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.

Functional Hemispheric (A)symmetries in the Aged Brain-Relevance for Working Memory.

Functional hemispheric asymmetries have been described in different cognitive processes, such as decision-making and motivation. Variations in the pattern of left/right activity have been associated with normal brain functioning, and with neuropsychiatric diseases. Such asymmetries in brain activity evolve throughout life and are thought to decrease with aging, but clear associations with cognitive function have never been established. Herein, we assessed functional laterality during a working memory task (N-Back) in a healthy aging cohort (over 50 years old) and associated these asymmetries with performance in the test. Activity of lobule VI of the cerebellar hemisphere and angular gyrus was found to be lateralized to the right hemisphere, while the precentral gyrus presented left > right activation during this task. Interestingly, 1-Back accuracy was positively correlated with left > right superior parietal lobule activation, which was mostly due to the influence of the left hemisphere. In conclusion, although regions were mostly symmetrically activated during the N-Back task, performance in working memory in aged individuals seems to benefit from lateralized involvement of the superior parietal lobule.

Adult Body Height Is a Good Predictor of Different Dimensions of Cognitive Function in Aged Individuals: A Cross-Sectional Study.

Background: Adult height, weight, and adiposity measures have been suggested by some studies to be predictors of depression, cognitive impairment, and dementia. However, the presence of confounding factors and the lack of a thorough neuropsychological evaluation in many of these studies have precluded a definitive conclusion about the influence of anthropometric measures in cognition and depression. In this study we aimed to assess the value of height, weight, and abdominal perimeter to predict cognitive impairment and depressive symptoms in aged individuals. Methods and Findings: Cross-sectional study performed between 2010 and 2012 in the Portuguese general community. A total of 1050 participants were included in the study and randomly selected from local area health authority registries. The cohort was representative of the general Portuguese population with respect to age (above 50 years of age) and gender. Cognitive function was assessed using a battery of tests grouped in two dimensions: general executive function and memory. Two-step hierarchical multiple linear regression models were conducted to determine the predictive value of anthropometric measures in cognitive performance and mood before and after correction for possible confounding factors (gender, age, school years, physical activity, alcohol consumption, and smoking habits). We found single associations of weight, height, body mass index, abdominal perimeter, and age with executive function, memory and depressive symptoms. However, when included in a predictive model adjusted for gender, age, school years, and lifestyle factors only height prevailed as a significant predictor of general executive function (ß = 0.139; p < 0.001) and memory (ß = 0.099; p < 0.05). No relation was found between mood and any of the anthropometric measures studied. Conclusions and Relevance: Height is an independent predictor of cognitive function in late-life and its effects on the general and executive function and memory are independent of age, weight, education level, gender, and lifestyle factors. Altogether, our data suggests that modulators of adult height during childhood may irreversibly contribute to cognitive function in adult life and that height should be used in models to predict cognitive performance.

Age effects on EEG correlates of the Wisconsin Card Sorting Test.

Body and brain undergo several changes with aging. One of the domains in which these changes are more remarkable relates with cognitive performance. In the present work, electroencephalogram (EEG) markers (power spectral density and spectral coherence) of age-related cognitive decline were sought whilst the subjects performed the Wisconsin Card Sorting Test (WCST). Considering the expected age-related cognitive deficits, WCST was applied to young, mid-age and elderly participants, and the theta and alpha frequency bands were analyzed. From the results herein presented, higher theta and alpha power were found to be associated with a good performance in the WCST of younger subjects. Additionally, higher theta and alpha coherence were also associated with good performance and were shown to decline with age and a decrease in alpha peak frequency seems to be associated with aging. Additionally, inter-hemispheric long-range coherences and parietal theta power were identified as age-independent EEG correlates of cognitive performance. In summary, these data reveals age-dependent as well as age-independent EEG correlates of cognitive performance that contribute to the understanding of brain aging and related cognitive deficits.

