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Post-operative cognitive dysfunction (POCD) refers to the functional impairment of the nervous system caused by prolonged exposure to anesthetics. It is known that prolonged exposure to anesthetics may increase the risk for the development of several cognitive impairments. The drugs used to induce general anesthesia are generally safe, owing to the CNS's direct and/or indirect self-protective activity against drug-induced damages. Non-coding RNAs have recently started to gain attention to better understand the mechanism of gene regulation correlated to cellular physiology and pathology. In order to provide new insights for the neuroprotective function of highly expressed ncRNAs in the central nervous system, we investigated their expression profile in the circulating exosomes of patients exposed to anesthesia vs healthy controls. The experimental design envisaged the recruitment of 30 adult patients undergoing general anesthesia and healthy controls. The effects of anesthetics have been evaluated on miR-34a and miR-124, on the lncRNAs MALAT-1, HOTAIR, GAS5, BLACAT1, HULC, PANDA, and on YRNAs. NcRNAs miR-34a, miR-124, MALAT-1, HOTAIR, GAS5, BLACAT1, and YRNA1 are significantly overexpressed following anesthesia, while YRNA5 is significantly down regulated. Some of them have neuroprotective function, while other correlate with neurological dysfunctions. Our data suggests that, during anesthesia, the toxic action of some non-coding RNAs could be compensated by other non-coding RNAs, both synthesized by the CNS or also transported into neurons from other tissues. It is reasonable to suppose a mutual action of these molecules likely to secure the CNS from anesthetics, that drive a convoluted cascade of ncRNA-dependent biological counter-responses. Our findings are novel in the field of brain dysfunction, indicating that some of the analyzed ncRNAs, although several of their functions still need to be addressed, could be suggested as potential biomarkers and therapeutic targets in post-operative cognitive dysfunction-related processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Frailty, cognitive decline, and depression are common syndromes among the elderly and are closely interconnected. However, it is still unclear whether the impact of frailty on depression depends on the role of cognitive decline., Method: We conducted the Mendelian randomization (MR) analysis based on the instrumental variables (IVs) from the genome-wide association study (GWAS) databases, and we also performed a cross-sectional study consisting of 1362 older adults aged ≥65 for validation., Results: The results of the multivariable MR analysis showed that frailty significantly increased the risk of depression, even after controlling for the influence of cognitive performance. Conversely, after controlling for frailty, the effect of cognitive performance on depression risk was noticeably reduced. In the cross-sectional study, frailty mediated 24.04 % of the relationship between cognition and depression, and cognition mediated 7.63 % of the relationship between frailty and depression., Conclusions: We provide evidence that frailty could increase depression risk independently of cognitive decline. Further research with a larger sample size is necessary., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yang Lv reports financial support was provided by Chongqing Talent Plan. Yang Lv reports financial support was provided by Key Project of Technological Innovation and Application Development of Chongqing Science & Technology Bureau. Yang Lv reports financial support was provided by Science Innovation Programs Led by the Academicians in Chongqing. Yang Lv reports financial support was provided by Chongqing Medical Key Discipline and Regional Medical Key Discipline Development Project. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cognitive impairment (CI) is a common complication of the non-motor symptoms in Parkinson's disease (PD), including PD with mild cognitive impairment (PD-MCI) and PD dementia. Recent studies reported the oral dysbiosis in PD and CI, respectively. Porphyromonas gingivalis (P. gingivalis), a pathogen of oral dysbiosis, plays an important role in PD, whose lysine-gingipain (Kgp) could lead to AD-type pathologies. No previous study investigated the composition of oral microbiota and role of P. gingivalis in PD-MCI. This study aimed to investigate the differences of oral microbiota composition, P. gingivalis copy number, and Kgp genotypes among PD-MCI, PD with normal cognition (PD-NC) and periodontal status-matched control (PC) groups. The oral bacteria composition, the copy number of P. gingivalis, and the Kgp genotypes in gingival crevicular fluid from PD-MCI, PD-NC, and PC were analyzed using 16S ribosomal RNA sequencing, quantitative real-time PCR, and MseI restriction. We found that the structures of oral microbiota in PD-MCI group were significantly different compared to that in PD-NC and PC group. The relative abundances of Prevotella, Lactobacillus, Megasphaera, Atopobium, and Howardella were negatively correlated with cognitive score. Moreover, there was a significant difference of Kgp genotypes among the three groups. The predominant Kgp genotypes of P. gingivalis in the PD-MCI group were primarily Kgp II, whereas in the PD-NC group, it was mainly Kgp I. The Kgp II correlated with lower MMSE and MoCA scores, which suggested that Kgp genotypes II is related to cognitive impairment in PD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction : Amyotrophic lateral sclerosis (ALS) has heterogeneous manifestations ranging from motor neuron degeneration to cognitive and behavioral impairment. This study aims to clarify the interactions between cognition and behavioral symptoms with relevant disease predictors and with cognitive reserve (CR), quantified through education, physical activity, and occupation proxies. Methods : A prospective sample of 162 ALS patients and 61 controls were evaluated with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) (dependent variable), a Cognitive Reserve Index questionnaire (CRIq) and demographic data (age and sex), and, for patients, clinical variables: disease duration, site of onset, the ALS Functional Rating Scale (ALSFRS), forced vital capacity (FVC), and gene mutation chromosome 9 open reading frame 72 ( C9orf72 ) (independent variables). Multiple regression and mediation analyses were performed to predict cognitive and behavioral symptoms. Results : For the ALS group, the statistical model explained 38.8% of variance in ECAS total ( p  < 0.001), 59.4% of executive functions ( p  < 0.001), and 55% of behavioral symptoms ( p  < 0.001). For controls, it accounted for 52.8% of variance in ECAS total ( p  < 0.001). Interaction effects and mediation analysis showed CR is an ECAS total modulator, with a differential effect within groups ( p  < 0.001). Verbal fluency was the single best cognitive score to differentiate patients from controls ( p  = 0.004), and the gene mutation C9orf72 was found to be a behavioral symptom' predictor in patients ( p  = 0.009). Conclusion : This study supports the proposed concept that CR acts as a cognitive modulator in ALS patients and healthy individuals. Moreover, CR also modulates behavioral manifestations in ALS.

Few studies have focused on the association between clonal hematopoiesis of indeterminate potential (CHIP) and β-amyloid (Aβ) deposition in the brain, which causes Alzheimer's disease. We aimed to investigate the potential role of CHIP in brain Aβ deposition in Korean patients. We enrolled 58 Korean patients over 50 yrs of age with cognitive impairment who underwent brain Aβ positron emission tomography. We explored CHIP in their peripheral blood using deep-targeted next-generation sequencing. Irrespective of the presence or absence of brain Aβ deposition, mutations in DNMT3A and the C:G>T:A single-nucleotide variants were identified as the primary characteristics, which reflect aged hematopoiesis in the study population. Multivariate logistic regression revealed that the presence of CHIP was not associated with brain Aβ deposition. As both CHIP and brain Aβ deposition are associated with aging, further research is required to elucidate their possible interplay.

The dysregulation of Angiotensin-converting enzyme 2 (ACE2) in central nervous system is believed associates with COVID-19 induced cognitive dysfunction. However, the detailed mechanism remains largely unknown. In this study, we performed a comprehensive system genetics analysis on hippocampal ACE2 based on BXD mice panel. Expression quantitative trait loci (eQTLs) mapping showed that Ace2 was strongly trans-regulated, and the elevation of Ace2 expression level was significantly correlated with impaired cognitive functions. Further Gene co-expression analysis showed that Ace2 may be correlated with the membrane proteins in Calcium signaling pathway. Further, qRT-PCR confirmed that SARS-CoV-2 spike S1 protein upregulated ACE2 expression together with eight membrane proteins in Calcium Signaling pathway. Moreover, such elevation can be attenuated by recombinant ACE2. Collectively, our findings revealed a potential mechanism of Ace2 in cognitive dysfunction, which could be beneficial for COVID-19-induced cognitive dysfunction prevention and potential treatment., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To investigate the relationship between apolipoprotein E (ApoE) gene polymorphism and cognitive impairment (PSCI) in patients after acute ischemic stroke (AIS)., Methods: A total of 150 AIS patients were treated in Chengde Central Hospital from December 2022 to December 2023 and were selected and divided into a disorder group (n=88) and a normal group (n=62) according to the presence or absence of PSCI. Clinical data of patients in the two groups were collected, ApoE genotype and allele distribution of patients in the disabled group and the normal group were detected, Montreal Cognitive Assessment and Mini-Mental State Examination scores of patients with different ApoE gene subtypes were compared, and the risk factors of PSCI after AIS were analyzed by unconditional Logistic regression., Results: The proportion of patients with acute lesions (≥3.0 cm) and the degree of carotid artery stenosis (moderate, severe, complete occlusion) in the disorder group was higher than that in the normal group, and the National Institutes of Health Stroke Scale score was higher than that in the control group, with statistical significance (P < .05). There were significant differences in the genotype and allelic distribution of ApoE between the two groups (P < .05). In both groups, the highest genotype frequency of ApoE was the ε3/3 homozygous type, which was 47.73% (in the disorder group) and 72.58% (in the normal group) respectively. In contrast, there were no significant differences in the genotype frequencies of ε2/2, ε2/3, ε2/4 and ε4/4 alleles in the two groups (P > .05). This means that in both groups of patients, the frequency of the ApoE ε3/3 genotype was the highest, while the genotype frequencies of ε2/2, ε2/3, ε2/4 and ε4/4 alleles were not significant between the two groups. difference. The distribution differences of these genotypes and alleles may be related to aspects such as disease risk and physiological function, providing valuable information for in-depth exploration of the role of ApoE in patients. The genotype frequency of ε3/3 in the disorder group was lower than that in the normal group. The frequency of the ε3/4 genotype was higher than that of the normal group, and the difference was statistically significant (P < .05). In both groups, the highest allele frequency was ε3 (68.75% in the disorder group and 83.06% in the normal group), and there was no difference in the frequency of ε2 allele between the two groups (P > .05). The frequency of the ε3 allele in the disorder group was lower than that in the normal group, and the frequency of the ε4 allele was higher than that in the normal group, the difference was statistically significant (P < .05). In the patients with cognitive impairment after AIS (disorder group), the MOCA and MMSE scores of patients with different ApoE subtypes (ε2, ε3, ε4) were compared, and the differences among the three groups were statistically significant (P < .05). The MOCA and MMSE scores in the ε4 group were lower than those in the ε2 and ε3 groups. The difference was statistically significant (P < .05). Logistic regression analysis showed that the degree of carotid artery stenosis, NIHSS score, and ApoEε4 gene were independent risk factors for PSCI in patients with AIS (P < .05)., Conclusion: APOE gene polymorphism is associated with cognitive impairment in post-AIS patients, and carrying the ApoE Epsilon 4 gene may be associated with PSCI in post-AIS patients.

