Association among abnormal glycolipids, reproductive hormones, and cognitive dysfunction in female patients with bipolar disorder.

BACKGROUND: Patients with bipolar disorder (BD) show abnormalities in glucolipid metabolism and reproductive hormone levels, which are of concern in women with BD. This study was dedicated to investigating the glucolipid and reproductive hormone levels of female patients, and to preliminarily investigating their relationships with cognition. METHODS: A total of 58 unmedicated female BD patients, 61 stable-medicated female BD patients, and 63 healthy controls (HC) were recruited in this study. Serum glycolipid indexes and reproductive hormones were measured. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Stroop Color-Word Test (Stroop test). RESULTS: Patients with BD showed significant cognitive impairment (p < 0.05), which was not affected by medication. Triglycerides (TG), luteinizing hormone (LH), and high-density lipoprotein cholesterol (HDL-c) were altered in stable-medicated BD patients. In addition, regression analysis showed that progesterone (PRGE) and prolactin (PRL) were negatively associated with cognitive performance in stable-medicated BD patients. CONCLUSIONS: Female BD patients may have cognitive deficits and abnormal levels of glycolipids and reproductive hormones. And abnormal levels of glycolipids and reproductive hormones may be associated with cognitive dysfunction in female BD patients.

Shedding Light on the Effects of Blood Pressure on Cognitive Decline and Dementia Risk by Way of Neurobiological Evidence.

Midlife cerebrovascular risk factors increase risk of late life cognitive impairment and dementia, while their presence in patients with dementia may lead to cognitive improvement or stabilization in late life. Defining the best measure of blood pressure (BP) to be associated with cognitive decline remains debatable, also due to possible bidirectionality. BP variability, pulse pressure, systolic and diastolic BP have been associated with cognitive status, dementia risk and Alzheimer's disease biomarkers. Proper BP control notwithstanding, BP variability increases risk for pathophysiological change in the Alzheimer's disease continuum, implying the need for selection of anti-hypertensive drugs with neurobiological evidence of benefits.

Neurocognition in Pediatric Temporal Lobe Tumor-Related Epilepsy.

Tumor-related epilepsy is a common and understudied neurological comorbidity among pediatric temporal lobe tumor patients that poses risk for neurocognitive impairment (NCI). Forty-one youth with either TLT+ (n = 23) or nonneoplastic temporal lobe epilepsy (n = 18) ages 6-20 years completed routine neuropsychological evaluations. Rates of NCI were similar across groups; however, NCI was more common in nonneoplastic participants on a task of phonemic fluency, p = .047. Younger age of seizure onset and greater number of antiseizure medications were associated with NCI among TLT+ participants only. Preliminary findings suggest separate prognostic models of cognitive outcomes between TLT+ and nonneoplastic epilepsy populations may be needed.

Melatonin improves maternal sleep deprivation-induced learning and memory impairment, inflammation, and synaptic dysfunction in murine male adult offspring.

INTRODUCTION: Maternal sleep deprivation (MSD), which induces inflammation and synaptic dysfunction in the hippocampus, has been associated with learning and memory impairment in offspring. Melatonin (Mel) has been shown to have anti-inflammatory, antioxidant, and neuroprotective function. However, the beneficial effect of Mel on MSD-induced cognitive impairment and its mechanisms are unknown. METHODS: In the present study, adult offspring suffered from MSD were injected with Mel (20 mg/kg) once a day during postnatal days 61-88. The cognitive function was evaluated by the Morris water maze test. Levels of proinflammatory cytokines were examined by enzyme-linked immunosorbent assay. The mRNA and protein levels of synaptic plasticity associated proteins were examined using reverse transcription-polymerase chain reaction and western blotting. RESULTS: The results showed that MSD impaired learning and memory in the offspring mice. MSD increased the levels of interleukin (IL)-1creIL-6, and tumor necrosis factor-α and decreased the expression levels of brain-derived neurotrophic factor, tyrosine kinase receptor B, postsynaptic density protein-95, and synaptophysin in the hippocampus. Furthermore, Mel attenuated cognitive impairment and restored markers of inflammation and synaptic plasticity to control levels. CONCLUSIONS: These findings indicated that Mel could ameliorate learning and memory impairment induced by MSD, and these beneficial effects were related to improvement in inflammation and synaptic dysfunction.

