Impaired Cognitive Performance Research Articles

Impact of Alcohol Use, Traumatic Stress, and Cigarette Smoking on Cognitive Functioning in Veterans With Co-occurring Alcohol Use Disorder and Posttraumatic Stress Disorder.

Alcohol use disorder (AUD) and PTSD have high rates of co-occurrence in U.S. Military Veterans resulting in incrementally worse functional outcomes relative to having either one of these disorders alone. Cognitive dysfunction can impede one's ability to benefit from standard behavioral AUD and PTSD treatments. Cigarette smoking is also highly prevalent among U.S. Military Veterans, and cognitive dysfunction is associated with chronic cigarette use among individuals with AUD and PTSD independently. However, much less is known about to what extent cigarette smoking further impairs cognitive functioning in individuals with both co-occurring AUD and PTSD. U.S. Veterans with co-occurring AUD and PTSD (n = 162) completed a comprehensive cognitive assessment covering various domains: working memory, processing speed, mental switching, cognitive inhibition, auditory-verbal learning, auditory-verbal memory, and verbal fluency. To examine the impact of alcohol use, traumatic stress, and cigarette smoking on cognitive function, we conducted a three-way interaction examining the moderated effects of smoking status on the association between alcohol use and PTSD symptoms on a composite domain of global cognition. Smoking status in Veterans with co-occurring AUD and PTSD moderated the relationship between alcohol use and global cognition (P = .042), such that higher levels of alcohol use in the past week were related to worse global cognitive function among Veterans cigarette smokers (P = .015) but not among nonsmokers (P = .833). On follow-up analyses of individual cognitive domains, greater alcohol use in the past week was associated with lower cognitive inhibition in smokers but not nonsmokers, with traumatic stress symptoms moderating this effect (P = .039). Additionally, smoking status moderated the relationship between alcohol use and auditory-verbal learning, such that there was a differential relationship between alcohol use and auditory-verbal learning between smokers and nonsmokers. Overall, results provide evidence for the compounding impact of alcohol use, traumatic stress, and cigarette smoking on cognitive functioning. Impaired cognitive performance on a global level as well as on individual domains of cognitive inhibition and auditory-verbal learning were evident. Cognitive dysfunction may impede a Veteran's ability to benefit from therapeutic treatment, and these cognitive domains may represent potential targets for cognitive training efforts. Further, study results support smoking cessation initiatives and smoke-free policies enacted at Veterans Affairs healthcare facilities and medical centers.

Resting-state fractal brain connectivity is associated with impaired cognitive performance in healthy aging

Aging affects cognitive functions even in the absence of ongoing pathologies. The neurophysiological basis of age-related cognitive decline (CD), however, is not completely understood. Alterations in both functional brain connectivity and in the fractal scaling of neuronal dynamics have been linked to aging and cognitive performance. Recently, fractal connectivity (FrC) has been proposed — combining the two concepts — for capturing long-term interactions among brain regions. FrC was shown to be influenced by increased mental workload; however, no prior studies investigated how resting-state FrC relates to cognitive performance and plausible CD in healthy aging. We recruited 19 healthy elderly (HE) and 24 young control (YC) participants, who underwent resting-state electroencephalography (EEG) measurements and comprehensive cognitive evaluation using 7 tests of the Cambridge Neurophysiological Test Automated Battery. FrC networks were reconstructed from EEG data using the recently introduced multiple-resampling cross-spectral analysis (MRCSA). Elderly individuals could be characterized with increased response latency and reduced performance in 4–4 tasks, respectively, with both reaction time and accuracy being affected in two tasks. Auto- and cross-spectral exponents — characterizing regional fractal dynamics and FrC, respectively, — were found reduced in HE when compared to YC over most of the cortex. Additionally, fractal scaling of frontoparietal connections expressed an inverse relationship with task performance in visual memory and sustained attention domains in elderly, but not in young individuals. Our results confirm that the fractal nature of brain connectivity — as captured by MRCSA — is affected in healthy aging. Furthermore, FrC appears as a sensitive neurophysiological marker of age-related CD.

