Deciphering the dual role of N-methyl-D-Aspartate receptor in postoperative cognitive dysfunction: A comprehensive review.

Postoperative cognitive dysfunction (POCD) is a common complication following surgery, adversely impacting patients' recovery, increasing the risk of negative outcomes, prolonged hospitalization, and higher mortality rates. The N-methyl-D-aspartate (NMDA) receptor, crucial for learning, memory, and synaptic plasticity, plays a significant role in the development of POCD. Various perioperative factors, including age and anesthetic use, can reduce NMDA receptor function, while surgical stress, inflammation, and pain may lead to its excessive activation. This review consolidates preclinical and clinical research to explore the intricate relationship between perioperative factors affecting NMDA receptor functionality and the onset of POCD. It discusses the influence of aging, anesthetic administration, perioperative injury, pain, and inflammation on the NMDA receptor-related pathophysiology of POCD. The comprehensive analysis presented aims to identify effective treatment targets for POCD, contributing to the improvement of patient outcomes post-surgery.

White matter microstructural alterations in patients with anti-N-methyl-D-aspartate receptor encephalitis: A tract-based spatial statistics study.

BACKGROUND: Cognitive impairment is common in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis; however, neural mechanisms underlying this impairment remain unclear. Diffusion tensor imaging (DTI) is a potential method for studying the condition of white matter fibers in patients with anti-NMDAR encephalitis, allowing for an analysis of the neuroimaging mechanisms of cognitive impairment in conjunction with cognitive scales. This study aimed to explore white matter microstructural alterations and their correlation with cognitive function in patients with anti-NMDAR encephalitis. METHODS: DTI data were collected from 22 patients with anti-NMDAR encephalitis (aged 29.00(19.75, 39.50) years; 12 males, 10 females) and 20 healthy controls (HCs) (aged 24.50(21.25, 32.00); 12 males, 8 females) matched for age, sex, and educational level. Changes in the white matter microstructure were analyzed using tract-based spatial statistics. Pearson correlation analysis was used to explore the correlation between white matter integrity and neuropsychological scores. RESULTS: Compared with HCs, patients with anti-NMDAR encephalitis showed decreased fractional anisotropy and increased mean diffusivity values in extensive white matter regions, which were associated with disease severity, memory, and executive and visuospatial functions. CONCLUSION: Widespread impairment of the structural integrity of the white matter in the brain is significantly associated with cognitive dysfunction in patients with anti-NMDAR encephalitis, providing neuroimaging evidence for studying the underlying mechanisms.

Variation in care and outcomes for people after hip fracture with and without cognitive impairment; results from the Australian and New Zealand Hip Fracture Registry.

BACKGROUND: People with dementia have poorer outcomes after hip fracture and this may be due in part to variation in care. We aimed to compare care and outcomes for people with and without cognitive impairment after hip fracture. METHODS: Retrospective cohort study using Australian and New Zealand Hip Fracture Registry data for people ≥50 years of age who underwent hip fracture surgery (n = 49,063). Cognitive impairment or known dementia and cognitively healthy groups were defined using preadmission cognitive status. Descriptive statistics and multivariable mixed effects models were used to compare groups. RESULTS: In general, cognitively impaired people had worse care and outcomes compared to cognitively healthy older people. A lower proportion of the cognitively impaired group had timely pain assessment (≤30 min of presentation: 61% vs 68%; p < 0.0001), were given the opportunity to mobilise (89% vs 93%; p < 0.0001) and achieved day-1 mobility (34% vs 58%; p < 0.0001) than the cognitively healthy group. A higher proportion of the cognitively impaired group had delayed pain management (>30 mins of presentation: 26% vs 20%; p < 0.0001), were malnourished (27% vs 15%; p < 0.0001), had delirium (44% vs 13%; p < 0.0001) and developed a new pressure injury (4% vs 3%; p < 0.0001) than the cognitively healthy group. Fewer of the cognitively impaired group received rehabilitation (35% vs 64%; p < 0.0001), particularly patients from RACFs (16% vs 39%; p < 0.0001) and were prescribed bone protection medication on discharge (24% vs 27%; p < 0.0001). Significantly more of the cognitively impaired group had a new transfer to residential care (46% vs 11% from private residence; p < 0.0001) and died at 30-days (7% vs 3% from private residence; 15% vs 10% from RACF; both p < 0.0001). In multivariable models adjusting for covariates with facility as the random effect, the cognitively impaired group had a greater odds of being malnourished, not achieving day-1 walking, having delirium in the week after surgery, dying within 30 days, and in those from private residences, having a new transfer to a residential care facility than the cognitively healthy group. CONCLUSIONS: We have identified several aspects of care that could be improved for patients with cognitive impairment - management of pain, mobility, nutrition and bone health, as well as delirium assessment, prevention and management strategies and access to rehabilitation. Further research is needed to determine whether improvements in care will reduce hospital complications and improve outcomes for people with dementia after hip fracture.

