively studied in psychiatry, few works have detailed cognitive regulation of decision-making. Stress may influence emotional behavior, cognition, and decision-making. In addition, the brain regions responsible for decision-making are sensitive to stress-induced changes. Thus, we hypothesize that chronic stress may disrupt the ability to regulate choices. Herein, we used a functional magnetic resonance imaging task where fourteen control and fifteen chronically stressed students had to cognitively upregulate or downregulate their craving before placing a bid to obtain food. We found that stressed participants placed lower bids to get the reward and chose less frequently higher bid values for food. Nevertheless, we did not find neural and behavioral differences during cognitive regulation of craving. Our outcomes revealed that chronic stress impacts decision-making after cognitive regulation of craving by reducing the valuation of food rewards but not cognitive modulation itself. Importantly, our results need further validation with larger sample sizes.MyHealth project (DoIT – Desenvolvimento e Operacionalização da Investigação de Translação, Contract DoIT-13853) and the BIAL Foundation, Porto, Portugal (Grant No. PT/FB/BL-2016-206). This work was also funded by the FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by national funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145-FEDER-007038. This manuscript has been developed under the scope of the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). PaM was supported by a fellowship of the project “SwitchBox” (Contract HEALTH-F2-2010-259772). SF was supported by a combined Ph.D. scholarship from the FCT and the company iCognitus4ALL – IT Solutions, Lda (PD/BDE/127839/2016). RM was supported by the combined FCT and Enlightenment, Lda fellowship (PDE/BDE/113604/2015) from the PhDiHES progra

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 (rs = -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.Project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER), and was funded by the European Commission (FP7) “SwitchBox—Maintaining health in old age through homeostasis” (Contract HEALTH-F2-2010-259772), and co-financed by the Portuguese North Regional Operational Program (ON.2—O Novo Norte), under the National Strategic Reference Framework (QREN), through FEDER, and by the Fundação Calouste Gulbenkian (Portugal; Contract grant number: P-139977; project “TEMPO—Better mental health during aging based on temporal prediction of individual brain aging trajectories”). NCS was supported during the work by a Research Assistantship by the Portuguese Foundation for Science and Technology (FCT, Portugal) through the “FCT Investigator Programme (200∞ Ciência),” CP-N by a “MyHealth” project (Contract DoIT-13853) research fellowship, and TC by a FCT doctoral fellowship (SFRH/BD/90078/2012