Disrupted topological properties of structural brain networks present a glutamatergic neuropathophysiology in people with narcolepsy.

STUDY OBJECTIVES: Growing evidences have documented various abnormalities of the white matter bundles in people with narcolepsy. We sought to evaluate topological properties of brain structural networks, and their association with symptoms and neuropathophysiological features in people with narcolepsy. METHODS: Diffusion tensor imaging (DTI) was conducted for people with narcolepsy (n = 30) and matched healthy controls as well as symptoms assessment. Structural connectivity for each participant was generated to analyze global and regional topological properties and their correlations with narcoleptic features. Further human brain transcriptome was extracted and spatially registered for connectivity vulnerability. Genetic functional enrichment analysis was performed and further clarified using in vivo emission computed tomography data. RESULTS: A wide and dramatic decrease in structural connectivities was observed in people with narcolepsy, with descending network degree and global efficiency. These metrics were not only correlated with sleep latency and awakening features, but also reflected alterations of sleep macrostructure in people with narcolepsy. Network-based statistics identified a small hyperenhanced subnetwork of cingulate gyrus that was closely related to rapid eye movement sleep behavior disorder (RBD) in narcolepsy. Further imaging genetics analysis suggested glutamatergic signatures were responsible for the preferential vulnerability of connectivity alterations in people with narcolepsy, while additional PET/SPECT data verified that structural alteration was significantly correlated with metabotropic glutamate receptor 5 (mGlutR5) and N-methyl-D-aspartate receptor (NMDA). CONCLUSIONS: People with narcolepsy endured a remarkable decrease in the structural architecture, which was not only be closely related to narcolepsy symptoms but also glutamatergic signatures.

ADHD in narcolepsy: A closer look at prevalence and ties.

The reported prevalence of attention deficit hyperactivity disorder (ADHD) in narcolepsy varies considerably, while the associated factors remain inadequately established. A systematic search of studies published in PubMed, EMBASE, and the Cochrane Library was performed from inception to March 2023. Ten studies with 839 patients with narcolepsy were included in the study. Utilizing a random effects model, the pooled prevalence of ADHD in narcolepsy was 25% (95% CI, 14-38%). Notably, patients with narcolepsy type 2 showed a significantly higher prevalence of ADHD than that of narcolepsy type 1 (46% vs. 20%, p = 0.045). Furthermore, the rate of ADHD was notably elevated in narcolepsy compared with the healthy controls (odds ratio 9.59, 95% CI, 4.06-22.63, p < 0.001). Several factors such as excessive daytime sleepiness (EDS), fatigue, insomnia severity, and the quality of life were significantly associated with ADHD in narcolepsy (all ps < 0.05). These findings highlight the importance of monitoring and managing ADHD in narcolepsy, and provide a clue to help reducing ADHD by intervening in these associated factors.

Changed epidemiology of narcolepsy before, during, and after the 2009 H1N1 pandemic: a nationwide narcolepsy surveillance network study in mainland China, 1990-2017.

STUDY OBJECTIVES: Increased incidence of narcolepsy was reported in children during the 2009 H1N1 pandemic following Pandemrix, a H1N1 flu vaccine. A link with A(H1N1) pdm09 infections remains controversial. Using nationwide surveillance data from China (1990 to 2017), the epidemiology of narcolepsy was analyzed. METHODS: Individual records of narcolepsy patients were collected from 15 of 42 hospitals across China known to diagnose cases. Incidence was estimated assuming the representativeness of these hospitals. Age-specific incidence, epidemiological and clinical characteristics of patients were evaluated before, during, and after the 2009 H1N1 pandemic. Sensitivity analyses were conducted by including NT1 cases only and excluding the effect of the 2009 H1N1 vaccination. RESULTS: Average annual incidence was 0.79 per 100 000 person-years (PY) from 1990 to 2017 and 1.08 per 100 000 PY from 2003 to 2017. Incidence increased 4.17 (95% CI 4.12, 4.22) and 1.42 (95% CI 1.41, 1.44) fold during and after the 2009 H1N1 pandemic when compared to baseline. These results were robust in sensitivity analyses. Patients with the onset of narcolepsy during the pandemic period were younger (notably in 5-9-year-old strata), and the age shift toward younger children reversed to baseline following the pandemic. CONCLUSIONS: Increased incidence of narcolepsy was observed during the 2009 H1N1 pandemic period. This is likely to be associated with the circulation of the wild type A(H1N1)pdm09 virus. This observation should be considered for future influenza pandemic preparedness plans.