Glypican-4 serum levels are associated with cognitive dysfunction and vascular risk factors in Parkinson's disease.

Glypicans are biomarkers for various pathologies, including cardiovascular disease, cancer and diabetes. Increasing evidence suggests that glypicans also play a role in the context of neurodegenerative disorders. Initially described as supporting functionality of synapses via glutamate receptors during CNS development, Glypican 4 (GPC-4) also plays a role in the context of dementia via tau hyperphosphorylation in Alzheimer's disease, which is also a co-pathology in Parkinson's disease dementia. However, clinical evidence of circulating GPC-4 in Parkinson's disease (PD) is missing so far. We therefore investigated GPC-4 in biofluids of PD patients. We analyzed GPC-4 levels in cerebrospinal fluid (CSF, n = 140), serum (n = 80), and tear fluid samples (n = 70) of PD patients and control subjects in a similar age range by ELISA (serum, CSF) and western blot (tear fluid). Expression of circulating GPC-4 was confirmed in all three biofluids, with highest levels in serum. Interestingly, GPC-4 levels were age-dependent, and multiple regression analysis revealed a significant association between GPC-4 serum levels and MoCA score, suggesting an involvement of GPC-4 in PD-associated cognitive decline. Furthermore, stratification of PD patients for vascular risk factors revealed a significant increase of GPC-4 serum levels in PD patients with vascular risk factors. Our results suggest GPC-4 as a clinical biomarker for vascular risk stratification in order to identify PD patients with increased risk of developing dementia.

Clinical characteristics and healthcare utilisation associated with undiagnosed cognitive impairment in elderly patients with diabetes in a primary care setting: a population-based cohort study.

OBJECTIVES: The objective of this study is to report the prevalence, clinical characteristics and healthcare utilisation of patients with type 2 diabetes (T2DM) and previously undiagnosed cognitive impairment who were identified as having a low Montreal Cognitive Assessment (MoCA) score. DESIGN: A population-based cohort study comparing clinical characteristics, medications, outpatient and inpatient care of patients with a MoCA score <19 to MoCA >26 using descriptive statistics, linear regression and multivariate logistic regression. SETTING: Electronic medical records of a large health maintenance organisation in Israel. PARTICIPANTS: 350 patients, age >65 with T2DM who participated in a cognitive function screening initiative using MoCA, and had a follow-up visit during the 12 months after screening. RESULTS: 130 (37.1%) had a MoCA score >26 and 68 (19.4%) <19. Patients with MoCA<19 had more diabetes-related complications, poorer glycaemic and lipid control, fewer visits to their main primary care physician (PCP; 3.9±3.2 vs 7.3±4.2 visits/year p=0.008), shorter duration of PCP visits (8.3±4.5 vs 4.0±3.5 min, p=0.007), fewer nutritionist and endocrinologist visits, and lower participation in diabetes or smoking cessation workshops. They were less likely to be treated with glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 inhibitor (DPP-4), or sodium-glucose transport protein 2 (SGLT-2) inhibitors and more likely to receive insulin or sulfonylurea. Moreover, they had more emergency room visits (ER; 15 (11.5%) vs 16 (23.5%), p=0.019), hospitalisations (8 (6.2%) vs 22 (32.4%), p=0.001), and longer hospital stays (4.3±3.2 vs 14.5±9.8, p=0.001). Using statistical models, MoCA<19 was identified as a risk factor for fewer and shorter PCP visits and more ER visits and hospitalisations. CONCLUSIONS: This study highlights the high prevalence of undiagnosed severe cognitive impairment in elderly patients with T2DM and its association with poor outpatient care. Appropriate interventions are needed to improve outcomes and prevent hospitalisation in this high-risk population.

Recent advances in HIV-associated neurocognitive disorders: a focus on older adults and sub-Saharan Africa.

