Long-term Cognitive Function Research Articles

Evaluation of the South Korean national long-term care insurance-funded cognitive function training programme for older people with mild dementia.

despite the extensive literature on the effectiveness of cognitive training, its effectiveness has not been demonstrated within a population-based long-term care system. To provide cognitive training services to older people with mild dementia, Korea introduced a special dementia rating, as a long-term care grades, in the national long-term care insurance in July 2014. These services are only offered to those with the special dementia rating. This study evaluated the national long-term care insurance-funded cognitive function training programme for older people with mild dementia. data were derived from the Korean National Health Insurance Elderly Cohort database between 2008 and 2015. We compared changes in function between the intervention (n = 352) and control (n = 1952) groups before (2014) and after (2015) introduction of the cognitive function training programme. Difference-in-differences analysis was performed, to compare changes in each score between the intervention and control groups before and after introduction of the cognitive function training programme. introduction of the cognitive function training programme was associated with significantly less cognitive function decline in the intervention group than in the control groups (β = -3.39; standard errors [SE] = 1.14; P = 0.003). A subgroup analysis revealed that this effect increased in subjects in the youngest group, low income bracket, who had a primary caregiver, who were supported in multiple activities of daily living by the primary caregiver, or who were not living alone. introduction of the cognitive function training programme was associated with positive effects on cognitive function.

Both GSK-3β/CRMP2 and CDK5/CRMP2 Pathways Participate in the Protection of Dexmedetomidine Against Propofol-Induced Learning and Memory Impairment in Neonatal Rats.

Dexmedetomidine has been reported to ameliorate propofol-induced neurotoxicity in neonatal animals. However, the underlying mechanism is still undetermined. Glycogen synthase kinase-3β (GSK-3β), cycline-dependent kinase-5 (CDK5), and Rho-kinase (RhoA) pathways play critical roles in neuronal development. The present study is to investigate whether GSK-3β, CDK5, and RhoA pathways are involved in the neuroprotection of dexmedetomidine. Seven-day-old (P7) Sprague Dawley rats were anesthetized with propofol for 6 h. Dexmedetomidine at various concentrations were administered before propofol exposure. Neuroapoptosis, the neuronal proliferation, and the level of neurotransmitter in the hippocampus were evaluated. The effects of GSK-3β inhibitor SB415286, CDK5 inhibitor roscovitine, or RhoA inhibitor Y276321 on propofol-induced neurotoxicity were assessed. Propofol-induced apoptosis in the hippocampal neurons and astrocytes, inhibited neuronal proliferation in the dentate gyrus region, down-regulated the level of γ-aminobutyric acid and glutamate in the hippocampus, and impaired long-term cognitive function. These harmful effects were reduced by pretreatment with 50 μg·kg-1 dexmedetomidine. Moreover, propofol-activated GSK-3β and CDK5 pathways, but not RhoA pathway, by reducing the phosphorylation of GSK-3β (ser 9), increasing the expression of CDK5 activator P25 and increasing the phosphorylation of their target sites on collapsin response mediator protein 2 (CRMP2) shortly after exposure. These effects were reversed by pretreatment with 50 μg·kg-1 dexmedetomidine. Furthermore, SB415286 and roscovitine, not Y276321, attenuated the propofol-induced neuroapoptosis, brain cell proliferation inhibition, γ-aminobutyric acid and glutamate downregulation, and learning and memory dysfunction. Our results indicate that dexmedetomidine reduces propofol-induced neurotoxicity and neurocognitive impairment via inhibiting activation of GSK-3β/CRMP2 and CDK5/CRMP2 pathways in the hippocampus of neonatal rats.

