Impaired Working Memory Research Articles

Behavior, synaptic mitochondria, and microglia are differentially impacted by chronic adolescent stress and repeated endotoxin exposure in male and female rats

Early life adversity and chronic inflammation have both been associated with cognitive impairment and neural compromise. In this study, we investigated the interactions between a history of chronic adolescent stress (CAS) and repeated endotoxin exposure on behavior, synaptic mitochondria, and microglia in adult male and female Wistar rats. Adult rats from chronic stress and control conditions were exposed to either repeated endotoxin (lipopolysaccharide; LPS) or saline injections every 3 days for 9 weeks. In both sexes, repeated LPS, regardless of stress history, impaired working memory in the Y maze. Regarding spatial memory, LPS impaired function for females; whereas, CAS altered function in males. Although males had an increase in anxiety-like behavior shortly after CAS, there were no long-term effects on anxiety-like behavior or social interaction observed in males or females. Stress did not alter synaptic mitochondrial function in either sex. Repeated LPS altered synaptic mitochondrial function such that ATP production was increased in females only. There were no observed increases in IBA-1 positive cells within the hippocampus for either sex. However, LPS and CAS altered microglia morphology in females. Impact of repeated LPS was evident at the terminal endpoint with increased spleen weight in both sexes and decreased adrenal weight in males only. Circulating cytokines were not impacted by repeated LPS at the terminal endpoint, but evidence of CAS effects on cytokines in females were evident. These data suggest a long-term impact of chronic stress and an impact of repeated endotoxin challenge in adulthood; however, not all physiological and behavioral metrics examined were impacted by the paradigm employed in this study and the two environmental challenges rarely interacted.

Negative Symptoms and Their Associations With Other Clinical Variables and Working Memory Across the Schizophrenia Spectrum and Bipolar Disorder.

Negative symptoms (NS) of schizophrenia spectrum disorders (SSD) are also prevalent in bipolar disorder I (BD-I) and show associations with impaired working memory (WM). However, empirical work on their relationship to other clinical factors across SSD and BD-I is sparse. Here, we characterized the associations of NS with key clinical variables and WM capacity across a combined sample of SSD and BD. We included 50 outpatients with SSD and 49 with BD-I and assessed NS domains using SANS global scores for avolition-apathy, anhedonia-asociality, alogia, and blunted affect. We assessed the transdiagnostic relationship between NS and other clinical variables, including positive symptoms, disorganization, depressive symptoms, and antipsychotic medication, using multiple regressions. The strength of these associations was further determined through dominance analyses. Finally, we used multiple regression to assess the relationship between NS domains and WM. To assess the generalizability of transdiagnostic associations, analyses were repeated in each diagnostic group separately. Across SSD and BD-I, disorganization was associated with avolition-apathy and anhedonia-asociality and depressive symptoms additionally predicted anhedonia-asociality. Antipsychotic dose was associated with blunted affect while group differences only predicted alogia. Higher avolition-apathy was related to impaired WM transdiagnostically, partially mediated by the severity of disorganization, whereas only in BD-I higher anhedonia-asociality was associated with better WM capacity. This study demonstrated transdiagnostic associations of both avolition-apathy and anhedonia-asociality with disorganization and identified avolition-apathy as a potential transdiagnostic predictor of WM impairments. Overall, our findings highlight the importance of understanding the relationship between NS domains and other clinical factors with cognitive function across SSD and BD.

Infecção crônica por Toxoplasma gondii está associada à diminuição de desempenho da memória de trabalho em mulheres

Abstract Objective The present study sought to investigate changes in mood, inhibitory control, and working memory associated with T. gondii infection in a sample of Brazilian women. Method Twenty-eight female participants were equally distributed into two groups, according to the serology for chronic infection by T. gondii. The participants answered a Sociodemographic questionnaire, the CES-D, and performed Simon and N-Back tasks. Results Infected participants presented less accuracy and longer response time in N-Back tasks. No significant differences were found in the Simon task performance or in the depression levels. Conclusion Our findings suggest that chronic infection by T. gondii may result in impaired working memory and point out the importance of public policies aiming at preventing this infection.

Evolving trends in neuropsychological profiles of post COVID-19 condition: A 1-year follow-up in individuals with cognitive complaints.

