Hippocampal Extracellular Matrix Levels and Stochasticity in Synaptic Protein Expression Increase with Age and Are Associated with Age-dependent Cognitive Decline

Age-related cognitive decline is a serious health concern in our aging society. Decreased cognitive function observed during healthy brain aging is most likely caused by changes in brain connectivity and synaptic dysfunction in particular brain regions. Here we show that aged C57BL/6J wild-type mice have hippocampus-dependent spatial memory impairments. To identify the molecular mechanisms that are relevant to these memory deficits, we investigated the temporal profile of mouse hippocampal synaptic proteome changes at 20, 40, 50, 60, 70, 80, 90, and 100 weeks of age. Extracellular matrix proteins were the only group of proteins that showed robust and progressive up-regulation over time. This was confirmed by immunoblotting and histochemical analysis, which indicated that the increased levels of hippocampal extracellular matrix might limit synaptic plasticity as a potential cause of age-related cognitive decline. In addition, we observed that stochasticity in synaptic protein expression increased with age, in particular for proteins that were previously linked with various neurodegenerative diseases, whereas low variance in expression was observed for proteins that play a basal role in neuronal function and synaptic neurotransmission. Together, our findings show that both specific changes and increased variance in synaptic protein expression are associated with aging and may underlie reduced synaptic plasticity and impaired cognitive performance in old age.As the proportion of aged individuals in our population continues to grow, we are faced with an increase in age-related health problems. Brain aging invariably leads to functional decline and impairments in cognitive function and motor skills, which can seriously affect quality of life. A better understanding of the neurobiological mechanisms underlying age-related cognitive decline is crucial to facilitate maintenance of cognitive health in the elderly and to reveal potential causes of highly prevalent age-related forms of dementia, in particular Alzheimer disease, in which cognitive decline is severely impaired by yet unknown mechanisms.Several studies showed that normal brain aging is associated with subtle morphological and functional alterations in specific neuronal circuits (1, 2) and that reduced cognitive function with increasing age is likely due to synaptic dysfunction (3). Increasing evidence supports the idea that alterations in hippocampal activity are correlated with deficits in learning and memory in healthy aging humans (4, 5). In addition, rodent models of healthy aging demonstrate strong correlations between impaired performance in learning and memory tests and disturbed hippocampal network activity (6, 7). Electrophysiological studies provide additional evidence that age-related disturbances in the hippocampus involve changes in the principal cellular features of learning and memory, synaptic long-term potentiation and long-term depression (8, 9). Together, these observations suggest that a decline in hippocampal synaptic efficacy and plasticity plays a critical role in age-dependent cognitive impairment.Aging is also the primary risk factor for Alzheimer disease, which clinically manifests as severe and accelerated age-dependent cognitive decline (10). Genetic causes of familial early-onset Alzheimer disease all point to a key role in disease etiology for increased brain levels of the protein amyloid-β (11). Familial Alzheimer disease, however, is rare, and it is likely that increased amyloid-β levels in sporadic Alzheimer disease result from age-dependent and/or genetically determined alterations in the expression of other genes or proteins (12, 13). Thus, the identification of molecular mechanisms of normal brain aging might also contribute to our understanding of cognitive decline under pathological conditions, in particular in Alzheimer disease.Although the exact mechanisms underlying brain aging remain to be fully determined, they likely include changes at the molecular, cellular, and neuronal-network levels. In particular, characterization of alterations in the molecular composition and dynamics of hippocampal synapses could potentially reveal important aspects of the underlying mechanisms of brain aging. Age-related changes in global hippocampal gene and protein expression have been investigated previously (14, 15), but these studies were not geared to identify the specific synaptic molecular substrates of brain aging. Here, we made use of iTRAQ¹ technology and high-coverage mass spectrometry to study the effects of aging on the proteomic composition of mouse hippocampal synaptosomes. We investigated the synaptic proteomes of individual mice at 20, 40, 50, 60, 70, 80, 90, and 100 weeks of age. Our findings show that both specific changes and increased variance in synaptic protein expression are associated with age-related cognitive decline.     