Xenon improves long-term cognitive function, reduces neuronal loss and chronic neuroinflammation, and improves survival after traumatic brain injury in mice

BackgroundXenon is a noble gas with neuroprotective properties that can improve short and long-term outcomes in young adult mice after controlled cortical impact. This follow-up study investigates the effects of xenon on very long-term outcomes and survival. MethodsC57BL/6N young adult male mice (n=72) received single controlled cortical impact or sham surgery and were treated with either xenon (75% Xe:25% O2) or control gas (75% N2:25% O2). Outcomes measured were: (i) 24 h lesion volume and neurological outcome score; (ii) contextual fear conditioning at 2 weeks and 20 months; (iii) corpus callosum white matter quantification; (iv) immunohistological assessment of neuroinflammation and neuronal loss; and (v) long-term survival. ResultsXenon treatment significantly reduced secondary injury (P<0.05), improved short-term vestibulomotor function (P<0.01), and prevented development of very late-onset traumatic brain injury (TBI)-related memory deficits. Xenon treatment reduced white matter loss in the contralateral corpus callosum and neuronal loss in the contralateral hippocampal CA1 and dentate gyrus areas at 20 months. Xenon's long-term neuroprotective effects were associated with a significant (P<0.05) reduction in neuroinflammation in multiple brain areas involved in associative memory, including reduction in reactive astrogliosis and microglial cell proliferation. Survival was improved significantly (P<0.05) in xenon-treated animals compared with untreated animals up to 12 months after injury. ConclusionsXenon treatment after TBI results in very long-term improvements in clinically relevant outcomes and survival. Our findings support the idea that xenon treatment shortly after TBI may have long-term benefits in the treatment of brain trauma patients.

The p75 Neurotrophin Receptor Is an Essential Mediator of Impairments in Hippocampal-Dependent Associative Plasticity and Memory Induced by Sleep Deprivation.

Sleep deprivation (SD) interferes with hippocampal structural and functional plasticity, formation of long-term memory and cognitive function. The molecular mechanisms underlying these effects are incompletely understood. Here, we show that SD impaired synaptic tagging and capture and behavioral tagging, two major mechanisms of associative learning and memory. Strikingly, mutant male mice lacking the p75 neurotrophin receptor (p75NTR) were resistant to the detrimental effects of SD on hippocampal plasticity at both cellular and behavioral levels. Mechanistically, SD increased p75NTR expression and its interaction with phosphodiesterase. p75NTR deletion preserved hippocampal structural and functional plasticity by preventing SD-mediated effects on hippocampal cAMP-CREB-BDNF, cAMP-PKA-LIMK1-cofilin, and RhoA-ROCK2 pathways. Our study identifies p75NTR as an important mediator of hippocampal structural and functional changes associated with SD, and suggests that targeting p75NTR could be a promising strategy to limit the memory and cognitive deficits that accompany sleep loss.SIGNIFICANCE STATEMENT The lack of sufficient sleep is a major health concern in today's world. Sleep deprivation (SD) affects cognitive functions such as memory. We have investigated how associative memory mechanisms, synaptic tagging and capture (STC), was impaired in SD mice at cellular and behavioral level. Interestingly, mutant male mice that lacked the p75 neurotrophin receptor (p75NTR) were seen to be resistant to the SD-induced impairments in hippocampal synaptic plasticity and STC. Additionally, we elucidated the molecular pathways responsible for this rescue of plasticity in the mutant mice. Our study has thus identified p75NTR as a promising target to limit the cognitive deficits associated with SD.

Clinical study on the factors associated with long-term cognitive function in patients with sepsis