PURPOSE OF REVIEW: We reviewed recent literature on prevalence and interventional approaches for cognitive impairment in the context of HIV infection alongside current controversies and challenges around its nomenclature, screening, and diagnosis. RECENT FINDINGS: Prevalence estimates for HIV-associated neurocognitive disorder (HAND) indicate that HAND remains highly prevalent despite combination antiretroviral treatment (cART) widely used. The available data are heterogeneous, particularly in sub-Saharan Africa (SSA) where recent reviews indicate substantial heterogeneity, wide prevalence estimates and lack of data from the majority SSA countries, despite them currently experiencing the greatest burden worldwide of both HIV and HAND.Several alternative approaches to diagnosis and classification of cognitive impairment in HIV have been published, taking into account changing clinical phenotypes. SUMMARY: Cognitive impairment remains a significant challenge in the care of people living with HIV despite advances in treatment. Ongoing controversies exist around nomenclature and classification, screening measures, and the phenotype and aetiology of observed impairments. Two current areas of research priority and focus include understanding current phenotypes of individuals living and ageing with treated HIV and differing levels of risk for HAND in these phenotypes, alongside the effects of commonly occurring comorbidities.The current evidence base for interventional approaches is limited, but growing. The most promising avenues appear to be multidisciplinary. These are currently focussed on high income settings rather than SSA where the majority of people living with HIV, and affected by cognitive impairment in the context of HIV, currently reside.

Exercise Improves Cerebral Blood Flow and Functional Outcomes in an Experimental Mouse Model of Vascular Cognitive Impairment and Dementia (VCID).

Vascular cognitive impairment and dementia (VCID) are a growing threat to public health without any known treatment. The bilateral common carotid artery stenosis (BCAS) mouse model is valid for VCID. Previously, we have reported that remote ischemic postconditioning (RIPostC) during chronic cerebral hypoperfusion (CCH) induced by BCAS increases cerebral blood flow (CBF), improves cognitive function, and reduces white matter damage. We hypothesized that physical exercise (EXR) would augment CBF during CCH and prevent cognitive impairment in the BCAS model. BCAS was performed in C57/B6 mice of both sexes to establish CCH. One week after the BCAS surgery, mice were randomized to treadmill exercise once daily or no EXR for four weeks. CBF was monitored with an LSCI pre-, post, and 4 weeks post-BCAS. Cognitive testing was performed for post-BCAS after exercise training, and brain tissue was harvested for histopathology and biochemical test. BCAS led to chronic hypoperfusion resulting in impaired cognitive function and other functional outcomes. Histological examination revealed that BCAS caused changes in neuronal morphology and cell death in the cortex and hippocampus. Immunoblotting showed that BCAS was associated with a significant downregulate of AMPK and pAMPK and NOS3 and pNOS3. BCAS also decreased red blood cell (RBC) deformability. EXR therapy increased and sustained improved CBF and cognitive function, muscular strength, reduced cell death, and loss of white matter. EXR is effective in the BCAS model, improving CBF and cognitive function, reducing white matter damage, improving RBC deformability, and increasing RBC NOS3 and AMPK. The mechanisms by which EXR improves CBF and attenuates tissue damage need further investigation.

Gemfibrozil Alleviates Cognitive Impairment by Inhibiting Ferroptosis of Astrocytes via Restoring the Iron Metabolism and Promoting Antioxidant Capacity in Type 2 Diabetes.

Diabetes-associated cognitive dysfunction (DACD) is considered a significant complication of diabetes and manifests as cognitive impairment. Astrocytes are vital to the brain energy metabolism and cerebral antioxidant status. Ferroptosis has been implicated in cognitive impairment, but it is unclear whether the ferroptosis of astrocytes is involved in the progression of DACD. PPARA/PPARα (peroxisome proliferator-activated receptor alpha) is a transcription factor that regulates glucose and lipid metabolism in the brain. In this study, we demonstrated that high glucose promoted ferroptosis of astrocytes by disrupting iron metabolism and suppressing the xCT/GPX4-regulated pathway in diabetic mice and astrocytes cultured in high glucose. Administration of gemfibrozil, a known PPARα agonist, inhibited ferroptosis and improved memory impairment in db/db mice. Gemfibrozil also prevented the accumulation of lipid peroxidation products and lethal reactive oxygen species induced by iron deposition in astrocytes and substantially reduced neuronal and synaptic loss. Our findings demonstrated that ferroptosis of astrocytes is a novel mechanism in the development of DACD. Additionally, our study revealed the therapeutic effect of gemfibrozil in preventing and treating DACD by inhibiting ferroptosis.