Virtual navigation in humans: the impact of age, sex, and hormones on place learning

Certain cognitive processes, including spatial ability, decline with normal aging. Spatial ability is also a cognitive domain with robust sex differences typically favoring males. However, tests of spatial ability do not seem to measure a homogeneous class of processes. For many, mentally matching rotated three-dimensional images is the gold standard for measuring spatial cognition in humans, while the Morris water task (MWT) is a preferred method in the domain of nonhuman animal research. The MWT is sensitive to hippocampal damage, a structure critical for normal learning and memory and often implicated in age-related cognitive decline. A computerized (virtual) version of the MWT (VMWT) appears to require and engage human hippocampal circuitry, and has proven useful in studying sex differences and testing spatial learning theories. In Experiment 1, we tested participants (20-90 years of age) in the VMWT and compared their performance to that on the Vandenberg Mental Rotation Test. We report an age-related deficit in performance on both tasks. In Experiment 2, we tested young (age 20-39) and elderly (age >60) participants in the VMWT and correlated their performance to the circulating levels of testosterone and cortisol. Our findings indicate that the persistence of male spatial advantage may be related to circulating testosterone, but not cortisol levels, and independent of generalized age-related cognitive decline.     

Subclinical Thyroid Dysfunction and Cognitive Decline in Old Age

Background

Subclinical thyroid dysfunction has been implicated as a risk factor for cognitive decline in old age, but results are inconsistent. We investigated the association between subclinical thyroid dysfunction and cognitive decline in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).

Methods

Prospective longitudinal study of men and women aged 70–82 years with pre-existing vascular disease or more than one risk factor to develop this condition (N = 5,154). Participants taking antithyroid medications, thyroid hormone supplementation and/or amiodarone were excluded. Thyroid function was measured at baseline: subclinical hyper- and hypothyroidism were defined as thyroid stimulating hormones (TSH) <0.45 mU/L or >4.50 mU/L respectively, with normal levels of free thyroxine (FT4). Cognitive performance was tested at baseline and at four subsequent time points during a mean follow-up of 3 years, using five neuropsychological performance tests.

Results

Subclinical hyperthyroidism and hypothyroidism were found in 65 and 161 participants, respectively. We found no consistent association of subclinical hyper- or hypothyroidism with altered cognitive performance compared to euthyroid participants on the individual cognitive tests. Similarly, there was no association with rate of cognitive decline during follow-up.

Conclusion

We found no consistent evidence that subclinical hyper- or hypothyroidism contribute to cognitive impairment or decline in old age. Although our data are not in support of treatment of subclinical thyroid dysfunction to prevent cognitive dysfunction in later life, only large randomized controlled trials can provide definitive evidence.     

Computer-Based Cognitive Programs for Improvement of Memory,Processing Speed and Executive Function during Age-Related Cognitive Decline: A Meta-Analysis

Background

Several studies have assessed the effects of computer-based cognitive programs (CCP) in the management of age-related cognitive decline, but the role of CCP remains controversial. Therefore, this systematic review evaluated the evidence on the efficacy of CCP for age-related cognitive decline in healthy older adults.

Methods

Six electronic databases (through October 2014) were searched. The risk of bias was assessed using the Cochrane Collaboration tool. The standardized mean difference (SMD) and 95% confidence intervals (CI) of a random-effects model were calculated. The heterogeneity was assessed using the Cochran Q statistic and quantified with the I² index.

Results

Twelve studies were included in the current review and were considered as moderate to high methodological quality. The aggregated results indicate that CCP improves memory performance (SMD, 0.31; 95% CI 0.16 to 0.45; p < 0.0001) and processing speed (SMD, 0.50; 95% CI 0.14 to 0.87; p = 0.007) but not executive function (SMD, -0.12; 95% CI -0.33 to 0.09; p = 0.27). Furthermore, there were long-term gains in memory performance (SMD, 0.59; 95% CI 0.13 to 1.05; p = 0.01).

Conclusion

CCP may be a valid complementary and alternative therapy for age-related cognitive decline, especially for memory performance and processing speed. However, more studies with longer follow-ups are warranted to confirm the current findings.     