Effectiveness of one-week internet-delivered cognitive behavioral therapy for insomnia to prevent progression from acute to chronic insomnia: A two-arm, multi-center, randomized controlled trial.

Acute insomnia is common and a substantial proportion of people with acute insomnia (i.e. 3 days to 3 months) transit into chronic insomnia (i.e. 3 months or longer). Therefore, early intervention for acute insomnia is vital to prevent chronicity. Previous trials with small sample sizes have shown that brief versions of both individual and group-based face-to-face cognitive behavioral therapy for insomnia (CBT-I) can improve insomnia symptoms among those with acute insomnia. However, it is unknown whether one-week internet-delivered cognitive behavioral therapy for insomnia (CBT-I) is effective in treating acute insomnia. This was a randomized controlled trial and 192 participants were randomly assigned to the CBT-I group (n = 95) or control group (n = 97). The primary outcome was the incidence of chronic insomnia, determined via a structured diagnostic questionnaire for insomnia disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Secondary outcomes were Insomnia Severity Index (ISI), Dysfunctional Beliefs and Attitudes about Sleep (DBAS), Epworth Sleepiness Scale (ESS), Pre-sleep Arousal Scale (PSAS), Ford Insomnia Response to Stress Test (FIRST), Sleep Hygiene and Practices Scale (SHPS), Hospital Anxiety and Depression Scale (HADS), and Short-Form 12-Item Health Survey version 2 (SF-12v2). At week 12, the incidence of chronic insomnia was significantly lower in the CBT-I group compared with control group (33.3% [27/81] vs. 65.8% [52/79]). Participants in the CBT-I group achieved significantly more improvements in ISI, ESS, PSAS, FIRST, SHPS, HADS-Depression, and the mental component summary and physical component summary of SF-12v2 than control group, but not DBAS and HADS-Anxiety. This one-week internet-delivered CBT-I program is an effective tool to prevent the chronicity of acute insomnia.

Case report: Overlapping anti-AMPAR encephalitis with anti-IgLON5 disease post herpes simplex virus encephalitis.

Autoimmune encephalitis (AE) is the result of an autoimmune process that occurs as a rapidly advancing encephalopathy. Autoimmune encephalitis was commonly linked to herpes simplex virus 1 (HSV-1) as the most frequently identified virus. The main areas affected by this invasion are the temporal lobe, frontal lobe, and limbic system. Limbic encephalitis is a highly uncommon occurrence involving anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis and anti-IgLON family member 5 (IgLON5) disease, both belonging to the rare category. As far as we know, this is the first report showing that a patient diagnosed with AMPAR encephalitis overlapped with anti-IgLON5 disease post herpes simplex virus encephalitis (HSE), which helps to broaden the range of this uncommon autoimmune disease. We recommend autoantibody testing in all patients with HSE, particularly those involving neurological relapses or progression.

Densely granulated adenoma pattern is associated with an increased risk of obstructive sleep apnea in patients with acromegaly.