Neurocognition in adults with congenital heart disease post-cardiac surgery: A systematic review.

BACKGROUND: Congenital heart disease (CHD) is the most common birth defect worldwide. Neurocognitive deficits and psychiatric disorders, which can impact daily life, have been reported in over 50% of adolescents and young adults with moderate to complex CHD. OBJECTIVE: Conduct a systematic review of sex, clinical, psychological and social determinants of health (SDoH) factors affecting neurocognition in adults with CHD post-cardiac surgery. METHODS: PubMed, Cumulated Index to Nursing and Allied Health Literature, and Embase were searched for relevant studies over the past 5 years. Thirteen articles met inclusion criteria of: 1) CHD post-cardiac surgery, 2) age ≥ 18 years, and 3) used a validated measure of neurocognition. RESULTS: A total of 507 articles were identified. After screening, 30 articles underwent full text review yielding 13 eligible articles. Twelve articles reported deficits in multiple domains including executive function, intellectual functioning, visuospatial ability, and verbal fluency in more complex CHD. Only three studies examined cognition based on sex, with female and lower parental SES associated with worse cognitive outcomes. Most studies were from Europe, predominantly sampled Caucasian participants, had heterogeneous samples of CHD complexity, and lacked standardized cognitive measures which limited generalizability of findings. CONCLUSIONS: Adults with CHD present with a wide variety of cognitive deficits, with some associations with sex, clinical history, and SDoH factors. It remains unclear to what degree these factors affect cognition in adults with moderate to complex CHD. Future longitudinal studies should focus on age-related effects on cognition and potential health care disparities in diverse CHD samples.

Influences of Cognitive Function and Depressive Symptoms on Pain Trajectories During the First Year Following Hip Fracture Surgery: A Prospective Cohort Study.

OBJECTIVES: The purposes of this study were to explore trajectories for patterns of postoperative pain intensity during the first year following hip fracture surgery and the relationships between pain trajectory groups, cognitive impairment, and depressive symptoms. DESIGN: A prospective cohort correlational study. SETTING AND PARTICIPANTS: A total of 325 patients aged 60 years or older who had received hip fracture surgery at a 3000-bed medical center in northern Taiwan from September 2012 to March 2020. METHODS: Data were collected before hospital discharge and at 1, 3, 6, and 12 months postdischarge. Pain intensity was measured using a numeric rating scale; cognitive function was measured with the Taiwan version of the Mini-Mental State Examination; and depressive symptoms were measured by the Geriatric Depression Scale-Short Form. Patients with similar postoperative pain trajectories were categorized into groups and compared with group-based trajectory modeling. Cognitive impairment and depressive symptoms associated with each group were identified by logistic regression. RESULTS: Three different pain trajectory groups were identified: drastic decline-minimum pain (47.7%), gentle decline-mild pain (45.5%), and slight decline-moderate pain (6.8%). Patients with cognitive impairment [odds ratio (OR) 11.01, 95% CI 2.99-10.51] and at risk for depression (OR 49.09, 95% CI 10.46-230.30) were more likely to be in the moderate pain group than the minimum pain group. Patients with cognitive impairment (OR 2.07, 95% CI 1.25-3.42) were more likely to be in the mild pain group than the minimum pain group. Patients at risk for depression (OR 9.68, 95% CI 3.16-29.63) were more likely to be in the moderate pain group than the mild pain group. CONCLUSIONS AND IMPLICATIONS: Identifying postoperative pain trajectories can provide insight into the most appropriate pain management for older persons following hip fracture surgery. Attention should focus on assessments for cognitive impairment and risk of depression to prevent persistent postoperative pain. Future studies of older patients with clinically diagnosed cognitive impairment and depression are suggested.

The functional trajectories of older women having surgery for gynaeoncology cancer: A single site prospective observational study.

