Deficits In Cognitive Function Research Articles

Results of the SHARP Study: A Randomized, Placebo-Controlled, Double-Blind, Repeated-Measures, Crossover, Phase IV Clinical Trial of the Effect of the Wake-Promoting Agent Solriamfetol on Cognitive Function in Obstructive Sleep Apnea With Excessive Daytime Sleepiness and Cognitive Impairment

Obstructive sleep apnea (OSA) causes episodes of fragmented sleep and intermittent hypoxia and leads to excessive daytime sleepiness (EDS). Deficits in cognitive function are a troublesome symptom in patients with OSA and EDS. How does solriamfetol affect cognitive function in patients with cognitive impairment associated with OSA and EDS? SHARP was a phase 4, randomized, double-blind, placebo-controlled, crossover trial. Participants (N=59) were randomized to receive placebo or solriamfetol (75 mg/day for 3 days, then 150 mg/day) for 2 weeks, with crossover separated by a 1-week washout. Efficacy measures included the Coding subtest, comparable to the Digit Symbol Substitution Test, of the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS), the British Columbia Cognitive Complaints Inventory (BC-CCI), Patient Global Impression of Severity (PGI-S), and Epworth Sleepiness Scale (ESS). The primary endpoint was change from baseline in average post-dose DSST RBANS scores. Secondary endpoints were changes from baseline in BC-CCI, PGI-S, ESS, and DSST RBANS scores at 2, 4, 6, and 8 hours post-dose. Safety was monitored by treatment-emergent adverse events (TEAEs). Solriamfetol significantly improved post-dose average DSST RBANS scores compared with placebo (P=0.009; effect size [Cohen's d] 0.37). When evaluated at each 2-hour timepoint, cognitive function was significantly improved at 2, 6, and 8 hours after dosing (all P<0.05). During solriamfetol treatment, there were significant improvements in BC-CCI (P=0.002; d=0.45), PGI-S (P=0.0mixed; d=0.29), and ESS (P=0.004; d=0.40) compared with placebo. The most common TEAEs were nausea (7%) and anxiety (3%). SHARP demonstrated that solriamfetol can improve objective and subjective measures of cognitive function in patients with cognitive impairment associated with OSA and EDS. NCT04789174; EudraCT: 2020-004243-92.

In Vivo Expression of an SCA27A-linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons.

Autosomal dominant mutations in FGF14 , which encodes intracellular fibroblast growth factor 14 (iFGF14), underlie spinocerebellar ataxia type 27A (SCA27A), a devastating multisystem disorder resulting in progressive deficits in motor coordination and cognitive function. Mice lacking iFGF14 ( Fgf14 -/- ) exhibit similar phenotypes, which have been linked to iFGF14-mediated modulation of the voltage-gated sodium (Nav) channels that control the high frequency repetitive firing of Purkinje neurons, the main output neurons of the cerebellar cortex. To investigate the pathophysiological mechanisms underlying SCA27A, we developed a targeted knock-in strategy to introduce the first point mutation identified in FGF14 into the mouse Fgf14 locus ( Fgf14 F145S ), we determined the impact of in vivo expression of the mutant Fgf14 F145S allele on the motor performance of adult animals and on the firing properties of mature Purkinje neurons in acute cerebellar slices. Electrophysiological experiments revealed that repetitive firing rates are attenuated in adult Fgf14 F145S/+ cerebellar Purkinje neurons, attributed to a hyperpolarizing shift in the voltage-dependence of steady-state inactivation of Nav channels. More severe effects on firing properties and Nav channel inactivation were observed in homozygous Fgf14 F145S/F145S Purkinje neurons. Interestingly, the electrophysiological phenotypes identified in adult Fgf14 F145S/+ and Fgf14 F145S/F145S cerebellar Purkinje neurons mirror those observed in heterozygous Fgf14 +/- and homozygous Fgf14 -/- Purkinje neurons, respectively, suggesting that the mutation results in the loss of the iFGF14 protein. Western blot analysis of lysates from adult heterozygous Fgf14 F145S/+ and homozygous Fgf14 F145S/F145S animals revealed reduced or undetectable, respectively, iFGF14 expression, supporting the hypothesis that the mutant allele results in loss of the iFGF14 protein and that haploinsufficiency underlies SCA27A neurological phenotypes.