Background: Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood., Methods: APOEε4 carriers and APOEε3 homozygotes enrolled in the Women's Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80. AD pathology (Aß 42/40 ) and neurodegeneration (NfL, tau) biomarkers, as well as 1007 proteins (Olink) were quantified in blood collected at study enrollment (on average 14 years prior) when participants were cognitively normal. We identified plasma proteins that distinguished between resilient and non-resilient APOEε4 carriers, examined whether these associations generalized to APOEε3 homozygotes, and replicated these findings in the UK Biobank., Results: A total of 1610 participants were included (baseline age: 71.3 [3.8 SD] years; all White; 42% APOEε4 carriers). Compared to resilient APOEε4 carriers, non-resilient APOEε4 carriers had lower Aß 42/40 /tau ratio and greater NfL at baseline. Proteomic analyses identified four proteins differentially expressed between resilient and non-resilient APOEε4 carriers at an FDR-corrected P < 0.05. While one of the candidate proteins, a marker of neuronal injury (NfL), also distinguished resilient from non-resilient APOEε3 homozygotes, the other three proteins, known to be involved in lipid metabolism (ANGPTL4) and immune signaling (PTX3, NCR1), only predicted resilient vs. non-resilient status among APOEε4 carriers (protein*genotype interaction-P < 0.05). Three of these four proteins also predicted 14-year dementia risk among APOEε4 carriers in the UK Biobank validation sample (N = 9420). While the candidate proteins showed little to no association with targeted biomarkers of AD pathology, protein network and enrichment analyses suggested that natural killer (NK) cell and T lymphocyte signaling (via PKC-θ) distinguished resilient from non-resilient APOEε4 carriers., Conclusions: We identified and replicated a plasma proteomic signature associated with cognitive resilience among APOEε4 carriers. These proteins implicate specific immune processes in the preservation of cognitive status despite elevated genetic risk for AD. Future studies in diverse cohorts will be needed to assess the generalizability of these results., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

microRNAs (miRNAs) have a broad influence on gene expression; however, we have limited insights into their contribution to rate of cognitive decline over time or Alzheimer's disease (AD). Given this, we tested associations of 528 miRNAs with cognitive trajectory, AD hallmark pathologies, and AD clinical diagnosis using small RNA sequencing from the dorsolateral prefrontal cortex of 641 community-based donors. We found 311 miRNAs differentially expressed in AD or its endophenotypes after adjusting for technical and sociodemographic variables. Among these, 137 miRNAs remained differentially expressed after additionally adjusting for several co-occurring age-related cerebral pathologies, suggesting that some miRNAs are associated with the traits through co-occurring pathologies while others through mechanisms independent from pathologies. Pathway enrichment analysis of downstream targets of these differentially expressed miRNAs found enrichment in transcription, postsynaptic signalling, cellular senescence, and lipoproteins. In sex-stratified analyses, five miRNAs showed sex-biased differential expression for one or more AD endophenotypes, highlighting the role that sex has in AD. Lastly, we used Mendelian randomization to test whether the identified differentially expressed miRNAs contribute to the cause or are the consequence of the traits. Remarkably, 15 differentially expressed miRNAs had evidence consistent with a causal role, laying the groundwork for future mechanistic studies of miRNAs in AD and its endophenotypes., (© 2024. The Author(s).)

Cognitive dysfunction has been accepted as a possible complication of type 2 diabetes (T2D), but few studies revealed the potential roles of Long non‑coding RNAs (lncRNAs) in cognitive dysfunction in T2D. The current research aims to demonstrate the specific expression patterns of lncRNA-mRNA in the hippocampi of T2D db/db mice exhibiting cognitive impairment. In this study, the results from behavioral tests showed that T2D db/db mice displayed short-term and spatial working memory deficits compared to db/m mice. Furthermore, western blot analysis demonstrated that compared with db/m mice, p-GSK3β (ser9) protein levels were markedly elevated in T2D db/db mice (P < 0.01). In addition, though not statistically significant, the ratio of p-Tau (Ser396) to Tau 46, α-Synuclein expression, and p-GSK3α (ser21) expression were also relatively higher in T2D db/db mice than in db/m mice. The microarray profiling revealed that 75 lncRNAs and 26 mRNAs were dysregulated in T2D db/db mice (> 2.0 fold change, P < 0.05). GO analysis demonstrated that the differentially expressed mRNAs participated in immune response, extracellular membrane-bounded organelle, and extracellular region. KEGG analysis revealed that the differentially expressed mRNAs were mainly involved in one carbon pool by folate, glyoxylate and dicarboxylate metabolism, autophagy, glycine, serine and threonine metabolism, and B cell receptor signaling pathway. A lncRNA‑mRNA coexpression network containing 71 lncRNAs and 26 mRNAs was built to investigate the interaction between lncRNA and mRNA. Collectively, these results revealed the differential hippocampal expression profiles of lncRNAs in T2D mice with cognitive dysfunction, and the findings from this study provide new clues for exploring the potential roles of lncRNAs in the pathogenesis of cognitive dysfunction in T2D., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mild cognitive impairment (MCI) is a prodromal stage in aging to possible progression to Alzheimer's disease and related dementia (ADRD), where co-occurrence of major depressive disorder (MDD) accelerates the progression. Metabolic and mitochondrial abnormalities in ADRD and other neurodegenerative disorders have been widely suggested, while possible mitochondrial dysfunction has been associated with etiopathology of both MCI and MDD. Hence, investigation of mitochondrial markers in MCI, MDD, and presence of both conditions is warranted. In total, 332 older adult participants were included: 168 with MCI, 108 with MCI plus remitted MDD (rMDD), and 56 with rMDD but without MCI. We measured plasma circulating mitochondrial DNA (ccf-mtDNA), lactate, and extracted nuclear mitochondrial encoded (NMt) single-nucleotide variants (SNVs) (n = 312). Non-parametric statistical tests on ccf-mtDNA and lactate levels were performed on the diagnosis, clinical and cardiometabolic variables. Binary sequence kernel association test (SKAT-O) and burden test were performed on NMt-SNV, adjusted for age, race, gender, type II diabetes, and APOE genotype. Lower level of lactate was observed in MCI (KW χ 2  = 14.8, P = 0.0024), more specifically, significant differences of lower plasma lactate between MCI only and rMDD, but not between MCI+rMDD and MCI were found, suggesting potential roles in MCI driving lactate lower levels. While higher levels of ccf-mtDNA were observed in APOE-ε4 carrier (χ 2  = 5.04, P = 0.05). This relationship was present only in MCI (P = 0.043) and MCI+rMDD groups (P = 0.023). No significant nuclear-encoded mitochondrial gene associations were observed with MCI or MDD. The results suggest decreased level of plasma lactate in individuals with MCI and MCI+rMDD, with inverse correlation with ccf-mtDNA, in addition to effect of APOE-ε4 in further increasing ccf-mtDNA specifically in participants with cognitive impairment. These findings contribute to a deeper understanding of the mitochondrial markers in MCI and MDD, warranting further research to explore the precise roles of mitochondrial abnormalities in the development and progression of MCI., (© 2024. The Author(s).)

Obesity confers risk for cardiovascular disease and vascular dementia. However, genomic alterations modulated by obesity in endothelial cells in the brain and their relationship to other neurovascular unit (NVU) cells are unknown. We performed single nuclei RNA sequencing (snRNAseq) of the NVU (endothelial cells, astrocytes, microglia, and neurons) from the hippocampus of obese ( ob / ob ) and wild-type (WT) male mice to characterize obesity-induced transcriptomic changes in a key brain memory center and assessed blood-brain barrier permeability (BBB) by gadolinium-enhanced magnetic resonance imaging (MRI). Ob / ob mice displayed obesity, hyperinsulinemia, and impaired glucose tolerance. snRNAseq profiled 14 distinct cell types and 32 clusters within the hippocampus of ob / ob and WT mice and uncovered differentially expressed genes (DEGs) in all NVU cell types, namely, 4462 in neurons, 1386 in astrocytes, 125 in endothelial cells, and 154 in microglia. Gene ontology analysis identified important biological processes such as angiogenesis in endothelial cells and synaptic trafficking in neurons. Cellular pathway analysis included focal adhesion and insulin signaling, which were common to all NVU cell types. Correlation analysis revealed significant positive correlations between endothelial cells and other NVU cell types. Differentially expressed long non-coding RNAs (lncRNAs) were observed in cells of the NVU-affecting pathways such as TNF and mTOR. BBB permeability showed a trend toward increased signal intensity in ob / ob mice. Taken together, our study provides in-depth insight into the molecular mechanisms underlying cognitive dysfunction in obesity and may have implications for therapeutic gene targeting.