INTRODUCTION: Population aging longevity and advances in robotic surgery suggest that increasing numbers of older women having gynaeoncological surgery is likely. Postoperative morbidity and mortality are more common in older than younger women with the age-associated characteristics of multimorbidity and frailty being generally predictive of worse outcome. Priorities that inform treatment decisions change during the life course: older patients often place greater' value on quality-of-life-years gained than on life expectancy following cancer treatments. However, data on post-operative cognition, frailty, or functional independence is sparse and not routinely collected. This study aimed to describe the clinical characteristics and trajectory of functional change of older women in the 12 months following gynaeoncological surgery and to explore the associations between them. MATERIALS AND METHODS: The prospective observational cohort study recruited consecutive women aged 65 or over scheduled for major gynaeoncologic surgery between July 2017 and April 2019. Baseline data on cancer stage, multimorbidity, and geriatric syndromes including cognition, frailty, and functional abilities were collected using standardised tools. Delirium and post-operative morbidity were recorded. Post hospital assessments were collected at 3-, 6-, and 12-months. RESULTS: Overall, of 103 eligible participants assessed pre-operatively, most (77, 70%) remained independent in personal care at all assessments from discharge to 12 months. Functional trajectories varied widely over the 12 months but overall there was no significant decline or improvement for the 85 survivors. Eleven experienced a clinically significant decline in function at six months. This was associated with baseline low mood (P < 0.05), albeit with small numbers (6 of 11). Cognitive impairment and frailty were associated with lower baseline function but not with subsequent functional decline. DISCUSSION: There was no clear clinical profile to identify the minority of older adults who experienced a clinically significant decline six months after surgery and for most, the decline was transient. This may be helpful in enabling informed patient consent. Assessment for geriatric syndromes and frailty may improve individual care but our findings do not indicate criteria for segmenting the patient population for selective attention. Future work should focus on causal pathways to potentially avoidable decline in those patients where this is not determined by the cancer itself.

HIF-1A regulates cognitive deficits of post-stroke depressive rats.

Post-stroke depression (PSD) is a serious neuropsychiatric complication post stroke and leads to cognitive deficits. This study was conducted to explore the molecular mechanism of hypoxia-inducible factor-1α (HIF-1A) in cognitive dysfunction in rats with PSD. The rat model of PSD was established by middle cerebral artery occlusion, followed by 3 weeks of treatment with chronic unpredictable mild stress. The levels of miR-582-5p, HIF-1A, and neighbor of Brca1 gene (NBR1) in brain tissues were determined using RT-qPCR. The behaviors and cognitive capacity of rats were evaluated by various behavioral tests. PSD rats were injected with HIF-1A/miR-582-5p lowexpression vectors or NBR1 overexpression vectors via stereotactic method. The binding of HIF-1A to NBR1 or miR-582-5p was analyzed by chromatin immunoprecipitation and dual-luciferase assay. HIF-1A and NBR1 were highly expressed while miR-582-5p was poorly expressed in the brain of PSD rats. HIF-1A inhibition alleviated cognitive dysfunction of PSD rats. miR-582-5p was the upstream miRNA of HIF-1A, and HIF-1A specifically interacted with the NBR1 promoter to enhance NBR1 expression. miR-582-5p downregulation and NBR1 upregulation reversed the alleviative role of HIF-1A inhibition in cognitive dysfunction of PSD rats. In summary, HIF-1A inhibition may be a therapeutic target for cognitive dysfunction post PSD.

Empagliflozin alleviates diabetes-induced cognitive impairments by lowering nicotinamide adenine dinucleotide phosphate oxidase-4 expression and potentiating the antioxidant defense system in brain tissue of diabetic rats.

BACKGROUND: Diabetes-induced cognitive impairment is a major challenge in patients with uncontrolled diabetes mellitus. It has a complicated pathophysiology, but the role of oxidative stress is central. Therefore, the use of antidiabetic drugs with extra-glycemic effects that reduce oxidative damage may be a promising treatment option. METHODS: Male Wistar rats were randomly divided into four groups as normal, normal treated, diabetic and diabetic treated (n = 8 per group). Type 1 diabetes was induced by a single intraperitoneal dose of streptozotocin (STZ) (40 mg/kg). Two treatment groups received empagliflozin for 5 weeks (20 mg/kg/po). Cognitive ability was evaluated using open field, Elevated Plus Maze (EPM) and the Morris Water Maze (MWM) tests at study completion. Blood and brain tissue samples were collected - and analysis for malondialdehyde (MDA) and glutathione (GLT) content and catalase (CAT) and superoxide dismutase (SOD) enzyme activity were performed. Additionally, expression of nicotinamide adenine dinucleotide phosphate oxidase-4 (Nox-4) enzyme in brain tissue was analyzed using RT-PCR. RESULTS: STZ increased blood glucose and induced diabetes with oxidative stress by lowering the antioxidant system potency and increasing Nox-4 expression after 5-weeks in brain tissue accompanied by reduction in cognitive performance. Also, diabetes induced anxiety-like behavior and impaired spatial memory in MWM, EPM and open field tests. However, empagliflozin reversed these changes, improving SOD and CAT activity, GLT content and reducing Nox-4 expression and MDA concentration in brain tissue while improving cognitive ability. It reduced anxiety and depression-related activities. It also improved spatial memory in MWM test. CONCLUSION: Uncontrolled diabetes negatively impacts mental function and impairs learning and cognitive performance via oxidative stress induction, the Nox-4 enzyme playing a central role. Empagliflozin reverses these effects, improving cognitive ability via promoting the anti-oxidative system and damping Nox-4 free radical generator enzyme expression. Therefore, empagliflozin is a promising treatment, providing both antidiabetic and extra-glycemic benefits for improving brain function in the diabetic milieu.