The Cognitive Profile of Older Adults With Treatment-Resistant Depression: An Analysis of the OPTIMUM Randomized Controlled Trial

ObjectiveMajor depressive disorder in older adults (late-life depression; LLD) is frequently associated with cognitive impairment, and some deficits (e.g., executive function) have been associated with a higher level of treatment resistance. However, the cognitive profile of treatment-resistant LLD (TR-LLD) has not been characterized. We hypothesized that patients with TR-LLD would show deficits in cognitive function, especially executive function, and that executive function deficits would predict poorer response to pharmacotherapy. DesignSecondary analysis of baseline cognitive data from OPTIMUM, a multicenter RCT evaluating pharmacotherapy strategies for TR-LLD. SettingFive outpatient academic medical centers (4 US, 1 Canada). ParticipantsAbout 369 participants aged 60 and older from the OPTIMUM study. MeasurementsBaseline scores on individual tasks and composite scores from the NIH Toolbox-Cognition Battery were transformed into demographically-adjusted T-scores and compared to published norms. Impairments in the set shifting and inhibitory control tasks were investigated as predictors of depressive symptom change following treatment using ANCOVA models. ResultsParticipants had low performance on tasks evaluating inhibitory control, processing speed, verbal/nonverbal memory, and the fluid composite, but normative performance on working memory and set shifting. Participants had high estimated premorbid IQ (superior Performance on oral reading recognition). Age and physical comorbidity negatively associated with processing speed. Impairments in set shifting predicted less improvement in depressive symptoms; impairments in inhibitory control did not. ConclusionsParticipants with TR-LLD presented with broad cognitive deficits relative to healthy norms. Given poorer outcomes following standard pharmacotherapy associated with impaired set shifting, future research needs to identify alternative treatment strategies.

Understanding treatment preferences and cognitive outcomes in patients with gliomas.

Understanding how glioma patients value cognitive outcomes is essential to personalizing their treatment plans. The purpose of this study was to identify the modifiable cognitive functions most affected by treatment and most important to patient quality of life. Patients with gliomas were prospectively enrolled in focus groups and individual interviews using a standardized guide focusing on cognitive functions until saturation was achieved. Patient values and treatment preferences were elicited and compared to the frequency of reported deficits. NVivo natural language processing software was used to perform thematic qualitative analyses. Quantitative analysis with Fischer's exact test was used for each cognitive function to assess for an association between experiencing a deficit and rating that function as important to quality of life. Twenty participants participated, of whom 60% were female. Racial identification consisted of 75% White, 15% Black/African American, and 10% OtherRacial Identification. The cognitive functions most essential to the quality of life in this cohort were sense of self (80% of participants), memory (70% of participants), and communication (25% of participants). The functions that experienced the most deficits because of treatment were memory (65% of participants), concentration (65% of participants), and special senses (40% of participants). "Dealbreakers" to treatment were complete loss of independence, sense of self, and/orthe ability to interact with loved ones. Fischer's exact test showed no associations between experiencing a cognitive function deficit and rating that function as important to quality of life. Glioma patients in this study prioritized cognitive functions according to memory, personal identity, and their ability to communicate with loved ones independently of experiencing deficits in these functions. Further study should comparepatient prioritization and decision-making between surgically curable and noncurable grade gliomas as well as investigate the quality of life benefits of incorporating the connectomics of highly valued cognitive functions in surgical planning.

A new test for evaluation of marginal cognitive function deficits in idiopathic normal pressure hydrocephalus through expressing texture recognition by sound symbolic words.

