Translation and validation of the audiovisual version of the Montreal cognitive assessment in older adults in Brazil.

BACKGROUND: The use of a reliable remote cognitive screening test for older adults is crucial for the diagnosis of cognitive impairment. This study aimed to translate and validate the audiovisual Montreal Cognitive Assessment (MoCA)for older adults in Brazil. METHODS: One hundred and fourteen older adults were recruited from the community and demographic, functional, mood, and cognitive data were collected. Participants were classified into two groups: cognitively healthy or mild cognitive impairment (MCI). Statistical analyses were performed in order to assess the validity of the test and the cutoff score. RESULTS: The psychometric properties of the audiovisual MoCA showed good convergent validity. The audiovisual MoCA was represented as a unifactorial adjusted model, the composite reliability value was acceptable and a cutoff point of ≥23 reached adequate sensitivity and specificity at 0.77 and 0.92, respectively. CONCLUSIONS: The translated audiovisual MoCA is a valid and reliable cognitive screening test that can be administered remotely in older adults in Brazil. The test demonstrated a great ability to discriminate older adults with MCI from cognitively healthy adults. Future studies should focus on validating the audiovisual MoCA using other target population groups in order to expand the use of this remote screening test.

Dysregulated noradrenergic response is associated with symptom severity in individuals with schizophrenia.

Introduction: The locus coeruleus-noradrenaline (LC-NA) system is involved in a wide range of cognitive functions and may be altered in schizophrenia. A non-invasive method to indirectly measure LC activity is task-evoked pupillary response. Individuals with schizophrenia present reduced pupil dilation compared to healthy subjects, particularly when task demand increases. However, the extent to which alteration in LC activity contributes to schizophrenia symptomatology remains largely unexplored. We aimed to investigate the association between symptomatology, cognition, and noradrenergic response in individuals with schizophrenia. Methods: We assessed task-evoked pupil dilation during a pro- and antisaccade task in 23 individuals with schizophrenia and 28 healthy subjects. Results: Both groups showed similar preparatory pupil dilation during prosaccade trials, but individuals with schizophrenia showed significantly lower pupil dilation compared to healthy subjects in antisaccade trials. Importantly, reduced preparatory pupil dilation for antisaccade trials was associated with worse general symptomatology in individuals with schizophrenia. Discussion: Our findings suggest that changes in LC-NA activity - measured by task-evoked pupil dilation - when task demand increases is associated with schizophrenia symptoms. Interventions targeting the modulation of noradrenergic responses may be suitable candidates to reduce schizophrenia symptomatology.

Age-related changes in prepulse inhibition of the startle response.

Introduction: Acoustic prepulse inhibition of the startle response (PPI) is a phenomenon characterized by the reduction in the startle reflex caused by the presence of weak and brief stimulus before an intense and sudden stimulus (pulse). These phenomena can be observed in several species, but in humans it is commonly measured by the eyeblink using electromyography. PPI works as an operational measure of sensorimotor gating, which is the ability to suppress motor responses for sensory stimulus. Healthy aging is marked by several changes in neural processing, like inhibitory functioning decline. In this line, PPI measure can be a potential biomarker for changes related to the aging process. Methods: In this research we aim to investigate if PPI is reduced with aging and if this reduction would be associated with cognitive functioning of older adults. To this aim, we compared PPI levels of older adults (over 60 years old) with PPI levels of young adults (from 18 to 28 years old). Results: With that, we found, significantly lower PPI level (F[1,25] = 7.44 p = 0.01) and lower startle amplitude startle amplitude: (U = 26.000 p = 0.001) in older adults than in young adults. However, we did not find differences in levels of habituation (T = -1.1 p = 0.28) and correlation between PPI and cognition within the sample of healthy older adults. Discussion: Our results demonstrate that aging is a factor that affects PPI and that it does not seem to predict cognition, however, future studies should explore the potential of using PPI for monitoring cognitive changes associated with techniques such as cognitive training.

Behaviour Change Techniques in Computerized Cognitive Training for Cognitively Healthy Older Adults: A Systematic Review.