Inflammatory subgroups of schizophrenia and their association with brain structure: A semi-supervised machine learning examination of heterogeneity

ObjectiveImmune system dysfunction is hypothesised to contribute to structural brain changes through aberrant synaptic pruning in schizophrenia. However, evidence is mixed and there is a lack of evidence of inflammation and its effect on grey matter volume (GMV) in patients. We hypothesised that inflammatory subgroups can be identified and that the subgroups will show distinct neuroanatomical and neurocognitive profiles. MethodsThe total sample consisted of 1067 participants (chronic patients with schizophrenia n = 467 and healthy controls (HCs) n = 600) from the Australia Schizophrenia Research Bank (ASRB) dataset, together with 218 recent-onset patients with schizophrenia from the external Benefit of Minocycline on Negative Symptoms of Psychosis: Extent and Mechanism (BeneMin) dataset. HYDRA (HeterogeneitY through DiscRiminant Analysis) was used to separate schizophrenia from HC and define disease-related subgroups based on inflammatory markers. Voxel-based morphometry and inferential statistics were used to explore GMV alterations and neurocognitive deficits in these subgroups. ResultsAn optimal clustering solution revealed five main schizophrenia groups separable from HC: Low Inflammation, Elevated CRP, Elevated IL-6/IL-8, Elevated IFN-γ, and Elevated IL-10 with an adjusted Rand index of 0.573. When compared with the healthy controls, the IL-6/IL-8 cluster showed the most widespread, including the anterior cingulate, GMV reduction. The IFN-γ inflammation cluster showed the least GMV reduction and impairment of cognitive performance. The CRP and the Low Inflammation clusters dominated in the younger external dataset. ConclusionsInflammation in schizophrenia may not be merely a case of low vs high, but rather there are pluripotent, heterogeneous mechanisms at play which could be reliably identified based on accessible, peripheral measures. This could inform the successful development of targeted interventions.

The Additive Benefits of Aerobic Exercise and Cognitive Training Postconcussion: Current Clinical Concepts.

Concussion induces the rapid onset of a short-lived neurophysiological disturbance that often results in autonomic nervous system dysfunction. This dysfunction affects both cardiovascular functioning and higher cognitive processing, inducing postconcussion clinical symptoms (somatic, cognitive, or emotional or a combination) and functional disturbances (impaired balance, cognition, and visual-vestibular performance). Current concussion rehabilitation paradigms using aerobic exercise may improve concussion symptoms. Additionally, cognitive training-focused rehabilitation interventions may enhance cognitive function postinjury. Though aerobic exercise and cognitive training-based concussion rehabilitation are successful independently, the multifaceted nature of concussion suggests the potential benefit of integrating both to improve concussion outcomes and clinician implementation. To support this clinical recommendation, we critiqued the existing research in which authors investigated aerobic exercise and cognitive training as postconcussion rehabilitation modalities, identified keys gaps in the literature, and proposed a practical clinical recommendation to integrate both modalities during concussion rehabilitation.

Application and validation of an algorithmic classification of early impairment in cognitive performance

Objective Due to the long prodromal period for dementia pathology, approaches are needed to detect cases before clinically recognizable symptoms are apparent, by which time it is likely too late to intervene. This study contrasted two theoretically-based algorithms for classifying early cognitive impairment (ECI) in adults aged ≥50 enrolled in the Baltimore Longitudinal Study of Aging. Method Two ECI algorithms were defined as poor performance (1 standard deviation [SD] below age-, sex-, race-, and education-specific means) in: (1) Card Rotations or California Verbal Learning Test (CVLT) immediate recall and (2) ≥1 (out of 2) memory or ≥3 (out of 6) non-memory tests. We evaluated concurrent criterion validity against consensus diagnoses of mild cognitive impairment (MCI) or dementia and global cognitive scores using receiver operating characteristic (ROC) curve analysis. Predictive criterion validity was evaluated using Cox proportional hazards models to examine the associations between algorithmic status and future adjudicated MCI/dementia. Results Among 1,851 participants (mean age = 65.2 ± 11.8 years, 50% women, 74% white), the two ECI algorithms yielded comparably moderate concurrent criterion validity with adjudicated MCI/dementia. For predictive criterion validity, the algorithm based on impairment in Card Rotations or CVLT immediate recall was the better predictor of MCI/dementia (HR = 3.53, 95%CI: 1.59–7.84) over 12.3 follow-up years. Conclusions Impairment in visuospatial ability or memory may be capable of detecting early cognitive changes in the preclinical phase among cognitively normal individuals.