Cognitive difficulties are reported as lasting sequelae within post COVID-19 condition. However, the chronicity of these difficulties and related factors of fatigue, mood, and perceived health have yet to be fully determined. To address this, the current longitudinal study aimed to clarify the trends of cognitive test performance and cognitive domain impairment following COVID-19 onset, and whether hospitalization influences outcomes. 57 participants who reported subjective cognitive difficulties after confirmed COVID-19 infection were assessed at baseline (~6 months post COVID-19) and follow-up (~15 months later) visits. Assessments included measures across multiple cognitive domains and self-report questionnaires of fatigue, mood, and overall health. Analyses were conducted in three stages: at the test score level (raw and adjusted scores), at the cognitive domain level, and stratified by hospitalization status during infection. Results at the test-score level indicate that cognitive performance remains relatively stable across assessments at the group level, with no significant improvements in any adjusted test scores at follow-up. Cognitive domain analyses indicate significant reductions in attention and executive functioning impairment, while memory impairment is slower to resolve. On self-report measures, there was a significant improvement in overall health ratings at follow-up. Finally, those hospitalized during infection performed worse on timed cognitive measures across visits and accounted for a larger proportion of cases with short-term and working memory impairment at follow-up. Overall, our findings indicate that cognitive difficulties persist both at test score and cognitive domain levels in many cases of post COVID-19 condition, but evidence suggests some improvement in global measures of attention, executive functioning and overall self-rated health. Furthermore, an effect of hospitalization on cognitive symptoms post COVID-19 may be more discernible over time.

Relationship of prefrontal cortex activity with anhedonia and cognitive function in major depressive disorder: an fNIRS study.

Major depressive disorder (MDD) is associated with deficits in cognitive function, thought to be related to underlying decreased hedonic experiences. Further research is needed to fully elucidate the role of functional brain activity in this relationship. In this study, we investigated the neurofunctional correlate of the interplay between cognitive function and hedonic experiences in medication-free MDD using functional near-infrared spectroscopy (fNIRS). We examine differences of brain activation corresponding to the verbal fluency test (VFT) between MDD patients and healthy controls (HCs). Fifty-six MDD patients and 35 HCs underwent fMRI scanning while performing the VFT. In exploratory analyses, cognitive performance, as assessed by the Cambridge Neuropsychological Test Automated Battery (CANTAB), four dimensions of hedonic processing (desire, motivation, effort, and consummatory pleasure) measured by the Dimensional Anhedonia Rating Scale (DARS), and relative changes in oxygenated hemoglobin concentration during the VFT were compared across groups. Patients with MDD demonstrated impairments in sustained attention and working memory, accompanied by lower total and subscale scores on the DARS. Compared to healthy controls, MDD patients exhibited reduced activation in the prefrontal cortex (PFC) during the VFT task (t = 2.32 to 4.77, p < 0.001 to 0.02, FDR corrected). DARS motivation, desire, and total scores as well as sustained attention, were positively correlated with activation in the dorsolateral PFC and Broca's area (p < 0.05, FDR corrected). These findings indicate that changes in prefrontal lobe oxygenated hemoglobin levels, a region implicated in hedonic motivation and cognitive function, may serve as potential biomarkers for interventions targeting individuals with MDD. Our results corroborate the clinical consensus that the prefrontal cortex is a primary target for non-invasive neuromodulatory treatments for depression.

The effects of standardized cannabis products in healthy volunteers and patients: a systematic literature review.

There is growing recognition of the potential of cannabis to treat various medical conditions and symptoms, such as chronic pain, spasticity, and epilepsy. However, one of the biggest challenges is the assurance of a standardized cannabis product that contains a consistent amount of its main psychoactive substances delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), and which is compliant with predetermined specifications for these compounds. This is crucial not only to ensure consistent cannabis quality and dosage for patients but also to effectively translate research findings into clinical practice. This systematic literature review provides an overview of the effects of standardized cannabis products from Bedrocan, a leading Dutch producer of pharmaceutical-quality standardized medicinal cannabis. Cannabis administration to healthy volunteers induces dose-dependent acute effects, such as rapidly rising THC and CBD blood concentrations, the subjective experience of high and anxiety, slower reaction time and impaired attention, learning and working memory. Patient studies suggest that treatment with medicinal cannabis reduces pain intensity across a broad range of chronic pain-related medical conditions. Medicinal cannabis showed a mild safety profile, with minor and transient side effects, such as feeling high, coughing and mental confusion. The strength of acute effects, the experience of side effects and the drop-out rate in patient studies may depend on cannabis dose, cannabis composition (CBD:THC ratio), and cannabis use history of participants. Safety and efficacy of standardized medicinal cannabis products should be further investigated in randomized clinical trials with sufficient sample size, with particular focus on cannabis dose and composition, age and differences between males and females.