We aimed to describe behaviour change techniques (BCT) used in trials evaluating computerised cognitive training (CCT) in cognitively healthy older adults, and explore whether BCTs are associated with improved adherence and efficacy. The 90 papers included in a recent meta-analysis were reviewed for information about adherence and use of BCTs in accordance with the Behaviour Change Taxonomy. Studies using a specific BCT were compared with studies not using that BCT on efficacy (difference in Hedges' g [Δg]) using three level meta-regression models and on median adherence using the Wilcoxon test. The median number of BCTs per study was 3 (interquartile range [IQR] = 2-5). 'Feedback on behaviour' (if provided by a person; Δg = -0.19, 95% confidence interval [CI] = -0.31;-0.07) and 'non-specific reward' (Δg = -0.19, CI = -0.34;-0.05) were associated with lower efficacy. Certain BCTs that involve personal contact may be beneficial, although none were statistically significantly associated with greater efficacy. The median percentage of adherence was 90% (IQR = 81-95). Adherence was higher in studies using the BCT 'self-monitoring of behaviour' and lower in studies using the BCT 'graded tasks' than studies not using these BCTs (p < 0.001). These findings provide first evidence that BCTs can influence both adherence to and efficacy of CCT programs in cognitively healthy older adults.

Association between motivation and engagement with changes in cognition and symptoms after digital cognitive training in schizophrenia.

BACKGROUND: Digital cognitive training can remediate cognitive deficits present in schizophrenia. However, limited motivation and engagement may impact adherence to training. Therefore, identifying factors that may enhance (facilitators) or decrease (barriers) engagement in digital cognitive training and possibly modulate its effects are of great clinical relevance. METHODS: We measured cognition, symptom severity, motivation (semi-structured interview), and engagement (adapted Utrecht Work Engagement Scale - UWES) of 27 patients with schizophrenia after a 40-h digital cognitive training. The interview transcript quotes were coded and categorized into facilitators and barriers. Thereafter, we tested the association of motivation and engagement with changes in cognition and symptoms after training. RESULTS: The facilitator 'good performance' and the barrier 'difficult exercise' were associated with larger gains in attention (p = 0.03) and reasoning and problem solving (p = 0.02), respectively. 'Poor performance' was associated with smaller gains in global cognition (p < 0.01), attention (p = 0.03), and working memory (p = 0.02). The facilitator 'welcoming setting' was associated with larger reductions in the negative (p = 0.01) and total (p = 0.01) symptoms measured by the Positive and Negative Syndrome Scale. The UWES engagement scale was associated with different facilitators and barriers that emerged from the interview, an indication of consistency among both qualitative and quantitative assessments. DISCUSSION: Using a mixed quantitative and qualitative research design, we showed associations between motivation and engagement and the response to digital cognitive training in schizophrenia. Facilitators and barriers were associated with engagement, gains in cognition, and reduced symptoms after the intervention, providing insights on how to increase engagement in the digital cognitive training delivered to subjects with schizophrenia.

Effects of Toxoplasma gondii infection on cognition, symptoms, and response to digital cognitive training in schizophrenia.

Studies indicate that neuroscience-informed digital cognitive training can remediate cognitive impairments in schizophrenia, but the factors contributing to these deficits and response to treatment remain unclear. Toxoplasma gondii is a neuroinvasive parasite linked to cognitive decline that also presents a higher prevalence in schizophrenia. Here, we compared the cognition and symptom severity of IgG seropositive (TOXO+; n = 25) and seronegative (TOXO-; n = 35) patients who participated in a randomized controlled trial of digital cognitive training. At baseline, TOXO+ subjects presented lower global cognition than TOXO- (F = 3.78, p = 0.05). Specifically, TOXO+ subjects showed worse verbal memory and learning (F = 4.48, p = 0.03), social cognition (F = 5.71, p = 0.02), and higher antibody concentrations were associated with increased negative (r = 0.42, p = 0.04) and total (r = 0.40, p = 0.04) schizophrenia symptoms. After training, the TOXO+ group showed higher adherence to the intervention (X2 = 9.31, p = 0.03), but there were no differences in changes in cognition and symptoms between groups. These findings highlight the association between seropositivity to T. gondii and deteriorated cognition and symptoms in schizophrenia. Further research is needed to assess the specific efficacy of digital cognitive training on this population.

Changes in emotion processing and social cognition with auditory versus visual neuroscience-informed cognitive training in individuals with schizophrenia.