The number of dementia patients is increasing with population aging. Preclinical detection of dementia in patients is essential for access to adequate treatment. In previous studies, dementia patients showed texture recognition difficulties. Onomatopoeia or sound symbolic words (SSW) are intuitively associated with texture impressions and are less likely to be affected by aphasia and description of material perception can be easily obtained. In this study, we aimed to create a test of texture recognition ability expressed by SSW to detect the presence of mild cognitive disorders. The sound symbolic words texture recognition test (SSWTRT) is constructed from 12 close-up photos of various materials and participants were to choose the best SSW out of 8 choices to describe surface texture in the images in Japanese. All 102 participants seen in Juntendo University Hospital from January to August 2023 had a diagnosis of possible iNPH (age mean 77.9, SD 6.7). The answers were scored on a comprehensive scale of 0 to 1. Neuropsychological assessments included MMSE, FAB, and the Rey Auditory Verbal Learning Test (RAVLT), Pegboard Test, and Stroop Test from the EU-iNPH Grading Scale (GS). In study 1 the correlation between SSWTRT and the neuropsychological tests were analyzed. In study 2, participants were divided into two groups: the Normal Cognition group (Group A, n = 37) with MMSE scores of 28 points or above, and the Mild Cognitive Impairment group (Group B, n = 50) with scores ranging from 22 to 27 points, and its predictability were analyzed. In study 1, the total SSWTRT score had a moderate correlation with the neuropsychological test results. In study 2, there were significant differences in the SSWTRT scores between groups A and B. ROC analysis results showed that the SSWTR test was able to predict the difference between the normal and mildly impaired cognition groups. The developed SSWTRT reflects the assessment results of neuropsychological tests in cognitive deterioration and was able to detect early cognitive deficits. This test not only relates to visual perception but is likely to have an association with verbal fluency and memory ability, which are frontal lobe functions.

Using harmonized FITBIR datasets to examine associations between TBI history and cognitive functioning

Objective Demonstrate how patient-level traumatic brain injury (TBI) data from studies in the Federal Interagency Traumatic Brain Injury Research (FITBIR) Informatics System can be harmonized and pooled to examine relationships between TBI and cognitive functioning. Method We harmonized and pooled data across studies and analyzed rates of probable cognitive functioning deficits by TBI history and severity. Results Four publicly available FITBIR studies with 3,445 participants included data on cognitive dysfunction, though only one included comparison groups (mild TBI vs. no history of TBI) and could be used in the final comparative analyses. Of the 1,539 participants, 82% had a history of mild TBI and 67% had data suggesting the presence of cognitive dysfunction. Participants with a history of mild TBI were mostly male (87%), 25–39 years old (53%), and Non-Hispanic White (60%). Conclusions: One publicly available FITBIR study reported cognitive dysfunction data as of January 2021, though findings were similar to prior research and supported an association between mild TBI and cognitive dysfunction. This proof-of-concept study shared newly developed methods including harmonization, analysis syntax, and meta-data via the FITBIR website to encourage dissemination of these TBI data resources in line with FAIR data goals.

Childhood Neighborhood Disadvantage and Cognitive Function among Veterans Recovering from Mild Traumatic Brain Injury

Abstract Objective Identifying risk factors and interventions for chronic symptoms following mild traumatic brain injury (TBI) is an important area of research for Veterans. Growing up in a disadvantaged neighborhood is associated with poorer health outcomes. We examined the relationship between childhood neighborhood disadvantage and cognitive outcomes among symptomatic Veterans with history of mild TBI. Method 58 Participants completed neuropsychological tests (CVLT-3, TMT A&amp;B, COWA, Category Test), NSI, and PCL-5. The Neighborhood Atlas was used to derive disadvantage scores using childhood addresses. Global deficit scores were calculated as described by Heaton (2004). Results Neighborhood disadvantage was significantly correlated with CVLT-3 Total Learning (r = −0.26, p = 0.046), but not the overall global deficit or deficit performance across CVLT-3 Delayed Recall, TMT-A, TMT-B, COWA, and Category Test. There was a significant difference in neighborhood disadvantage between participants scoring in the deficit and normal ranges on CVLT-3 Total Learning (p = 0.046). There were no other differences in neighborhood disadvantage across other neuropsychological tests. There was a significant difference in PTSD symptoms between participants scoring within the deficit and normal ranges on the COWA (p = 0.002). There were no other significant group differences in neuropsychiatric symptoms or PTSD symptom severity. Conclusions Among Veterans in this sample, neighborhood disadvantage was not associated with cognitive function or cognitive deficits. Although neighborhood disadvantage is an important psychosocial risk factor for poor outcomes in the civilian literature, these results suggest that it may not be an important contributing factor in recovery from mild TBI for military Veterans.