To investigate the occurrence and influencing factors of long-term cognitive impairment in patients with sepsis. The septic patients admitted to intensive care unit (ICU) of Tianjin Third Central Hospital from July 2014 to September 2017 were enrolled. Montreal cognitive assessment scale (MoCA) was used to assess the cognitive function of patients at 3, 12 and 24 months after discharge from hospital. The patients were divided into cognitive impairment group (MoCA score < 26) and normal cognitive function group (MoCA score ≥ 26) according to the MoCA scores at 12 months after discharge from hospital. The basic characteristics and clinical data were recorded in both groups, the variables with statistical significance in univariate analysis were enrolled in bivariate Logistic regression analysis, and the influencing factors of cognitive impairment in patients with sepsis were screened. During the study period, 1 748 patients with sepsis were admitted, 210 survived and discharged, and 125 patients participated in the follow-up. Cognitive impairment occurred in 61.6% (77/125), 54.4% (56/103) and 54.2% (39/72) of the septic patients at 3, 12 and 24 months after discharge, respectively. The MoCA score of 103 patients who completed 12-month follow-up was significantly higher than that of 3-month follow-up (23.4±5.7 vs. 23.0±6.0, P < 0.01); the MoCA score of 72 patients who completed 24-month follow-up was only slightly lower than that of 12-month follow-up (23.6±5.4 vs. 23.7±5.0, P > 0.05). Following up for 12 months, 47 patients were enrolled in the normal cognitive function group and 56 in the cognitive impairment group. Compared with the normal cognitive function group, the cognitive dysfunction group had more female [51.8% (29/56) vs. 31.9% (15/47)] and older patients (years old: 66.1±15.9 vs. 52.4±18.9), also had shorter time to receive education (years: 7.6±4.0 vs. 11.2±3.1), longer duration of delirium [days: 2 (0, 3) vs. 0 (0, 1)], with significant differences (all P < 0.05). There was no significant difference in the marital status, severity of infection, underlying diseases, routes of transfer, total length of hospital stay, the length of ICU stay, acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, Charlson comorbidity index (CCI) score within 24 hours of admission to ICU, hypoxemia, hypotension, mechanical ventilation, hemofiltration, or drug use between the two groups. Bivariate Logistic regression analysis showed that the duration of education was a protective factor for cognitive impairment in patients with sepsis who were followed up for 12 months [odds ratio (OR) = 0.791, 95% confidence interval (95%CI) = 0.678-0.923, P = 0.003], and age and duration of delirium were risk factors (age: OR = 1.038, 95%CI = 1.009-1.068, P = 0.010; duration of delirium: OR = 1.314, 95%CI = 1.002-1.724, P = 0.048). Long-term cognitive impairment occurs in many septic patients after discharge and improves over time. Duration of education is a protective factor for cognitive impairment in patients with sepsis, while age and delirium duration are risk factors.

Dexmedetomidine reduced sevoflurane-induced neurodegeneration and long-term memory deficits in neonatal rats

Exposure to sevoflurane and other inhalational anesthetics can induce neurodegeneration in the developing brain. Although dexmedetomidine (DEX) has provided neuroprotection against hypoxic ischemic injury, relatively little is known about whether it has the neuroprotective effects against anesthetic-induced neurodegeneration. This study examined whether DEX improves the long-term cognitive dysfunction observed after exposure of neonatal rats to 3% sevoflurane. Seven-day-old rats received intraperitoneal saline (DEX 0) or DEX (6.6, 12.5, 25 μg/kg) 30 min before exposure to 3% sevoflurane with 21% oxygen for 4 h (n = 10 per group). The pups in the control group received only DEX 25 μg/kg without anesthesia. The escape latency in the Morris water maze was significantly increased in the DEX 0 group compared with the sham and control group, and the escape latency, but not the swimming path length, was significantly shorter at post-natal day 47 in the DEX 25 than in the DEX 0 group. The percent time spent in the quadrant was significantly decreased in the DEX 0 group compared with the sham and control group, and the percent time spent in the quadrant was significantly increased in the DEX 25 group compared with the DEX 0 groups. The freezing times of the DEX 0 and 6.6 groups were significantly decreased compared with those in the sham, control and DEX 25 groups. The number of NeuN-positive cells in the CA1 region was significantly decreased in the DEX 0 and 6.6 groups compared with the sham, control and DEX 25 groups. These findings indicate pre-treatment with DEX may improve long-term cognitive function and ameliorate the neuronal degeneration induced by sevoflurane exposure in neonatal rats.

Effects of leptin on brain injury and long-term cognitive function in rats undergoing orthotopic liver transplantation