BACKGROUND: Neuroscience-informed cognitive training has been used to remediate cognitive deficits in schizophrenia, but their effect on emotion processing and social cognition deficits, which may involve auditory and visual impairments, remain relatively unknown. In this study, we compared the efficacy of auditory versus visual neuroscience-informed cognitive training on emotion processing and social cognition in individuals with schizophrenia. METHODS: In this randomised, double-blind clinical trial, 79 participants with chronic schizophrenia performed 40-hours auditory or visual dynamically equivalent computerised cognitive training. We assessed emotion processing and social cognition using Emotion Recognition, Affective Go-NoGo, Mayer-Salovey-Caruso Emotional-Intelligence, Theory of mind, and Hinting tests before and after 20 h and 40 h of training. RESULTS: After training, participants from both groups decreased their reaction time for facial emotion recognition (p = 3 × 10-6, d = 0.9). This was more remarkable for the auditory group when analysing individual emotions. Both groups also reduced omissions in the affective go-no go (p = 0.01, d = 0.6), which was also attributed, post hoc, to the auditory group. Trends for improvement were observed in theory of mind (p = 0.06, d = 0.6) for both groups. Improvement in emotion processing was associated with improvement in reasoning and problem solving and global cognition and improvement in theory of mind was associated with improvement in attention and global cognition. CONCLUSIONS: Both the auditory and the visual neuroscience-informed cognitive training were efficacious at improving emotion processing and social cognition in individuals with schizophrenia, although improvement was more remarkable for the auditory training group. These improvements were related to cognitive - but not symptom - improvement.

D-Serine Signaling and NMDAR-Mediated Synaptic Plasticity Are Regulated by System A-Type of Glutamine/D-Serine Dual Transporters.

D-serine is a physiologic coagonist of NMDA receptors (NMDARs) required for synaptic plasticity, but mechanisms that terminate D-serine signaling are unclear. In particular, the identity of unidirectional plasma membrane transporters that mediate D-serine reuptake has remained elusive. We report that D-serine and glutamine share the same neuronal transport system, consisting of the classic system A transporters Slc38a1 and Slc38a2. We show that these transporters are not saturated with glutamine in vivo and regulate the extracellular levels of D-serine and NMDAR activity. Glutamine increased the NMDAR-dependent long-term potentiation and the isolated NMDAR potentials at the Schaffer collateral-CA1 synapses, but without affecting basal neurotransmission in male mice. Glutamine did not increase the NMDAR potentials in slices from serine racemase knock-out mice, which are devoid of D-serine, indicating that the effect of glutamine is caused by outcompeting D-serine for a dual glutamine-D-serine transport system. Inhibition of the system A reduced the uptake of D-serine in synaptosomes and neuronal cultures of mice of either sex, while increasing the extracellular D-serine concentration in slices and in vivo by microdialysis. When compared with Slc38a2, the Slc38a1 transporter displayed more favorable kinetics toward the D-enantiomer. Biochemical experiments with synaptosomes from Slc38a1 knock-down mice of either sex further support its role as a D-serine reuptake system. Our study identifies the first concentrative and electrogenic transporters mediating D-serine reuptake in vivo In addition to their classical role in the glutamine-glutamate cycle, system A transporters regulate the synaptic turnover of D-serine and its effects on NMDAR synaptic plasticity.SIGNIFICANCE STATEMENT Despite the plethora of roles attributed to D-serine, the regulation of its synaptic turnover is poorly understood. We identified the system A transporters Slc38a1 and Slc38a2 as the main pathway for neuronal reuptake of D-serine. These transporters are not saturated with glutamine in vivo and provide an unexpected link between the serine shuttle pathway, responsible for regulating D-serine synaptic turnover, and the glutamine-glutamate cycle. Our observations suggest that Slc38a1 and Slc38a2 have a dual role in regulating neurotransmission. In addition to their classical role as the glutamine providers, the system A transporters regulate extracellular D-serine and therefore affect NMDAR-dependent synaptic plasticity. Higher glutamine export from astrocytes would increase extracellular D-serine, providing a feedforward mechanism to increase synaptic NMDAR activation.

Auditory cognitive training improves prepulse inhibition in serine racemase mutant mice.

