The relationship between APOE genotype, CSF Tau and cognition across the Alzheimer's disease spectrum, moderation and mediation role of insula network connectivity.

AIMS: To investigate whether insula network connectivity modulates the relationship between apolipoprotein E (APOE) ε4 genotype, cerebrospinal fluid (CSF) biomarkers (Aß, Tau, and pTau) and cognition across Alzheimer's disease (AD) spectrum. METHODS: Forty-six cognitive normal (CN), 35 subjective memory complaint (SMC), 41 mild cognitive impairment (MCI), and 32 AD subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were obtained. Multivariable linear regression analyses were conducted to investigate the main effects and interaction of the APOE genotype and disease status on the insula functional connectivity (IFC) network. Mediation and moderation analysis were performed to investigate whether IFC strengths regulate the association between APOE genotype, CSF biomarkers and cognition. Additionally, the support vector machine (SVM) model integrating APOE genotype, CSF biomarkers, and neuroimaging biomarkers (insula volumes and altered regional IFCs) was used to classify the AD spectrum. RESULTS: The interactive effect of the APOE genotype and disease on the insula network was found in the left medial superior frontal gyrus (SFGmed.L), right anterior medial prefrontal cortex (aMPFC.R), and bilateral thalamus (THA.B). The functional connectivities (FCs) in the left insula (LIns) connecting with the left posterior middle temporal gyrus (pMTG.L), SFGmed.L, and right lingual gyrus (LING.R) were correlated with cognition. LIns-SFGmed.L and LIns-pMTG.L FCs could moderate the effects of Tau on cognition. Furthermore, LIns-SFGmed.L FC may suppress the association between APOE genotype and cognition. More importantly, the integrated biomarkers from the SVM model yielded strong powers for classifying the AD spectrum. CONCLUSIONS: Insula functional connectivity regulated the association between APOE genotype, CSF Tau and cognition and provided stage-dependent biomarkers for early differentiation of the AD spectrum. The present study used a cross-sectional design. Follow-up studies are needed to validate the relationship.

Interictal Activity Is Associated With Slower Binocular Rivalry in Idiopathic Generalized Epilepsy.

Objective: Perceptual alternations evoked by binocular rivalry (BR) reflect cortical dynamics strongly dependent on the excitatory-inhibitory balance, suggesting potential utility as a biomarker for epileptogenesis. Therefore, we investigated the characteristics of BR in patients with idiopathic generalized epilepsy (IGE) and potential associations with clinical variables. Methods: Sixty-two healthy controls (HCs) and 94 IGE patients completed BR task. Perceptual alternation rates were compared between HC and IGE groups as well as among the HC group and IGE patients stratified according to the presence or absence of interictal activity on the ambulatory electroencephalogram (EEG), termed the abnormal ambulatory EEG group (AB-AEEG, n = 64) and normal ambulatory EEG group (N-AEEG, n = 30), respectively. Results: The IGE patients demonstrated a slower rate of BR perceptual alternation than HC subjects (t = -4.364, p < 0.001). The alternation rate also differed among the HC, AB-AEEG, and N-AEEG groups (F = 44.962, df = 2, p < 0.001), and post hoc comparisons indicated a significantly slower alternation rate in the AB-AEEG group compared with the N-AEEG and HC groups (0.28 vs. 0.46, and 0.43 Hz). Stepwise linear regression revealed positive correlations between the BR alternation rate and both the ambulatory EEG status (ß, 0.173; standard error, 0.022 p < 0.001) and Montreal Cognitive Assessment score (ß, 0.013; standard error, 0.004; p = 0.003). Receiver operating characteristic curve analysis of the BR alternation rate distinguished AB-AEEG from N-AEEG subjects with 90.00% sensitivity and 76.90% specificity (area under the curve = 0.881; 95% confidence interval = 0.801- 0.961, cut-off = 0.319). Alternatively, Montreal Cognitive Assessment score did not accurately distinguish AB-AEEG from N-AEEG subjects and the area under the receiver operating characteristic curve combining the BR alternation rate and Montreal Cognitive Assessment score was not markedly larger than that of the BR alternation rate alone (0.894, 95% confidence interval = 0.822-0.966, p < 0.001). K-fold cross-validation was used to evaluate the predictive performance of BR alternation rate, MoCA score, and the combination of both, which yielded average AUC values of 0.870, 0.584 and 0.847, average sensitivity values of 89.36, 92.73, and 91.28%, and average specificity values of 62.25, 13.42, and 61.78%, respectively. The number of interictal epileptiform discharges was significantly correlated with the alternation rate in IGE patients (r = 0.296, p = 0.018). A forward stepwise linear regression model identified the number of interictal epileptiform discharges (ß, 0.001; standard error, 0.001; p = 0.025) as an independent factor associated with BR alternation rate in these patients. Conclusion: These results suggest that interictal epileptiform discharges are associated with disruptions in perceptual awareness, and that the BR may be a useful auxiliary behavioral task to diagnosis and dynamically monitor IGE patients with interictal discharge.