Objective To evaluate the effects of leptin on brain injury and long-term cognitive function in rats undergoing orthotopic liver transplantation. Methods Ninety clean-grade male Sprague-Dawley rats, aged 3 months, weighing 200-250 g, were divided into 3 groups by a random number table method: sham operation group(S group), liver ischemia-reperfusion(I/R) group(I/R group) and leptin group(L group), with 18 rats in each group.Orthotopic liver transplantation was performed to establish the model of liver I/R injury in I/R and L groups.Leptin 1 mg/kg was intraperitoneally injected at the onset of ischemia in L group, and the equal volume of normal saline was given instead of leptin in S and I/R groups.Twelve rats in each group were sacrificed at 3 days after operation, and brains were removed for examination of the pathological changes in hippocampal CA1 region(with a light microscope) and for determination of apoptosis in hippocampal neurons(by TUNEL assay) and expression of aquaporin 4(AQP4) and protein kinase C(PKC) in the hippocampus(by Western blot). The apoptosis rate was calculated.The remaining 6 rats in each group underwent a Morris water maze test at 30 days after surgery to evaluate long-term cognitive function. Results Compared with S group, the apoptosis rate of hippocampal neurons was significantly increased, the expression of AQP4 and PKC was up-regulated, the escape latency was prolonged, and the time of staying at the platform quadrant was shortened in I/R and L groups(P<0.05). Compared with I/R group, the apoptosis rate of hippocampal neurons was significantly decreased, the expression of AQP4 and PKC was down-regulated, the escape latency was shortened, and the time of staying at the platform quadrant was prolonged in L group(P<0.05). Conclusion Leptin can reduce the brain damage in rats undergoing orthotopic liver transplantation, the mechanism may be related to down-regulating the expression of PKC and AQP4, and leptin can also improve long-term cognitive function after orthotopic liver transplantation in rats. Key words: Leptin; Liver transplantation; Reperfusion injury; Cognition disorders

Association Between Postoperative Delirium and Long-term Cognitive Function After Major Nonemergent Surgery

Postoperative delirium is associated with decreases in long-term cognitive function in elderly populations. To determine whether postoperative delirium is associated with decreased long-term cognition in a younger, more heterogeneous population. A prospective cohort study was conducted at a single academic medical center (≥800 beds) in the southeastern United States from September 5, 2017, through January 15, 2018. A total of 191 patients aged 18 years or older who were English-speaking and were anticipated to require at least 1 night of hospital admission after a scheduled major nonemergent surgery were included. Prisoners, individuals without baseline cognitive assessments, and those who could not provide informed consent were excluded. Ninety-day follow-up assessments were performed on 135 patients (70.7%). The primary exposure was postoperative delirium defined as any instance of delirium occurring 24 to 72 hours after an operation. Delirium was diagnosed by the research team using the Confusion Assessment Method (CAM). The primary outcome was change in cognition at 90 days after surgery compared with baseline, preoperative cognition. Cognition was measured using a telephone version of the Montreal Cognitive Assessment (T-MoCA) with cognitive impairment defined as a score less than 18 on a scale of 0 to 22. Of the 191 patients included in the study, 110 (57.6%) were women; the mean (SD) age was 56.8 (16.7) years. For the primary outcome of interest, patients with and without delirium had a small increase in T-MoCA scores at 90 days compared with baseline on unadjusted analysis (with delirium, 0.69; 95% CI, -0.34 to 1.73 vs without delirium, 0.67; 95% CI, 0.17-1.16). The initial multivariate linear regression model included age, preoperative American Society of Anesthesiologists Physical Status Classification System score, preoperative cognitive impairment, and duration of anesthesia. Preoperative cognitive impairment proved to be the only notable confounder: when adjusted for preoperative cognitive impairment, patients with delirium had a 0.70-point greater decrease in 90-day T-MoCA scores than those without delirium compared with their respective baseline scores (with delirium, 0.16; 95% CI, -0.63 to 0.94 vs without delirium, 0.86; 95% CI, 0.40-1.33). Although a statistically significant association between 90-day cognition and postoperative delirium was not noted, patients with preoperative cognitive impairment appeared to have improvements in cognition 90 days after surgery; however, this finding was attenuated if they became delirious. Preoperative cognitive impairment alone should not preclude patients from undergoing indicated surgical procedures.