Evidence indicates that neuroplasticity-based cognitive training can improve cognition in patients with schizophrenia, but the individual response to training varies greatly between subjects. Hence, there is a need to understand the neurological underpinnings of cognitive training to reveal predictors of treatment response. D-serine is a crucial modulator of neuroplasticity, and decreased levels of D-serine may contribute to deficits in neuroplasticity in schizophrenia. Interestingly, we observed that training mice to identify auditory oddballs increased extracellular levels of D-serine in the hippocampus during training. Serine racemase (Srr) is the only source of brain D-serine; thus, it is possible that Srr may mediate the response to training. To test this hypothesis, we trained mice that have a mutated version of Srr (SrrY269*/SrrY269*) and reduced levels of D-serine in the same auditory training. SrrY269*/SrrY269* mice showed decreased performance during auditory training (defined as the capacity to discriminate an oddball during a sequence of tones). Importantly, auditory training improved prepulse inhibition (PPI) in SrrY269*/SrrY269* but not in wild-type mice. Finally, D-serine (100 mg/kg i.p.) given 30 min before training sessions to SrrY269*/SrrY269* mice improved training performance, but it did not enhance PPI. Taken together, our results show that D-serine is involved in the response to neuroplasticity-based auditory training and that PPI deficits can be improved by auditory oddball training even in the presence of neuroplasticity deficits.

The relationship between the number of neurons and behavioral performance in Swiss mice.

Neuronal number varies by several orders of magnitude across species, and has been proposed to predict cognitive capability across species. Remarkably, numbers of neurons vary across individual mice by a factor of 2 or more. We directly addressed the question of whether there is a relationship between performance in behavioral tests and the number of neurons in functionally relevant structures in the mouse brain. Naïve Swiss mice went through a battery of behavioral tasks designed to measure cognitive, motor and olfactory skills. We estimated the number of neurons in different brain regions (cerebral cortex, hippocampus, olfactory bulb, cerebellum and remaining areas) and crossed the two datasets to test the a priori hypothesis of correlation between cognitive abilities and numbers of neurons. Surprisingly, performance in the behavioral tasks did not correlate strongly with number of neurons in any of the brain regions studied. Our results show that whereas neuronal number is a predictor of cognitive skills across species, it is not a good predictor of cognitive, sensory or motor ability across individuals within a species, which suggests that other factors are more relevant for explaining cognitive differences between individuals of the same species.

Auditory versus visual neuroscience-informed cognitive training in schizophrenia: Effects on cognition, symptoms and quality of life.

BACKGROUND: Cognitive impairments are related to deficits in primary auditory and visual sensory processes in schizophrenia. These impairments can be remediated by neuroscience-informed computerized cognitive trainings that target auditory and visual processes. However, it is not clear which modality results in greater improvements in cognition, symptoms and quality of life. We aimed to investigate the impact of training auditory versus visual cognitive processes in global cognition in patients with schizophrenia. METHODS: Seventy-nine schizophrenia participants were randomly assigned to either 40 h of auditory or visual computerized training. Auditory and visual exercises were chosen to be dynamically equivalent and difficulties increased progressively during the training. We evaluated cognition, symptoms and quality of life before, after 20 h, and after 40 h of training. ClinicalTrials.gov (1R03TW009002-01). RESULTS: Participants who received the visual training showed significant improvements in global cognition compared to the auditory training group. The visual training significantly improved attention and reasoning and problem-solving, while the auditory training improved reasoning and problem-solving only. Schizophrenia symptoms improved after training in both groups, whereas quality of life remained unchanged. Interestingly, there was a significant and positive correlation between improvements in attention and symptoms in the visual training group. CONCLUSIONS: We conclude that the visual training and the auditory training are differentially efficient at remediating cognitive deficits and symptoms of clinically stable schizophrenia patients. Ongoing follow-up of participants will evaluate the durability of training effects on cognition and symptoms, as well as the potential impact on quality of life over time.

Association between increased serum d-serine and cognitive gains induced by intensive cognitive training in schizophrenia.

Neuroscience-guided cognitive training induces significant improvement in cognition in schizophrenia subjects, but the biological mechanisms associated with these changes are unknown. In animals, intensive cognitive activity induces increased brain levels of the NMDA-receptor co-agonist d-serine, a molecular system that plays a role in learning-induced neuroplasticity and that may be hypoactive in schizophrenia. Here, we investigated whether training-induced gains in cognition were associated with increases in serum d-serine in outpatients with schizophrenia. Ninety patients with schizophrenia and 53 healthy controls were assessed on baseline serum d-serine, l-serine, and glycine. Schizophrenia subjects performed neurocognitive tests and were assigned to 50 h of either cognitive training of auditory processing systems (N = 47) or a computer games control condition (N = 43), followed by reassessment of cognition and serum amino acids. At study entry, the mean serum d-serine level was significantly lower in schizophrenia subjects vs. healthy subjects, while the glycine levels were significantly higher. There were no significant changes in these measures at a group level after the intervention. However, in the active training group, increased d-serine was significantly and positively correlated with improvements in global cognition and in Verbal Learning. No such associations were observed in the computer games control subjects, and no such associations were found for glycine. d-Serine may be involved in the neurophysiologic changes induced by cognitive training in schizophrenia. Pharmacologic strategies that target d-serine co-agonism of NMDA-receptor functioning may provide a mechanism for enhancing the behavioral effects of intensive cognitive training.