Haploinsufficiency of the transcriptional repressor ZBTB18/RP58 is associated with intellectual disability. However, the mechanisms causing this disability are unknown, and preventative measures and treatments are not available. Here, we assessed multiple behaviors in Zbtb18/Rp58 heterozygous-knockout mice, and examined local field potentials, DNA fragmentation, mitochondrial morphology, and performed histochemical and transcriptome analyses in the hippocampus to evaluate chronic inflammation. In wild-type mice, object location memory was present at a similar level at 2 and 4-5 months of age, and became impaired at 12-18 months. In contrast, Zbtb18/Rp58 heterozygous-knockout mice displayed early onset impairments in object location memory by 4-5 months of age. These mice also exhibited earlier accumulation of DNA and mitochondrial damage, and activated microglia in the dentate gyrus, which are associated with defective DNA repair. Notably, chronic minocycline therapy, which has neuroprotective and anti-inflammatory effects, attenuated age-related phenotypes, including accumulation of DNA damage, increased microglial activation, and impairment of object location memory. Our results suggest that Zbtb18/Rp58 activity is required for DNA repair and its reduction results in DNA and mitochondrial damage, increased activation of microglia, and inflammation, leading to accelerated declines in cognitive functions. Minocycline has potential as a therapeutic agent for the treatment of ZBTB18/RP58 haploinsufficiency-associated cognitive dysfunction., (© 2024. The Author(s).)

With the increasing prevalence of diabetes mellitus worldwide, type 2 diabetes mellitus (T2D) combined with cognitive impairment and aging has become one of the common and important complications of diabetes mellitus, which seriously affects the quality of life of the patients, and imposes a heavy burden on the patients' families and the society. Currently, there are no special measures for the treatment of cognitive impairment and aging in type 2 diabetes mellitus. Therefore, the search for potential biological markers of type 2 diabetes mellitus combined with cognitive impairment and aging is of great significance for future precisive treatment. We downloaded three gene expression datasets from the GEO database: GSE161355 (related to T2D with cognitive impairment and aging), GSE122063, and GSE5281 (related to Alzheimer's disease). Differentially expressed genes (DEGs) were identified, followed by gene set enrichment analysis (GSEA). A protein-protein interaction (PPI) network was constructed using the STRING database, and the top 15 hub genes were identified using the CytoHubba plugin in Cytoscape. Core genes were ultimately determined using three machine learning methods: LASSO regression, Support Vector Machine Recursive Feature Elimination (SVM-RFE), and Linear Discriminant Analysis (LDA). The diagnostic performance of these genes was assessed using ROC curve analysis and validated in an independent dataset (GSE5281). Regulatory genes related to ferroptosis were screened from the FerrDb database, and their biological functions were further explored through GO and KEGG enrichment analyses. Finally, the CIBERSORT algorithm was used to analyze immune cell infiltration, and the correlation between core genes and immune cell infiltration levels was calculated, leading to the construction of an mRNA-miRNA regulatory network. In the GSE161355 and GSE122063 datasets, 217 common DEGs were identified. GSEA analysis revealed their enrichment in the PI3K-PLC-TRK signaling pathway, TP53 regulation of metabolic genes pathway, Notch signaling pathway, among others. PPI network analysis identified 15 candidate core genes, and further selection using LASSO, LDA, and SVM-RFE machine learning algorithms resulted in 6 core genes: BCL6, TP53, HSP90AA1, CRYAB, IL1B, and DNAJB1. ROC curve analysis indicated that these genes had good diagnostic performance in the GSE161355 dataset, with TP53 and IL1B achieving an AUC of 0.9, indicating the highest predictive accuracy. BCL6, HSP90AA1, CRYAB, and DNAJB1 also had AUCs greater than 0.8, demonstrating moderate predictive accuracy. Validation in the independent dataset GSE5281 showed that these core genes also had good diagnostic performance in Alzheimer's disease samples (AUC > 0.6). Ferroptosis-related analysis revealed that IL1B and TP53 play significant roles in apoptosis and immune response. Immune cell infiltration analysis showed that IL1B is significantly positively correlated with infiltration levels of monocytes and NK cells, while TP53 is significantly negatively correlated with infiltration levels of follicular helper T cells. The construction of the miRNA-mRNA regulatory network suggested that miR-150a-5p might play a key role in the regulation of T2D-associated cognitive impairment and aging by TP53. This study, by integrating bioinformatics and machine learning methods, identified BCL6, TP53, HSP90AA1, CRYAB, IL1B, and DNAJB1 as potential diagnostic biomarkers for T2D with cognitive impairment and aging, with a particular emphasis on the significance of TP53 and IL1B in immune cell infiltration. These findings not only enhance our understanding of the molecular mechanisms linking type 2 diabetes to cognitive impairment and aging, providing new targets for early diagnosis and treatment, but also offer new directions and targets for basic research., (© 2024. The Author(s).)

CACNA1C, coding for the α1 subunit of L-type voltage-gated calcium channel (LTCC) Ca v 1.2, has been associated with multiple psychiatric disorders. Clinical studies have revealed alterations in behavior as well as in brain structure and function in CACNA1C risk allele carriers. These findings are supported by rodent models of Ca v 1.2 deficiency, which showed increased anxiety, cognitive and social impairments as well as a shift towards active stress-coping strategies. These behavioral alterations were accompanied by functional deficits, such as reduced long-term potentiation (LTP) and an excitation/inhibition (E/I) imbalance. However, these preclinical studies are largely limited to male rodents, with few studies exploring sex-specific effects. Here, we investigated the effects of Ca v 1.2 deficiency in forebrain glutamatergic neurons in female conditional knockout (CKO) mice. CKO mice exhibited hyperlocomotion in a novel environment, increased anxiety-related behavior, cognitive deficits, and increased active stress-coping behavior. These behavioral alterations were neither influenced by the stage of the estrous cycle nor by the Nex/Neurod6 haploinsufficiency or Cre expression, which are intrinsically tied to the utilization of the Nex-Cre driver line for conditional inactivation of Cacna1c. In the hippocampus, Ca v 1.2 inactivation enhanced presynaptic paired-pulse facilitation without altering postsynaptic LTP at CA3-CA1 synapses. In addition, CA1 pyramidal neurons of female CKO mice displayed a reduction in dendritic complexity and spine density. Taken together, our findings extend the existing knowledge suggesting Ca v 1.2-dependent structural and functional alterations as possible mechanisms for the behavioral alterations observed in female Ca v 1.2-Nex mice., (© 2024. The Author(s).)

Alzheimer's disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction-driven by genes different from APOE-which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ ., (© 2024. The Author(s).)