Are Drivers Allowed to Sleep? Sleep Inertia Effects Drivers’ Performance after Different Sleep Durations in Automated Driving

Higher levels of automated driving may offer the possibility to sleep in the driver’s seat in the car, and it is foreseeable that drivers will voluntarily or involuntarily fall asleep when they do not need to drive. Post-sleep performance impairments due to sleep inertia, a brief period of impaired cognitive performance after waking up, is a potential safety issue when drivers need to take over and drive manually. The present study assessed whether sleep inertia has an effect on driving and cognitive performance after different sleep durations. A driving simulator study with n = 13 participants was conducted. Driving and cognitive performance were analyzed after waking up from a 10–20 min sleep, a 30–60 min sleep, and after resting without sleep. The study’s results indicate that a short sleep duration does not reliably prevent sleep inertia. After the 10–20 min sleep, cognitive performance upon waking up was decreased, but the sleep inertia impairment faded within 15 min. Although the driving parameters showed no significant difference between the conditions, participants subjectively felt more tired after both sleep durations compared to resting. The small sample size of 13 participants, tested in a within-design, may have prevented medium and small effects from becoming significant. In our study, take-over was offered without time pressure, and take-over times ranged from 3.15 min to 4.09 min after the alarm bell, with a mean value of 3.56 min in both sleeping conditions. The results suggest that daytime naps without previous sleep deprivation result in mild and short-term impairments. Further research is recommended to understand the severity of impairments caused by different intensities of sleep inertia.

Does stress influence executive functions through mechanisms other than control itself? Examining the effects of stress on cognitive inhibition within the theory of emotional foundations of cognitive control

Stress is known to impair the ability to suppress task-irrelevant stimuli (i.e., cognitive inhibition), but the mechanisms underpinning those effects are relatively unclear. Drawing on the theory of emotional foundations of cognitive control, I tested whether stress impaired cognitive inhibition performance by modulating affective bases of executive control. Participants (N=164 with usable data) were randomly assigned to a Zoom-adapted Trier Social Stress Test (TSST) or control TSST, and 18 min post-manipulation completed a modified Stroop that probabilistically assessed current affect following errors and correct responses for each trial type (congruent, incongruent). Saliva samples were collected both pre- and 15-min-post-manipulation offset, from which cortisol and other analytes are being assayed. Consistent with prior work, stress impaired cognitive inhibition. Importantly, stress modulated the effects of both errors and exerting executive control on affect. In particular, stress increased the extent to which exerting executive control (incongruent correct minus congruent correct affect) contributed to negative affect, whereas stress decreased the extent to which making an error in the task (error minus correct affect) contributed to negative affect. However, none of the affective results mediated the effects of stress on cognitive inhibition. Although stress modulated the effects of making an error and exerting executive control on affect, these affective effects did not explain the effects of stress on cognitive inhibition. These results suggest that the effects of stress on cognitive inhibition do not occur through affective or motivational pathways, but instead through other pathways, such as impairing control itself.