Cerebral Multimodal Monitoring in Sepsis: An Experimental Study.

Acute brain dysfunction is a complication of sepsis, and its pathophysiology remains poorly understood. We studied the brain metabolism in a resuscitated animal model of sepsis. Twelve anesthetized, mechanically ventilated, and invasively monitored pigs were allocated to a sham procedure (N = 5) or sepsis (N = 7). Sepsis was induced through fecal inoculation in the peritoneum. Fluid resuscitation was maintained during the entire study period. Animals were observed until spontaneous death or for a maximum of 24 h. In addition to global hemodynamic and laboratory assessment, intracranial pressure and cerebral microdialysis (MD) were evaluated at baseline, 6, 12, 18, and 24 h after sepsis induction. After euthanasia, the brain was rapidly removed and a fragment from the frontal cortex was analyzed for markers of neuroinflammation, metabolism, and neurotransmission. Septic animals developed a hyperdynamic state associated with increased arterial lactate. Cerebral microdialysis showed unchanged levels of lactate/pyruvate ratios and brain glucose between the groups. Brain/serum glucose ratios were increased in the septic animals during the study period despite a progressive decrease in serum glucose. Moreover, extracellular glutamine levels were elevated starting at 6 h after sepsis. Tissue analysis showed elevated glutamate, glutamine, and glutamine synthetase in the sepsis group. However, C-Fos, a marker of neuronal activity, was unchanged between groups. In this animal model of resuscitated sepsis, we found increased oxidative stress and alterations in neuroenergetics characterized by exacerbated activity of the glutamate/glutamine cycle and increased glucose utilization by the brain, however without any evidence of decompensated energy metabolism.

Elevated Glutamate and Glutamine Levels in the Cerebrospinal Fluid of Patients With Probable Alzheimer's Disease and Depression.

Recent evidence suggests that Alzheimer's disease (AD) and depression share common mechanisms of pathogenesis. In particular, deregulation of glutamate-mediated excitatory signaling may play a role in brain dysfunction in both AD and depression. We have investigated levels of glutamate and its precursor glutamine in the cerebrospinal fluid (CSF) of patients with a diagnosis of probable AD or major depression compared to healthy controls and patients with hydrocephalus. Patients with probable AD or major depression showed significantly increased CSF levels of glutamate and glutamine compared to healthy controls or hydrocephalus patients. Furthermore, CSF glutamate and glutamine levels were inversely correlated to the amyloid tau index, a biomarker for AD. Results suggest that glutamate and glutamine should be further explored as potential CSF biomarkers for AD and depression.

Potential and Challenges for the Clinical Use of d-Serine As a Cognitive Enhancer.

After 25 years of its discovery in the rat brain, d-serine is a recognized modulator of synaptic plasticity and cognitive processes through its actions on the NMDA-glutamate receptor. Importantly, cognitive impairment is a core feature of conditions, such as schizophrenia, Alzheimer's disease, depression, and aging, and is associated to disturbances in NMDA-glutamate receptors. The d-serine pathway has been associated with cognitive deficits and these conditions, and, for this reason, d-serine signaling is subject of intense research to probe its role in aiding diagnosis and therapy. Nevertheless, this has not resulted in new therapies being incorporated into clinical practice. Therefore, in this review we will address many questions that need to be solved by future studies, regarding d-serine pharmacokinetics, possible side effects, other strategies to modulate its levels, and combination with other therapies to increase its efficacy.

Blood Levels of Glutamate and Glutamine in Recent Onset and Chronic Schizophrenia.

Converging evidence indicates that dysfunctions in glutamatergic neurotransmission and in the glutamate-glutamine cycle play a role in the pathophysiology of schizophrenia. Here, we investigated glutamate and glutamine levels in the blood of patients with recent onset schizophrenia or chronic schizophrenia compared to healthy controls. Compared with healthy controls, patients with recent onset schizophrenia showed increased glutamine/glutamate ratio, while patients with chronic schizophrenia showed decreased glutamine/glutamate ratio. Results indicate that circulating glutamate and glutamine levels exhibit a dual behavior in schizophrenia, with an increase of glutamine/glutamate ratio at the onset of schizophrenia followed by a decrease with progression of the disorder. Further studies are warranted to elucidate the mechanisms and consequences of changes in circulating glutamate and glutamine in schizophrenia.

