Effects of bottom-up versus top-down digital cognitive training in older adults: A randomized controlled trial.

INTRODUCTION: Impairments in bottom-up perceptual processing have been associated to the age-related cognitive decline. Digital cognitive training focusing on bottom-up and/or top-down processes have been studied as a tool to remediate age-related cognitive decline. However, the most effective training type and order of application remain unclear. METHODS: One hundred and fifteen older adults were randomly assigned to 40 h of bottom-up then top-down or top-down then bottom-up digital cognitive training or an active control group. We evaluated cognition at baseline, after 20 h and 40 h of training and at follow-up using a mixed-model analysis. RESULTS: Global cognition improved, for the top-down group, after 20 h of training (p = 0.04; d = 0.7) and for all three groups after 40 h. The improvement in global cognition remained five months after the bottom-up/ top-down training (p = 0.009; d = 4.0). There were also improvements in the recall cognitive domain, after 20 h of training, for the bottom-up group and, after 40 h, for all three groups. Gains were observed in verbal fluency after 40 h of training for both therapeutic groups. Processing speed was significantly slower, after 20 h of training, for the control and bottom-up groups and, after 40 h, only for the control group. Emotion recognition improved, after 20 h, for the control group as compared to the therapeutic groups. CONCLUSIONS: These results indicate that the bottom-up/top-down training has the most endurable effects, which reveals the importance of the order of application of the exercises for gains in cognition in older adults.

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.

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.

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.

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.

Genetic correlate of cognitive training response in schizophrenia.

Intensive computerized auditory training results in improved cognition for schizophrenia patients, but participants show variation in their cognitive gains and the biological factors that affect the response to training are unknown. Single nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase (COMT) gene have been related to cognitive function. Here we asked if functional variation in this gene has an impact on the response of schizophrenia patients to cognitive training. We genotyped 48 schizophrenia patients who completed 50 h of computerized cognitive training and analyzed the association between DNA variants in the COMT gene and the improvement in global cognition. Although conventional analyses did not reveal any significant associations, a set-based analysis examining the aggregate effect of common variation in the COMT gene (42 SNPs) suggested association with improvement in global cognition. Eight SNPs, mostly located in the 3' end of the COMT gene, were nominally associated with improvement in cognition. These data suggest that genotype influences the response to intensive cognitive training in schizophrenia, and may indicate that cognitive training regimens need to be personalized to the underlying biosignatures of each individual patient. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Plasma levels of D-serine in Brazilian individuals with schizophrenia.

Changes in D-serine availability in the brain may contribute to the hypofunction of NMDA-glutamate receptors in schizophrenia; however, measurements of blood levels of D-serine in individuals with schizophrenia have not been consistent amongst previous studies. Here we studied plasma levels of D-serine and L-serine in 84 Brazilian individuals with schizophrenia and 75 gender- and age-matched controls. Plasma levels of D-serine and the ratio of plasma D-serine to total serine were significantly lower in individuals with schizophrenia as compared to the control group. Levels of D-serine were significantly and negatively correlated to the severity of negative symptoms of schizophrenia. We also observed that plasma levels of D-serine significantly decreased with aging in healthy controls. Our results suggest that the possible role of D-serine in the pathophysiology of schizophrenia should be further investigated, with possible implications for the drug treatment of this disorder.

Astrocyte-induced synaptogenesis is mediated by transforming growth factor ß signaling through modulation of D-serine levels in cerebral cortex neurons.

Assembly of synapses requires proper coordination between pre- and postsynaptic elements. Identification of cellular and molecular events in synapse formation and maintenance is a key step to understand human perception, learning, memory, and cognition. A key role for astrocytes in synapse formation and function has been proposed. Here, we show that transforming growth factor ß (TGF-ß) signaling is a novel synaptogenic pathway for cortical neurons induced by murine and human astrocytes. By combining gain and loss of function approaches, we show that TGF-ß1 induces the formation of functional synapses in mice. Further, TGF-ß1-induced synaptogenesis involves neuronal activity and secretion of the co-agonist of the NMDA receptor, D-serine. Manipulation of D-serine signaling, by either genetic or pharmacological inhibition, prevented the TGF-ß1 synaptogenic effect. Our data show a novel molecular mechanism that might impact synaptic function and emphasize the evolutionary aspect of the synaptogenic property of astrocytes, thus shedding light on new potential therapeutic targets for synaptic deficit diseases.