Autoimmune hypothesis of Alzheimer's disease: unanswered question.

Alzheimer's disease (AD) was described more than a century ago. However, there are still no effective approaches to its treatment, which may suggest that the search for the cure is not being conducted in the most productive direction. AD begins as selective impairments of declarative memory with no deficits in other cognitive functions. Therefore, understanding of the AD pathogenesis has to include the understanding of this selectivity. Currently, the main efforts aimed at prevention and treatment of AD are based on the dominating hypothesis for the AD pathogenesis: the amyloid hypothesis. But this hypothesis does not explain selective memory impairments since β-amyloid accumulates extracellularly and should be toxic to all types of cerebral neurons, not only to "memory engram neurons." To explain selective memory impairment, I propose the autoimmune hypothesis of AD, based on the analysis of risk factors for AD and molecular mechanisms of memory formation. Memory formation is associated with epigenetic modifications of chromatin in memory engram neurons and, therefore, might be accompanied by the expression of memory-specific proteins recognized by the adaptive immune system as "non-self" antigens. Normally, the brain is protected by the blood-brain barrier (BBB). All risk factors for AD provoke BBB disruptions, possibly leading to an autoimmune reaction against memory engram neurons. This reaction would make them selectively sensitive to tauopathy. If this hypothesis is confirmed, the strategies for AD prevention and treatment would be radically changed.

Outpatient Prescriptions for Insomnia Medications During the First Year Following Combat-Related Amputations.

Sleep-related disorders are associated with pain, fatigue, and deficits in cognitive performance, which may interfere with successful rehabilitation. The study objectives were to (1) quantify outpatient prescriptions for insomnia medications during the first year following combat-related amputations, (2) examine longitudinal changes in prescriptions for insomnia medications, and (3) analyze patient characteristics associated with prescriptions for insomnia medications. This was a retrospective study of DoD casualty records from the Expeditionary Medical Encounter Dataset and prescriptions for outpatient medications from the Pharmacy Data Transaction Service. Patients were a total of 1,651 U.S. service members who sustained major limb amputations in Operations Iraqi and Enduring Freedom from 2001 through 2017 and had outpatient prescriptions for any medication during the first year postinjury. Prescriptions for medications recommended for insomnia were low-dose antidepressants, anxiolytic sedatives, benzodiazepines, melatonin receptor agonist, and low-dose quetiapine. These prescription medications were analyzed by medication type, postinjury time, and patient characteristics during the first year postinjury. During the first year postinjury, 78% of patients (1,291 of 1,651) had outpatient prescriptions for insomnia medications, primarily anxiolytic sedative drugs (e.g., zolpidem), averaging a total of 86 prescription days (median = 66). The prevalence of these prescriptions declined substantially during the first year, from 57% of patients during the first quarter to 28% during the fourth quarter postinjury. In univariate analyses, multiple patient characteristics, including high Injury Severity Score, continued opioid and non-opioid analgesic prescriptions, and diagnoses of chronic pain, mood disorder, and posttraumatic stress disorder, were significantly associated with higher prevalence and duration of outpatient prescriptions for insomnia medications. The present results indicate a high prevalence of outpatient prescriptions for insomnia medications following combat-related amputations, a prevalence that is substantially higher than previously reported among active duty personnel. These findings can inform DVA/DoD guidelines for amputation care and insomnia among military subpopulations. The results highlight the need for more research on the treatment of insomnia during early postinjury rehabilitation among patients who sustained serious combat injuries.