Li et al. [1] have commented on our recent paper investigating the association between exposure to fine particulate matter (PM 2.5 ) constituents and the risk of cognitive impairment [2]. They provided a Mendelian randomization (MR) analysis using large-scale genome-wide association study (GWAS) datasets from the European population, confirming a causal relationship between PM 2.5 exposure and cognitive performance. In our reply, we employed three causal inference models, including a generalized propensity score (GPS) adjusted Cox model, an inverse-probability weights (IPW) weighted Cox model, and a trimmed IPW-weighted Cox model, to confirm the relationship of PM 2.5 and cognitive impairment in our study cohort., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Cardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD)., Methods: Two hundred forty-seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non-carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing., Results: Among variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories., Discussion: Better baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD., Highlights: Better cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD). Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD. More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume. Optimized cardiovascular health relates to more favorable outcomes in genetic dementia., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: To assess the diagnostic utility of lncRNA 51 A in detecting cognitive decline among aluminum-exposed workers occupationally., Methods: 921 male workers from an aluminum manufacturing facility underwent cognitive assessments, measurement of plasma aluminum levels and quantification of lncRNA 51 A levels. Receiver Operating Characteristic (ROC) curves were constructed to assess the diagnostic potential of lncRNA 51 A. Bayesian network model was utilized to predict the likelihood of cognitive decline among the study population., Results: Significant differences in lncRNA 51 A levels, plasma aluminum concentration and MMSE scores were observed between cognitive normal and decline groups. The lncRNA 51 A expression was negatively correlated with MMSE scores. The area under the curve (AUC) was 0.894, with 89.3 % sensitivity and 73.9 % specificity. The Bayesian network model indicated varying probabilities of cognitive decline based on lncRNA 51 A expression levels., Conclusion: Plasma lncRNA 51 A shows potential as an excellent biomarker for cognitive decline diagnosis in aluminum-exposed workers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: CD33 rs3865444 and hypertension (HTN) are related to cognitive impairment, individually. However, little is known about their combined effects on cognitive function in older adults., Methods: This population-based study included 4368 dementia-free participants (age ≥65 years) in the Multimodal Interventions to Delay Dementia and Disability in Rural China (MIND-China), with data available in 1044 persons for gray matter volume and 85 persons for cerebral blood flow (CBF). We used general linear regression and mediation models to examine the associations of rs3865444 and HTN with cognition, brain atrophy, and CBF., Results: Among rs3865444 CC carriers, HTN and late-life HTN were significantly associated with impaired cognition. Midlife and late-life HTN were correlated with brain atrophy. CD33 rs3865444 CC moderated the mediation effect of gray matter volume on the association between HTN and global cognition. HTN was correlated with low CBF in rs3865444 CC carriers., Discussion: There are synergistic associations of CD33 rs3865444 and HTN with brain and cognitive aging in dementia-free older adults., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Blood-derived microRNAs (miRNAs) are potential candidates for detecting and preventing subclinical cognitive dysfunction. However, replication of previous findings and identification of novel miRNAs associated with cognitive domains, including their relation to brain structure and the pathways they regulate, are still lacking., Methods: We examined blood-derived miRNAs and miRNA co-expression clusters in relation to cognitive domains, structural magnetic resonance imaging measures, target gene expression, and genetic variants in 2869 participants of a population-based cohort., Results: Five previously identified and 14 novel miRNAs were associated with cognitive domains. Eleven of these were also associated with cortical thickness and two with hippocampal volume. Multi-omics analysis showed that certain identified miRNAs were genetically influenced and regulated genes in pathways like neurogenesis and synapse assembly., Discussion: We identified miRNAs associated with cognitive domains, brain regions, and neuronal processes affected by aging and neurodegeneration, making them promising candidate blood-based biomarkers or therapeutic targets of subclinical cognitive dysfunction., Highlights: We investigated the association of blood-derived microRNAs with cognitive domains. Five previously identified and 14 novel microRNAs were associated with cognition. Eleven cognition-related microRNAs were also associated with cortical thickness. Identified microRNAs were linked to genes associated with neuronal functions. Results provide putative biomarkers or therapeutic targets of cognitive aging., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: Contemporary research suggests reduced telomere length in schizophrenia spectrum disorders (SZ) compared to age-adjusted non-affected individuals. However, the role of telomere maintenance and telomere repair in SZ is poorly understood as well as the involvement of telomere biology in cognitive abnormalities in SZ., Methods: The study consisted of 758 participants (SZ [n = 357] and healthy controls, HC [n = 401]) collected as part of the Norwegian TOP study. Participants were assessed with standardized neuropsychological tests measuring five cognitive domains. Leucocyte telomere length (TL) was measured via blood and determined by quantitative real-time Polymerase Chain Reaction (qPCR) providing a telomere to single copy ratio (T/S ratio), used to estimate the mean telomere length. Telomerase activity was assessed by the expression levels of the Telomerase Reverse Transcriptase (TERT) and Telomerase RNA Component (TERC) genes. To assess telomere maintenance and telomere repair we calculated the telomerase expression to TL ratio (TERT/TL and TERC/TL respectively)., Results: Patients had reduced TERT (F = 5.03, p = 0.03), but not TERC expression (F = 1.04, p = 0.31), and higher TERT/TL (F = 6.68, p = 0.01) and TERC/TL (F = 6.71, p = 0.01), adjusted for age, sex, and ethnicity. No statistically significant association was observed between any of the telomere biology markers and the cognitive domains (p > 0.05)., Conclusion: Our study shows changes in TERT expression and telomere maintenance and telomere repair in SZ compared HC. However, the role of telomere biology in the mechanism underlying cognitive impairment in psychosis seems limited., Competing Interests: Declaration of competing interest Authors declare no conflict of interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Cancer-related cognitive impairment (CRCI) is a highly prevalent and debilitating symptom reported by breast cancer survivors (BCS). The etiology of CRCI remains unclear, leading to poor symptom management. Building from prior studies, BCS with the C/C genotype of apolipoprotein E (APOE) rs7412 and the T/T genotype of brain-derived neurotrophic factor (BDNF) rs6265 were hypothesized to experience more severe CRCI. Therefore, we investigated the relationships between the severity of CRCI and polymorphisms of APOE and BDNF among BCS., Methods: This was a subanalysis of data from a larger descriptive, correlational, and cross-sectional study. Subjective and objective CRCI were measured using the Patient-Reported Outcomes Measurement Information System and CANTAB Cambridge Cognitive assessment, respectively. Buccal swab samples were collected to evaluate the single nucleotide polymorphisms. Multivariable generalized linear regression models were used to analyze data., Results: APOE rs7412 and BDNF rs6265 were significantly associated with lower self-reported cognitive abilities in a total of 353 BCS. Age was positively associated with self-reported cognitive scores, indicating that younger BCS perceived lower cognitive abilities. Individuals carrying genotype of C/T for APOE with the C/C or C/T for BDNF showed positive associations with cognitive abilities., Conclusions: Younger BCS with the C/C genotype for APOE rs7412 and the T/T genotype for BDNF rs6265 may be at risk for CRCI. Knowledge regarding predictive markers for CRCI symptoms is essential for precision symptom management. Further investigation with a longitudinal and translational design is necessary to explore the etiologies for CRCI., Implications for Nursing Practice: Integrating genetic phenotyping into routine clinical practice will provide nurses with unique opportunities to understand individual susceptibilities, and how symptoms may trigger other symptoms. Further, findings from these innovative investigations will provide symptom interventionists and implementation scientists with critical data to optimize individualized strategies for symptom prevention, detection, and management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The established link between DNA methylation and pathophysiology of dementia, along with its potential role as a molecular mediator of lifestyle and environmental influences, positions blood-derived DNA methylation as a promising tool for early dementia risk detection., Methods: In conjunction with an extensive array of machine learning techniques, we employed whole blood genome-wide DNA methylation data as a surrogate for 14 modifiable and non-modifiable factors in the assessment of dementia risk in independent dementia cohorts., Results: We established a multivariate methylation risk score (MMRS) for identifying mild cognitive impairment cross-sectionally, independent of age and sex (P = 2.0 × 10 -3 ). This score significantly predicted the prospective development of cognitive impairments in independent studies of Alzheimer's disease (hazard ratio for Rey's Auditory Verbal Learning Test (RAVLT)-Learning = 2.47) and Parkinson's disease (hazard ratio for MCI/dementia   = 2.59)., Discussion: Our work shows the potential of employing blood-derived DNA methylation data in the assessment of dementia risk., Highlights: We used whole blood DNA methylation as a surrogate for 14 dementia risk factors. Created a multivariate methylation risk score for predicting cognitive impairment. Emphasized the role of machine learning and omics data in predicting dementia. The score predicts cognitive impairment development at the population level., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Alzheimer's disease (AD) is a neurodegenerative disorder with a distinct sex bias. Age-related vascular alterations, a hallmark of AD onset and progression, are consistently associated with sexual dimorphism. Here, we conducted an integrative meta-analysis of 335,803 single-nucleus transcriptomes and 667 bulk transcriptomes from the vascular system in AD and normal aging to address the underlying sex-dependent vascular aging in AD. All vascular cell types in male AD patients exhibited an activated hypoxia response and downstream signaling pathways including angiogenesis. The female AD vasculature is characterized by increased antigen presentation and decreased angiogenesis. We further confirmed that these sex-biased alterations in the cerebral vascular emerged and were primarily determined in the early stages of AD. Sex-stratified analysis of normal vascular aging revealed that angiogenesis and various stress-response genes were downregulated concurrently with female aging. Conversely, the hypoxia response increased steadily in males upon aging. An investigation of upstream driver transcription factors (TFs) revealed that altered communication between estrogen receptor alpha (ESR1) and hypoxia induced factors during menopause contributes to the inhibition of angiogenesis during normal female vascular aging. Additionally, inhibition of CREB1, a TF that targets estrogen, is also related to female AD. Overall, our study revealed a distinct cerebral vascular profile in females and males, and revealed novel targets for precision medicine therapy for AD., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Numerous academic literature suggests that amyloid-β (Aβ) deposition, tau protein phosphorylation, and irreversible neuronal death are the three major causes of AD. The chloride intracellular channel (CLIC) protein family not only regulates the polarisation of neurons, but also has important implications for neuronal survival. Chloride intracellular channel 4 (CLIC4) can be pathologically activated by cyclin-dependent kinase 5 (Cdk5), which causes a significant increase in the expression of CLIC4 and mediates neuronal apoptosis. CLIC4 knockdown inhibits H2O2-induced neuronal apoptosis; however, the relationship between CLIC4 and AD remains unknown. In the present study, we showed that CLIC4 expression was elevated in the hippocampus of AD mice; knockdown of hippocampal CLIC4 alleviated Aβ25-35-induced cognitive impairment in mice; overexpression of hippocampal CLIC4 accelerated Aβ deposition and tau protein hyperphosphorylation in young AD mice (APP/PS1 mice at three months of age). CLIC4 overexpressing mice had a longer escape latency compared to controls in behavioural testing (Morris water maze and T-maze tests). By Co-immunoprecipitation/mass spectrometry (Co-IP/MS) of HT22 cells to identify proteins that specifically bind to CLIC4, we found interactions with CCAAT enhancer binding protein (C/EBPβ); a critical pathway involved in the development of various neurodegenerative diseases. In addition, the knockdown of hippocampal CLIC4 alleviated AD-like pathology by inhibiting the C/EBPβ/AEP signaling pathway. These data suggest an essential role for high CLIC4 expression in the pathophysiology of AD and reveal that inhibition of CLIC4 expression may provide an opportunity for treatment., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) and dementia disproportionately burden patients with chronic kidney disease (CKD). The association between CHIP and cognitive impairment in CKD patients is unknown., Methods: We conducted time-to-event analyses in up to 1452 older adults with CKD from the Chronic Renal Insufficiency Cohort who underwent CHIP gene sequencing. Cognition was assessed using four validated tests in up to 6 years mean follow-up time. Incident cognitive impairment was defined as a test score one standard deviation below the baseline mean., Results: Compared to non-carriers, CHIP carriers were markedly less likely to experience impairment in attention (adjusted hazard ratio [HR] [95% confidence interval {CI}] = 0.44 [0.26, 0.76], p = 0.003) and executive function (adjusted HR [95% CI] = 0.60 [0.37, 0.97], p = 0.04). There were no significant associations between CHIP and impairment in global cognition or verbal memory., Discussion: CHIP was associated with lower risks of impairment in attention and executive function among CKD patients., Highlights: Our study is the first to examine the role of CHIP in cognitive decline in CKD. CHIP markedly decreased the risk of impairment in attention and executive function. CHIP was not associated with impairment in global cognition or verbal memory., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Disrupted cellular communication, inflammatory responses and mitochondrial dysfunction are consistently observed in late-life depression (LLD). Exosomes (EXs) mediate cellular communication by transporting molecules, including mitochondrial DNA (EX-mtDNA), playing critical role in immunoregulation alongside tumor necrosis factor (TNF). Changes in EX-mtDNA are indicators of impaired mitochondrial function and might increase vulnerability to adverse health outcomes. Our study examined EX-mtDNA levels and integrity, exploring their associations with levels of TNF receptors I and II (TNFRI and TNFRII), and clinical outcomes in LLD., Methods: Ninety older adults (50 LLD and 40 controls (HC)) participated in the study. Blood was collected and exosomes were isolated using size-exclusion chromatography. DNA was extracted and EX-mtDNA levels and deletion were assessed using qPCR. Plasma TNFRI and TNFRII levels were quantified by multiplex immunoassay. Correlation analysis explored relationships between EX-mtDNA, clinical outcomes, and inflammatory markers., Results: Although no differences were observed in EX-mtDNA levels between groups, elevated levels correlated with poorer cognitive performance (r = -0.328, p = 0.002) and increased TNFRII levels (r = 0.367, p = 0.004). LLD exhibited higher deletion rates (F (83,1)  = 4.402, p = 0.039), with a trend remaining after adjusting for covariates (p = 0.084). Deletion correlated with poorer cognitive performance (r = -0.335, p = 0.002). No other associations were found., Limitation: Cross-sectional study with a small number of participants from a specialized geriatric psychiatry treatment center., Conclusion: Our findings suggest that EX-mtDNA holds promise as an indicator of cognitive outcomes in LLD. Additional research is needed to further comprehend the role of EX-mtDNA levels/integrity in LLD, paving the way for its clinical application in the future., Competing Interests: Declaration of competing interest Dr. James L. Kennedy is a member of the Scientific Advisory Board of Myriad Neuroscience (unpaid) and holds several patents relating to pharmacogenetic tests for psychiatric medications. Dr. Tarek K. Rajji has received research support from Brain Canada, Brain and Behavior Research Foundation, BrightFocus Foundation, Canada Foundation for Innovation, Canada Research Chair, Canadian Institutes of Health Research, Centre for Aging and Brain Health Innovation, National Institutes of Health, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute. Dr. Rajji also received for an investigator-initiated study in-kind equipment support from Newronika, and in-kind research online accounts from Scientific Brain Training Pro, and participated in 2021 and 2022 in an advisory activity for Biogen Canada Inc. Dr. Rajji is also an inventor on the United States Provisional Patent No. 17/396,030 that describes cell-based assays and kits for assessing serum cholinergic receptor activity. Dr. Diniz receives research support from the US National Institute of Health (NIH). All other authors report no conflict of interest related to this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Type II diabetes mellitus (T2D) is a chronic metabolic disease and a risk factor for cardiovascular disease and cerebrovascular dysfunction including vascular dementia. Sex differences in the prevalence of T2D, dementia, and global genomic changes in the brain have been observed; however, most studies have been performed in males. Therefore, our aim was to evaluate the consequence of T2D on cognitive function and decipher the underlying molecular transcriptomic mechanisms of endothelial cells in an important brain memory center, the hippocampus, using a female murine diabetes model. We assessed cognitive function, metabolic parameters, and then performed hippocampal single-nuclei RNA sequencing (snRNA seq) in adult female db/db and control wild-type (WT) mice. db/db mice exhibited characteristic T2D metabolism with hyperglycemia, hyperinsulinemia, and hyperlipidemia when compared with WT mice. Female db/db mice presented cognitive decline compared with wild-type mice, as determined by open field and Morris water maze tests. snRNAseq showed that T2D induced significant changes in the global transcriptomic profile of hippocampal endothelial cells by modulating the expression of not only protein-coding genes but also long noncoding RNAs. These genes regulate cell-cell junctions, cell chemotaxis, actin cytoskeleton organization, and cell adhesion, suggesting that diabetes increases endothelial cell permeability. Observed genomic changes also correlated with the genetics of persons with clinical Alzheimer's disease and vascular dementia. In conclusion, T2D, by transcriptional and posttranscriptional regulation, regulates endothelial cell dysfunction predictive of increased vascular permeability, and negatively impacts cognitive function. Our work has implications for sex-specific molecular therapeutic targets for dementia in females. NEW & NOTEWORTHY Female db/db mice presented cognitive decline as determined by open field and Morris water maze tests. snRNAseq showed that T2D induced changes in the global transcriptomic profile of hippocampal endothelial cells by modulating the expression of not only protein-coding genes but also long noncoding RNAs. These genes regulate cell-cell junctions, cell chemotaxis, or cell adhesion, suggesting increased endothelial permeability. Genomic changes correlated with the genetics of persons with clinical Alzheimer's disease and vascular dementia.