Poor Decision Making Is a Consequence of Cognitive Decline among Older Persons without Alzheimer's Disease or Mild Cognitive Impairment

Objective

Decision making is an important determinant of health and well-being across the lifespan but is critical in aging, when many influential decisions are made just as cognitive function declines. Increasing evidence suggests that older adults, even those without dementia, often make poor decisions and are selectively vulnerable to scams. To date, however, the factors associated with poor decision making in old age are unknown. The objective of this study was to test the hypothesis that poor decision making is a consequence of cognitive decline among older persons without Alzheimer’s disease or mild cognitive impairment.

Methods

Participants were 420 non-demented persons from the Memory and Aging Project, a longitudinal, clinical-pathologic cohort study of aging in the Chicago metropolitan area. All underwent repeated cognitive evaluations and subsequently completed assessments of decision making and susceptibility to scams. Decision making was measured using 12 items from a previously established performance-based measure and a self-report measure of susceptibility to scams.

Results

Cognitive function data were collected over an average of 5.5 years prior to the decision making assessment. Regression analyses were used to examine whether the prior rate of cognitive decline predicted the level of decision making and susceptibility to scams; analyses controlled for age, sex, education, and starting level of cognition. Among 420 persons without dementia, more rapid cognitive decline predicted poorer decision making and increased susceptibility to scams (p’s<0.001). Further, the relations between cognitive decline, decision making and scams persisted in analyses restricted to persons without any cognitive impairment (i.e., no dementia or even mild cognitive impairment).

Conclusions

Poor decision making is a consequence of cognitive decline among older persons without Alzheimer’s disease or mild cognitive impairment, those widely considered “cognitively healthy.” These findings suggest that even very subtle age-related changes in cognition have detrimental effects on judgment.     

Aging Affects the Mental Rotation of Left and Right Hands

Background

Normal aging significantly influences motor and cognitive performance. Little is known about age-related changes in action simulation. Here, we investigated the influence of aging on implicit motor imagery.

Methodology/Principal Findings

Twenty young (mean age: 23.9±2.8 years) and nineteen elderly (mean age: 78.3±4.5 years) subjects, all right-handed, were required to determine the laterality of hands presented in various positions. To do so, they mentally rotated their hands to match them with the hand-stimuli. We showed that: (1) elderly subjects were affected in their ability to implicitly simulate movements of the upper limbs, especially those requiring the largest amplitude of displacement and/or with strong biomechanical constraints; (2) this decline was greater for movements of the non-dominant arm than of the dominant arm.

Conclusions/Significance

These results extend recent findings showing age-related alterations of the explicit side of motor imagery. They suggest that a general decline in action simulation occurs with normal aging, in particular for the non-dominant side of the body.     

The critical period hypothesis of estrogen effects on cognition: Insights from basic research

Background

In addition to its primary role in reproduction estrogen impacts brain areas important for cognition, including the hippocampus and prefrontal cortex. It has been hypothesized that decline in estrogen levels in women following menopause is associated with, or can exacerbate, age-related cognitive decline. However, clinical evidence to support a role for estrogen in preventing cognitive decline in women as they age is equivocal. The critical period hypothesis of estrogen effects on cognition, which proposes that estrogen administration has to be initiated within a critical time period following the loss of ovarian function in order for it to exert positive effects on the central nervous system, is offered as one explanation for inconsistencies across studies.

Scope of review

This review details results from basic research using rodent models investigating the effects of estrogen on cognition in the aging female. Emphasis is placed on work investigating effects of timing of initiation of estrogen administration on its subsequent efficacy.

Major conclusions

Results of basic research provide support for the critical period hypothesis. Furthermore, results of work in rodent models suggest mechanisms by which the response to estrogen is altered if treatment is initiated following long-term ovarian hormone deprivation.

General significance

Understanding if and under what conditions hormone administration following the loss of ovarian function positively affects the brain and behavior could have important implications with regard to female cognitive aging. Results of basic research can contribute to this understanding and provide insight into the complex mechanisms by which estrogen affects cognition.     