Influence of Neostigmine on Early Postoperative Cognitive Dysfunction in Older Adult Patients Undergoing Noncardiac Surgery: A Double-Blind, Placebo-Controlled, Randomized Controlled Trial.

BACKGROUND: The goal of this study was to investigate the efficacy of neostigmine on postoperative cognitive dysfunction (POCD) and determine its effect on systematic markers of oxidative stress in older patients. METHODS: This double-blind placebo-controlled trial enrolled 118 elderly patients (≥65 years) undergoing noncardiac surgeries who were allocated to a neostigmine treatment group (0.04 mg/kg) or a placebo control group (normal saline) postoperatively. POCD was diagnosed if the Z -scores for the mini-mental state examination and the Montreal Cognitive Assessment were both ≤-1.96. Postoperative serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), and brain-derived neurotrophic factor (BDNF) were also compared. Multivariable regression analysis with dose adjustment of atropine was used to demonstrate the influence of neostigmine on the incidence of POCD. RESULTS: Patients receiving neostigmine had a significantly reduced incidence of POCD compared to patients who were treated with placebo on the first day after surgery (-22%, 95% confidence interval [CI], -37 to -7), but not on the third (8%, 95% CI, -4 to 20) or seventh day after surgery (3%, 95% CI, -7 to 13). Postoperative plasma MDA levels were significantly lower ( P = .016), but SOD and BDNF levels were increased ( P = .036 and .013, respectively) in the neostigmine group compared to the control group on the first day after surgery. CONCLUSIONS: Neostigmine reduced POCD on the first day after noncardiac surgery in older patients. Neostigmine treatment inhibited oxidative stress and increased serum BDNF levels. There was no significant influence of neostigmine on POCD on the third or seventh day after surgery. The clinical influence of neostigmine on POCD should be further investigated.

Loss of TDP-43 splicing repression occurs early in the aging population and is associated with Alzheimer's disease neuropathologic changes and cognitive decline.

LATE-NC, the neuropathologic changes of limbic-predominant age-related TAR DNA-binding protein 43 kDa (TDP-43) encephalopathy are frequently associated with Alzheimer's disease (AD) and cognitive impairment in older adults. The association of TDP-43 proteinopathy with AD neuropathologic changes (ADNC) and its impact on specific cognitive domains are not fully understood and whether loss of TDP-43 function occurs early in the aging brain remains unknown. Here, using a large set of autopsies from the Baltimore Longitudinal Study of Aging (BLSA) and another younger cohort, we were able to study brains from subjects 21-109 years of age. Examination of these brains show that loss of TDP-43 splicing repression, as judged by TDP-43 nuclear clearance and expression of a cryptic exon in HDGFL2, first occurs during the 6th decade, preceding by a decade the appearance of TDP-43+ neuronal cytoplasmic inclusions (NCIs). We corroborated this observation using a monoclonal antibody to demonstrate a cryptic exon-encoded neoepitope within HDGFL2 in neurons exhibiting nuclear clearance of TDP-43. TDP-43 nuclear clearance is associated with increased burden of tau pathology. Age at death, female sex, high CERAD neuritic plaque score, and high Braak neurofibrillary stage significantly increase the odds of LATE-NC. Faster rates of cognitive decline on verbal memory (California Verbal Learning Test immediate recall), visuospatial ability (Card Rotations Test), mental status (MMSE) and semantic fluency (Category Fluency Test) were associated with LATE-NC. Notably, the effects of LATE-NC on verbal memory and visuospatial ability are independent of ADNC. However, the effects of TDP-43 nuclear clearance in absence of NCI on the longitudinal trajectories and levels of cognitive measures are not significant. These results establish that loss of TDP-43 splicing repression is an early event occurring in the aging population during the development of TDP-43 proteinopathy and is associated with increased tau pathology. Furthermore, LATE-NC correlates with high levels of ADNC but also has an impact on specific memory and visuospatial functions in aging that is independent of AD.