Sex-specific associations of plasma neutrophil gelatinase-associated lipocalin (NGAL) with cognition in patients with drug-naïve schizophrenia.

This present study aimed to investigate the sex-specific association of plasma neutrophil gelatinase-associated lipocalin (NGAL) with cognition in drug-naïve schizophrenia patients for the first time. A total of 204 participants in this study, including 137 drug-naïve schizophrenia (DNS) patients and 67 healthy controls (HCs). All participants completed the Measurements and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB), and were collected fasting venous blood for NGAL measurement. DNS patients also complete the Positive and Negative Syndrome Scale (PANSS). Partial correlation analysis and multiple linear regression were used to explore sex-specific associations between NGAL and cognition. All dimensions of MCCB scores were significantly lower in both male and female DNS patients than HCs. Sex differences were significant in cognitive performance in both DNS patients and HCs. Female DNS patients experienced poorer working memory and reason& problem solving than male patients. Female HCs performed a better attention/vigilance and visual learning, a poorer reason& problem solving than male HCs. In patients with DNS, NGAL levels were negatively associated with positive subscale of PANSS and positively associated with working memory and visual learning only in female. However, there was no significant correlation between NGAL levels and all cognitive tests in both male and female HCs. Regression model showed that higher level of NGAL was an independent protective factor for cognitive performance in female patients with DNS, whereas there was no such role in male patients. Our findings suggest sex specificity between NGAL levels and cognitive performance in DNS patients.

Cardiovascular Health, Race, and Decline in Cognitive Function in Midlife Women: The Study of Women's Health Across the Nation.

BACKGROUND: Cognitive decline may progress for decades before dementia onset. Better cardiovascular health (CVH) has been related to less cognitive decline, but it is unclear whether this begins early, for all racial subgroups, and all domains of cognitive function. The purpose of this study was to determine the impact of CVH on decline in the 2 domains of cognition that decline first in White and Black women at midlife. METHODS AND RESULTS: Subjects were 363 Black and 402 White women, similar in baseline age (mean±SD, 46.6±3.0 years) and education (15.7±2.0 years), from the Chicago site of the Study of Women's Health Across the Nation. Cognition, measured as processing speed and working memory, was assessed annually or biennially over a maximum of 20 years (mean±SD, 9.8±6.7 years). CVH was measured as Life's Essential 8 (blood pressure, body mass index, glucose, non-high-density lipoprotein cholesterol, smoking, physical activity, diet, sleep). Hierarchical linear mixed models identified predictors of cognitive decline with progressive levels of adjustment. There was a decline in processing speed that was explained by race, age, and the 3-way interaction of race, CVH, and time (F1,4308=8.8, P=0.003). CVH was unrelated to decline in White women but in Black women poorer CVH was associated with greater decline. Working memory did not decline in the total cohort, by race, or by CVH. CONCLUSIONS: In midlife Black women, CVH promotion may be a target for preventing the beginnings of cognitive decline, thereby enhancing independent living with aging.

Association Between Subjective Masticatory Function and Mild Cognitive Impairment in Older Adults.

AIM: This study aimed to examine the effect of subjective masticatory function on the occurrence of mild cognitive impairment (MCI) by analysing the Korean Longitudinal Study of Ageing (KLoSA) data. METHODS: The study participants were 2954 KLoSA participants aged 60 years or older in the first wave (2006) who had normal cognitive function. The subjective masticatory function was determined using a survey item, and the responses were grouped into 3 categories, ie, good, moderate, and poor. The occurrence of MCI in the 3 groups was followed up until 2020. Cognitive function was assessed based on the Korean Mini-Mental State Examination score. Age, sex, education level, residence, health insurance type, smoking status, drinking status, and the number of chronic diseases were considered as potential confounders. To examine the occurrence of MCI according to subjective masticatory function, Cox proportional hazard regression analysis was performed. RESULTS: Cox proportional hazard regression models adjusted for confounders yielded the following results: in men, the risk of MCI was higher in those whose subjective masticatory function was moderate and poor, as compared to those with good subjective masticatory function (adjusted hazard ratio [aHR], 1.33; 95% confidence interval [CI], 1.12-1.58; aHR, 1.23; 95% CI, 1.04-1.46). In contrast, in women, subjective masticatory function did not significantly influence the occurrence of MCI (aHR, 1.05; 95% CI, 0.89-1.24; aHR, 1.08; 95% CI, 0.92-1.28). CONCLUSIONS: This study suggests that poor masticatory function may be a risk factor for MCI in older men.