Age-Related Decline in Associative Learning in Healthy Chinese Adults

Paired associates learning (PAL) has been widely used in aging-related research, suggesting an age-related decline in associative learning. However, there are several cognitive processes (attention, spatial and recognition memory, strategy, and associative learning) involved in PAL. It is unclear which component contributes to the decline in PAL performance associated with age effects. The present study determines whether age effects on associative learning are independent of other cognitive processes involved in PAL. Using a validated computerized cognitive program (CANTAB), we examined cognitive performance of associative learning, spatial and recognition memory, attention and strategy use in 184 Singaporean Chinese adults aged from 21 to 80 years old. Linear regression revealed significant age-related decline in associative learning, spatial and recognition memory, and the level of strategy use. This age-related decline in associative learning remains even after adjusting for attention, spatial and recognition memory, and strategy use. These results show that age effects on associative learning are independent of other cognitive processes involved in PAL.     

Modafinil Increases the Latency of Response in the Hayling Sentence Completion Test in Healthy Volunteers: A Randomised Controlled Trial

Background

Modafinil is a medication licensed for the treatment of narcolepsy. However, it has been reported that healthy individuals without wakefulness disorders are using modafinil off-label to enhance cognitive functioning. Although some studies have reported that modafinil improves cognitive task performance in healthy volunteers, numerous other studies have failed to detect cognitive enhancing effects of modafinil on several well-established neuropsychological tasks. Interestingly, several clinical and preclinical studies have found that improved cognitive task performance by modafinil is accompanied by slower response times. This observation raises the question as to whether this slowing of response time in healthy volunteers is a necessary and sufficient condition for cognitive enhancement with modafinil. The aim of the current experiment was to explore this question by investigating the effects of modafinil on the Hayling Sentence Completion Test (HSCT).

Methodology

Sixty-four healthy volunteers received either a single dose (200 mg) of modafinil (n = 32) or placebo (n = 32) in a randomized, double-blind, placebo-controlled, parallel group study in which the principal outcome measures were response latencies on the response initiation and response inhibition sections of the HSCT.

Principal Findings

Participants dosed with modafinil had significantly longer mean response latencies on the HSCT for both the response initiation and response inhibition compared to participants dosed with placebo. However, participants in both groups made a similar number of errors on each of these measures, indicating that modafinil did not enhance the accuracy of performance of the task relative to placebo.

Conclusions

This study demonstrated that administration of single 200 mg doses of modafinil to healthy individuals increased the latency of responses in the performance of the HSCT, a task that is highly sensitive to prefrontal executive function, without enhancing accuracy of performance. This finding may provide important clues to defining the limitations of modafinil as a putative cognitive enhancer.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02051153","term_id":"NCT02051153"}}NCT02051153     

What’s Behind the Decline? The Role of White Matter in Brain Aging

The specific molecular events that underlie the age-related loss of cognitive function are poorly understood. Although not experimentally substantiated, age-dependent neuronal loss has long been considered central to age-related cognitive decline. More recently, age-related changes in brain white matter have taken precedence in explaining the steady decline in cognitive domains seen in non-diseased elderly. Characteristic alterations in the ultrastructure of myelin coupled with evidence of inflammatory processes present in the white matter of several different species suggest that specific molecular events within brain white matter may better explain observed pathological changes and cognitive deficits. This review focuses on recent evidence highlighting the importance of white matter in deciphering the course of “normal” brain aging. Special issue in honor of Naren Banik.     

Large-scale cortical functional organization and speech perception across the lifespan

Aging is accompanied by substantial changes in brain function, including functional reorganization of large-scale brain networks. Such differences in network architecture have been reported both at rest and during cognitive task performance, but an open question is whether these age-related differences show task-dependent effects or represent only task-independent changes attributable to a common factor (i.e., underlying physiological decline). To address this question, we used graph theoretic analysis to construct weighted cortical functional networks from hemodynamic (functional MRI) responses in 12 younger and 12 older adults during a speech perception task performed in both quiet and noisy listening conditions. Functional networks were constructed for each subject and listening condition based on inter-regional correlations of the fMRI signal among 66 cortical regions, and network measures of global and local efficiency were computed. Across listening conditions, older adult networks showed significantly decreased global (but not local) efficiency relative to younger adults after normalizing measures to surrogate random networks. Although listening condition produced no main effects on whole-cortex network organization, a significant age group x listening condition interaction was observed. Additionally, an exploratory analysis of regional effects uncovered age-related declines in both global and local efficiency concentrated exclusively in auditory areas (bilateral superior and middle temporal cortex), further suggestive of specificity to the speech perception tasks. Global efficiency also correlated positively with mean cortical thickness across all subjects, establishing gross cortical atrophy as a task-independent contributor to age-related differences in functional organization. Together, our findings provide evidence of age-related disruptions in cortical functional network organization during speech perception tasks, and suggest that although task-independent effects such as cortical atrophy clearly underlie age-related changes in cortical functional organization, age-related differences also demonstrate sensitivity to task domains.     