#6315 CHARACTERIZATION OF BRAIN DAMAGE AFTER ACUTE KIDNEY INJURY

Abstract Background and Aims Acute kidney injury (AKI) is a very common condition in inpatients. Severe AKI is frequently associated with by neurological disorders such as confusion, the mechanisms of which are poorly understood. We have shown in several animal models that chronic kidney disease is associated with impaired cognitive performance such as memory and increased permeability of the blood-brain barrier (BBB), related to the accumulation of uremic toxin indoxyl sulfate. The goal of these experiments was to highlight the influence of AKI on cerebral impairment in mice, particularly the BBB permeability, and to describe the mechanisms involved. Method We performed an AKI in C57/Bl6 WT mice, by unilateral nephrectomy and transient ischemia-reperfusion of the remaining kidney for 20 minutes (RIRI20 group) and compared them to two other groups: control mice and mice with unilateral ischemia-reperfusion without nephrectomy (IR20). Modified neurological severity score (mNSS) was performed daily. BBB permeability was assessed by quantification of the Evans Blue leakage in the brain and by cerebral 68Ga-DTPA TEP/CT imaging. Cerebral immuno-histochemistry was performed to evaluate the neuro-inflammatory processes. Results Glomerular filtration rate at Day 1 was lower in AKI group compared to the control group 0.21 ± 0.26 vs. 0.94 ± 0.13 mL/min/100g b.w (p<0.0001) and IR group: 0.75 ± 0.17 mL/min/100g b.w (p = 0.0007). Mice with AKI displayed a neurological impairment at day 1 and day 2 post-AKI, compared to control mice and IR20 mice, with mainly an impairment of the balance. Mean mNSS score at Day 1 was 2.6 ± 4.5 in AKI group, and 0.0 ±-0.0 in both the control and IR groups (p = 0.002). BBB permeability at Day 2 was higher in the AKI group than in the control group (p = 0.10) and the IR group (p = 0.0006) by Evans blue staining. Cerebral TEP imaging found similar results with increased BBB permeability in AKI mice to compared to control mice at D1 and D2 (p = 0.004 and p = 0.009, respectively). On immunohistochemistry, brains of mice after AKI displayed more astrocytosis and microglial activation compared to brains of control mice. Conclusion AKI in mice is specifically associated with early neurological damage, unlike renal ischemia-reperfusion alone, related to a BBB disruption in the first two days after AKI. AKI appears to induce astrocytosis and altered microglial phenotype, potentially due to increased neuroinflammatory processes following BBB disruption.

Clinical Manifestations And Intensities Of Intestinal Helminthic Infections Among Primary School Children In Gombe, North Eastern Nigeria

Background: Children are susceptible to Intestinal helminthiasis and can develop severe complications such as malnutrition, anaemia, chronic diarrhoea, and impaired cognitive performance, which can limit their potential. Objective: The objective of this study was to determine the clinical manifestations and intensities of intestinal helminthic infections among primary school children in Gombe, Nigeria. Methodology: This was a cross-sectional study that used a multistage sampling technique to study 350 pupils from 24 primary schools in Gombe, Nigeria, from 4thJuly 2018 to - 31stJanuary 2019. The means and standard deviations of quantitative variables such as age, height, and weight were computed. Stools were examined by the Direct method and Formol ether concentration methods. The prevalence of intestinal helminths, clinical manifestations, types and intensities of helminthic infections were determined, and Chi-square was used to test for the association at 95% confidence intervals. A p-value of <0.05 was considered statistically significant. Data was analysed using SPSS version 24. Results: The prevalence of intestinal helminthic infection was 23.7% (83/350). There was a significant association between intestinal helminths and blood in stools (OR= 15.400, p<0.001), abdominal pain (OR=1.889, p=0.023), pallor (OR=2.146, P = 0.027). More than half of the recorded infections (51.8%) were classified as light. Only, 2.4%, exhibited moderate infections, and there were no recorded cases of severe infection. Conclusions: Intestinal helminthic infection is a public health burden, especially in children. Abdominal pains, blood in stools, poor hand hygiene and pallor were significantly associated with intestinal helminthic infections. However, most of the infestations are of light to moderate intensity. Regular health education and provision of clean water with deworming of school children at intervals are highly recommended.

0301 Associations between sleep and cognitive function in patients with Neurological post-acute sequelae of SARS-CoV-2 infection