OBJECTIVES: To explore the prevalence of obstructive sleep apnea (OSA) and the association between the adenoma granulation patterns and OSA in patients with acromegaly. METHODS: An overnight polysomnography (PSG) assessment was carried out on participants with acromegaly. Results classified participants into a non-OSA group, mild to moderate OSA group, and severe OSA group. Morphological and biochemical analyses were performed. Demographic, clinical, biochemical, and polysomnographic data were compared among the three groups. Using logistic regression models, the risk of OSA in acromegalic subjects was estimated. RESULTS: OSA was reported in 36 of 49 patients (74%) with acromegaly. Contrasted with the non-OSA group, OSA patients had a larger proportion of the densely granulated (DG) pattern. The OSA groups with DG acromegaly had a smaller maximum tumor diameter and Vol/2 than those with the sparsely granulated (SG) pattern. Furthermore, a higher growth hormone (GH) level (45.0 ± 36.9 vs 18.6 ± 15.8, P = 0.047) and GH index (28.4 ± 13.8 vs 6.6 ± 8.2, P = 0.003) were found in DG acromegaly patients with severe OSA. Additionally, there was a trend toward higher standardized insulin-like growth factor 1 (IGF-1) in patients with DG acromegaly than in those with SG acromegaly in the severe OSA group. After adjusting for potential confounding variables, the DG pattern was correlated with the risk of OSA (OR = 14.84, 95%CI 1.36-162.20, P = 0.027) in patients with acromegaly. CONCLUSIONS: The findings indicate that a high prevalence of OSA exists in patients with acromegaly, and the DG pattern may be a risk factor for OSA in acromegaly.

Characteristics of Objective Sleep and Its Related Risk Factors Among Parkinson's Disease Patients With and Without Restless Legs Syndrome.

Objective: This study aimed to investigate the objective sleep characteristics and their related risk factors among Parkinson's disease (PD) patients with and without restless legs syndrome (RLS). Methods: A total of 125 patients with PD who underwent overnight polysomnography (PSG) were recruited consecutively. Eighty-one patients, including 27 PD with RLS (PD-RLS) and 54 PD without RLS (PD-NRLS), were included in the final analysis after 1:2 propensity score matching. Demographic, clinical, and polysomnographic data were compared between PD patients with and without RLS. The risk factors for sleep quality were examined using a multiple linear regression model. Results: The prevalence of RLS among PD patients was 28.0% (35/125). The PD-RLS group exhibited a higher score for the Unified Parkinson Disease Rating Scale (UPDRS) III than the PD-NRLS group. Also, the PD-RLS patients displayed significantly shorter total sleep times, worse sleep quality, decreased stage 3 duration, a longer wake time after sleep onset, and a higher arousal index than those without RLS (all p < 0.05). In the multiple linear regression model, PD duration (ß = -0.363, 95% CI: -0.652 to -0.074; p = 0.016), UPDRS-III (ß = -0.356, 95% CI: -0.641 to -0.071; p = 0.016), and periodic limb movement index (PLMI) (ß = -0.472, 95% CI: -0.757 to -0.187; p = 0.002) were determined to be the risk factors influencing sleep quality in PD-RLS patients. The UPDRS-III (ß = -0.347, 95% CI: -0.590 to -0.104; p = 0.006) and HAMD scores (ß = -0.343, 95% CI: -0.586 to -0.100; p = 0.007) were significantly associated with sleep quality after adjusting for confounding factors in PD-NRLS patients, respectively. Conclusions: PD-RLS patients exhibited more disturbed and fragmented sleep in objective sleep architecture than PD-NRLS patients. The severity of motor symptoms in PD was significantly associated with poor sleep quality in both PD-RLS and PD-NRLS patients. Notably, our findings indicated that periodic limb movements during sleep (PLMS) was the risk factor that influenced the objective sleep quality in PD patients with RLS.

Rapid eye movement sleep and slow wave sleep rebounded and related factors during positive airway pressure therapy.

This study aimed to investigate the clinical characteristics and predictors of increased rapid eye movement (REM) sleep or slow wave sleep (SWS) in patients with obstructive sleep apnea (OSA) following positive airway pressure (PAP) therapy. The study retrospectively analyzed data from patients with OSA who underwent both diagnostic polysomnography (PSG) and pressure titration PSG at the Tangdu Hospital Sleep Medicine Center from 2011-2016. Paired diagnostic PSG and pressure titration studies from 501 patients were included. REM rebound was predicted by a higher oxygen desaturation index, lower REM proportion, higher arousal index, lower mean pulse oxygen saturation (SpO2), higher Epworth sleepiness score and younger age (adjusted R2 = 0.482). The SWS rebound was predicted by a longer total duration of apneas and hypopneas, lower N3 duration, lower SpO2 nadir, lower REM proportion in diagnostic PSG and younger age (adjusted R2 = 0.286). Patients without REM rebound or SWS rebound had a high probability of comorbidities with insomnia and mood complaints. Some parameters (subjective and objective insomnia, excessive daytime sleepiness, age and OSA severity) indicate changes in REM sleep and SWS between diagnostic and titration PSG tests. Treatment of insomnia and mood disorders in patients with OSA may helpful to improve the use PAP.