TREM-1 Exacerbates Neuroinflammatory Injury via NLRP3 Inflammasome-Mediated Pyroptosis in Experimental Subarachnoid Hemorrhage.

Neuroinflammation contributes to the pathogenesis of early brain injury induced by subarachnoid hemorrhage (SAH). Previous reports have demonstrated that triggering receptor expressed on myeloid cells 1 (TREM-1) regulates inflammatory response caused by ischemic stroke or myocardial infarction. However, whether TREM-1 could modulate neuroinflammation after SAH remains largely unknown. Here, using a mouse model of SAH, we found that the expression of TREM-1 was mainly located in microglia cells and increased to peak at 24 h following SAH. Then, TREM-1 antagonist or mimic was intranasally administrated to investigate its effect on SAH. TREM-1 inhibition with LP17 improved neurological deficits, mitigated brain water content, and preserved brain-blood barrier integrity 24 h after SAH, whereas recombinant TREM-1, a mimic of TREM-1, deteriorated these outcomes. In addition, LP17 administration restored long-term sensorimotor coordination and cognitive deficits. Pharmacological blockade of TREM-1 reduced TUNEL-positive and FJC-positive neurons, and CD68-stained microglia in ipsilateral cerebral cortex. Neutrophil invasion was inhibited as protein level of myeloperoxidase (MPO), and MPO-positive cells were both decreased. Moreover, we found that LP17 treatment ameliorated microglial pyroptosis by diminishing levels of N-terminal fragment of GSDMD (GSDMD-N) and IL-1ß production. Mechanistically, both in vivo and in vitro, we depicted that TREM-1 can trigger microglial pyroptosis via activating NLRP3 inflammasome. In conclusion, our results revealed the critical role of TREM-1 in neuroinflammation following SAH, suggesting that TREM-1 inhibition might be a potential therapeutic approach for SAH.

The Working Memory and Dorsolateral Prefrontal-Hippocampal Functional Connectivity Changes in Long-Term Survival Breast Cancer Patients Treated with Tamoxifen.

Background: Tamoxifen is the most widely used drug for treating patients with estrogen receptor-sensitive breast cancer. There is evidence that breast cancer patients treated with tamoxifen exhibit cognitive dysfunction. However, the underlying neural mechanism remains unclear. The present study aimed to investigate the neural mechanisms underlying working memory deficits in combination with functional connectivity changes in premenopausal women with breast cancer who received long-term tamoxifen treatment. Methods: A total of 31 premenopausal women with breast cancer who received tamoxifen and 32 matched healthy control participants were included. The participants completed n-back tasks and underwent resting-state functional magnetic resonance imaging, which measure working memory performance and brain functional connectivity, respectively. A seed-based functional connectivity analysis within the whole brain was conducted, for which the dorsolateral prefrontal cortex was chosen as the seed region. Results: Our results indicated that the tamoxifen group had significant deficits in working memory and general executive function performance and significantly lower functional connectivity of the right dorsolateral prefrontal cortex with the right hippocampus compared with the healthy controls. There were no significant changes in functional connectivity in the left dorsolateral prefrontal cortex within the whole brain between the tamoxifen group and healthy controls. Moreover, significant correlations were found in the tamoxifen group between the functional connectivity strength of the dorsolateral prefrontal cortex with the right hippocampus and decreased working memory performance. Conclusion: This study demonstrates that the prefrontal cortex and hippocampus may be affected by tamoxifen treatment, supporting an antagonistic role of tamoxifen in the long-term treatment of breast cancer patients.

Moral judgment in patients with idiopathic generalized epilepsy.

PURPOSE: The aim of the current study was to investigate morality while also investigating frontal lobe function with the goal of studying the relationship between frontal lobe and morality in patients with idiopathic generalized epilepsy. METHOD: A total of 23 right-handed patients with IGE and 25 right-handed healthy participants agreed to participate. Participants made judgments on a series of 50 hypothetical scenarios, which were adapted from a previously published set. The Stroop Test, verbal fluency, Digit Span tests and Wisconsin Card-Sorting Test were used to assess the frontal lobe function. RESULTS: IGE patients with impaired frontal lobe function choosed more utilitarian options than healthy controls in impersonal dilemmas but not in personal dilemmas. The performance of impersonal judgments were correlated positively with total errors positively and correlated negatively with categories completed. CONCLUSIONS: IGE patients with impaired frontal lobe function possessed unusual impersonal moral decision-making and those decisions may be caused more by cognitive impairment than by social-emotional impairment. Correlation analysis indicated that the unusual moral decisions correlated with frontal lobe dysfunction in patients with IGE.