Preoperative recovery sleep ameliorates postoperative cognitive dysfunction aggravated by sleep fragmentation in aged mice by enhancing EEG delta-wave activity and LFP theta oscillation in hippocampal CA1.

Sleep fragmentation (SF) is a common sleep problem experienced during the perioperative period by older adults, and is associated with postoperative cognitive dysfunction (POCD). Increasing evidence indicates that delta-wave activity during non-rapid eye movement (NREM) sleep is involved in sleep-dependent memory consolidation and that hippocampal theta oscillations are related to spatial exploratory memory. Recovery sleep (RS), a self-regulated state of sleep homeostasis, enhances delta-wave power and memory performance in sleep-deprived older mice. However, it remains unclear whether RS therapy has a positive effect on cognitive changes following SF in older mouse models. Therefore, this study aimed to explore whether preoperative RS can alleviate cognitive deficits in aged mice with SF. A model of preoperative 24-h SF combined with exploratory laparotomy-induced POCD was established in 18-month-old mice. Aged mice were treated with preoperative 6-h RS following SF and postoperative 6-h RS following surgery, respectively. The changes in hippocampus-dependent cognitive function were investigated using behavioral tests, electroencephalography (EEG), local field potential (LFP), magnetic resonance imaging, and neuromorphology. Mice that underwent 24-h SF combined with surgery exhibited severe spatial memory impairment; impaired cognitive performance could be alleviated by preoperative RS treatment. In addition, preoperative RS increased NREM sleep; enhanced EEG delta-wave activity and LFP theta oscillation in the hippocampal CA1; and improved hippocampal perfusion, microstructural integrity, and neuronal damage. Taken together, these results provide evidence that preoperative RS may ameliorate the severity of POCD aggravated by SF by enhancing delta slow-wave activity and hippocampal theta oscillation, and by ameliorating the reduction in regional cerebral blood flow and white matter microstructure integrity in the hippocampus.

Matrix metalloproteinase 9 (MMP-9) activity, hippocampal extracellular free water, and cognitive deficits are associated with each other in early phase psychosis.

Increasing evidence points toward the role of the extracellular matrix, specifically matrix metalloproteinase 9 (MMP-9), in the pathophysiology of psychosis. MMP-9 is a critical regulator of the crosstalk between peripheral and central inflammation, extracellular matrix remodeling, hippocampal development, synaptic pruning, and neuroplasticity. Here, we aim to characterize the relationship between plasma MMP-9 activity, hippocampal microstructure, and cognition in healthy individuals and individuals with early phase psychosis. We collected clinical, blood, and structural and diffusion-weighted magnetic resonance imaging data from 39 individuals with early phase psychosis and 44 age and sex-matched healthy individuals. We measured MMP-9 plasma activity, hippocampal extracellular free water (FW) levels, and hippocampal volumes. We used regression analyses to compare MMP-9 activity, hippocampal FW, and volumes between groups. We then examined associations between MMP-9 activity, FW levels, hippocampal volumes, and cognitive performance assessed with the MATRICS battery. All analyses were controlled for age, sex, body mass index, cigarette smoking, and years of education. Individuals with early phase psychosis demonstrated higher MMP-9 activity (p < 0.0002), higher left (p < 0.05) and right (p < 0.05) hippocampal FW levels, and lower left (p < 0.05) and right (p < 0.05) hippocampal volume than healthy individuals. MMP-9 activity correlated positively with hippocampal FW levels (all participants and individuals with early phase psychosis) and negatively with hippocampal volumes (all participants and healthy individuals). Higher MMP-9 activity and higher hippocampal FW levels were associated with slower processing speed and worse working memory performance in all participants. Our findings show an association between MMP-9 activity and hippocampal microstructural alterations in psychosis and an association between MMP-9 activity and cognitive performance. Further, more extensive longitudinal studies should examine the therapeutic potential of MMP-9 modulators in psychosis.

Social isolation and cognitive function in patients with schizophrenia: A two years follow-up study.