Longitudinal Associations Between Cognition and Grip Strength, Differentiated by Sex and Physical Activity: A Population-Based Study in Older Adults From 17 European Countries.

Objectives (1) To investigate longitudinal associations between grip strength (GS) and cognition over 4 years in European older adults, (2) to examine differences in temporal associations between men and women and between levels of physical activity, (3) to explore in each year 2015 and 2019 associations between GS quartiles and cognitive performance, and (4) to explore longitudinal associations between GS quartiles (year 2015) and cognitive performance (year 2019). Methods: 25,281 individuals (14,200 women) from 17 European countries aged ≥50 years responded to waves 6th and 8th of the SHARE project. We analyzed GS, a general cognition index, and physical activity level. Results: Panel analyses revealed a bidirectional relationship over 4 years between GS and cognition, with differences between sex, as well as between participants with moderate-to-vigorous and low physical activity levels. Conclusion: Women and participants with low physical activity were more likely to experience cognitive performance deficits 4 years later.

Biobank for craniosynostosis and faciocraniosynostosis, rare pediatric congenital craniofacial disorders: a study protocol.

Craniosynostosis (CRS) is a rare congenital cranial malformation in which 1 or more cranial or facial sutures are fused in utero or rapidly fused in early infancy. The cranial sutures separate the skull bone plates and enable rapid growth of the skull in the first 2years of life, in which growth is largely dictated by growth of the brain. CRS is a rare disease that occurs in 1 in 2100 to 1 in 2500 births and may be either nonsyndromic (also referred to as isolated) or syndromic. In syndromic CRS, other birth defects are present next to the CRS. The distinction between nonsyndromic and syndromic manifestations is made on the basis of dysmorphologic evaluation and genetic evaluation. Owing to advances in genetic diagnostics, nonsyndromic patients are increasingly recognized as syndromic patients. CRS treatment is almost entirely surgical and is sometimes paired with postoperative helmet therapy for maintenance. Corrective procedures are complex, long, and associated with the risk of numerous complications, including heavy blood loss and its sequelae. Although surgery may restore a normal appearance, even in nonsyndromic patients, patients may experience persistent deficits in intellectual ability and cognitive function. The European Commission (EC) has prioritized rare diseases in recent horizon European research programs; indeed, collections or even individual samples may be extremely valuable for research. Here, we present a study protocol in which the combined expertise of clinicians and researchers will be exploited to generate a biobank dedicated to CRS. The generation of the CRS biobank presented in this study will include the collection of different types of biological materials as well as advanced radiological images available to the scientific community. The activation of a CRS biobank will provide an opportunity to improve translational research on CRS and to share its benefits with the scientific community and patients and their families.

A developmental neurotoxicity adverse outcome pathway (DNT-AOP) with voltage gate sodium channel (VGSC) inhibition as a molecular initiating event (MiE).

The adverse outcome pathway (AOP) framework serves as a practical tool for organising scientific knowledge that can be used to infer cause-effect relationships between stressor events and toxicity outcomes in intact organisms. However, a major challenge in the broader application of the AOP concept within regulatory toxicology is the development of a robust AOPs that can withstand peer review and acceptance. This is mainly due to the considerable amount of work required to substantiate the modular units of a complete AOP, which can take years from inception to completion. The methodology used here consisted of an initial assessment of a single chemical hazard using the Integrated Approach to Testing and Assessment (IATA) framework. An evidence-based approach was then used to gather empirical evidence combining systematic literature review methods with expert knowledge to ensure the effectiveness of the AOP development methodology. The structured framework used assured transparency, objectivity and comprehensiveness, and included expert knowledge elicitation for the evaluation of key event relationships (KERs). This stepwise approach led to the development of an AOP that begins with binding of chemicals to Voltage Gate Sodium Channels (VGSC/Nav) during mammalian development leading to adverse consequences in neurodevelopment evidenced as deficits in cognitive functions. Disruption of the formation of precise neural circuits by alterations in VGSC kinetics during the perinatal stages of brain development may also underlie neurodevelopmental disorders. Gaps in our understanding include the specific critical developmental windows and the quantitative relationship of binding to VGSC and subsequent disruption and cognitive function. Despite the limited quantitative information at all KER levels, regulatory applications of this AOP for DNT assessment have been identified.