Introduction: Brain glucose hypometabolism, indexed by the fluorodeoxyglucose positron emission tomography ([ 18 F]FDG-PET) imaging, is a metabolic signature of Alzheimer's disease (AD). However, the underlying biological pathways involved in these metabolic changes remain elusive., Methods: Here, we integrated [ 18 F]FDG-PET images with blood and hippocampal transcriptomic data from cognitively unimpaired (CU, n = 445) and cognitively impaired (CI, n = 749) individuals using modular dimension reduction techniques and voxel-wise linear regression analysis., Results: Our results showed that multiple transcriptomic modules are associated with brain [ 18 F]FDG-PET metabolism, with the top hits being a protein serine/threonine kinase activity gene cluster (peak-t (223)  = 4.86, P value < 0.001) and zinc-finger-related regulatory units (peak-t (223)  = 3.90, P value < 0.001)., Discussion: By integrating transcriptomics with PET imaging data, we identified that serine/threonine kinase activity-associated genes and zinc-finger-related regulatory units are highly associated with brain metabolic changes in AD., Highlights: We conducted an integrated analysis of system-based transcriptomics and fluorodeoxyglucose positron emission tomography ([ 18 F]FDG-PET) at the voxel level in Alzheimer's disease (AD). The biological process of serine/threonine kinase activity was the most associated with [ 18 F]FDG-PET in the AD brain. Serine/threonine kinase activity alterations are associated with brain vulnerable regions in AD [ 18 F]FDG-PET. Zinc-finger transcription factor targets were associated with AD brain [ 18 F]FDG-PET metabolism., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Elevated plasma total homocysteine (tHcy) is associated with the development of Alzheimer's disease and other forms of dementia. In this study, we report the relationship between tHcy and epigenetic age in older adults with mild cognitive impairment from the VITACOG study. Epigenetic age and rate of aging (ROA) were assessed using various epigenetic clocks, including those developed by Horvath and Hannum, DNAmPhenoAge, and with a focus on Index, a new principal component-based epigenetic clock that, like DNAmPhenoAge, is trained to predict an individual's "PhenoAge." We identified significant associations between tHcy levels and ROA, suggesting that hyperhomocysteinemic individuals were aging at a faster rate. Moreover, Index revealed a normalization of accelerated epigenetic aging in these individuals following treatment with tHcy-lowering B-vitamins. Our results indicate that elevated tHcy is a risk factor for accelerated epigenetic aging, and this can be ameliorated with B-vitamins. These findings have broad relevance for the sizable proportion of the worldwide population with elevated tHcy., (© 2024 Elysium Health, Inc and The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

The functional integrity of the central nervous system relies on complex mechanisms in which the mitochondria are crucial actors because of their involvement in a multitude of bioenergetics and biosynthetic pathways. Mitochondrial diseases are among the most prevalent groups of inherited neurological disorders, affecting up to 1 in 5000 adults and despite considerable efforts around the world there is still limited curative treatments. Harlequin mice correspond to a relevant model of recessive X-linked mitochondrial disease due to a proviral insertion in the first intron of the Apoptosis-inducing factor gene, resulting in an almost complete depletion of the corresponding protein. These mice exhibit progressive degeneration of the retina, optic nerve, cerebellum, and cortical regions leading to irremediable blindness and ataxia, reminiscent of what is observed in patients suffering from mitochondrial diseases. We evaluated the progression of cerebellar degeneration in Harlequin mice, especially for Purkinje cells and its relationship with bioenergetics failure and behavioral damage. For the first time to our knowledge, we demonstrated that Harlequin mice display cognitive and emotional impairments at early stage of the disease with further deteriorations as ataxia aggravates. These functions, corresponding to higher-order cognitive processing, have been assigned to a complex network of reciprocal connections between the cerebellum and many cortical areas which could be dysfunctional in these mice. Consequently, Harlequin mice become a suitable experimental model to test innovative therapeutics, via the targeting of mitochondria which can become available to a large spectrum of neurological diseases., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Marisol CORRAL-DEBRINSKI reports financial support was provided by French Muscular Dystrophy Association. Marisol Corral-Debrinski has patent #EP22306002.1 (Intravenous administration of neuroglobin for treating neurological disorders) pending to None. NONE If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD), with increased odds ratios in female carriers. Targeting amyloid plaques shows modest improvement in male non-APOE4 carriers. Leveraging single-cell transcriptomics across APOE variants in both sexes, multiplex flow cytometry and validation in two independent cohorts of APOE4 female carriers with AD, we identify a new subset of neutrophils interacting with microglia associated with cognitive impairment. This phenotype is defined by increased interleukin (IL)-17 and IL-1 coexpressed gene modules in blood neutrophils and in microglia of cognitively impaired female APOE ε4 carriers, showing increased infiltration to the AD brain. APOE4 female IL-17 + neutrophils upregulated the immunosuppressive cytokines IL-10 and TGFβ and immune checkpoints, including LAG3 and PD-1, associated with accelerated immune aging. Deletion of APOE4 in neutrophils reduced this immunosuppressive phenotype and restored the microglial response to neurodegeneration, limiting plaque pathology in AD mice. Mechanistically, IL-17F upregulated in APOE4 neutrophils interacts with microglial IL-17RA to suppress the induction of the neurodegenerative phenotype, and blocking this axis supported cognitive improvement in AD mice. These findings provide a translational basis to target IL-17F in APOE ε4 female carriers with cognitive impairment., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Chronic stress is associated with anxiety and cognitive impairment. Repeated social defeat (RSD) in mice induces anxiety-like behavior driven by microglia and the recruitment of inflammatory monocytes to the brain. Nonetheless, it is unclear how microglia communicate with other cells to modulate the physiological and behavioral responses to stress. Using single-cell (sc)RNAseq, we identify novel, to the best of our knowledge, stress-associated microglia in the hippocampus defined by RNA profiles of cytokine/chemokine signaling, cellular stress, and phagocytosis. Microglia depletion with a CSF1R antagonist (PLX5622) attenuates the stress-associated profile of leukocytes, endothelia, and astrocytes. Furthermore, RSD-induced social withdrawal and cognitive impairment are microglia-dependent, but social avoidance is microglia-independent. Furthermore, single-nuclei (sn)RNAseq shows robust responses to RSD in hippocampal neurons that are both microglia-dependent and independent. Notably, stress-induced CREB, oxytocin, and glutamatergic signaling in neurons are microglia-dependent. Collectively, these stress-associated microglia influence transcriptional profiles in the hippocampus related to social and cognitive deficits., (© 2024. The Author(s).)