Brain structure across the lifespan: the influence of stress and mood.

Normal brain aging is an inevitable and heterogeneous process characterized by a selective pattern of structural changes. Such heterogeneity arises as a consequence of cumulative effects over the lifespan, including stress and mood effects, which drive different micro- and macro-structural alterations in the brain. Investigating these differences in healthy age-related changes is a major challenge for the comprehension of the cognitive status. Herein we addressed the impact of normal aging, stress, mood, and their interplay in the brain gray and white matter (WM) structure. We showed the critical impact of age in the WM volume and how stress and mood influence brain volumetry across the lifespan. Moreover, we found a more profound effect of the interaction of aging/stress/mood on structures located in the left hemisphere. These findings help to clarify some divergent results associated with the aging decline and to enlighten the association between abnormal volumetric alterations and several states that may lead to psychiatric disorders.

Clinical, physical and lifestyle variables and relationship with cognition and mood in aging: a cross-sectional analysis of distinct educational groups.

It is relevant to unravel the factors that may mediate the cognitive decline observed during aging. Previous reports indicate that education has a positive influence on cognitive performance, while age, female gender and, especially, depressed mood were associated with poorer performances across multiple cognitive dimensions (memory and general executive function). Herein, the present study aimed to characterize the cognitive performance of community-dwelling individuals within distinct educational groups categorized by the number of completed formal school years: "less than 4," "4, completed primary education," and "more than 4." Participants (n = 1051) were randomly selected from local health registries and representative of the Portuguese population for age and gender. Neurocognitive and clinical assessments were conducted in local health care centers. Structural equation modeling was used to derive a cognitive score, and hierarchical linear regressions were conducted for each educational group. Education, age and depressed mood were significant variables in directly explaining the obtained cognitive score, while gender was found to be an indirect variable. In all educational groups, mood was the most significant factor with effect on cognitive performance. Specifically, a depressed mood led to lower cognitive performance. The clinical disease indices cardiac and stroke associated with a more negative mood, while moderate increases in BMI, alcohol consumption and physical activity associated positively with improved mood and thus benefitted cognitive performance. Results warrant further research on the cause-effect (longitudinal) relationship between clinical indices of disease and risk factors and mood and cognition throughout aging.

Telephone-based screening tools for mild cognitive impairment and dementia in aging studies: a review of validated instruments.

The decline of cognitive function in old age is a great challenge for modern society. The simultaneous increase in dementia and other neurodegenerative diseases justifies a growing need for accurate and valid cognitive assessment instruments. Although in-person testing is considered the most effective and preferred administration mode of assessment, it can pose not only a research difficulty in reaching large and diverse population samples, but it may also limit the assessment and follow-up of individuals with either physical or health limitations or reduced motivation. Therefore, telephone-based cognitive screening instruments can be an alternative and attractive strategy to in-person assessments. In order to give a current view of the state of the art of telephone-based tools for cognitive assessment in aging, this review highlights some of the existing instruments with particular focus on data validation, cognitive domains assessed, administration time and instrument limitations and advantages. From the review of the literature, performed using the databases EBSCO, Science Direct and PubMed, it was possible to verify that while telephone-based tools are useful in research and clinical practice, providing a promising approach, the methodologies still need refinement in the validation steps, including comparison with either single instruments or neurocognitive test batteries, to improve specificity and sensitivity to validly detect subtle changes in cognition that may precede cognitive impairment.

Plasticity of resting state brain networks in recovery from stress.