Behavioral and histological analyses of the mouse Bassoon p.P3882A mutation corresponding to the human BSN p.P3866A mutation.

Tauopathy is known to be a major pathognomonic finding in important neurodegenerative diseases such as progressive supranuclear palsy (PSP) and corticobasal degeneration. However, the mechanism by which tauopathy is triggered remains to be elucidated. We previously identified the point mutation c.11596C > G, p.Pro3866Ala in the Bassoon gene (BSN) in a Japanese family with PSP-like syndrome. We showed that mutated BSN may have been involved in its own insolubilization and tau accumulation. Furthermore, BSN mutations have also been related to various neurological diseases. In order to further investigate the pathophysiology of BSN mutation in detail, it is essential to study it in mouse models. We generated a mouse model with the mouse Bassoon p.P3882A mutation, which corresponds to the human BSN p.P3866A mutation, knock-in (KI) and we performed systematic behavioral and histological analyses. Behavioral analyses revealed impaired working memory in a Y-maze test at 3 months of age and decreased locomotor activity in the home cage at 3 and 12 months of age in KI mice compared to those in wild-type mice. Although no obvious structural abnormalities were observed at 3 months of age, immunohistochemical studies showed elevation of Bsn immunoreactivity in the hippocampus and neuronal loss without tau accumulation in the substantia nigra at 12 months of age in KI mice. Although our mice model did not show progressive cognitive dysfunction and locomotor disorder like PSP-like syndrome, dopaminergic neuronal loss was observed in the substantia nigra in 12-month-old KI mice. It is possible that BSN mutation may result in dopaminergic neuronal loss without locomotor symptoms due to the early disease stage. Thus, further clinical course can induce cognitive dysfunction and locomotor symptoms.

Sildenafil prevents chronic psychosocial stress-induced working memory impairment: Role of brain-derived neurotrophic factor

BackgroundPsychosocial stress, a common feature in modern societies, impairs cognitive functions. It is suggested that stress hormones and elevated excitatory amino acids during stress are responsible for stress-induced cognitive deficits. Reduced brain-derived neurotrophic factor (BDNF) levels, increased oxidative stress, and alteration of synaptic plasticity biomarkers are also possible contributors to the negative impact of stress on learning and memory. Sildenafil citrate is a selective phosphodiesterase type 5 (PDE5) inhibitor and the first oral therapy for the treatment of erectile dysfunction. It has been shown that sildenafil improves learning and memory and possesses antioxidant properties. We hypothesized that administering sildenafil to stressed rats prevents the cognitive deficit induced by chronic psychosocial stress. MethodsPsychosocial stress was generated using the intruder model. Sildenafil 3 mg/kg/day was administered intraperitoneally to animals. Behavioral studies were conducted to test spatial learning and memory using the radial arm water maze. Then, the hippocampal BDNF level and several antioxidant markers were assessed. ResultsThis study revealed that chronic psychosocial stress impaired short-term but not long-term memory. The administration of sildenafil prevented this short-term memory impairment. Chronic psychosocial stress markedly reduced the level of hippocampal BDNF (P˂0.05), and this reduction in BDNF was normalized by sildenafil treatment. In addition, neither chronic psychosocial stress nor sildenafil significantly altered the activity of measured oxidative parameters (P > 0.05). ConclusionChronic psychosocial stress induces short-term memory impairment. The administration of sildenafil citrate prevented this impairment, possibly by normalizing the level of BDNF.

Five Digit Test in neuropsychological assessment of working memory in aged individuals:normative data.