[Association between vitamin E intake and mild cognitive impairment in people aged 55 years and older in Hebei Province].

OBJECTIVE: To investigate the relationship between dietary vitamin E(VE) intake and mild cognitive impairment(MCI). METHODS: Based on the data of Hebei Province in the 2018 National Key Research and Development Program Nervous system disease CCSNSD, 612 subjects were included in this study. All study participants were surveyed for dietary VE intake by the Dietary Frequency Questionnaire and assessed for cognitive function by the Montreal Cognitive Assessment Scale. The relationship between dietary VE intake and MCI and its subtypes was analyzed using logistic regression and restricted cubic splines. RESULTS: The study subjects included 260(42.5%) males and 352(57.5%) females, with an average age of(66.8±7.4) years and an average dietary VE intake of(12.17±4.91) mg/d. The prevalence of cognitive impairment in the study population was 41.3%. After adjusting the covariates of age, gender, energy intake, residence, education level, employment status, BMI, smoking, drinking, physical activity, hypertension, diabetes, VE intake was not associated with the risk of non-amnesic(naMCI), single-domain amnesic(aMCI-SD), but relate to the risk of multi-domain amnesic(aMCI-MD). What's more, compared to dietary vitamin E intake Q1 group, the OR(95%CI) for multi-domain amnesic mild cognitive impairment in Q2, Q3 and Q4 groups were 1.628(0.836-3.170), 0.313(0.124-0.791) and 0.727(0.330-1.602), respectively. Using vitamin E intake as a continuous-type variable, a non-linear dose-response relationship was found between VE intake and mild cognitive dysfunction of the multi-domain amnesic type(P=0.02). When VE intake was about 17 mg/d, the risk of aMCI-MD was the lowest. CONCLUSION: There is an approximate "U" shaped dose-response relationship between dietary VE intake and the risk of mild cognitive impairment with multi-domain amnesia type. Research suggests that moderate VE intake has a preventive effect on the development of mild cognitive impairment.

Association between the blood pressure variability and cognitive decline in Parkinson's disease.

OBJECTIVES: High visit-to-visit blood pressure variability (BPV) was found to be associated with cognitive decline in the elderly. This study aimed to investigate the impact of visit-to-visit BPV on cognition in patients with early-stage Parkinson's disease (PD). DESIGN: This is a retrospective analysis of a prospective cohort. SETTING AND PARTICIPANTS: A total of 297 patients with early-stage PD (103 mild cognitive impairments [PD-MCI] and 194 normal cognitions [PD-NC] at baseline) were included from the Parkinson's Progression Markers Initiative study. METHODS: Variation independent of mean (VIM) of the first year was used as the indicator of BPV. The Montreal Cognitive Assessment (MoCA) was used to assess global cognition. Patients were divided into PD-MCI and PD-NC according to the MoCA score at baseline. Longitudinal cerebrospinal fluid (Aß-42, Aß, α-synuclein, neurofilament light protein, tau phosphorylated at the threonine 181 position, total tau, glial fibrillary acidic protein) and serum (neurofilament light protein) biomarkers were assessed. The Bayesian linear growth model was used to evaluate the relationship between baseline BPV and the rate of change in cognition and biomarkers. RESULTS: Higher systolic VIM of the first year was related to a greater rate of decline in MoCA score in the following years in PD-MCI (ß = -.15 [95% CI -.29, -.01]). No association was found between BPV and biomarkers. CONCLUSION AND IMPLICATIONS: Higher systolic VIM predicted a steeper decline in cognitive tests in PD-MCI independently from the mean value of blood pressure, orthostatic hypotension, and supine hypertension.

Attenuation of estrogen and its receptors in the post-menopausal stage exacerbates dyslipidemia and leads to cognitive impairment.