Wavelet-Based EEG Processing for Epilepsy Detection Using Fuzzy Entropy and Associative Petri Net

Epilepsy is a common neurological disease that can cause seizures and loss of consciousness and can have a severe negative impact on long-term cognitive function. Reducing the severity of impact requires early diagnosis and treatment. Epilepsy is traditionally diagnosed using electroencephalography (EEG) performed by trained physicians or technicians but this process is time-consuming and prone to interference, which can negatively impact accuracy. This paper develops a model for epilepsy diagnosis using discrete wavelet transform to analyze sub-bands within the EEG parameter and select EEG characteristics for epilepsy detection. The minimize entropy principle approach is used to build fuzzy membership functions of the characteristics of each brain wave and are then used as the basis for the construction of an associative Petri net model. Using our APN model, the associative Petri net approach provides diagnosis accuracy rates of 93.8%, outperforming similar approaches using decision tree, support vector machine, neural network, Bayes net, naive Bayes, and tree augmented naive Bayes. Thus, the proposed approach shows promise for fast, accurate, and objective diagnosis of epilepsy in clinical settings.

Impact of Preeclampsia on Long-Term Cognitive Function.

Preeclampsia increases a woman's risk of stroke and leads to short-term cognitive complaints. Our objective was to assess the impact of preeclampsia on long-term cognitive performance. This is a retrospective cohort study using data from the Coronary Artery Risk Development in Young Adults cohort of healthy individuals (18-30 years) recruited from the general population in 3 cities in the United States, followed for 25 years (1985-2010). Psychomotor speed (Digit Symbol Substitution Test), executive function (Stroop Test), and memory (Rey Auditory Verbal Learning Test) were contrasted between women with and without preeclampsia using multivariate linear regression. We included 568 parous women (193 with preeclampsia and 375 with normotensive pregnancy) without baseline neurological disease or depression matched according to delivery period. Approximately 18 years after delivery, preeclamptic women scored significantly lower on Digit Symbol Substitution Test than women with normotensive pregnancy (73.21±14.79 versus 75.87±15.22; P=0.047) and on the third trial of Stroop Test (correct answers: 38.85±3.62 versus 39.42±1.87; P=0.014; completion time: 44.02±10.48 versus 41.62±10.61 seconds; P=0.01), but there were no differences in Rey Auditory Verbal Learning Test. These differences were attenuated after adjustment for age, body mass index, hypertension, education, and depression. Similar differences in neurocognitive scores were noted between women with other hypertensive disorders of pregnancy and normotensive pregnancy. Hypertension in pregnancy does not seem to be independently associated with neurocognitive impairment later in life.

Cognitive Function 3 and 12 Months After ICU Discharge-A Prospective Cohort Study.

Studies have shown impaired cognitive function after ICU discharge. We aimed to describe long-term cognitive function in Danish ICU patients. Prospective cohort study. Single-center ICU at Zealand University Hospital, Køge, Denmark. Adult patients admitted for over 24 hours. Three and 12 months after discharge, the patients were visited at home and tested with the Repeatable Battery for the Assessment of Neuropsychological Status. We included 161 patients, 79 patients had a 3-month and 53 a 12-month follow-up visit. The primary reasons for not being visited at 3-month were death (44 patients), decline (26 patients), or transferal to another ICU (6 patients). Visited patients were median 67 years old (interquartile range, 59-73), had a median Acute Physiology and Chronic Health Evaluation score of 20 (interquartile range, 16-26), 58% were on a ventilator, and 30% were surgical patients. The mean Repeatable Battery for the Assessment of Neuropsychological Status score was 67 (SD, 21), compared with a normal value of 100 (15). A total of 57% had Repeatable Battery for the Assessment of Neuropsychological Status scores corresponding to moderate traumatic brain injury, 46% scored corresponding to light Alzheimer's disease, and 73% corresponding to mild cognitive impairment. After 12 months, the Repeatable Battery for the Assessment of Neuropsychological Status was still reduced (71 [25]). We examined protective and risk factors using multiple linear regression and found protective effects of being employed before admission (p = 0.0005) or being admitted from a surgical ward (p = 0.019). In this prospective cohort study of Danish ICU patients, we found significantly reduced cognitive function for intensive care patients 3 and 12 months after discharge.