To provide validity evidence for FDT in the neuropsychological assessment of working memory in the aged. A total of 100 subjects, aged between 56 and 86 years, representing both genders with varying levels of education, underwent a comprehensive clinical history and neuropsychological evaluation using FDT. The mean age of participants was 71.04 years, with 67.3% having intermediate education. Participants were categorized into two groups: Control Group and Cognitive Decline Group. To establish validity evidence, FDT scores (both time and errors) were correlated with the WAIS-III Digits scale. Spearman's correlation coefficient and ROC curve methodology were employed to determine psychometric properties. A significant and moderate negative correlation was evident between FDT Shifting (number of errors) and Digits score (rho=-0.51; p<0.0001), Direct Order (rho=-0.39; p<0.0001), and Indirect Order (rho=-0.46; p<0.0001). The area under the curve was higher for FDT Shifting (errors) (AUC=0.935) for a cutoff point greater than or equal to 5 points, compared to Digits (AUC=0.748). The assessment of the number of errors in FDT Shifting appears to be a statistically significant tool for evaluating working memory impairment in the aged.

The neural substrates of transdiagnostic cognitive-linguistic heterogeneity in primary progressive aphasia

BackgroundClinical variants of primary progressive aphasia (PPA) are diagnosed based on characteristic patterns of language deficits, supported by corresponding neural changes on brain imaging. However, there is (i) considerable phenotypic variability within and between each diagnostic category with partially overlapping profiles of language performance between variants and (ii) accompanying non-linguistic cognitive impairments that may be independent of aphasia magnitude and disease severity. The neurobiological basis of this cognitive-linguistic heterogeneity remains unclear. Understanding the relationship between these variables would improve PPA clinical/research characterisation and strengthen clinical trial and symptomatic treatment design. We address these knowledge gaps using a data-driven transdiagnostic approach to chart cognitive-linguistic differences and their associations with grey/white matter degeneration across multiple PPA variants.MethodsForty-seven patients (13 semantic, 15 non-fluent, and 19 logopenic variant PPA) underwent assessment of general cognition, errors on language performance, and structural and diffusion magnetic resonance imaging to index whole-brain grey and white matter changes. Behavioural data were entered into varimax-rotated principal component analyses to derive orthogonal dimensions explaining the majority of cognitive variance. To uncover neural correlates of cognitive heterogeneity, derived components were used as covariates in neuroimaging analyses of grey matter (voxel-based morphometry) and white matter (network-based statistics of structural connectomes).ResultsFour behavioural components emerged: general cognition, semantic memory, working memory, and motor speech/phonology. Performance patterns on the latter three principal components were in keeping with each variant’s characteristic profile, but with a spectrum rather than categorical distribution across the cohort. General cognitive changes were most marked in logopenic variant PPA. Regardless of clinical diagnosis, general cognitive impairment was associated with inferior/posterior parietal grey/white matter involvement, semantic memory deficits with bilateral anterior temporal grey/white matter changes, working memory impairment with temporoparietal and frontostriatal grey/white matter involvement, and motor speech/phonology deficits with inferior/middle frontal grey matter alterations.ConclusionsCognitive-linguistic heterogeneity in PPA closely relates to individual-level variations on multiple behavioural dimensions and grey/white matter degeneration of regions within and beyond the language network. We further show that employment of transdiagnostic approaches may help to understand clinical symptom boundaries and reveal clinical and neural profiles that are shared across categorically defined variants of PPA.

Frontal lobe epilepsy: an eye tracking study of memory and attention.