Loss of Munc18-1 long splice variant in GABAergic terminals is associated with cognitive decline and increased risk of dementia in a community sample

Background

Presynaptic terminals contribute to cognitive reserve, balancing the effects of age-related pathologies on cognitive function in the elderly. The presynaptic protein Munc18-1, alternatively spliced into long (M18L) or short (M18S) isoforms, is a critical modulator of neurotransmission. While subtle alterations in Munc18-1 have been shown to cause severe neuropsychiatric disorders with cognitive impairment, little information is known regarding the specific roles of Munc18-1 splice variants. We first investigated functional and anatomical features evidencing the divergent roles of M18L and M18S, and then evaluated their contribution to the full range of age-related cognitive impairment in the dorsolateral prefrontal cortex of a large sample of participants from a community-based aging study, including subjects with no-(NCI, n?=?90), or mild-(MCI, n?=?86) cognitive impairment, or with clinical dementia (n?=?132). Finally, we used APP23 mutant mice to study the association between M18L/S and the time-dependent accumulation of common Alzheimer’s disease pathology.

Results

Using isoform-specific antibodies, M18L was localized to the synaptosomal fraction, with a distribution matching lipid raft microdomains. M18S was found widely across cytosolic and synaptosomal compartments. Immunocytochemical studies identified M18L in perisomatic, GABAergic terminals, while M18S was broadly distributed in GABAergic and glutamatergic terminals. Using regression models taking into account multiple age-related pathologies, age, education and sex, global cognitive function was associated with the level of M18L (p?=?0.006) but not M18S (p?=?0.88). Mean M18L in dementia cases was 51 % lower than in NCI cases (p?<?0.001), and each unit of M18L was associated with a lower likelihood of dementia (odds ratio?=?0.68, 95 % confidence interval?=?0.50–0.90, p?=?0.008). In contrast, M18S balanced across clinical and pathologically diagnosed groups. M18L loss may not be caused by age-related amyloid pathology, since APP23 mice (12- and 22-months of age) had unchanged cortical levels of M18L/S compared with wild-type animals.

Conclusions

M18L was localized to presynaptic inhibitory terminals, and was associated with cognitive function and protection from dementia in an elderly, community-based cohort. Lower M18L in inhibitory presynaptic terminals may be an early, independent contributor to cognitive decline.

     

Age-Related Changes in Task Related Functional Network Connectivity

Aging has a multi-faceted impact on brain structure, brain function and cognitive task performance, but the interaction of these different age-related changes is largely unexplored. We hypothesize that age-related structural changes alter the functional connectivity within the brain, resulting in altered task performance during cognitive challenges. In this neuroimaging study, we used independent components analysis to identify spatial patterns of coordinated functional activity involved in the performance of a verbal delayed item recognition task from 75 healthy young and 37 healthy old adults. Strength of functional connectivity between spatial components was assessed for age group differences and related to speeded task performance. We then assessed whether age-related differences in global brain volume were associated with age-related differences in functional network connectivity. Both age groups used a series of spatial components during the verbal working memory task and the strength and distribution of functional network connectivity between these components differed across the age groups. Poorer task performance, i.e. slower speed with increasing memory load, in the old adults was associated with decreases in functional network connectivity between components comprised of the supplementary motor area and the middle cingulate and between the precuneus and the middle/superior frontal cortex. Advancing age also led to decreased brain volume; however, there was no evidence to support the hypothesis that age-related alterations in functional network connectivity were the result of global brain volume changes. These results suggest that age-related differences in the coordination of neural activity between brain regions partially underlie differences in cognitive performance.     

Age-Related Changes in Sentence Production Abilities and Their Relation to Working-Memory Capacity: Evidence from a Verb-Final Language

Objectives

This study investigated the best predictor to capture age-related changes in passive-sentence production using a constrained sentence-production paradigm and explored the role of working-memory capacity in relation to the task demands of the sentence-production tasks.