Chronic stress has been widely reported to have deleterious impact in multiple biological systems. Specifically, structural and functional remodeling of several brain regions following prolonged stress exposure have been described; importantly, some of these changes are eventually reversible. Recently, we showed the impact of stress on resting state networks (RSNs), but nothing is known about the plasticity of RSNs after recovery from stress. Herein, we examined the "plasticity" of RSNs, both at functional and structural levels, by comparing the same individuals before and after recovery from the exposure to chronic stress; results were also contrasted with a control group. Here we show that the stressed individuals after recovery displayed a decreased resting functional connectivity in the default mode network (DMN), ventral attention network (VAN), and sensorimotor network (SMN) when compared to themselves immediately after stress; however, this functional plastic recovery was only partial as when compared with the control group, as there were still areas of increased connectivity in dorsal attention network (DAN), SMN and primary visual network (VN) in participants recovered from stress. Data also shows that participants after recovery from stress displayed increased deactivations in DMN, SMN, and auditory network (AN), to levels similar to those of controls, showing a normalization of the deactivation pattern in RSNs after recovery from stress. In contrast, structural changes (volumetry) of the brain areas involving these networks are absent after the recovery period. These results reveal plastic phenomena in specific RSNs and a functional remodeling of the activation-deactivation pattern following recovery from chronic-stress, which is not accompanied by significant structural plasticity.

Do genes and environment meet to regulate cerebrospinal fluid dynamics? Relevance for schizophrenia.

Schizophrenia is a neurodevelopment disorder in which the interplay of genes and environment contributes to disease onset and establishment. The most consistent pathological feature in schizophrenic patients is an enlargement of the brain ventricles. Yet, so far, no study has related this finding with dysfunction of the choroid plexus (CP), the epithelial cell monolayer located within the brain ventricles that is responsible for the production of most of the cerebrospinal fluid (CSF). Enlarged brain ventricles are already present at the time of disease onset (young adulthood) and, of notice, isolated mild ventriculomegaly detected in utero is associated with subsequent mild neurodevelopmental abnormalities similar to those observed in children at high risk of developing schizophrenia. Here we propose that altered CP/CSF dynamics during neurodevelopment may be considered a risk, causative and/or participating factor for development of schizophrenia.

Modulation of iron metabolism in aging and in Alzheimer's disease: relevance of the choroid plexus.

Iron is essential for mammalian cellular homeostasis. However, in excess, it promotes free radical formation and is associated with aging-related progressive deterioration and with neurodegenerative disorders such as Alzheimer's disease (AD). There are no mechanisms to excrete iron, which makes iron homeostasis a very tightly regulated process at the level of the intestinal absorption. Iron is believed to reach the brain through receptor-mediated endocytosis of iron-bound transferrin by the brain barriers, the blood-cerebrospinal fluid (CSF) barrier, formed by the choroid plexus (CP) epithelial cells and the blood-brain barrier (BBB) formed by the endothelial cells of the brain capillaries. Importantly, the CP epithelial cells are responsible for producing most of the CSF, the fluid that fills the brain ventricles and the subarachnoid space. Recently, the finding that the CP epithelial cells display all the machinery to locally control iron delivery into the CSF may suggest that the general and progressive senescence of the CP may be at the basis of the impairment of regional iron metabolism, iron-mediated toxicity, and the increase in inflammation and oxidative stress that occurs with aging and, particularly, in AD.

Activity of retinoic acid receptor-alpha is directly regulated at its protein kinase A sites in response to follicle-stimulating hormone signaling.

Retinoic acid receptor-alpha (RARA) is crucial for germ cell development in the testis, as shown by the degenerated testis in Rara gene knockout mice, which are sterile. Similarly, FSH is known to regulate Sertoli cell proliferation and differentiation, indirectly controlling the quantity of the spermatogenic output. Interestingly, FSH inhibited, via activation of FSH receptor, cAMP, and protein kinase A (PKA), the nuclear localization and transcriptional activity of RARA. Given that retinoic acid, the ligand for RARA, is known to regulate cell proliferation and differentiation, we investigated whether FSH regulates RARA by a direct posttranslational phosphorylation mechanism. Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity. The negative charges at the PKA sites, whether they are from glutamic acids or phosphorylation of serines, decreased the nuclear localization of RARA, heterodimerization with retinoid X receptor-alpha, and the transcriptional activity of the receptor. On the other hand, the double-alanine mutant that cannot be phosphorylated at the 219 and 369 amino acid positions did not respond to cAMP and PKA activation. Wild-type and double-mutant RARA interacted with PKA, but only in the presence of cAMP or FSH. These results together suggest that FSH may regulate cell proliferation and differentiation of Sertoli cells, at least partially, by directly affecting the PKA sites of RARA and controlling the transcriptional function of the receptor.