Elective caesarean delivery and offspring’s cognitive impairment: Implications of methylation alteration in hippocampus glucocorticoid signaling genes

Elective caesarean delivery (CD) is an atypical early-life stressful event towards infants. It can pose a long-term effect to children's development by programming hypothalamus-pituitary-adrenal axis. However, the effect of elective CD on offspring’s long-term cognitive function and the potential molecular mechanism remains unknown. In this study, by establishing CD mice model, we found that mice born with CD had lower corticosterone level at birth compared with those born by vaginal delivery (VD). Impairment in learning and memory was observed in CD offspring in adolescence, while the effect did not persist in the adulthood. In hippocampus, the expression of glucocorticoid receptor gene (Nr3c1) and FK506 binding protein gene 5 (Fkbp5) was higher in CD offspring in all postnatal time points. In hippocampus, the average methylation level at nerve growth factor-inducible protein A (NGFI-A) binding sites in exon 17 of Nr3c1, and the methylation in intron 1, intron 5 of Fkbp5 were all lower in CD offspring at infancy. Our data implicated that elective CD will cause delayed but non-permanent cognitive impairment in offspring. Insufficient glucocorticoid function caused by elective CD may bridge the association between this operative delivery mode and offspring’s cognitive impairment. Methylation alterations in key regions of glucocorticoid signaling genes may partially explain the function of glucocorticoid related with elective CD.

Inhibition of ferroptosis attenuates tissue damage and improves long-term outcomes after traumatic brain injury in mice.

Ferroptosis, a new form of iron-dependent programmed cell death, has been shown to be involved in a range of diseases. However, the role of ferroptosis in traumatic brain injury (TBI) has yet to be elucidated. We aimed to investigate whether ferroptosis is induced after TBI and whether the inhibition of ferroptosis would protect against traumatic brain injury in a controlled cortical impact injury (CCI) mouse model. After establishing the TBI model in mice, we determined the biochemical and morphological changes associated with ferroptosis, including iron accumulation with Perl's staining, neuronal cell death with Fluoro-Jade B (FJB) staining, iron metabolism dysfunction with Western blotting, reactive oxygen species (ROS) accumulation with malondialdehyde (MDA) assays, and shrunken mitochondria with transmission electron microscopy. Furthermore, a specific inhibitor of ferroptosis, ferrostatin-1(fer-1), was administrated by cerebral ventricular injection after CCI. We used cresyl violet (CV) staining to assess lesion volume, along with the Morris water maze and beam walk test to evaluate long-term outcomes. TBI was followed by iron accumulation, dysfunctional iron metabolism, the upregulation of ferroptosis-related genes, reduced glutathione peroxidase (GPx) activity, and the accumulation of lipid-reactive oxygen species (ROS). Three days (d) after TBI, transmission electron microscopy (TEM) confirmed that the mitochondria had shrunk a typical characteristic of ferroptosis. Importantly, the administration of Fer-1 by cerebral ventricular injection significantly reduced iron deposition and neuronal degeneration while attenuating injury lesions and improving long-term motor and cognitive function. This study demonstrated an effective method with which to treat TBI by targeting ferroptosis.

Signaling network between the dysregulated expression of microRNAs and mRNAs in propofol-induced developmental neurotoxicity in mice

Mounting evidence has demonstrated that general anesthetics could induce acute neuroapoptosis in developing animals followed by long-term cognitive dysfunction, with the mechanisms remaining largely unknown. The aim of this study was to investigate the effect of the intravenous anesthetic propofol on the profiles of microRNAs (miRNAs) and messenger RNAs (mRNAs), and their interactive signaling networks in the developing mouse hippocampus. Postnatal day 7 (P7) mice were exposed to propofol for 3 hours. Hippocampi were harvested from both P7 (3 hours after exposure) and P60 mice for the analysis of the expression of 726 miRNAs and 24,881 mRNAs, and apoptosis. Long-term memory ability of P60 mice was analyzed using the Morris Water Maze. Propofol induced acute apoptosis in the hippocampus, and impaired memory function of mice. There were 100 altered mRNAs and 18 dysregulated miRNAs in the propofol-treated hippocampi compared with the intralipid-treated control tissues on P7. Bioinformatics analysis of these abnormally expressed genes on P7 indicated that 34 dysregulated miRNA-mRNA target pairs were related to pathological neurological and developmental disorder processes such as cell viability, cell morphology and migration, neural stem cell proliferation and neurogenesis, oligodendrocyte myelination, reactive oxygen species, and calcium signaling. Neonatal propofol exposure also resulted in the abnormal expression of 49 mRNAs and 4 miRNAs in P60 mouse hippocampi. Specifically, bioinformatics analysis indicates that among these dysregulated mRNAs and miRNAs, there were 2 dysregulated miRNA-mRNA targets pairs (Fam46a/miR-363-3p and Rgs3/miR-363-3p) that might be related to the effect of propofol on long-term cognitive function. Collectively, our novel investigation indicates that acute and long-term dysregulated miRNA-mRNA signaling networks potentially participate in propofol-induced developmental neurotoxicity.