To explore the characteristics and mechanisms of working memory impairment in patients with frontal lobe epilepsy (FLE) through a memory game paradigm combined with eye tracking technology. We included 44 patients with FLE and 50 healthy controls (HC). All participants completed a series of neuropsychological scale assessments and a short-term memory game on an automated computer-based memory evaluation platform with an eye tracker. Memory scale scores of FLE patients including digit span (U = 747.50, p = 0.007), visual recognition (U = 766.50, p = 0.010), and logical memory (U = 544.00, p < 0.001) were significantly lower than HC. The patients with FLE took longer to complete the four levels of difficulty of the short-term memory game than healthy controls (level 1: U = 2974.50, p = 0.000; level 2: U = 3060.50, p = 0.000; level 3: U = 2465.00, p = 0.000; level 4: U = 2199.00, p = 0.000). During the memory decoding period, first fixation on the targets took significantly longer for FLE patients for all difficulty levels compared to controls (level 1: U = 3407.00, p = 0.008; level 2: U = 3618.00, p = 0.036; level 3: U = 3345.00, p = 0.006; level 4: U = 2781.00, p = 0.000). The average fixation duration per target among patients with FLE was found to be significantly longer compared to HC (level 1: U = 2994.50, p = 0.000; level 2: U = 3101.00, p = 0.000; level 3: U = 2559.50, p = 0.000; level 4: U = 2184.50, p = 0.000). The total fixation duration on AOI/total completion time of FLE patients was significantly lower than those of HC for levels 1 to 3 (level 1: U = 1557.00, p = 0.000; level 2: U = 2333.00, p = 0.000; level 3: U = 2757.00, p = 0.000). Furthermore, the eye tracking data during the memory decoding phase were correlated with neuropsychological scale scores (p < 0.05). Patients with FLE exhibited short-term memory impairment probably due to deficits in attentional maintenance, especially during the memory decoding phase. Eye tracking technology provided the possibility to help separate and quantify visual attention from memory processing, contributing to exploring underlying mechanisms of memory impairment in FLE.

Perseverations and switching during a verbal fluency task

AbstractBackgroundPerseverations during a verbal fluency task can be immediate or delayed. There is a general agreement that delayed perseveration may occur due to impaired working memory (WM). However, experiments to establish this have been complex and time consuming. It is also not known if perseverations are caused by similar mechanisms of impairment in WM in healthy controls and in the cognitively impaired. On a semantic fluency task, switching between subcategories produces an automatic self‐generated interference. Impairment in WM capacity may lead to perseveration when switchback to a previous subcategory occurs. The number of switches preceding this switchback may also be considered to extend the WM load and result in perseveration. We hypothesize that individuals with WM impairment (aMCI and AD) are likely to perseverate only after few initial switches. In contrast, a healthy control (HC), with a relatively intact WM, may have fewer perseverations for similar number of switches and may be able to sustain more switches quantitatively.ObjectiveTo study how clusters and switches during verbal fluency tasks can help understand WM contributions to perseveration in patients with cognitive impairment as opposed to cognitively normal controls.MethodWe studied three groups, aMCI (n = 30), AD (n = 30) and HC (n = 60) based on their performance on a semantic fluency task along with tests of executive function. Our primary analysis, focussed on number of switches in between subcategories of index word and first perseverative error. Additionally, average word distance between the two was analysed. Finally, relationship between perseveration, switching and switch back was also studied.ResultsForty‐eight percent of perseverative errors occurred after the third switch for individuals with cognitive decline. In contrast, thirty‐five percent of cognitively healthy perseverated after three switches and forty‐three percent after five. Further, perseverations in HC group, were found to be more attributable to longer subcategory lists exceeding the normal word list span, even within the same cluster. Finally, at a given distance between index word and perseveration, cognitively impaired performed hierarchically worse than HC.ConclusionThese findings suggest that switching across subcategories creates self‐generated interference which further amplifies working memory impairment among the cognitively impaired.

Sex‐specific impact of brain estrogen deficiency on astrocyte reactivity, neurodegeneration, and memory loss in aromatase knockout mouse models