Disulfide isomerase glucose-regulated protein 58 is required for the nuclear localization and degradation of retinoic acid receptor alpha.

Retinoic acid receptor alpha (RARA) is critical for spermatogenesis, as shown by a sterility phenotype observed in Rara knockout mice. RARA is important in both Sertoli and germ cells of the testis. Here, we demonstrate that a disulfide isomerase glucose-regulated protein 58 (GRp58) participates in the nuclear import and degradation of RARA in Sertoli cells. GRp58 interacted with RARA in the presence of all-trans retinoic acid (ATRA) ligand and, as a complex, it was translocated from the cytoplasm to the nucleus and, then with time, GRp58 dissociated from RARA and was found in the cytoplasm. The GRp58 RNAi treatment disrupted ATRA-dependent RARA nuclear localization, indicating the requirement of GRp58 for RARA nuclear localization. Moreover, treatment with sulfhydryl-modifying agents that oxidize SH-groups of cysteine residues to disulfide bonds abolished ATRA-mediated RARA nuclear localization, suggesting that the thiol oxidoreductase activity of GRp58 may be required for RARA nuclear import. Additionally, the proteasome inhibitor treatment resulted in the co-localization of GRp58 and RARA at the endoplasmic reticulum (ER), suggesting that GRp58 may bring RARA to the ER for the ER-associated degradation (ERAD) of RARA before it is de-coupled from RARA for recycling. In this regard, proteasome inhibitor treatment also increased the interaction of RARA with UBE2J2, an ERAD-associated ubiquitin E2 enzyme. Collectively, the results indicate that GRp58 may act as a molecular chaperone that alters the protein conformation of RARA for its delivery to the nucleus and, then with time, accompanies RARA to the ER for RARA ubiquitination and proteasome-mediated ERAD.

Small ubiquitin-like modifier-2 modification of retinoic acid receptor-alpha regulates its subcellular localization and transcriptional activity.

The retinoic acid receptor-alpha (Rara) gene is critical for germ cell development in the testis, as demonstrated by infertile Rara knockout male mice. The encoded protein for Rara (RARA) is expressed in both Sertoli cells and germ cells, but it is not always in the nucleus. Previously, all-trans retinoic acid (ATRA) was shown to increase the nuclear localization and transcriptional activity of RARA in Sertoli cells. Here, we identified a small ubiquitin-like modifier-2 (SUMO-2) modification as a novel posttranslational regulatory mechanism controlling the ATRA-dependent RARA subcellular localization and transcription. ATRA increased the SUMO-2 modification of RARA. In the presence of ATRA, lysine 166 (K166) and K171 of RARA were modified at a physiological concentration of SUMO-2, whereas in the absence of ATRA, K399 was the only site that was modified, but at a higher SUMO-2 concentration. However, K399 was critical for ATRA-controlled nuclear trafficking of RARA. In the presence of ATRA, a K399 mutation to arginine resulted in the cytoplasmic localization of K399R mutant, indicating that K166 and K171 sumoylations were inhibitory to nuclear localization. This may be due to SUMO/sentrin-specific peptidase 6 (SENP6) not being able to bind K399R mutant to desumoylate K166 and K171 in Sertoli cells, whereas it can bind RARA with intact K399. On the other hand, functional K166 and K171 sites for sumoylation were required for a full transcriptional activity, when K399 was intact. These results together suggest that both K166 and K171 sumoylation and desumoylation are critical for optimal RARA function.