Ginsenoside Rd attenuates mouse experimental autoimmune neuritis by modulating monocyte subsets conversion.

Guillain-Barré Syndrome (GBS), characterized by peripheral nerve demyelination and axonal damage, is initiated and aggravated through various of immunopathogenesis. Ginsenoside Rd, main active components extracted from ginseng saponins, is known to exhibit immune-regulate functions in many immune-mediated diseases. However, the evidence of preventive effect of Ginsenoside Rd on GBS is lacking. Experimental autoimmune neuritis (EAN) mice, classic model of GBS, were established and treated with GSRd or vehicle. Clinical score and nerve tissue histomorphology were evaluated. Monocytes in peripheral blood and tissue were detected by flow cytometry analysis and immunofluorescence staining. For the in vitro study, GSRd and vehicle were added in the culture medium to assess their regulatory function on monocytes phenotype. In vivo data showed a protective role of GSRd on alleviating symptoms and tissue damage on Day 20 and 25. Administration of GSRd increased non-classical Ly6Clo monocytes in both peripheral blood and injured nerve tissue, and also switched tissue macrophages phenotype into resolution-phase. In vitro study indicated similar role of GSRd on monocytes differentiation status. Transcription factors like Nr4a1 were elevated after GSRd treatment. These findings revealed the protective role of GSRd against EAN, and potential preventive function on GBS patients.

Effects of transcranial direct current stimulation on performance and recovery sleep during acute sleep deprivation: a pilot study.

BACKGROUND: Previous studies claimed that transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) improves cognition in neuropsychiatric patients with cognitive impairment, schizophrenia, organic hypersomnia, etc, but few studies evaluated the effects of tDCS on cognitive improvement following sleep deprivation. The objective of this study was to determine whether tDCS (anode on the left DLPFC and cathode on the right DLPFC with a 2-mA current for 30 min) improves cognition following sleep deprivation. METHODS: Seven participants received active tDCS and eight participants received sham tDCS when their cognition declined during at least 30 h of sleep deprivation. All participants completed the psychomotor vigilance task, Trail Making Tests A and B, digit cancellation test, Stroop color word test, the Brief Visuospatial Memory Test-Revised and a procedural game every 2 h during the sleep deprivation and after recovery sleep. RESULTS: Compared to the sham stimulation, active tDCS (anode on the left DLPFC and cathode on the right DLPFC at a 2-mA current for 30 min) had beneficial effects on attention, memory, executive function, processing speed, and the ability to inhibit cognitive interference, and improved in subjective drowsiness and fatigue following sleep deprivation. The lasting effect of a single tDCS on cognition during sleep deprivation was greater than 2 h. In all participants, tDCS did not disturb recovery sleep, and cognitive performance recovered to the baseline levels after recovery sleep. CONCLUSIONS: The study results indicate that tDCS can improve cognition following sleep deprivation and does not disturb recovery sleep or cognitive performance after recovery sleep. The possible pathophysiological mechanisms might be related to the modulation of the corticothalamic pathway. We believe that tDCS can be applied in the treatment of sleep disorders involving sleepiness. TRIAL REGISTRATION NUMBER: ChiCTR2000029420. DATE OF REGISTRATION: 2020-1-31.

Association between leg motor restlessness and depression among Chinese males living at high-altitude: the mediating role of insomnia.