AbstractBackgroundNearly two‐thirds of Americans with Alzheimer’s disease (AD) are women, however, the molecular mechanisms underlying this sex difference in AD vulnerability remain unclear. Prior research has reported that women with AD have lower brain estrogen. Yet, how estrogen deficiency modulates this sex difference in AD is not well understood. Aromatase, the key enzyme for estrogen biosynthesis, is expressed in both neurons and astrocytes of the brain, with high levels in the hippocampus. To explore the underlying mechanism of estrogen deficiency in sex‐specific AD vulnerability, we generated mouse models with brain‐specific aromatase knockout (bArKO) and whole‐body total aromatase knockout (tArKO).MethodWe performed a series of memory and behavior tests including spontaneous alternation, social interaction, and tail suspension tests on 6‐ and 19‐month‐old bArKO and tArKO mice with both sexes (n = 10/group). Hippocampus tissues from these mice (n = 3∼4) were collected for bulk RNA‐seq and qPCR. Brain tissues (n = 5) were fixed and stained for astrocytes and neurons by immunofluorescence. Serum and tissue estrogen were measured using liquid chromatography‐mass spectrometry.ResultAromatase deletion decreased brain estrogen levels in bArKO mice and circulating and brain estrogen levels in tArKO mice. Impairments of spatial working memory and social interaction behavior were found in 19‐month‐old female bArKO and tArKO mice. Female tArKO mice also displayed depression‐like behavior at 6‐ and 19‐month‐old. The number of neurons in the CA1 region was significantly decreased in 19‐month‐old female (but not male) tArKO mice. Bulk RNA‐seq showed abnormal expression of genes associated with astrocyte reactivity (e.g., Gfap, Ctgf, Apoe, Lcn2, Sparc, Bdnf, Col1a1, Col1a2) only in aged female bArKO mice. Given growing evidence indicating a causal relationship between neurotoxic reactive astrocytes and neurodegeneration, this finding indicates brain estrogen deficiency triggering neurotoxic astrocyte reactivity in the hippocampus of aged female bArKO mice.ConclusionOur findings provide novel mechanisms that link estrogen deficiency to sex‐specific astrocyte reactivity in the hippocampus, and neurodegeneration and memory loss in aged female mice. Future studies will focus on defining impact of estrogen signaling deficiency on AD mouse models and identifying druggable targets to inform the development of new therapeutic strategies for the prevention and treatment of AD.

Basic Science and Pathogenesis - Part 2.

Traumatic Brain Injury (TBI) is a known risk factor for developing a neurodegenerative disease later in life, including Alzheimer's Disease (AD) and other forms of tauopathy such as chronic traumatic encephalopathy (CTE) and frontal-temporal dementia (FTD). Although several studies highlight the relationship between the severity and frequency of a TBI and the development of these tauopathies, the mechanism behind this association remains unknown. Proper meningeal lymphatic function is required for clearance of waste products and protein aggregates such as amyloid beta and tau from the brain parenchyma. While post-TBI inflammation is beneficial for clearing debris and promoting tissue repair, prolonged glial activation and decreased meningeal lymphatic drainage have been linked to worsened cognitive function. A mild TBI (mTBI) was delivered to three-month-old young adult mice overexpressing P301S mutant human tau (PS19) through the skull on the right inferior temporal lobe of the brain. Sham and TBI injured mice were tested on behavioral tests at 5 months of age. At 7 months of age, brains were examined for tau pathology and neuroinflammation using confocal microscopy. Four months after mTBI, the brains of TBI PS19 mice exhibit increased levels of microglia and astrocytes, and increased P-S202/T-205-Tau in the cortex and thalamus of the ipsilateral hemisphere compared to the contralateral side and to Sham PS19 controls. These findings correlate with our behavior study showing increased hyperactivity, risk-taking behavior, and impaired short term working memory. PS19 TBI mice also present larger ventricles than their uninjured controls suggesting a potential loss of white matter in the cortex and/or hippocampus. P-S202/T-205-Tau orginated from the cortex near the injury site can aggregate and promote the formation of more toxic tau that spreads to deeper regions of the cortex and in the thalamus primarily through the thalamocortical circuit. Also, microglia and astrocyte activation and production of inflammatory mediators has been associated with synapse pruning and engulfment of damaged neurons expressing 'eat me signals' leading to neurodegeneration.

The dynamics of auditory working memory impairment in logopenic aphasia and Alzheimer’s disease

AbstractBackgroundImpaired auditory verbal working memory is a diagnostic hallmark and integral driver of the clinical phenotype in logopenic aphasia. However, the physiology of the working memory buffer in this syndrome is poorly characterised. Here we addressed the temporal dynamics of auditory verbal working memory in patients with logopenic aphasia and typical Alzheimer’s disease.MethodIn a cohort of patients with logopenic aphasia and typical Alzheimer’s disease and in healthy age‐matched controls, we assessed how temporal manipulations of standard auditory verbal working memory tasks (forward and reverse digit span and phrasal repetition) affected performance. We varied tempo of delivery and inter‐trial gap and performed a detailed analysis of error types. Participants also had pure tone audiometry to assess peripheral hearing function and a comprehensive general neuropsychological assessment.ResultCompared with healthy controls, patients with logopenic aphasia and Alzheimer’s disease showed increased sensitivity to temporal manipulation of auditory verbal working memory tasks and error profiles suggesting a dynamic physiological lesion of the working memory buffer. These effects were particularly marked in the logopenic group.ConclusionOur findings open a novel physiological window on working memory dynamics in Alzheimer’s disease syndromes. Further work is warranted to assess how this dynamic deficit impacts communication in patients’ daily lives, how it can best inform management interventions and its potential as a novel, rapid read‐out of neural function in the era of disease‐modifying therapies.