Abstract Introduction Fatigue and sleep disturbance are among the most common neurological post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC). We tested the hypothesis that impaired sleep and disrupted rest-activity rhythms are associated with impaired cognitive performance and greater burden of self-reported Neuro-PASC symptoms. Methods Forty adults (mean age 45 years, 69% female, 15% hospitalized post COVID) recruited from the Neuro-COVID-19 Clinic at Northwestern Memorial Hospital. Patients were evaluated via clinical assessment/history, chart review, patient reported outcomes for symptom severity (PROMIS cognitive function, fatigue, sleep disturbance, anxiety, depression), cognitive performance tests (NIH Toolbox modules for processing speed, attention, executive function, working memory), and 7 days of wrist actigraphy with a sleep log. We tested associations between objective and subjective measures using Pearson’s correlation and difference from population normative data using Student’s t test. Results 39 participants provided sufficient data for analysis. The median number of discrete neurologic symptoms attributed to PASC was 6 with 87% reporting ≥4 neurologic symptoms. Fatigue, insomnia, and depression were common (~70% reporting each). Participants reported significant symptom burden in all PROMIS domains, and had measurably worse attention function along with borderline executive function, compared to population normative data (all p< 0.001 except executive cognition p=0.056). Actigraphy showed Neuro-PASC patients had lower sleep efficiency and greater sleep latency (both p< 0.001) but similar wakefulness after sleep onset (WASO) compared to age-matched population controls. Self-reported cognitive symptoms were correlated with severity of fatigue (p< 0.001), anxiety (p=0.05), and depression (p< 0.01), but not subjective sleep disturbance. There were no associations between actigraphy-measured sleep or rest-activity characteristics and self-reported symptoms. Patients with abnormal sleep characteristics (WASO, sleep efficiency, sleep latency) demonstrated impaired objective attention and executive function. Conclusion Neuro-PASC patients presenting to a post-COVID clinic have a significant burden of subjective mental health, sleep, fatigue and cognitive impairment symptoms, along with objectively abnormal cognitive performance and sleep, compared to population controls. Interventions to improve sleep could benefit cognitive performance. Prospective studies including larger populations of patients are needed to fully determine the interplay of sleep/circadian rhythm disruption on the cognitive function and quality of life in patients with PASC. Support (if any) Center for Circadian and Sleep Medicine

0170 When to Sleep and Work to Optimize Alertness

Abstract Introduction Currently, millions of individuals work outside of the conventional 9-to-5 work shift and are often required to sleep at times that are not conducive to maximizing restorative sleep. This insufficient sleep leads to health and cognitive performance impairments that compromise workers’ safety and productivity. This can be mitigated by sleeping at the time of day that maximizes the restorative benefits of sleep and working at favorable hours, within their particular opportunity windows. Here, we present an optimization algorithm to identify sleep and work schedules that maximize alertness during work hours, while reducing impairment during non-working hours to the greatest extent possible. Methods We developed an optimization algorithm that searches through a large number of possible sleep and work schedules to identify the one that maximizes alertness during work times, while meeting user-provided constraints, such as the periods during which the user has flexible opportunities to sleep and work. To generate the possible sleep and work schedules, we used the well-validated Unified Model of Performance (UMP), including its ability to predict sleep latency and sleep duration. To assess the algorithm, we simulated four experimental studies, where we compared the effectiveness of the sleep schedules obtained by the algorithm against those of the sleep schedules used in the studies. In addition, we tested the algorithm’s ability to simultaneously optimize sleep and work schedules in one of the studies. Results Using the same amount of sleep as in the studies, the algorithm proposed sleep schedules that optimally allocated sleep, reducing alertness impairment during work hours by an average of 29%. Similarly, by simultaneously optimizing sleep and work schedules during a recovery period following a chronic sleep-restriction challenge, the algorithm’s solutions resulted in recovery to baseline alertness levels two days earlier than the conventional 9-to-5 work schedule. Conclusion Our work provides the first quantitative tool to optimize sleep and work schedules and complements other existing fatigue-management tools to provide a more comprehensive set of countermeasure strategies to mitigate alertness impairment due to limited sleep. Support (if any)