Methods

A total of 60 participants participated in the study ranging in age from 21 to 86. All were administered a syntactic-priming and a sentence-completion task under either canonical or noncanonical word-order conditions.

Results

Age was significantly and negatively correlated with sentence-production tasks, and the most demanding condition with a noncanonical word order under the syntactic priming paradigm was the best predictor of aging. Working-memory capacity was significantly and positively correlated with all conditions, but the significant correlation remained only for the most demanding condition (the priming task with a noncanonical word order) after controlling for age.

Discussion

Sentence-production abilities were vulnerable to aging, and these effects manifested most clearly when the task demands were high enough to tax individuals’ cognitive capacity. Working-memory capacity partially accounted for age-related changes in sentence-production abilities.     

Detecting Cheaters without Thinking: Testing the Automaticity of the Cheater Detection Module

Evolutionary psychologists have suggested that our brain is composed of evolved mechanisms. One extensively studied mechanism is the cheater detection module. This module would make people very good at detecting cheaters in a social exchange. A vast amount of research has illustrated performance facilitation on social contract selection tasks. This facilitation is attributed to the alleged automatic and isolated operation of the module (i.e., independent of general cognitive capacity). This study, using the selection task, tested the critical automaticity assumption in three experiments. Experiments 1 and 2 established that performance on social contract versions did not depend on cognitive capacity or age. Experiment 3 showed that experimentally burdening cognitive resources with a secondary task had no impact on performance on the social contract version. However, in all experiments, performance on a non-social contract version did depend on available cognitive capacity. Overall, findings validate the automatic and effortless nature of social exchange reasoning.     

Patterns of cognitive performance in healthy ageing in Northern Portugal: a cross-sectional analysis

Background

The Minho Integrative Neuroscience Database (MIND)-Ageing project aims to identify predictors of healthy cognitive ageing, including socio-demographic factors. In this exploratory analysis we sought to establish baseline cohorts for longitudinal assessment of age-related changes in cognition.

Methods

The population sample (472 individuals) was strictly a convenient one, but similar to the Portuguese population in the age profile. Participants older than 55 years of age were included if they did not present defined disabling pathologies or dementia. A standardized clinical interview was conducted to assess medical history and a battery of neuropsychological tests was administered to characterize global cognition (Mini Mental State Examination), memory and executive functions (Selective Reminding Test; Stroop Color and Word Test; and Block Design subtest of the Wechsler Adult Intelligence Scale). Cross-sectional analysis of the neuropsychological performance with individual characteristics such as age, gender, educational level and setting (retirement home, senior university, day care center or community), allowed the establishment of baseline clusters for subsequent longitudinal studies.

Results

Based on different socio-demographic characteristics, four main clusters that group distinctive patterns of cognitive performance were identified. The type of institution where the elders were sampled from, together with the level of formal education, were the major hierarchal factors for individual distribution in the four clusters. Of notice, education seems to delay the cognitive decline that is associated with age in all clusters.

Conclusions

Social-inclusion/engagement and education seem to have a protective effect on mental ageing, although this effect may not be effective in the eldest elders.     

C-reactive protein and genetic variants and cognitive decline in old age: the PROSPER study

Background

Plasma concentrations of C-reactive protein (CRP), a marker of chronic inflammation, have been associated with cognitive impairment in old age. However, it is unknown whether CRP is causally linked to cognitive decline.

Methods and Findings

Within the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial, with 5680 participants with a mean age of 75 years, we examined associations of CRP levels and its genetic determinants with cognitive performance and decline over 3.2 years mean follow-up. Higher plasma CRP concentrations were associated with poorer baseline performance on the Stroop test (P = 0.001) and Letter Digit Tests (P<0.001), but not with the immediate and delayed Picture Learning Test (PLT; both P>0.5). In the prospective analyses, higher CRP concentrations associated with increased rate of decline in the immediate PLT (P = 0.016), but not in other cognitive tests (all p>0.11). Adjustment for prevalent cardiovascular risk factors and disease did not change the baseline associations nor associations with cognitive decline during follow-up. Four haplotypes of CRP were used and, compared to the common haplotype, carrierships associated strongly with levels of CRP (all P<0.007). In comparison to strong associations of apolipoprotein E with cognitive measures, associations of CRP haplotypes with such measures were inconsistent.