Blast-related mild TBI: LIMBIC-CENC focused review with implications commentary.

A significant factor for the high prevalence of traumatic brain injury (TBI) among U.S. service members is their exposure to explosive munitions leading to blast-related TBI. Our understanding of the specific clinical effects of mild TBI having a component of blast mechanism remains limited compared to pure blunt mechanisms. The purpose of this review is to provide a synopsis of clinical research findings on the long-term effects of blast-related mild TBI derived to date from the Long-Term Impact of Military-Relevant Brain Injury Consortium - Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC). Publications on blast-related mild TBI from LIMBIC-CENC and the LIMBIC-CENC prospective longitudinal study (PLS) cohort were reviewed and their findings summarized. Findings from the broader literature on blast-related mild TBI that evaluate similar outcomes are additionally reviewed for a perspective on the state of the literature. The most consistent and compelling evidence for long-term effects of blast-related TBI is for poorer psychological health, greater healthcare utilization and disability levels, neuroimaging impacts on brain structure and function, and greater headache impact on daily life. To date, evidence for chronic cognitive performance deficits from blast-related mild TBI is limited, but futher research including crucial longitudinal data is needed. Commentary is provided on: how LIMBIC-CENC findings assimilate with the broader literature; ongoing research gaps alongside future research needs and priorities; how the scientific community can utilize the LIMBIC-CENC database for independent or collaborative research; and how the evidence from the clinical research should be assimilated into clinical practice.

Extracorporeal life support use in patients with bronchopulmonary dysplasia: A single center case series.

Preterm pediatric patients with bronchopulmonary dysplasia (BPD) represent a subgroup previously deemed high risk candidates for ECLS (extracorporeal life support) due to suspected high mortality or increased post ECLS morbidity. The aim of this study was to determine outcomes for patients with an established history of BPD who subsequently required ECLS. A single center retrospective review was performed between 01/2010-06/2022 for patients less than 2years of age, born prematurely (<32weeks) with a subsequent diagnosis of BPD, and who required ECLS for respiratory failure. Demographic and clinical data, including ECLS data, were collected. Speech, language, feeding/swallowing, cognitive, hearing, vision, or motor function deficits were obtained with a median follow up of 42months following discharge. Nineteen patients met criteria. The median birth weight and gestational age was 0.86kg (IQR 0.73, 1.0) and 26weeks (IQR 25, 27), respectively. The median chronological age at cannulation was 12.1months. The most common etiologies for respiratory failure requiring ECLS were viral (68.4%) and bacterial (21.1%) pneumonia. Survival to decannulation was 78.9% (15/19) and survival to hospital discharge was 63.2% (12/19). Amongst survivors to discharge, 42% (5/12) required new or additional home oxygen and 50% (6/12) were noted to have neurodevelopmental/behavioral concerns on follow up at 1year with 25% (3/12) with concerns beyond a year. Patients with underlying BPD who require ECLS have comparable mortality and long-term neurodevelopmental outcomes to non-BPD patients with respiratory failure. This information can be useful when considering ECLS candidacy and providing family counseling.

Frontoparietal Response to Working Memory Load Mediates the Association between Sleep Duration and Cognitive Function in Children.