OBJECTIVE: Previous research has documented an association between insomnia and depression among patients with restless legs syndrome (RLS)/Willis-Ekbom disease. Given that leg motor restlessness (LMR) is closely related to RLS, the purpose of this study was to investigate the prevalence of insomnia and depression among individuals with LMR. In addition, we examined the associations among LMR, insomnia, and depression in a sample of young Chinese men living in high-altitude areas. METHODS: Chinese military personnel working on the Qinghai Tibet Plateau (Lhasa, an altitude of 3600 m) were recruited in 2019 to complete a series of questionnaires. Participants having the urge to move their legs but not meeting the diagnostic criteria for RLS were classified as having LMR. Hierarchical linear regressions and mediational analyses using the SPSS PROCESS macro in SPSS were conducted to examine the associations among LMR, insomnia, and depression. RESULTS: Of 196 participants, 36 (18%) had LMR. Only 1 participant was diagnosed with RLS. The proportions of participants suffering from insomnia who had LMR and did not have LMR were 44% and 22%, respectively. For depression, the proportions were 47% and 28%, respectively. Results of the hierarchical linear regressions showed that both LMR and depression were associated with increased insomnia symptoms. In addition, results from the mediational analyses indicated that the indirect effect of LMR on depression was significant and accounted for 52% of the total effect. CONCLUSIONS: Participants with LMR had a higher prevalence of insomnia and depression compared with those without LMR. In addition, LMR was correlated with depression, and insomnia played a significant role in this co-occurrence.

Mediator Med23 Regulates Adult Hippocampal Neurogenesis.

Mammalian Mediator (Med) is a key regulator of gene expression by linking transcription factors to RNA polymerase II (Pol II) transcription machineries. The Mediator subunit 23 (Med23) is a member of the conserved Med protein complex and plays essential roles in diverse biological processes including adipogenesis, carcinogenesis, osteoblast differentiation, and T-cell activation. However, its potential functions in the nervous system remain unknown. We report here that Med23 is required for adult hippocampal neurogenesis in mouse. Deletion of Med23 in adult hippocampal neural stem cells (NSCs) was achieved in Nestin-CreER:Med23flox/flox mice by oral administration of tamoxifen. We found an increased number of proliferating NSCs shown by pulse BrdU-labeling and immunostaining of MCM2 and Ki67, which is possibly due to a reduction in cell cycle length, with unchanged GFAP+/Sox2+ NSCs and Tbr2+ progenitors. On the other hand, neuroblasts and immature neurons indicated by NeuroD and DCX were decreased in number in the dentate gyrus (DG) of Med23-deficient mice. In addition, these mice also displayed defective dendritic morphogenesis, as well as a deficiency in spatial and contextual fear memory. Gene ontology (GO) analysis of hippocampal NSCs revealed an enrichment in genes involved in cell proliferation, Pol II-associated transcription, Notch signaling pathway and apoptosis. These results demonstrate that Med23 plays roles in regulating adult brain neurogenesis and functions.

Gender differences in clinical manifestations and polysomnographic findings in Chinese patients with obstructive sleep apnea.

PURPOSE: The gender differences in patients with obstructive sleep apnea (OSA) are not fully understood so far, as previous studies had conflicting results. No reports have addressed the differences in OSA between Chinese men and women. Therefore, the purpose of this study was to investigate the clinical and polysomnographic differences between Chinese men and women with OSA. METHODS: This case-paired control retrospective study included 580 consecutive Chinese patients (290 males and 290 females) newly diagnosed as OSA by overnight polysomnography from the Sleep Disorders Center of Tangdu Hospital affiliated to the Fourth Military Medical University of China. Demographic, clinical, and polysomnographic data of men and women with OSA were compared. Order logistic regression analysis was used to determine the risk factors for OSA severity. RESULTS: Male and female patients had similar age (57.3 ± 9.2 vs. 58.2 ± 8.9, p > 0.05) and body mass index (BMI) (25.4 ± 3.4 vs. 25.5 ± 3.9, p > 0.05). Women more commonly presented with insomnia (70.3% vs. 40.3%, p < 0.001), poor sleep quality (58.3% vs. 40.7%, p < 0.001), and headache on awakening (23.1% vs. 13.8%, p < 0.01) than men, while men more frequently reported habitual snoring (69.0% vs. 52.1%, p < 0.001) compared with women. The apnea-hypopnea index (AHI) during total sleep time and non-rapid eye movement sleep was higher in men compared with women (25.8 ± 20.4 vs. 19.3 ± 16.8; 22.0 ± 18.2 vs. 15.1 ± 15.4; p < 0.001, respectively), whereas AHI during rapid eye movement sleep was higher in women than in men (4.2 ± 3.6 vs. 3.7 ± 4.3, p < 0.01). Compared with men, women had lower sleep efficiency (75.4 ± 15.7 vs. 78.1 ± 15.5, p < 0.05), longer REM latency (128.9 ± 88.6 vs. 107.7 ± 72.4, p < 0.01), and greater wakefulness after sleep onset (WASO) (98.3 ± 70.2 vs. 88.0 ± 70.3, p < 0.05). No significant differences in the lowest oxygen desaturation and oxygen desaturation index (ODI) were observed between men and women (80.4 ± 10.8 vs. 80.8 ± 9.0; 17.0 ± 20.9 vs. 13.1 ± 16.5; p > 0.05, respectively). In addition, ordinal logistic regression analysis identified neck circumference as an independent risk factor for OSA severity in male patients (OR, 1.161; 95% CI, 1.020-1.325; p < 0.05) and in female patients (OR, 1.163; 95% CI, 1.013-1.338; p < 0.05). CONCLUSIONS: Overall, female patients had less severe OSA when compared with male patients. The female patients more commonly reported "atypical" OSA symptoms, while male patients more frequently reported "typical" OSA symptoms. In clinical practices, physicians dealing with OSA need to take the gender disparity into consideration for more precise diagnosis and treatment, as women may be atypically symptomatic at a less severe OSA.