Effects of low-dose D-serine on recognition and working memory in mice.

RATIONALE: D -Serine is an endogenous co-agonist of the N-methyl-D: -aspartate (NMDA) receptor and has been suggested to improve cognitive deficits in schizophrenia. OBJECTIVES: The present study investigates the effects of treatment with D -serine in mice on tasks that require recognition learning and working memory, two cognitive domains that are impaired in schizophrenia. METHODS: We studied the effects of various regimens of systemic administration of D -serine (50 mg/kg/day) on BALB/c mice performing object recognition, T-maze alternation, and open-field exploration tasks. For the object recognition task, we also contrasted the effects of D -serine and D -cycloserine and investigated whether D -serine could reverse alterations induced by subchronic injections of the NMDA antagonist MK-801. D -Serine levels after injections were measured by high-performance liquid chromatography. RESULTS: In the object recognition task, pre-training treatment with D -serine or D -cycloserine significantly enhanced recognition memory 24 h after training. A single administration of D -serine 30 min (but not 6 h) after training produced similar enhancement, suggesting an effect on memory consolidation. Daily treatment with D: -serine enhanced both object recognition and T-maze performance over multiple days and improved short-term memory in MK-801-treated mice. D -Serine treatment did not alter open-field exploration. Behavioral effects were accompanied by increased levels of D -serine in the hippocampus of treated animals. CONCLUSIONS: Our results show that treatment with D -serine can improve performance in tasks related to recognition learning and working memory, suggesting that this agent can be useful for the treatment of disorders involving declines in these cognitive domains.

Protein kinase C activity regulates D-serine availability in the brain.

D-serine is a co-agonist of NMDA receptor (NMDAR) and plays important roles in synaptic plasticity mechanisms. Serine racemase (SR) is a brain-enriched enzyme that converts L-serine to D-serine. SR interacts with the protein interacting with C-kinase 1 (PICK1), which is known to direct protein kinase C (PKC) to its targets in cells. Here, we investigated whether PKC activity regulates SR activity and D-serine availability in the brain. In vitro, PKC phosphorylated SR and decreased its activity. PKC activation increased SR phosphorylation in serine residues and reduced D-serine levels in astrocyte and neuronal cultures. Conversely, PKC inhibition decreased basal SR phosphorylation and increased cellular D-serine levels. In vivo modulation of PKC activity regulated both SR phosphorylation and D-serine levels in rat frontal cortex. Finally, rats that completed an object recognition task showed decreased SR phosphorylation and increased D-serine/total serine ratios, which was markedly correlated with decreased PKC activity in both cortex and hippocampus. Results indicate that PKC phosphorylates SR in serine residues and regulates D-serine availability in the brain. This interaction may be relevant for the regulation of physiological and pathological mechanisms linked to NMDAR function.

Human apolipoprotein A-I binds amyloid-beta and prevents Abeta-induced neurotoxicity.

Aggregates of the amyloid-beta peptide (Abeta) play a central role in the pathogenesis of Alzheimer's disease (AD). Identification of proteins that physiologically bind Abeta and modulate its aggregation and neurotoxicity could lead to the development of novel disease-modifying approaches in AD. By screening a phage display peptide library for high affinity ligands of aggregated Abeta(1-42), we isolated a peptide homologous to a highly conserved amino acid sequence present in the N-terminus of apolipoprotein A-I (apoA-I). We show that purified human apoA-I and Abeta form non-covalent complexes and that interaction with apoA-I affects the morphology of amyloid aggregates formed by Abeta. Significantly, Abeta/apoA-I complexes were also detected in cerebrospinal fluid from AD patients. Interestingly, apoA-I and apoA-I-containing reconstituted high density lipoprotein particles protect hippocampal neuronal cultures from Abeta-induced oxidative stress and neurodegeneration. These results suggest that human apoA-I modulates Abeta aggregation and Abeta-induced neuronal damage and that the Abeta-binding domain in apoA-I may constitute a novel framework for the design of inhibitors of Abeta toxicity.