Akt3 deletion in mice impairs spatial cognition and hippocampal CA1 long long-term potentiation through downregulation of mTOR.

Loss-of-function mutation of Akt3 in humans has been associated with microcephaly and cognitive defects. Two Akt isoforms, Akt1 and Akt3, are highly expressed in hippocampal pyramidal cells. We explored the roles of Akt1 and Akt3, respectively, in spatial cognition and underlying mechanisms. We used Akt1 knockout (Akt1-KO) and Akt3 knockout (Akt3-KO) mice to examine the influence of Akt1 and Akt3 deficiency on spatial memory, as well as induction and maintenance of hippocampal CA1 NMDA receptor-dependent and protein synthesis-dependent long-term potentiation (LTP). Long-term spatial memory was impaired in Akt3-KO mice, but not in Akt1-KO mice, as assessed by the Morris water maze task. Akt3-KO and Akt1-KO mice displayed reductions in brain size without concurrent changes in the number of pyramidal cells or basal properties of synaptic transmission. One-train high-frequency stimulation (HFS × 1) induced NMDA receptor-dependent LTP in Akt3-KO mice and Akt1-KO mice. Four-train HFS (HFS × 4) induced rapamycin-sensitive long-LTP in Akt1-KO mice, but not Akt3-KO mice. Basal level of mTOR phosphorylation was reduced in Akt3-KO mice rather than Akt1-KO mice. HFS × 4 induced an elevation of mTOR and p70S6K phosphorylation in Akt1-KO mice, which led to enhanced 4EBP2 and eIF4E phosphorylation along with an increase in AMPA receptor protein. However, the same protocol of HFS × 4 failed to trigger the mTOR-p70S6K signalling cascade or increase 4EBP2 and eIF4E phosphorylation in Akt3-KO mice. The Akt3 deficiency via inactivation of mTOR suppresses HFS × 4-induced mTOR-p70S6K signalling to reduce phosphorylation of 4EBP and eIF4E, which impairs protein synthesis-dependent long-LTP and long-term spatial cognitive function.

RAS modulation prevents progressive cognitive impairment after experimental stroke: a randomized, blinded preclinical trial

BackgroundWith the aging population, the prevalence and incidence of cerebrovascular disease will continue to rise, as well as the number of individuals with vascular cognitive impairment/dementia (VCID). No specific FDA-approved treatments for VCID exist. Although clinical evidence supports that angiotensin receptor blockers (ARBs) prevent cognitive decline in older adults, whether ARBs have a similar effect on VCID after stroke is unknown. Moreover, these agents reduce BP, which is undesirable in the acute stroke period, so we believe that giving C21 in this acute phase or delaying ARB administration would enable us to achieve the neurovascular benefits without the risk of unintended and potentially dangerous, acute BP lowering.MethodsThe aim of our study was to determine the impact of candesartan (ARB) or compound-21 (an angiotensin type 2 receptor––AT2R––agonist) on long-term cognitive function post-stroke, in spontaneously hypertensive rats (SHRs). We hypothesized that AT2R stimulation, either directly with C21, or indirectly by blocking the angiotensin type 1 receptor (AT1R) with candesartan, initiated after stroke, would reduce cognitive impairment. Animals were subjected to a 60-min transient middle cerebral artery occlusion and randomly assigned to either saline/C21 monotherapy, for the full study duration (30 days), or given sequential therapy starting with saline/C21 (7 days) followed by candesartan for the remainder of the study (21 days). Outcome measures included sensorimotor/cognitive-function, amyloid-β determination, and histopathologic analyses.ResultsTreatment with RAS modulators effectively preserved cognitive function, reduced cytotoxicity, and prevented chronic-reactive microgliosis in SHRs, post-stroke. These protective effects were apparent even when treatment was delayed up to 7 days post-stroke and were independent of blood pressure and β-amyloid accumulation.ConclusionCollectively, our findings demonstrate that RAS modulators effectively prevent cognitive impairment after stroke, even when treatment is delayed.