The effect of D-serine administration on cognition and mood in older adults.

BACKGROUND: D-serine is an endogenous co-agonist of the N-Methyl D-Aspartate Receptor (NMDAR) that plays a crucial role in cognition including learning processes and memory. Decreased D-serine levels have been associated with age-related decline in mechanisms of learning and memory in animal studies. Here, we asked whether D-serine administration in older adults improves cognition. RESULTS: D-serine administration improved performance in the Groton Maze learning test of spatial memory and learning and problem solving (F(3, 38)= 4.74, p = 0.03). Subjects that achieved higher increases in plasma D-serine levels after administration improved more in test performance (r2=-0.19 p = 0.009). D-serine administration was not associated with any significant changes in the other cognitive tests or in the mood of older adults (p > 0.05). METHODS: Fifty healthy older adults received D-serine and placebo in a randomized, double blind, placebo-controlled, crossover design study. We studied the effect of D-serine administration on the performance of cognitive tests and an analogue mood scale. We also collected blood samples to measure D-serine, L-serine, glutamate and glutamine levels. CONCLUSIONS: D-serine administration may be a strategy to improve spatial memory, learning and problem solving in healthy older adults. Future studies should evaluate the impact of long-term D-serine administration on cognition in older adults.

Mechanisms involving Ang II and MAPK/ERK1/2 signaling pathways underlie cardiac and renal alterations during chronic undernutrition.

BACKGROUND: Several studies have correlated protein restriction associated with other nutritional deficiencies with the development of cardiovascular and renal diseases. The driving hypothesis for this study was that Ang II signaling pathways in the heart and kidney are affected by chronic protein, mineral and vitamin restriction. METHODOLOGY/PRINCIPAL FINDINGS: Wistar rats aged 90 days were fed from weaning with either a control or a deficient diet that mimics those used in impoverished regions worldwide. Such restriction simultaneously increased ouabain-insensitive Na+-ATPase and decreased (Na++K+)ATPase activity in the same proportion in cardiomyocytes and proximal tubule cells. Type 1 angiotensin II receptor (AT1R) was downregulated by that restriction in both organs, whereas AT2R decreased only in the kidney. The PKC/PKA ratio increased in both tissues and returned to normal values in rats receiving Losartan daily from weaning. Inhibition of the MAPK pathway restored Na+-ATPase activity in both organs. The undernourished rats presented expanded plasma volume, increased heart rate, cardiac hypertrophy, and elevated systolic pressure, which also returned to control levels with Losartan. Such restriction led to electrical cardiac remodeling represented by prolonged ventricular repolarization parameters, induced triggered activity, early after-depolarization and delayed after-depolarization, which were also prevented by Losartan. CONCLUSION/SIGNIFICANCE: The mechanisms responsible for these alterations are underpinned by an imbalance in the PKC- and PKA-mediated pathways, with participation of angiotensin receptors and by activation of the MAPK/ERK1/2 pathway. These cellular and molecular alterations culminate in cardiac electric remodeling and in the onset of hypertension in adulthood.

The co-agonist site of NMDA-glutamate receptors: a novel therapeutic target for age-related cognitive decline.

The world population is growing older and age-related cognitive decline is becoming a burden of societal importance. D-serine is an endogenous amino acid that activates the co-agonist site of the NMDA-glutamate receptor, which is related to cognitive functions, such as learning and memory. Studies in aged rodents have shown a marked decrease in the levels of D-serine in brain regions such as the hippocampus, a key region for encoding memory. Exogenous administration of D-serine in rodents has demonstrated pro-cognitive effects in several brain functions, including memory and executive function. Further to animal studies, our group has observed an agerelated decrease in D-serine in the blood of healthy adults and elderly. The oral administration of D-serine induced significant improvement in executive function and spatial problem solving in elderly, some of the key cognitive domains affected by aging. In this review we propose the activation of the co-agonist site of NMDA receptors as a target to remediate features of the age-related cognitive decline. The cognitive effects of other agents targeting the co-agonist site of NMDA receptors are also discussed.