Effect of photobiological modulation therapy on cognitive impairment and cardiovascular structure in an APP/PS1 mouse model of Alzheimer’s Disease

AbstractBackgroundPhotobiological modulation (PBM) therapy, a form of low‐dose light therapy, is beneficial in treating various disease conditions including Alzheimer’s disease (AD). Double‐transgenic mice (APPswe/PS1dE9) develop progressive accumulation of amyloid‐β (Aβ) plaques, cognitive impairment, and alterations in cardiovascular structure and function, and represent a model of AD. Prior studies have shown that PBM therapy reduces the size and number of Aβ plaques in the neocortex and hippocampus in the mouse models of AD. The aim of this study was to investigate the effects of PBM on cardiovascular structure and function and cognitive function in the aged AD mice.MethodsSix‐month old female AD (APPswe/PS1dE9; AD‐PBM, n = 8) and wild type mice (WT‐PBM, n = 8) were exposed to near‐infrared light (wavelength 850 nm, 4.5 J/cm2, 3min/day, 5 days/week) for 6 months. Control mice (AD‐CNT, n = 6; WT‐CNT, n = 6) were placed under the PBM apparatus without turning the light on for 3min/day, 5 days/week. Cardiac parameters were measured by echocardiography. Gait analysis (DigiGait), home cage activity (HCA), and spatial working memory (indicated by alternation rate in cross maze test, CM) were assessed after 6 months of treatment. Group differences were identified by two‐way ANOVA.ResultsIn HCA test, the AD‐CNT mice exhibited circadian locomotor hyperactivity at night‐time relative to WT‐CNT mice (Figure 1A, B), which was reduced by PBM. AD‐CNT mice had lower alternation rates in CM, indicating spatial working memory impairment. PBM had minimal effect on this parameter (Table 1). The AD‐CNT vs. WT‐CNT mice manifested differences in several gait parameters, specifically, they demonstrated a lower fore propel time than WT‐CNT. PBM normalized this parameter in AD‐PBM mice to the level of WT‐CNT (Figure 1C). Both WT‐PBM and AD‐PBM mice had improved cardiovascular structure, which was demonstrated by lower relative wall thickness of left ventricle (LV) and LV mass, and higher LV volume at the end of diastole in PBM‐treated vs. correspondent CNT groups (Table 1, Figure 2).ConclusionPBM improved cardiovascular structure and AD‐associated cognitive impairment in the APP/PS1 mouse model. It is possible that more effective cardiovascular structure and function contributes to Aβ removal from the brain after PBM treatment. Supported by NIA/NIH/IRP

Do non-traumatic stressful life events and ageing negatively impact working memory performance and do they interact to further impair working memory performance?

Stress and normal ageing produce allostatic load, which may lead to difficulties with cognition thereby degrading quality of life. The current study's objective was to assess whether ageing and cumulative stress interact to accelerate cognitive decline. With 60 participants, Marshall et al. found that ageing and cumulative stress interact significantly to impair working memory performance in older adults, suggesting vulnerability to the cumulative effects of life events beyond 60 years old. To replicate and extend this finding, we increased the sample size by conducting 3 independent studies with 156 participants and improved the statistical methods by conducting an iterative Bayesian meta-analysis with Bayes factors. Bayes factors deliver a more comprehensive result because they provide evidence for either the null hypothesis (H0), the alternative hypothesis (H1) or for neither hypothesis due to evidence not being sufficiently sensitive. Young (18-35 yrs) and older (60-85 yrs) healthy adults were categorised as high or low stress based on their life events score derived from the Life Events Scale for Students or Social Readjustment Rating Scale, respectively. We measured accuracy and reaction time on a 2-back working memory task to provide: a) Bayes factors and b) Bayesian meta-analysis, which iteratively added each study's effect sizes to evaluate the overall strength of evidence that ageing, cumulative stress and/or the combination of the two detrimentally affect working memory performance. Using a larger sample (N = 156 vs. N = 60) and a more powerful statistical approach, we did not replicate the robust age by cumulative stress interaction effect found by Marshall et al.. The effects of ageing and cumulative stress also fell within the anecdotal range (⅓<BF<3). We therefore conclude that there was inconclusive statistical evidence, as measured with a life events scale, that ageing and cumulative life stress interact to accelerate cognitive decline.