Cognitive dysfunction caused by diabetes has become a serious global medical issue. Diabetic kidney disease (DKD) exacerbates cognitive dysfunction in patients, although the precise mechanism behind this remains unclear. Here, we conducted an investigation using RNA sequencing data from the Gene Expression Omnibus (GEO) database. We analyzed the differentially expressed genes in DKD and three types of neurons in the temporal cortex (TC) of diabetic patients with cognitive dysfunction. Through our analysis, we identified a total of 133 differentially expressed genes (DEGs) shared between DKD and TC neurons (62 up-regulated and 71 down-regulated). To identify potential common biomarkers, we employed machine learning algorithms (LASSO and SVM-RFE) and Venn diagram analysis. Ultimately, we identified 8 overlapping marker genes (ZNF564, VPS11, YPEL4, VWA5B1, A2ML1, KRT6A, SEC14L1P1, SH3RF1) as potential biomarkers, which exhibited high sensitivity and specificity in ROC curve analysis. Functional analysis using Gene Ontology (GO) revealed that these genes were primarily enriched in autophagy, ubiquitin/ubiquitin-like protein ligase activity, MAP-kinase scaffold activity, and syntaxin binding. Further enrichment analysis using Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) indicates that these biomarkers may play a crucial role in the development of cognitive dysfunction and diabetic nephropathy. Building upon these biomarkers, we developed a diagnostic model with a reliable predictive ability for DKD complicated by cognitive dysfunction. To validate the 8 biomarkers, we conducted RT-PCR analysis in the cortex, hippocampus and kidney of animal models. The results demonstrated the up-regulation of SH3RF1 in the cortex, hippocampus and kidney of mice, which was further confirmed by immunofluorescence and Western blot validation. Notably, SH3RF1 is a scaffold protein involved in cell survival in the JNK signaling pathway. Based on these findings, we support that SH3RF1 may be a common gene expression feature that influences DKD and cognitive dysfunction through the apoptotic pathway., (© 2024. The Author(s).)

Background: During brain aging, disturbances in neuronal phospholipid metabolism result in impaired cognitive function and dysregulation of neurological processes. Mutations in iPLA2β are associated with neurodegenerative conditions that significantly impact brain phospholipids. iPLA2β deficiency exacerbates mitochondrial dysfunction and abnormal mitochondrial accumulation. We hypothesized that iPLA2β contributes to age-related cognitive decline by disrupting neuronal mitophagy., Methodology: We used aged wild-type (WT) mice and iPLA2β -/- mice as natural aging models to assess cognitive performance, iPLA2β expression in the cortex, levels of chemokines and inflammatory cytokines, and mitochondrial dysfunction, with a specific focus on mitophagy and the mitochondrial phospholipid profile. To further elucidate the role of iPLA2β, we employed adeno-associated virus (AAV)-mediated iPLA2β overexpression in aged mice and re-evaluated these parameters., Results: Our findings revealed a significant reduction in iPLA2β levels in the prefrontal cortex of aged brains. Notably, iPLA2β-deficient mice exhibited impaired learning and memory. Loss of iPLA2β in the PFC of aged mice led to increased levels of chemokines and inflammatory cytokines. This damage was associated with altered mitochondrial morphology, reduced ATP levels due to dysregulation of the parkin-independent mitophagy pathway, and changes in the mitochondrial phospholipid profile. AAV-mediated overexpression of iPLA2β alleviated age-related parkin-independent mitophagy pathway dysregulation in primary neurons and the PFC of aged mice, reduced inflammation, and improved cognitive function., Conclusions: Our study suggests that age-related iPLA2β loss in the PFC leads to cognitive decline through the disruption of mitophagy. These findings highlight the potential of targeting iPLA2β to ameliorate age-related neurocognitive disorders., (© 2024. The Author(s).)

Background: Neurocognitive dysfunction is observationally associated with the risk of psychiatric disorders. Blood metabolites, which are readily accessible, may become highly promising biomarkers for brain disorders. However, the causal role of blood metabolites in neurocognitive function, and the biological pathways underlying their association with psychiatric disorders remain unclear., Methods: To explore their putative causalities, we conducted bidirectional two-sample Mendelian randomization (MR) using genetic variants associated with 317 human blood metabolites (n max  = 215,551), g-Factor (an integrated index of multiple neurocognitive tests with n max  = 332,050), and 10 different psychiatric disorders (n = 9,725 to 807,553) from the large-scale genome-wide association studies of European ancestry. Mediation analysis was used to assess the potential causal pathway among the candidate metabolite, neurocognitive trait and corresponding psychiatric disorder., Results: MR evidence indicated that genetically predicted acetylornithine was positively associated with g-Factor (0.035 standard deviation units increase in g-Factor per one standard deviation increase in acetylornithine level; 95% confidence interval, 0.021 to 0.049; P = 1.15 × 10 -6 ). Genetically predicted butyrylcarnitine was negatively associated with g-Factor (0.028 standard deviation units decrease in g-Factor per one standard deviation increase in genetically proxied butyrylcarnitine; 95% confidence interval, -0.041 to -0.015; P = 1.31 × 10 -5 ). There was no evidence of associations between genetically proxied g-Factor and metabolites. Furthermore, the mediation analysis via two-step MR revealed that the causal pathway from acetylornithine to bipolar disorder was partly mediated by g-Factor, with a mediated proportion of 37.1%. Besides, g-Factor mediated the causal pathway from butyrylcarnitine to schizophrenia, with a mediated proportion of 37.5%. Other neurocognitive traits from different sources provided consistent findings., Conclusion: Our results provide genetic evidence that acetylornithine protects against bipolar disorder through neurocognitive abilities, while butyrylcarnitine has an adverse effect on schizophrenia through neurocognition. These findings may provide insight into interventions at the metabolic level for risk of neurocognitive and related disorders., (© 2024. The Author(s).)

Objective: Sarcopenia and cognitive impairment often coexist in the elderly. In this study, we investigated the causal relationship between sarcopenia-related muscle characteristics and cognitive performance., Methods: We used linkage disequilibrium score regression (LDSC) and Mendelian Randomization (MR) analyses to estimate genetic correlations and causal relationships between genetically predicted sarcopenia-related muscle traits and cognitive function, as well as cognitive function-based discovery samples and replicated samples. Estimated effect sizes were derived from a fixed-effects meta-analysis., Results: Our univariate genome-wide association study (GWAS) meta-analysis indicated a causal relationship between appendicular lean mass (ALM) (β = 0.049; 95% confidence interval (CI): 0.032-0.066, P < 0.001) and walking pace (β = 0.349; 95% CI: 0.210-0.487, P < 0.001) with cognitive function, where a causal relationship existed between ALM in both male and female (βALM-Male(M) = 0.060; 95% CI: 0.031-0.089, PALM-M < 0.001; βALM-Female(F) = 0.045; 95% CI: 0.020-0.069, PALM-F < 0.001) with cognitive function. Low grip strength was not causally associated with cognitive function (β = -0.045; 95% CI: -0.092 - -0.002, P = 0.062). A reverse causality GWAS meta-analysis showed a causal relationship between cognitive function and ALM (β = 0.033; 95% CI: 0.018-0.048, P < 0.001) and walking pace (β = 0.039; 95% CI: 0.033-0.051, P < 0.001), where ALM in both male and female showed a causality (βALM-M = 0.041; 95% CI: 0.019-0.063, PALM-M < 0.001; βALM-F = 0.034; 95% CI: 0.010-0.058, PALM-F = 0.005). Cognitive function was not causally related to low grip strength (β = -0.024; 95% CI: -0.073-0.025, P = 0.344). Multivariable MR1 (MVMR1) analyses showed a significant causal relationship for ALM (β = 0.077; 95% CI: 0.044-0.109, P = 0.000) and walking pace (β = 0.579; 95% CI: 0.383-0.775, P = 0.000) and cognitive function. Multivariable MR2 (MVMR2) multivariate analysis showed that ALM causality remained (β = 0.069; 95% CI: 0.033-0.106, P = 0.000), and walking pace (β = 0.589; 95% CI: 0.372-0.806, P = 0.000)., Conclusions: Bidirectional two-sample MR demonstrated that sarcopenia-related muscle characteristics and cognitive performance were positive causal genetic risk factors for each other, while a multivariable MR study demonstrated that low ALM and a slow walking pace were causally involved in reduced cognitive performance. This study suggests a causal relationship between sarcopenia and cognitive impairment in older adults and provide new ideas for prevention and treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Excessive environmental exposure to manganese (Mn) has been linked to cognitive impairments, circular RNAs (circRNAs) have been recognized for their roles in epigenetic regulation in various biological processes, including neurological pathogenesis. Previous studies found that ferroptosis, an iron ion-dependent programmed cell death, may be involved in cognitive impairments. However, specific mechanisms underlying the relationship among circRNA, ferroptosis, and neurotoxicity of Mn are not well-understood. In the current study, RNA sequencing was performed to profile RNA expression in Neuro-2a (N2a) cells that were treated with 300 μM Mn. The potential molecular mechanisms of circHmbox1(3,4) in Mn-induced cognitive impairments were investigated via various experiments, such as Western blot and intracerebroventricular injection in mice. We observed a significant decrease in the expression of circHmbox1(3,4) both in vitro and in vivo following Mn treatment. The results of Y maze test and Morris water maze test demonstrated an improvement in learning and memory abilities following circHmbox1(3,4) overexpression in Mn treated mice. Mn treatment may reduce circHmbox1(3,4) biogenesis through lowered expression of E2F1/QKI. Inhibiting circHmbox1(3,4) expression led to GPX4 protein degradation through protein ligation and ubiquitination. Overall, the current study showed that Mn exposure-induced cognitive dysfunction may be mediated through ferroptosis regulated by circHmbox1(3,4)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Manganese (Mn) induced learning and memory deficits through mechanisms that are not fully understood. In this study, we discovered that the demethylase FTO was significantly downregulated in hippocampal neurons in an experimental a mouse model of Mn exposure. This decreased expression of FTO was associated with Mn-induced learning and memory impairments, as well as the dysfunction in synaptic plasticity and damage to regional neurons. The overexpression of FTO, or its positive modulation with agonists, provides protection against neurological damage and cognitive impairments. Mechanistically, FTO interacts synergistically with the reader YTHDF3 to facilitate the degradation of GRIN1 and GRIN3B through the m 6 A modification pathway. Additionally, Mn decreases the phosphorylation of SOX2, which specifically impairs the transcriptional regulation of FTO activity. Additionally, we found that the natural compounds artemisinin and apigenin that can bind molecularly with SOX2 and reduce Mn-induced cognitive dysfunction in mice. Our findings suggest that the SOX2-FTO-Grins axis represents a viable target for addressing Mn-induced neurotoxicity and cognitive impairments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis and represents a crucial factor contributing to high mortality and adverse prognosis in septic patients. This study explored the contribution of NAT10-mediated messenger RNA (mRNA) acetylation in cognitive dysfunction associated with SAE, utilizing a cecal ligation and puncture (CLP)-induced SAE mouse model. Our findings demonstrate that CLP significantly upregulates NAT10 expression and mRNA acetylation in the excitatory neurons of the hippocampal dentate gyrus (DG). Notably, neuronal-specific Nat10 knockdown improved cognitive function in septic mice, highlighting its critical role in SAE. Proteomic analysis, RNA immunoprecipitation, and real-time qPCR identified GABA B R1 as a key downstream target of NAT10. Nat10 deletion reduced GABA B R1 expression, and subsequently weakened inhibitory postsynaptic currents in hippocampal DG neurons. Further analysis revealed that microglia activation and the release of inflammatory mediators lead to the increased NAT10 expression in neurons. Microglia depletion with PLX3397 effectively reduced NAT10 and GABA B R1 expression in neurons, and ameliorated cognitive dysfunction induced by SAE. In summary, our findings revealed that after CLP, NAT10 in hippocampal DG neurons promotes GABA B R1 expression through mRNA acetylation, leading to cognitive dysfunction., Competing Interests: Competing interests statement:The authors declare no competing interest.