0163 Impact of cold-water hand immersion on cognitive performance and sleepiness during sleep inertia

Abstract Introduction Sleep inertia is a state of impaired cognitive performance upon awakening that dissipates with time awake. Manipulation of the distal-to-proximal skin temperature gradient using cold water has been hypothesized as a potential countermeasure to sleep inertia, but not previously explored (Krauchi et al., 2004). This study examined the effects of cold-water hand immersion on subsequent cognitive performance and sleepiness during sleep inertia. Methods Ten healthy adults (mean±standard deviation [SD] age 23.2±4.96 years; 6M, 4F) have thus far completed an ongoing 8-day protocol. Prior to an overnight in-laboratory visit, participants maintained habitual 8h sleep schedules for 1 week at home. In-laboratory sleep opportunities were timed to coincide with habitual sleep time. Following at least 5-min of electroencephalogram (EEG) verified continuous slow wave sleep (SWS), participants were awakened twice during the night to submerge their non-dominant hand in warm (34 C) or ice-cold water (0 C) for 3 min in a randomized, crossover design. Sleep inertia was assessed with a Mathematical Addition Test (ADD) and the Karolinska Sleepiness Scale (KSS) at ~ 5, 15, and 25 min after each awakening. Outcomes included number of correct responses and median reaction time for correct responses on the ADD and KSS scores. Data were analyzed with mixed-model ANOVA with condition, condition order and time since awakening as fixed factors and subject as a random factor. Results The average (Mean±SD) amount of SWS prior awakening was similar before the cold 7.0±2.3 min and warm 6.6±1.0min conditions (p>0.10). Following cold water immersion, subjective sleepiness was reduced and the median reaction time for correct responses was faster compared with warm water immersion (main effects of condition, p’s< 0.05). The number of correct responses was not significantly different between conditions, nor were there any significant interaction effects among the fixed factors. Conclusion These preliminary findings indicate that cold-water hand immersion may reduce sleepiness and increase the speed of arithmetic calculations during sleep inertia, which could have important implications for military and first responders performing after awakenings from sleep. Support (if any) Office of Naval Research MURI N00014-15-1-2809; NIH RHL165343A and CTSA Grant UL1 TR002535; Undergraduate Research Opportunities Grant, University of Colorado Boulder.

Neurocognitive Suicide and Homicide Markers in Patients with Schizophrenia Spectrum Disorders: A Systematic Review.

Suicide and homicide are considered important problems in public health. This study aims to identify the cognitive performance of suicidal and homicidal behaviors in people with schizophrenia spectrum disorders, as well as examining whether there are shared neuropsychological mechanisms. A systematic review of the recent literature was carried out from September 2012 to June 2022 using the Medline (via PubMed), Scopus, Embase, and Cochrane databases. Among the 870 studies initially identified, 23 were finally selected (15 related to suicidal behaviors and 8 to homicidal behaviors). The results evidenced a relationship between impairment of cognitive performance and homicidal behavior; meanwhile, for suicidal behaviors, no consistent results were found. High neuropsychological performance seems to act as a protective factor against violent behavior in people with schizophrenia spectrum disorders, but not against suicidal behavior; indeed, it can even act as a risk factor for suicidal behavior. To date, there is insufficient evidence that shared neurocognitive mechanisms exist. However, processing speed and visual memory seem to be affected in the presence of both behaviors.

Within-subject, double-blind, randomized, placebo-controlled evaluation of combining the cannabinoid dronabinol and the opioid hydromorphone in adults with chronic pain

The potential synergistic effects of combining cannabinoids and opioids for analgesia has received considerable attention. No studies to date have evaluated this combination in patients with chronic pain. The present study aimed to evaluate the combined analgesic and drug effects of oral opioid (hydromorphone) and delta-9-tetrahydrocannabinol (dronabinol), as well as their effects on physical and cognitive functioning, and human abuse potential (HAP) outcomes among individuals with knee osteoarthritis (KOA). This was a within-subject, double-blind, randomized, placebo-controlled study. Participants (N = 37; 65% women; mean age = 62) diagnosed with knee osteoarthritis of ≥3/10 average pain intensity were included. Participants received (1) placebo-placebo, (2) hydromorphone (4 mg)-placebo; (3) dronabinol (10 mg)-placebo, and (4) hydromorphone (4 mg)-dronabinol (10 mg). Clinical and experimentally-induced pain, physical and cognitive function, subjective drug effects, HAP, adverse events, and pharmacokinetics were evaluated. No significant analgesic effects were observed for clinical pain severity or physical functioning across all drug conditions. Little enhancement of hydromorphone analgesia by dronabinol was observed on evoked pain indices. While subjective drug effects and some HAP ratings were increased in the combined drug condition, these were not significantly increased over the dronabinol alone condition. No serious adverse events were reported; hydromorphone produced more mild adverse events than placebo, but hydromorphone + dronabinol produced more moderate adverse events than both placebo and hydromorphone alone. Only hydromorphone impaired cognitive performance. Consistent with laboratory studies on healthy adults, the present study shows minimal benefit of combining dronabinol (10 mg) and hydromorphone (4 mg) for analgesia and improving physical functioning in adults with KOA.