Intermittent hypoxia training effectively protects against cognitive decline caused by acute hypoxia exposure.

Intermittent hypoxia training (IHT) is a promising approach that has been used to induce acclimatization to hypoxia and subsequently lower the risk of developing acute mountain sickness (AMS). However, the effects of IHT on cognitive and cerebrovascular function after acute hypoxia exposure have not been characterized. In the present study, we first confirmed that the simplified IHT paradigm was effective at relieving AMS at 4300m. Second, we found that IHT improved participants' cognitive and neural alterations when they were exposed to hypoxia. Specifically, impaired working memory performance, decreased conflict control function, impaired cognitive control, and aggravated mental fatigue induced by acute hypoxia exposure were significantly alleviated in the IHT group. Furthermore, a reversal of brain swelling induced by acute hypoxia exposure was visualized in the IHT group using magnetic resonance imaging. An increase in cerebral blood flow (CBF) was observed in multiple brain regions of the IHT group after hypoxia exposure as compared with the control group. Based on these findings, the simplified IHT paradigm might facilitate hypoxia acclimatization, alleviate AMS symptoms, and increase CBF in multiple brain regions, thus ameliorating brain swelling and cognitive dysfunction.

Interactions between functional networks in Parkinson's disease mild cognitive impairment

The study of mild cognitive impairment (MCI) is critical to understand the underlying processes of cognitive decline in Parkinson’s disease (PD). Functional connectivity (FC) disruptions in PD-MCI patients have been observed in several networks. However, the functional and cognitive changes associated with the disruptions observed in these networks are still unclear. Using a data-driven methodology based on independent component analysis, we examined differences in FC RSNs among PD-MCI, PD cognitively normal patients (PD-CN) and healthy controls (HC) and studied their associations with cognitive and motor variables. A significant difference was found between PD-MCI vs PD-CN and HC in a FC-trait comprising sensorimotor (SMN), dorsal attention (DAN), ventral attention (VAN) and frontoparietal (FPN) networks. This FC-trait was associated with working memory, memory and the UPDRS motor scale. SMN involvement in verbal memory recall may be related with the FC-trait correlation with memory deficits. Meanwhile, working memory impairment may be reflected in the DAN, VAN and FPN interconnectivity disruptions with the SMN. Furthermore, interactions between the SMN and the DAN, VAN and FPN network reflect the intertwined decline of motor and cognitive abilities in PD-MCI. Our findings suggest that the memory impairments observed in PD-MCI are associated with reduced FC within the SMN and between SMN and attention networks.

A Molecular Framework for Delirium.

Over 2.6 million adults over the age of 65 develop delirium each year in the United States (US). Delirium is associated with a significant increase in mortality and the US health care costs associated with delirium are estimated at over $164 billion annually. Despite the prevalence of the condition, the molecular pathophysiology of delirium remains unexplained, limiting the development of pharmacotherapies. Delirious patients can be identified by prominent impairments in attention and working memory (WM), two cognitive domains that localize to the dorsolateral prefrontal cortex (dlPFC). The dlPFC is also a key site for Alzheimer's disease (AD) pathology, and given the high risk of delirium in AD patients, suggests that efforts at understanding delirium might focus on the dlPFC as a final common endpoint for cognitive changes. Preclinical studies of the dlPFC reproduce many of the pharmacological observations made of delirious patients, including sensitivity to anticholinergics and an 'inverted U' pattern of dependence on monoaminergic input, with diminished performance outside a narrow range of signaling. Medications like guanfacine, which influence the dlPFC in the context of attention-deficit/hyperactivity disorder (ADHD), have emerged as therapies for delirium and motivate a detailed understanding of the influence of α-2 agonists on WM. In this review, I will discuss the neural circuitry and molecular mechanisms underlying WM and the function of the dlPFC. Localizing the cognitive deficits that are commonly seen in delirious patients may help identify new molecular targets for this highly prevalent disease.