The study aims to evaluate the effect of Kaixin Powder(KXP) on the behavior and brain tissue of chemotherapy-treated mice to explore its mechanism in alleviating chemotherapy-induced cognitive impairment in tumor-bearing mice. Thirty female BALB/c mice were inoculated with 4T1 breast cancer cells to establish a tumor-bearing mouse model and randomly divided into the tumor group, a doxorubicin group, and a KXP group. Behavioral tests, including open field test, elevated plus maze test, forced swimming test, tail suspension test, Morris water maze test, and novel object recognition test, were conducted. Pathological examinations, including hematoxylin-eosin staining, Nissl staining, toluidine blue staining, Fluoro-Jade B staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL) assay, immunofluorescence staining, and transmission electron microscopy, were performed. Network pharmacology and whole transcriptome sequencing methods were used to analyze the mechanism of chemotherapy-induced cognitive impairment and the targets of KXP. The results showed that KXP prevented chemotherapy-induced behavioral changes(P&lt;0.001), increased the total movement distance and central zone residence time in the open field test, increased exploration time in the open arm area in the elevated plus maze test, reduced immobility time in the forced swimming test and tail suspension test, reduced escape latency in the Morris water maze test and increased platform crossings, and improved cognitive index in the novel object recognition test. KXP also inhibited chemotherapy-induced neuroinflammation, apoptosis, and autophagy in the prefrontal cortex, and reshaped the RNA expression profile of the prefrontal cortex tissue during chemotherapy(P&lt;0.05). In conclusion, KXP may alleviate chemotherapy-induced cognitive impairment in tumor-bearing mice by reshaping the RNA expression profile of prefrontal cortex tissue, thereby reducing neuronal tissue damage.

Purpose: This study investigated the relationship between mucopolysaccharidosis II (MPS II) iduronate-2-sulfatase gene (IDS) variants and phenotypic characteristics, particularly cognitive impairment, using data from the Hunter Outcome Survey (HOS) registry., Methods: HOS data for male patients (n = 650) aged ≥5 years at latest cognitive assessment with available genetic data were analyzed. Predefined genotype categories were used to classify IDS variants and report phenotypic characteristics by genotype., Results: At their latest cognitive assessment, 411 (63.2%) of 650 patients had cognitive impairment. Missense variants were the most common MPS II genotype, with about equal frequency for patients with and patients without cognitive impairment. Complete deletions/large rearrangements were associated with cognitive impairment. Cognitive impairment and behavioral issues were most common, and height and weight abnormalities most apparent, in patients with large IDS structural changes. Broadly, missense variants NM-000202.8:c.998C>T p.(Ser333Leu), NM-000202.8:c.1402C>T p.(Arg468Trp), NM-000202.8:c.1403G>A p.(Arg468Gln) and NM-000202.8:c.262C>T p.(Arg88Cys), and splice site variant NM-000202.8:c.257C>T p.(Pro86Leu), were associated with cognitive impairment, and variants NM-000202.8:c.253G>A p.(Ala85Thr), NM-000202.8:c.187 A>G p.(Asn63Asp), NM-000202.8:c.1037C>T p.(Ala346Val), NM-000202.8:c.182C>T p.(Ser61Phe) and NM-000202.8:c.1122C>T were not., Conclusion: This analysis contributes toward the understanding of MPS II genotype-phenotype relationships, confirming and expanding on existing findings in a large, geographically diverse population., Competing Interests: Declaration of competing interest J.M. has received consulting fees from and/or has participated in advisory boards for Denali Therapeutics, JCR Pharmaceuticals, REGENXBIO, Sanofi Genzyme, and Shire (a Takeda company). He is a Principal Investigator for a post-trial access program for intrathecal ERT for the neuronopathic form of MPS II (sponsored by Shire, a Takeda company), a Phase 1/2 gene editing trial for adults with MPS II (sponsored by Sangamo Therapeutics), and Phase 1/2 and Phase 2/3 intravenous ERT trials for MPS II (sponsored by Denali Therapeutics). H.A. has received consulting and/or other fees from and/or has participated in advisory boards for Amicus Therapeutics, BioMarin Pharmaceutical, Biopas, Passage Bio, PTC Therapeutics, Sanofi Genzyme, and Takeda. He has performed contracted research for Allievex, Amicus Therapeutics, bluebird bio, PTC Therapeutics, Sanofi Genzyme, and Takeda. B.K.B. has received consulting and/or speaker fees from and/or has participated in advisory boards for Aeglea, Agios, Alexion, AstraZeneca Rare Disease, Alltrna, BioMarin Pharmaceutical, Chiesi Farmaceutici, Horizon Therapeutics, JCR Pharmaceuticals, Jnana Therapeutics, Moderna, Orchard Therapeutics, Passage Bio, REGENXBIO, Sanofi Genzyme, Shire (a Takeda company), Travere, and Ultragenyx. She has performed contracted research for Shire (a Takeda company) and has been involved in company-sponsored clinical trials with BioMarin Pharmaceutical, Denali Therapeutics, Homology Medicines, JCR Pharmaceuticals, Jnana Therapeutics, Sangamo Therapeutics, Shire (a Takeda company), Synlogic, and Ultragenyx. M.S. has received consulting, speaker, and/or other fees from and/or has participated in advisory boards for Actelion, Alexion, AstraZeneca Rare Disease, BioMarin Pharmaceutical, Chiesi Farmaceutici, Orchard Therapeutics, Orphazyme, Paradigm, PTC Therapeutics, Sanofi Genzyme, Takeda, and Ultragenyx. He has performed contracted research for Alexion, AstraZeneca Rare Disease, BioMarin Pharmaceutical, CTD Holdings, Orchard Therapeutics, Orphazyme, Paradigm, PTC Therapeutics, Sanofi Genzyme, and Takeda. A.T.-S. has received consulting and/or other fees from and/or has participated in advisory boards for Alexion, AstraZeneca Rare Disease, BioMarin Pharmaceutical, Chiesi Farmaceutici, Orphazyme, Sanofi Genzyme, Synageva BioPharma, and Takeda. J.A. was an employee of Takeda and stockholder of Takeda Pharmaceuticals Company Limited at the time of this analysis (current affiliation is Ultragenyx Europe GmbH, Allschwil, Basel, Switzerland). J.B. is a full-time employee of Takeda and stockholder of Takeda Pharmaceuticals Company Limited. D.F. was an employee of Takeda and stockholder of Takeda Pharmaceuticals Company Limited at the time of this analysis; and is currently an employee of Denali Therapeutics, Zurich, Switzerland. D.M., D.A.H.W., and M.N. were employees of Takeda and stockholders of Takeda Pharmaceuticals Company Limited at the time of this analysis. M.N. is currently an employee of Crosswalk Therapeutics, Cambridge, MA, USA. R.G. has received consulting fees, fees for service, speaker fees, and/or travel expenses from and/or has participated in advisory boards for Abeona Therapeutics, Alnylam Pharmaceuticals, Amicus Therapeutics, BioMarin Pharmaceutical, Chiesi Farmaceutici, Inventiva Pharma, Janssen, JCR Pharmaceuticals, Novartis, the Orphan Disease Center, Praxis Precision Medicines, PTC Therapeutics, REGENXBIO, Sanofi Genzyme, Shire (a Takeda company), Sigilon Therapeutics, Swedish Orphan Biovitrum, Takeda, and Ultragenyx. He has performed contracted research for or received research grants from Allievex, Amicus Therapeutics, BioMarin Pharmaceutical, GC Pharma, Idorsia, Janssen, JCR Pharmaceuticals, Lysogene, Sanofi Genzyme, Takeda, and Ultragenyx., (Copyright © 2024 Takeda. Published by Elsevier Inc. All rights reserved.)