Acute stressors do not impair short-term memory or attention in an aged mouse model of amyloidosis.

Memory impairment in Alzheimer's disease patients is thought to be associated with the accumulation of amyloid-beta peptides and tau proteins. However, inconsistent reports of cognitive deficits in pre-clinical studies have raised questions about the link between amyloid-beta and cognitive decline. One possible explanation may be that studies reporting memory deficits often involve behavioral assessments that entail a high stress component. In contrast, in tasks without a high stress component transgenic mice do not consistently show declines in memory. The glucocorticoid cascade hypothesis of aging and the vicious cycle of stress framework suggest that stress exacerbates dementia progression by initiating a cycle of hypothalamic-pituitary-adrenal axis activation and subsequent brain deterioration. Using the APPswe/PS1dE9 mouse model of amyloidosis, we assessed whether stressor exposure prior to testing differentially impaired cognitive performance of aged male and female mice. As part of a larger study, mice performed a delayed match-to-position (DMTP) or a 3-choice serial-reaction time (3CSRT) task. Unexpectedly, these mice did not exhibit cognitive declines during aging. Therefore, at 73 and 74 weeks of age, we exposed mice to a predator odor or forced swim stressor prior to testing to determine if stress revealed cognitive deficits. We predicted stressor exposure would decrease performance accuracy more robustly in transgenic vs. non-transgenic mice. Acute stressor exposure increased accuracy in the DMTP task, but not in the 3CSRT task. Our data suggest that acute stressor exposure prior to testing does not impair cognitive performance in APPswe/PS1dE9 mice.

Impaired neurocognitive functioning 3months following diagnosis of high-risk acute lymphoblastic leukemia: A report from the Children's Oncology Group.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer diagnosis. Cognitive late effects develop in 20%-40% of ALL survivors, but the course of declines is unclear. The aim of this paper is to characterize cognitive functioning, and its association with patient-reported outcomes, early in treatment. A total of 483 children with high-risk ALL, aged 6-12years at diagnosis, consented to the neurocognitive study embedded in a prospective therapeutic trial, Children's Oncology Group (COG) AALL1131. A computerized neurocognitive battery (Cogstate) was administered 3months post diagnosis assessing reaction time, visual attention, working memory, visual learning, and executive functioning. Parent-reported executive functioning and patient-reported physical symptoms were also collected. Data from 390 participants (mean age at diagnosis=9.2years, 55.4% male) were obtained. Relatively few patients reported pain (16.0%) or nausea (22.6%), but a majority (68.5%) reported feeling at least some fatigue at testing. Mean Cogstate Z-scores were within normal limits across tasks; however, rates of impairment (Z-scores ≤ -1.5) for reaction time, working memory, visual learning, and visual attention were all higher than expected compared to the standardization sample. Patients reporting fatigue were significantly more likely to have impaired reaction time and visual attention compared to those reporting no fatigue. Findings support feasibility of computerized cognitive assessments and suggest higher-than-expected rates of impaired cognitive performance early during treatment for pediatric ALL, notably within 3months of diagnosis, suggesting intervention efforts may be indicated. These results also highlight acute factors that may impact reliability of "baseline" assessments conducted soon after diagnosis.