Expression of DCX and Transcription Factor Profiling in Photothrombosis-Induced Focal Ischemia in Mice.

Adult neurogenesis is present in the dentate gyrus and the subventricular zone in mammalian brain under physiological conditions. Recently, adult neurogenesis has also been reported in other brain regions after brain injury. In this study, we established a focal striatal ischemic model in adult mice via photothrombosis (PT) and investigated how focal ischemia elicits neurogenesis in the striatum. We found that astrocytes and microglia increased in early post-ischemic stage, followed by a 1-week late-onset of doublecortin (DCX) expression in the striatum. The number of DCX-positive neurons reached the peak level at day 7, but they were still observed at day 28 post-ischemia. Moreover, Rbp-J (a key effector of Notch signaling) deletion in astrocytes has been reported to promote the neuron regeneration after brain ischemia, and we provided the change of gene expression profile in the striatum of astrocyte-specific Rbp-J knockout (KO) mice glial fibrillary acidic protein (GFAP-CreER:Rbp-Jfl/fl), which may help to clarify detailed potential mechanisms for the post-ischemic neurogenesis in the striatum.

Expression of transcription factor Satb2 in adult mouse brain.

Previous investigations on the expression and function of special AT-rich sequence binding protein 2 (Satb2) are largely limited to the cerebral cortex. Here, we explore the expression of Satb2 thoroughly by immunohistochemistry in the adult mouse central nervous system (CNS). Besides the cerebral cortex, we found that Satb2 is specifically expressed in the bed nucleus of the stria terminalis, horizontal limb of the diagonal band, lateral hypothalamic area, arcuate nucleus, hypothalamic paraventricular nucleus, ventral tegmental nucleus, laterodorsal tegmental nucleus, dorsal raphe nucleus, rostral periolivary region, and parabrachial nucleus. Double immunostaining showed that Satb2 is exclusively expressed in the excitatory neurons of neocortex. In addition, Satb2 is specifically expressed in A12 group of hypothalamic dopaminergic neurons and in serotonergic neurons in the dorsal part of the dorsal raphe nucleus. Our results present a comprehensive overview of Satb2 expression in the adult brain and provide insights for studying the role of Satb2 in the mature CNS.

Citalopram alleviates chronic stress induced depression-like behaviors in rats by activating GSK3ß signaling in dorsal hippocampus.