Objective: Cognitive decline is common in patients with amyotrophic lateral sclerosis (ALS), especially in carriers of the mutation C9ORF72HRE . However, cognitive impairment is poorly understood in carriers of mutations in other genes causing ALS. We performed a comprehensive neuropsychological testing in patients with mutations in the SOD1 (m SOD1 ) gene., Methods: We examined 5 cognitive domains in 48 symptomatic patients with either hereditary or sporadic ALS. These were compared with 37 matched controls., Results: Carriers of SOD1 -mutations and sporadic ALS had circumscribed deficits, but in a pattern different from C9ORF72HRE . All groups had deficits in working memory, although m SOD1- carriers significantly outperform sporadic ALS and C9ORF72HRE in an attention-driven visuospatial task involving copying a complex figure. Carriers of the D90A- SOD1 mutation overall performed as well as or better than carriers of other SOD1- mutations, except complex working memory. Bayesian analyses suggest (with evidence of moderate strength) that tasks involving the language domain did not differ between controls, m SOD1 and sporadic ALS., Conclusion: Distinct cognitive impairments are prevalent in different ALS-syndromes and vary in patients with different pathogenic SOD1 mutations. The type and degree of impairment differed depending on genotype and was significantly least pronounced in patients homozygous for the D90A SOD1 mutation. The presence of cognitive deficits may influence optimal clinical management and intervention. We propose that cognitive assessment should be included in the routine examination of new patients suspected of ALS. Neuropsychological assessment is an under-recognized outcome parameter in clinical drug trials.

Alzheimer's disease (AD) has recently been associated with diverse cell states 1-11 , yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the brain's cellular environment and identified a trajectory leading to AD that is distinct from other ageing-related effects. First, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.65 million single-nucleus RNA-sequencing profiles sampled from 437 older individuals, and identified specific glial and neuronal subpopulations associated with AD-related traits. Causal modelling then prioritized two distinct lipid-associated microglial subpopulations-one drives amyloid-β proteinopathy while the other mediates the effect of amyloid-β on tau proteinopathy-as well as an astrocyte subpopulation that mediates the effect of tau on cognitive decline. To model the dynamics of cellular environments, we devised the BEYOND methodology, which identified two distinct trajectories of brain ageing, each defined by coordinated progressive changes in certain cellular communities that lead to (1) AD dementia or (2) alternative brain ageing. Thus, we provide a cellular foundation for a new perspective on AD pathophysiology that informs personalized therapeutic development, targeting different cellular communities for individuals on the path to AD or to alternative brain ageing., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The single nucleotide polymorphism (SNP)-rs6922617 in the triggering receptor expressed on myeloid cells (TREM) gene cluster is a potential risk factor for Alzheimer's disease (AD). Here, we examined whether rs6922617 is associated with AD-defining neuropathological hallmarks and memory performance. We assessed the interaction between the variant rs6922617 and levels of beta-amyloid (Aβ), tau pathology, neurodegeneration, namely amyloid-tau-neurodegeneration framework, and cognition functions in 660 healthy controls, 794 mild cognitively impaired, and 272 subjects with AD. We employed linear regression and linear mixed models to examine the association. Here we find that the SNP-rs6922617 in the TREM gene cluster is associated with a higher global amyloid-ligands positron emission tomography (Aβ-PET) burden and lower fluorodeoxyglucose positron emission tomography (FDG-PET) load. Interestingly, rs6922617 risk allele carriers exhibit a significantly reduced tau accumulation compared to the non-carriers, indicating a discrepant association with Aβ and tau pathologies. Though the participants carrying the rs6922617 risk allele do not show a correlation with poorer cognitive performance, stronger neuropathological phenotypes, and memory impairments are evident in ApoE ε4 carriers with the rs6922617 risk allele. These results support the notion that the SNP-rs6922617 in the TREM gene cluster is associated with AD-related neuropathological hallmarks, such as Aβ and FDG-mediated neurodegeneration, rather than tau accumulation. Although the direct association with memory impairment in the Alzheimer's continuum remains inconclusive, our findings suggest a potential role of rs6922617 in facilitating neuropathology hallmarks., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Vascular cognitive impairment (VCI) is a heterogenous form of cognitive impairment that results from cerebrovascular disease. It is a result of both genetic and non-genetic factors. Although much research has been conducted on the genetic contributors to other forms of cognitive impairment (e.g. Alzheimer's disease), knowledge is lacking on the genetic factors associated with VCI. A better understanding of the genetics of VCI will be critical for prevention and treatment. To begin to fill this gap, the genetic contributors are reviewed with VCI from the literature. Phenome-wide scans of the identified genes are conducted and genetic variants identified in the review in large-scale resources displaying genetic variant-trait association information. Gene set are also carried out enrichment analysis using the genes identified from the review. Thirty one articles are identified meeting the search criteria and filters, from which 107 unique protein-coding genes are noted related to VCI. The phenome-wide scans and gene set enrichment analysis identify pathways associated with a diverse set of biological systems. This results indicate that genes with evidence of involvement in VCI are involved in a diverse set of biological functions. This information can facilitate downstream research to better dissect possible shared biological mechanisms for future therapies., (© 2024 The Author(s). Advanced Biology published by Wiley‐VCH GmbH.)

Recent studies have identified a correlation between chronic viral hepatitis and cognitive impairment, yet the underlying mechanisms remain unclear. This study investigated the influence of TGFB1 genetic polymorphisms on cognitive function in individuals with and without hepatitis infections, hypothesizing that these polymorphisms and the viral hepatitis-induced inflammatory environment interact to affect cognitive abilities. Participants (173 with viral hepatitis and 258 healthy controls) were recruited. Genotyping of TGFB1 SNPs was performed using the C2-58 Axiom Genome-Wide TWB 2.0 Array Plate. Cognitive function was assessed using the MMSE and MoCA tests. Our results showed that healthy individuals carrying the C allele of rs2241715 displayed better performance in sentence writing (p = 0.020) and language tasks (p = 0.022). Notably, viral hepatitis was found to moderate the impact of the rs2241715 genotype on language function (p = 0.002). Similarly, those carrying the T allele of rs10417924 demonstrated superior orientation to time (p = 0.002), with viral hepatitis modifying the influence of the SNP on this particular cognitive function (p = 0.010). Our findings underscore the significant role of TGFβ1 in cognitive function and the moderating impact of viral hepatitis on TGFB1 SNP effects. These findings illuminate the potential of TGFB1 as a therapeutic target for cognitive impairment induced by viral hepatitis, thus broadening our understanding of TGFβ1 functionality in the pathogenesis of neurodegeneration., (© 2024 The Author(s). The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Perioperative neurocognitive dysfunction (PND) occurs in elderly individuals undergoing anesthesia and surgery. To explore the potential molecular mechanisms, we performed right-sided cervical exploratory surgery under sevoflurane anesthesia in 18-month-old male Sprague-Dawley rats. Anxiety-depression-like behaviors and learning memory abilities were assessed using the Open Field Test (OFT) and Novel Object Recognition (NOR). Additionally, the hippocampus was collected one day after surgery for inflammatory factor detection, TUNEL staining, and metabolomics analysis. Mendelian randomization (MR) analyses were subsequently conducted to validate the causal relationships by using a series of GWAS datasets related to representative differential metabolites as exposures and cognitive impairment as endpoints. The results indicated that rats exposed to anesthesia and surgery exhibited poorer cognitive performance, significant elevations in hippocampal inflammatory factors such as IL-1β and TNF-α, and extensive neuronal apoptosis. LC-MS/MS-based untargeted metabolomics identified 19 up-regulated and 32 down-regulated metabolites in the test group, with 6 differential metabolites involved in metabolic pathways enriched according to the KEGG database. ROC analysis revealed a correlation between α-linolenic acid (ALA) and linoleic acid (LA) and the development of PND. Further MR analysis confirmed that ALA was significantly associated with cognitive performance and the risk of depression, while LA was significantly associated with the risk of memory loss. Taken together, our results identified ALA and LA as potentially powerful biomarkers for PND., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Cognitive dysfunctions are core-enduring symptoms of schizophrenia, with important sex-related differences. Genetic variants of the DTBPN1 gene associated with reduced dysbindin-1 protein (Dys) expression negatively impact cognitive functions in schizophrenia through a functional epistatic interaction with Catechol-O-methyltransferase (COMT). Dys is involved in the trafficking of dopaminergic receptors, crucial for prefrontal cortex (PFC) signaling regulation. Moreover, dopamine signaling is modulated by estrogens via inhibition of COMT expression. We hypothesized a sex dimorphism in Dys-related cognitive functions dependent on COMT and estrogen levels. Our multidisciplinary approach combined behavioral-molecular findings on genetically modified mice, human postmortem Dys expression data, and in vivo fMRI during a working memory task performance. We found cognitive impairments in male mice related to genetic variants characterized by reduced Dys protein expression (p Bonferroni = 0.0001), as well as in male humans through a COMT/Dys functional epistatic interaction involving PFC brain activity during working memory (t(23) = -3.21; p FDR  = 0.004). Dorsolateral PFC activity was associated with lower working memory performance in males only (p = 0.04). Also, male humans showed decreased Dys expression in dorsolateral PFC during adulthood (p FDR = 0.05). Female Dys mice showed preserved cognitive performances with deficits only with a lack of estrogen tested in an ovariectomy model (p Bonferroni = 0.0001), suggesting that genetic variants reducing Dys protein expression could probably become functional in females when the protective effect of estrogens is attenuated, i.e., during menopause. Overall, our results show the differential impact of functional variants of the DTBPN1 gene interacting with COMT on cognitive functions across sexes in mice and humans, underlying the importance of considering sex as a target for patient stratification and precision medicine in schizophrenia., (© 2024. The Author(s).)