Pneumoviruses can impair the central nervous system by different mechanisms

Abstract Pneumoviruses such as the respiratory syncytial virus (hRSV) and the human metapneumovirus (hMPV) are the leading cause of acute lower tract respiratory infection, mainly in infants, elderly and immunocompromised individuals, causing high morbidity and mortality rates. However, these viruses can cause neurological alterations, such as encephalitis and encephalopathy. Viral RNA and pro-inflammatory molecules have been found in patients with neurological signs, supporting the notion of neuroinvasion and/or neuroinflammation caused by hRSV and hMPV. Therefore, this work seeks to evaluate the effects of these viruses on the brain. Accordingly, mice were infected with either hRSV or hMPV or treated with non-infectious controls (mock). Despite detecting viral load in the lungs of hMPV-infected mice, no viral load was detected in their brains, as it was shown for hRSV. However, pro-inflammatory cytokines such as IL-6 and IFN-g were increased only in the sera of hMPV-infected mice. Also, we observed differential patterns in the increase of cytokines in the brain of hRSV or hMPV-infected mice, including IL-6, TNF-a, and IL-4. Moreover, increased blood-brain barrier permeability was observed in mice infected with both viruses. Additionally, after several weeks post-infection, a Marble Burying (MB) test was performed, and we observed an impaired cognitive performance in mice infected with both viruses. All these results suggest that infection with these pneumoviruses can cause long-term behavioral impairment in mice. Our work provides new insight into the effect of hRSV and hMPV on the central nervous system and underscores the need to further understand how respiratory virus can damage brain function in humans. This work was supported by ANID/FONDECYT grants #11221280; #1190830, ANID scholarship # 21210662, the Millennium Institute on Immunology and Immunotherapy ACE 210015, ICN09_016 / ICN 2021_045; former P09/016-F.

Effects of gestational inflammation on age-related cognitive decline and hippocampal Gdnf-GFRα1 levels in F1 and F2 generations of CD-1 Mice

BackgroundIt has been reported that age-associated cognitive decline (AACD) accelerated by maternal lipopolysaccharide (LPS) insult during late pregnancy can be transmitted to the second generation in a sex-specificity manner. In turn, recent studies indicated that glial cell line‐derived neurotrophic factor (GDNF) and its cognate receptor (GFRα1) are critical for normal cognitive function. Based on this evidence, we aimed to explore whether Gdnf-GFRα1 expression contributes to cognitive decline in the F1 and F2 generations of mouse dams exposed to lipopolysaccharide (LPS) during late gestation, and to evaluate also the potential interference effect of pro-inflammatory cytokines.MethodsDuring gestational days 15–17, pregnant CD-1 mice (8–10 weeks old) received a daily intraperitoneal injection of LPS (50 μg/kg) or saline (control). In utero LPS-exposed F1 generation mice were selectively mated to produce F2 generation mice. In F1 and F2 mice aged 3 and 15 months, the Morris water maze (MWM) was used to evaluated the spatial learning and memory ability, the western blotting and RT-PCR were used for analyses of hippocampal Gdnf and GFRα1 expression, and ELISA was used to analyse IL-1β, IL-6 and TNF-α levels in serum.ResultsMiddle-aged F1 offspring from LPS-treated mothers exhibited longer swimming latency and distance during the learning phase, lower percentage swimming time and distance in targe quadrant during memory phase, and lower hippocampal levels of Gdnf and GFRα1 gene products compared to age-matched controls. Similarly, the middle-aged F2 offspring from the Parents-LPS group had longer swimming latency and distance in the learning phase, and lower percentage swimming time and distance in memory phase than the F2-CON group. Moreover, the 3-month-old Parents-LPS and 15-month-old Parents- and Father-LPS groups had lower GDNF and GFRα1 protein and mRNAs levels compared to the age-matched F2-CON group. Furthermore, hippocampal levels of Gdnf and GFRα1 were correlated with impaired cognitive performance in the Morris water maze after controlling for circulating pro-inflammatory cytokine levels.ConclusionsOur findings indicate that accelerated AACD by maternal LPS exposure can be transmitted across at least two generations through declined Gdnf and GFRα1 expression, mainly via paternal linage.

Brain Connectivity: A Journal of Clinical Neurology, Neuroscience, & Neuroimaging Advancing the Field of Neurology

Brain Connectivity: A Journal of Clinical Neurology, Neuroscience, & Neuroimaging Advancing the Field of Neurology

The consequences of sleep deprivation on cognitive performance

Although not fully understood, sleep is accepted as a vital and organized sequence of events that follows a regular cyclic program each night to ensure the human body can perform at its optimum. A lack of sleep, or sleep deprivation (SD), is a widespread phenomenon that can induce adverse changes in cognitive performance. This review focused on the biological explanation as well as the research investigating the numerous effects that SD can have on cognition. A reduction in sleep does not occur independently of the effects on memory, attention, alertness, judgment, decision-making, and overall cognitive abilities in the brain, resulting in decreased function and impaired cognitive performance.