Lack of sleep has been found to be associated with cognitive impairment in children, yet the neural mechanism underlying this relationship remains poorly understood. To address this issue, this study utilized the data from the Adolescent Brain Cognitive Development (ABCD) study (n = 4930, aged 9-10), involving their sleep assessments, cognitive measures, and functional magnetic resonance imaging (fMRI) during an emotional n-back task. Using partial correlations analysis, we found that the out-of-scanner cognitive performance was positively correlated with sleep duration. Additionally, the activation of regions of interest (ROIs) in frontal and parietal cortices for the 2-back versus 0-back contrast was positively correlated with both sleep duration and cognitive performance. Mediation analysis revealed that this activation significantly mediated the relationship between sleep duration and cognitive function at both individual ROI level and network level. After performing analyses separately for different sexes, it was revealed that the mediation effect of the task-related activation was present in girls (n = 2546). These findings suggest that short sleep duration may lead to deficit in cognitive function of children, particularly in girls, through the modulation of frontoparietal activation during working memory load.

NHE1 Protein in Repetitive Mild TBI-Mediated Neuroinflammation and Neurological Function Impairment.

Mild traumatic brain injuries (mTBIs) are highly prevalent and can lead to chronic behavioral and cognitive deficits often associated with the development of neurodegenerative diseases. Oxidative stress and formation of reactive oxygen species (ROS) have been implicated in mTBI-mediated axonal injury and pathogenesis. However, the underlying mechanisms and contributing factors are not completely understood. In this study, we explore these pathogenic mechanisms utilizing a murine model of repetitive mTBI (r-mTBI) involving five closed-skull concussions in young adult C57BL/6J mice. We observed a significant elevation of Na+/H+ exchanger protein (NHE1) expression in GFAP+ reactive astrocytes, IBA1+ microglia, and OLIG2+ oligodendrocytes across various brain regions (including the cerebral cortex, corpus callosum, and hippocampus) after r-mTBI. This elevation was accompanied by astrogliosis, microgliosis, and the accumulation of amyloid precursor protein (APP). Mice subjected to r-mTBI displayed impaired motor learning and spatial memory. However, post-r-mTBI administration of a potent NHE1 inhibitor, HOE642, attenuated locomotor and cognitive functional deficits as well as pathological signatures of gliosis, oxidative stress, axonal damage, and white matter damage. These findings indicate NHE1 upregulation plays a role in r-mTBI-induced oxidative stress, axonal damage, and gliosis, suggesting NHE1 may be a promising therapeutic target to alleviate mTBI-induced injuries and restore neurological function.

ZBTB21 suppresses CRE-mediated transcription to impair synaptic function in Down syndrome.

Down syndrome (DS) is the most common chromosomal disorder and a major cause of intellectual disability. The genetic etiology of DS is the extra copy of chromosome 21 (HSA21)-encoded genes; however, the contribution of specific HSA21 genes to DS pathogenesis remains largely unknown. Here, we identified ZBTB21, an HSA21-encoded zinc-finger protein, as a transcriptional repressor in the regulation of synaptic function. We found that normalization of the Zbtb21 gene copy number in DS mice corrected deficits in cognitive performance, synaptic function, and gene expression. Moreover, we demonstrated that ZBTB21 binds to canonical cAMP-response element (CRE) DNA and that its binding to CRE could be competitive with CRE-binding factors such as CREB. ZBTB21 represses CRE-dependent gene expression and results in the negative regulation of synaptic plasticity, learning and memory. Together, our results identify ZBTB21 as a CRE-binding protein and repressor in cAMP-dependent gene regulation, contributing to cognitive defects in DS.

Evaluating an Autistic Burnout Measurement in Women.