Aside from monoamine disturbances, recent evidence has implicated particular intracellular pathways, including Wnt signaling, in the pathogenesis of major depressive disorder. In the present study, we investigated the role of Wingless (Wnt)-Dishevelled (DVL)-glycogen synthase kinase 3ß (GSK3ß) signaling in the depression-like behaviors exhibited by rats exposed to chronic forced swim stress. We found that the rats subjected to forced swim stress for 14 consecutive days exhibited obvious depression-like behaviors and showed decreased levels of phosphorylated GSK3ß and ß-catenin in the hippocampus. Chronic citalopram treatment alleviated the depression-like behaviors and reversed the disruptions of the phosphorylated GSK3ß and ß-catenin in stressed rats. Furthermore, when the stressed rats with citalopram treatment received bilateral, dorsal hippocampus infusions of a DVL inhibitor, sulindac, the depression-like effects induced by chronic stress reappeared. These findings suggest that the Wnt-DVL-GSK3ß signaling in the hippocampus is markedly involved in the pathophysiology of depression induced by chronic stress. The Wnt-DVL-GSK3ß pathway may mediate the therapeutic action of citalopram, and the manipulation of DVL could be a target for novel antidepressants.

Early memory deficits precede plaque deposition in APPswe/PS1dE9 mice: involvement of oxidative stress and cholinergic dysfunction.

A large body of evidence has shown that cognitive deficits occur early, before amyloid plaque deposition, suggesting that soluble amyloid-ß protein (Aß) contributes to the development of early cognitive dysfunction in Alzheimer disease (AD). However, the underlying mechanism(s) through which soluble Aß exerts its neurotoxicity responsible for cognitive dysfunction in the early stage of AD remains unclear so far. In this study, we used preplaque APPswe/PS1dE9 mice ages 2.5 and 3.5 months to examine alterations in cognitive function, oxidative stress, and cholinergic function. We found that only soluble Aß, not insoluble Aß, was detected in these preplaque APPswe/PS1dE9 mice. APPswe/PS1dE9 mice 2.5 months of age did not show any significant changes in the measures of cognitive function, oxidative stress, and cholinergic function, whereas 3.5-month-old APPswe/PS1dE9 mice exhibited spatial memory impairment in the Morris water maze, accompanied by significantly decreased acetylcholine (ACh), choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-px) as well as increased malondialdehyde (MDA) and protein carbonyls. In 3.5-month-old preplaque APPswe/PS1dE9 mice, correlational analyses revealed that the performance of impaired spatial memory was inversely correlated with soluble Aß, MDA, and protein carbonyls, as well as being positively correlated with ACh, ChAT, SOD, and GSH-px; soluble Aß level was inversely correlated with ACh, ChAT, SOD, and GSH-px, as well as being positively correlated with MDA and protein carbonyls; ACh level showed a significant positive correlation with ChAT, SOD, and GSH-px, as well as a significant inverse correlation with MDA and protein carbonyls. Collectively, this study provides direct evidence that increased oxidative damage and cholinergic dysfunction may be early pathological responses to soluble Aß and involved in early memory deficits in the preplaque stage of AD. These findings suggest that early antioxidant therapy and improving cholinergic function may be a promising strategy to prevent or delay the onset and progression of AD.

Multiple inflammatory pathways are involved in the development and progression of cognitive deficits in APPswe/PS1dE9 mice.

Increased accumulation of amyloid-beta peptide (Aß) and neuroinflammation is known to exist within the Alzheimer's disease (AD) brain. However, it remains unclear which form of Aß pathologies triggers neuroinflammation and whether increased neuroinflammation contributes to cognitive deficits in AD. In the present study we found that increased inflammatory responses might occur early in preplaque APPswe/PS1dE9 mice, and were significantly enhanced in both early- and late-plaque APPswe/PS1dE9 mice. Correlational analysis revealed that multiple inflammatory indexes significantly correlated with soluble Aß level, rather than amyloid plaque burden or insoluble Aß level, in APPswe/PS1dE9 mice. Moreover, multiple inflammatory indexes highly correlated with the impaired spatial learning and memory in APPswe/PS1dE9 mice. Collectively, these results provide evidence that inflammatory responses might be likely triggered by soluble toxic Aß species. Importantly, we demonstrate for the first time that multiple inflammatory pathways might be involved in the development and progression of cognitive deficits in APPswe/PS1dE9 mice, suggesting that a pharmacological approach targeting multiple inflammatory pathways may be a novel promising strategy to prevent or delay AD.