Conclusion

Plasma CRP concentrations associate with cognitive performance in part through pathways independent of (risk factors for) cardiovascular disease. However, lifelong exposure to higher CRP levels does not associate with poorer cognitive performance in old age. The current data weaken the argument for a causal role of CRP in cognitive performance, but further study is warranted to draw definitive conclusions.     

Endogenous testosterone levels, mental rotation performance, and constituent abilities in middle-to-older aged men

Evidence from both human and animal studies suggests that gonadal steroids, such as testosterone, exert activational effects on adult spatial behavior. Endogenous testosterone levels decline gradually but variably as men age; it remains to be shown whether these decreases are associated with age-related declines in visuo-spatial performance or constituent abilities indicative of generalized age-related cognitive decline. Ninety-six healthy, community dwelling men aged between 38 and 69 years completed the Vandenberg and Kuse Mental Rotation Test (MRT) together with a battery of tests including processing speed, executive function, perceptual discrimination, working memory, and reaction time measures. Significant main effects of tertiles of calculated free testosterone levels (cEFT) were found on composite measures of processing speed, executive function, and perceptual discrimination ability in a subset of men aged over 50 years in age and crystallized intelligence controlled analyses; higher cEFT levels were associated with poorer performance. Hierarchical multiple regression and path analyses on the whole data set showed that cEFT levels negatively moderated processing speed performance, which in turn predicted both working memory and MRT performance with aging. Together these data suggest that age-related declines in endogenous testosterone levels in healthy middle-to-older aged men are not associated with generalized age-related cognitive decline.     

Khat use is associated with impaired working memory and cognitive flexibility

Rationale

Khat consumption has increased during the last decades in Eastern Africa and has become a global phenomenon spreading to ethnic communities in the rest of the world, such as The Netherlands, United Kingdom, Canada, and the United States. Very little is known, however, about the relation between khat use and cognitive control functions in khat users.

Objective

We studied whether khat use is associated with changes in working memory (WM) and cognitive flexibility, two central cognitive control functions.

Methods

Khat users and khat-free controls were matched in terms of sex, ethnicity, age, alcohol and cannabis consumption, and IQ (Raven''s progressive matrices). Groups were tested on cognitive flexibility, as measured by a Global-Local task, and on WM using an N-back task.

Result

Khat users performed significantly worse than controls on tasks tapping into cognitive flexibility as well as monitoring of information in WM.

Conclusions

The present findings suggest that khat use impairs both cognitive flexibility and the updating of information in WM. The inability to monitor information in WM and to adjust behavior rapidly and flexibly may have repercussions for daily life activities.     

Electromyographic activity of hand muscles in a motor coordination game: effect of incentive scheme and its relation with social capital

Background

A vast body of social and cognitive psychology studies in humans reports evidence that external rewards, typically monetary ones, undermine intrinsic motivation. These findings challenge the standard selfish-rationality assumption at the core of economic reasoning. In the present work we aimed at investigating whether the different modulation of a given monetary reward automatically and unconsciously affects effort and performance of participants involved in a game devoid of visual and verbal interaction and without any perspective-taking activity.

Methodology/Principal Findings

Twelve pairs of participants were submitted to a simple motor coordination game while recording the electromyographic activity of First Dorsal Interosseus (FDI), the muscle mainly involved in the task. EMG data show a clear effect of alternative rewards strategies on subjects'' motor behavior. Moreover, participants'' stock of relevant past social experiences, measured by a specifically designed questionnaire, was significantly correlated with EMG activity, showing that only low social capital subjects responded to monetary incentives consistently with a standard rationality prediction.

Conclusions/Significance

Our findings show that the effect of extrinsic motivations on performance may arise outside social contexts involving complex cognitive processes due to conscious perspective-taking activity. More importantly, the peculiar performance of low social capital individuals, in agreement with standard economic reasoning, adds to the knowledge of the circumstances that makes the crowding out/in of intrinsic motivation likely to occur. This may help in improving the prediction and accuracy of economic models and reconcile this puzzling effect of external incentives with economic theory.