This study evaluated the suitability of an unpublished autistic burnout assessment tool, focusing on autistic women. Distinguishing autistic burnout from conditions like depression or anxiety is crucial for effective interventions, emphasizing the need for nuanced research and refined measures in understanding and addressing autistic burnout. The Dutch version of the AASPIRE Autistic Burnout Measure (AABM-NL) was evaluated within a sample of 45 autistic women from the Autism Expertise Center. Preliminary findings of the AABM-NL scores demonstrated promising evidence of good internal consistency and convergent validity. Positive associations were observed between AABM-NL scores and a Likert scale assessing identification with autistic burnout, as well as with an instrument measuring physical and psychological complaints (SCL-90-R; Symptom Checklist-90-Revised). Specifically, anxiety, somatization, cognitive-performance deficits, and depression were correlated with the severity of autistic burnout. There was no significant difference between work status and the severity of autistic burnout, implying no employment-related connection. The AABM-NL effectively differentiated between women with and without autistic burnout, with 62 points as a suitable cut-off point. However, these results may not be generalized to women requiring daily living support, individuals beyond outpatient psychiatric settings, or those in institutionalized populations. The preliminary findings provide empirical evidence supporting the use of the AABM-NL as a potential tool for assessing autistic burnout in women receiving outpatient psychiatric care. Its implementation may contribute to programs aimed at recognizing and preventing autistic burnout in women. Further research is needed to enhance intervention strategies for mitigating the risk of autistic burnout.

The impact of COVID-19 post-infection on the cognition of adults from Peru.

The COVID-19 pandemic, with over 83 million confirmed cases and 1.8 million deaths, has raised concerns about long-term cognitive issues, especially in populations facing disparities. Despite a few years since Peru's first COVID-19 wave, the cognitive effects on adults remain unclear. This study is the first in Peru to explore COVID-19's impact on general cognition and executive function. A retrospective cross-sectional study compared individuals with COVID-19 history to controls, assessing general cognition, verbal fluency, attention, and executive function. Among 240 assessed, 154 met the study inclusion criteria, with about 60% female and an average age of 38.89 ± 16.001 years. Groups included controls (n = 42), acute phase (AP, n = 74) (1-14 days of symptoms), and hyperinflammatory phase (HP, n = 38) (>14 days of symptoms). Significant cognitive differences were observed. The HP group exhibited lower general cognitive performance (p = 0.02), working memory (p = 0.01), and executive function (planning; p < 0.001; flexibility; p = 0.03) than controls. Those with <14 days of illness (AP vs. HP) had deficits in general cognitive performance (p = 0.02), working memory (p = 0.02), and planning (p < 0.001), mainly during the hyperinflammatory phase, showing differences in working memory (p = 0.003) and planning (p = 0.01). Gender differences emerged, with males in the HP phase having poorer working memory (p = 0.003) and planning (p = 0.01). This study underscores COVID-19's negative impact on cognitive function, even in mild cases, with potential heightened effects in men during acute or hyperinflammatory phases. The findings provide Peru's first evidence, highlighting the vulnerability of populations facing socioeconomic disparities.

Functional and Structural Cerebellar-Behavior Relationships in Aging.

Healthy aging is associated with deficits in cognitive performance and brain changes, including in the cerebellum. Yet, the precise link between cerebellar function/structure and cognition in aging remains poorly understood. We explored this relationship in 138 healthy adults (aged 35-86, 53% female) using resting-state functional connectivity MRI (fcMRI), cerebellar volume, and cognitive and motor assessments in an aging sample. We expected to find negative relationships between lobular volume for with age, and positive relationships between specific lobular volumes with motor and cognition respectively. We predicted lower cerebellar fcMRI to cortical networks and circuits with increased age. Behaviorally, we expected higher cerebello-frontal fcMRI cerebellar connectivity with association areas to correlate with better behavioral performance. Behavioral tasks broadly assessed attention, processing speed, working memory, episodic memory, and motor abilities. Correlations were conducted between cerebellar lobules I-IV, V, Crus I, Crus II, vermis VI and behavioral measures. We found lower volumes with increased age as well as bidirectional cerebellar connectivity relationships with increased age, consistent with literature on functional connectivity and network segregation in aging. Further, we revealed unique associations for both cerebellar structure and connectivity with comprehensive behavioral measures in a healthy aging population. Our findings underscore cerebellar involvement in behavior during aging.