早期二甲双胍治疗对糖尿病前期合并短暂局灶脑缺血后长期认知功能的影响 Effect of Early Metformin Treatment on Long-term Cognitive Function in Prediabetic Rats after Transient Focal Cerebral Ischemia

早期二甲双胍治疗对糖尿病前期合并短暂局灶脑缺血后长期认知功能的影响 Effect of Early Metformin Treatment on Long-term Cognitive Function in Prediabetic Rats after Transient Focal Cerebral Ischemia

Long-Term Cognitive Prognosis of Profoundly Deaf Older Adults After Hearing Rehabilitation Using Cochlear Implants.

To analyze long-term cognitive status and function after cochlear implantation in profoundly deaf individuals. Prospective observational longitudinal study. Ten academic medical centers referent for cochlear implantation. Individuals aged 65 and older who qualified for cochlear implantation (N=70). Cognitive tests were administered before cochlear implantation and 1 and 5 or more years after cochlear implantation. Evaluation consisted of 6 tests assessing attention, memory, orientation, executive function, mental flexibility, and fluency. Cognitive status was determined as normal, mild cognitive impairment (MCI), or dementia. Speech perception in quiet and noisy conditions was assessed using disyllabic words, and quality of life was assessed using the Nijmegen Cochlear Implant Questionnaire. Mean follow-up was 6.8 years (range 5.5-8.5 years). Speech perception scores and quality of life remained stable from 1 to 7 years after cochlear implantation. Of 31 participants (45%) with MCI before cochlear implantation, 2 (6%) developed dementia during follow-up, 19 (61%) remained stable, and 10 (32%) returned to normal cognition. None of the 38 with normal cognition developed dementia during follow-up, although 12 (32%) developed MCI. MCI is highly prevalent in older adults with profound hearing loss. Nevertheless, we observed a low rate of progression to dementia, and cognitive function improved in some individuals with MCI at baseline. These results highlight that cochlear implantation should be strongly considered in profoundly deaf individuals, even those with MCI, who may have a specific subtype of MCI, with a possible positive effect of hearing rehabilitation on neurocognitive functioning.

Cognitive declines in relationship with severe hypogonadism in long-term testicular germ cell tumor survivors: A prospective survivorship study.

e22104Background: Long-term testicular germ cell tumor (GCT) survivors suffer from long-term cognitive function declines. We aimed to evaluate, whether patients with hypogonadism are more vulnerabl...

Nitrogen narcosis induced by repetitive hyperbaric nitrogen oxygen mixture exposure impairs long-term cognitive function in newborn mice.

Human beings are exposed to compressed air or a nitrogen-oxygen mixture, they will produce signs and symptoms of nitrogen narcosis such as amnesia or even loss of memory, which may be disappeared once back to the normobaric environment. This study was designed to investigate the effect of nitrogen narcosis induced by repetitive hyperbaric nitrogen-oxygen mixture exposure on long-term cognitive function in newborn mice and the underlying mechanisms. The electroencephalogram frequency was decreased while the amplitude was increased in a pressure-dependent manner during 0.6, 1.2, 1.8 MPa (million pascal) nitrogen-oxygen mixture exposures in adult mice. Nitrogen narcosis in postnatal days 7–9 mice but not in adult mice induced by repetitive hyperbaric exposure prolonged the latency to find the platform and decreased the number of platform-site crossovers during Morris water maze tests, and reduced the time in the center during the open field tests. An increase in the expression of cleaved caspase-3 in the hippocampus and cortex were observed immediately on the first day after hyperbaric exposure, and this lasted for seven days. Additionally, nitrogen narcosis induced loss of the dendritic spines but not of the neurons, which may mainly account for the cognitive dysfunction. Nitrogen narcosis induced long-term cognitive and emotional dysfunction in the postnatal mice but not in the adult mice, which may result from neuronal apoptosis and especially reduction of dendritic spines of neurons.