Cognitive dysfunction increases as menopause progresses. We previously found that estrogen receptors (ERs) contribute to dyslipidemia, but the specific relationship between ERs, dyslipidemia and cognitive dysfunction remains poorly understood. In the present study, we analyzed sequencing data from female hippocampus and normal breast aspirate samples from normal and Alzheimer's disease (AD) women, and the results suggest that abnormal ERs signaling is associated with dyslipidemia and cognitive dysfunction. We replicated a mouse model of dyslipidemia and postmenopausal status in LDLR-/- mice and treated them with ß-estradiol or simvastatin, and found that ovariectomy in LDLR-/- mice led to an exacerbation of dyslipidemia and increased hippocampal apoptosis and cognitive impairment, which were associated with reduced estradiol levels and ERα, ERß and GPER expression. In vitro, a lipid overload model of SH-SY-5Y cells was established and treated with inhibitors of ERs. ß-estradiol or simvastatin effectively attenuated dyslipidemia-induced neuronal apoptosis via upregulation of ERs, whereas ERα, ERß and GPER inhibitors together abolished the protective effect of simvastatin on lipid-induced neuronal apoptosis. We conclude that decreased estrogen and its receptor function in the postmenopausal stage promote neuronal damage and cognitive impairment by exacerbating dyslipidemia, and that estrogen supplementation or lipid lowering is an effective way to ameliorate hippocampal damage and cognitive dysfunction via upregulation of ERs.

Relationship Between Disease Activity, Levels of IFN-a, IL-4, IL-6, and Anti-NMDA to Cognitive Dysfunction (MoCA-INA Score) in Systemic Lupus Erythematosus (SLE) Patients with Cognitive Dysfunction.

BACKGROUND: Neuropsychiatric Systemic Lupus Erythematosus (NPSLE) is a condition that impacts the patients' brain with SLE, and cognitive dysfunction (CD) is the most common manifestation. Subsequently, the CD hurts the life quality of SLE patients and creates impaired social function. Furthermore, the Montreal Cognitive Assessment (MoCA-INA) is a screening instrument to evaluate cognitive function. In the context of lupus, cytokines, and autoantibodies act as biomarkers in SLE disease control activities. PURPOSE: The aim of this study was to analyze the correlation between disease activity, IFN-a, IL-4, IL-6 and Anti-NMDA on CD (MoCA-INA Score) in SLE patients with CD. METHODS: This analytical observational study was performed with a cross-sectional design and included a sample of 56 SLE patients. The independent variables were the degree of the disease activity, and levels of IFN-a, IL-4, IL-6, and anti-NMDA. The dependent variable consisted of the degree of CD (MoCA-INA score), while the confounding variables were age, DM, gender, hypertension, obesity, and dyslipidemia. Subsequently, the CD was described as a MoCA-INA score <26, and disease activity was estimated based on the SLEDAI score. RESULTS: Increased IL-6 levels were correlated with decreased MoCA-INA scores (p=0.003; r= -0.387). Younger age was found to be associated with more severe CD (p=0.006) Conclusion:In conclusion, IL-6 levels can be used as a predictor severity of CD in SLE patients.

Coronary Artery Calcium and Cognitive Decline in the Diabetes Prevention Program Outcomes Study.

Background Our aim was to investigate the association of coronary artery calcium (CAC) with cognitive function in adults with impaired glucose tolerance or type 2 diabetes. Methods and Results The Diabetes Prevention Program was a randomized controlled trial comparing an intensive lifestyle intervention, metformin, or placebo for prevention of type 2 diabetes among patients with prediabetes. After 3 years, intensive lifestyle intervention and placebo were stopped, the metformin arm was unmasked, and participants continued in the DPPOS (Diabetes Prevention Program Outcomes Study). Approximately 14 years after randomization (Y14), CAC (Agatston score) was assessed with computed tomography, and cognitive performance was assessed with the Spanish English Verbal Learning Test (SEVLT) and Digit Symbol Substitution Test. SEVLT and Digit Symbol Substitution Test were reassessed 5 years later (Y19) along with the Modified Mini-Mental State Exam. We examined cross-sectional and longitudinal associations between CAC and cognition among 1931 participants using linear and logistic regression. In unadjusted analyses, compared with no calcification, CAC score >300 was associated with decreased performance on all cognitive tests at Y14 in both sexes. Additionally, CAC >300 was associated with a greater 5-year decline in SEVLT Immediate Recall in both sexes and SEVLT Delayed Recall in women. After adjustment for demographic, genetic, metabolic, vascular, and behavioral covariates, CAC score >300 remained associated with greater decline in only SEVLT Delayed Recall in women. Conclusions In women with prediabetes or diabetes, CAC >300, compared with no calcification, was independently associated with greater decline in verbal memory. Registration information clinicaltrials.gov. Identifier: NCT00038727.