Cognitive impairment is a core characteristic of schizophrenia. Social isolation has been linked to impaired cognitive function among the general population. In this longitudinal study, we examined the association between social isolation and cognitive function among inpatients with schizophrenia. Two waves of data (2019 and 2021) were collected from chronic psychiatric wards. A total of 166 inpatients completed all measurements at baseline and follow-up. Social isolation was measured by incorporating the frequency of social contact and participation, while cognitive functions were assessed by the Taiwan version of the Montreal Cognitive Assessment (MoCA-T). We used multiple linear regression to evaluate the link between baseline social isolation and cognitive function. For the total sample, social isolation was significantly related to poor language abilities (ß = -0.17, p = 0.013) and delayed recall (ß = -0.15, p = 0.023). Sex-stratified analysis showed that social isolation was significantly related to poor global cognitive function (ß = -0.14, p = 0.021) and domain-specific cognitive functions including language abilities (ß = -0.26, p = 0.003) and delayed recall (ß = -0.19, p = 0.045) in male inpatients. No significant association was found between social isolation and global cognitive function or any cognitive domain (all ps > 0.05) for females. All associations were independent of loneliness and other covariates. These findings suggested that social isolation could predict poor subsequent cognitive function in inpatients with schizophrenia, especially in males. Interventions aimed at enhancing social connections could potentially improve cognitive function in this population.

An exploratory research report on brain mineralization in postoperative delirium and cognitive decline.

Delirium is a severe postoperative complication associated with poor overall and especially neurocognitive prognosis. Altered brain mineralization is found in neurodegenerative disorders but has not been studied in postoperative delirium and postoperative cognitive decline. We hypothesized that mineralization-related hypointensity in susceptibility-weighted magnetic resonance imaging (SWI) is associated with postoperative delirium and cognitive decline. In an exploratory, hypothesis-generating study, we analysed a subsample of cognitively healthy patients ≥65 years who underwent SWI before (N = 65) and 3 months after surgery (N = 33). We measured relative SWI intensities in the basal ganglia, hippocampus and posterior basal forebrain cholinergic system (pBFCS). A post hoc analysis of two pBFCS subregions (Ch4, Ch4p) was conducted. Patients were screened for delirium until the seventh postoperative day. Cognitive testing was performed before and 3 months after surgery. Fourteen patients developed delirium. After adjustment for age, sex, preoperative cognition and region volume, only pBFCS hypointensity was associated with delirium (regression coefficient [90% CI]: B = -15.3 [-31.6; -0.8]). After adjustments for surgery duration, age, sex and region volume, perioperative change in relative SWI intensities of the pBFCS was associated with cognitive decline 3 months after surgery at a trend level (B = 6.8 [-0.9; 14.1]), which was probably driven by a stronger association in subregion Ch4p (B = 9.3 [2.3; 16.2]). Brain mineralization, particularly in the cerebral cholinergic system, could be a pathomechanism in postoperative delirium and cognitive decline. Evidence from our studies is limited because of the small sample and a SWI dataset unfit for iron quantification, and the analyses presented here should be considered exploratory.

Impact of cataract surgery on cognitive impairment in older people.

OBJECTIVES: To examine the impact of cataract surgery on mild cognitive impairment (MCI) and dementia in older people. METHODS: This prospective observational study included patients aged 75 years and older who underwent cataract surgery between 2019 and 2021. Mini-mental state examination (MMSE) and MMSE for the visually impaired (MMSE-blind) were measured to evaluate cognitive function before and 3 months after cataract surgery. MMSE score at baseline was used to categorize patients into dementia (MMSE ≤ 23) and MCI groups (23 < MMSE ≤ 27). Logistic regression models were used to estimate associations between improvement in cognitive function and other factors. RESULTS: Of 132 patients screened for inclusion in the study, 88 met the inclusion criteria; 39 patients were assigned to the dementia group (mean age, 85.7 ± 4.2 years) and 49 to the MCI group (mean age, 84.2 ± 3.4 years). The MCI group showed significant improvement from before to after surgery in the MMSE score (25.65 ± 1.03 vs. 27.08 ± 1.99, respectively, p < 0.001) and MMSE-blind score (18.04 ± 1.14 vs. 19.41 ± 2.01, respectively, p < 0.001). Cognitive function improved significantly in the MCI group compared with the dementia group (odds ratio, 2.85; 95% confidence interval, 1.02-7.97; and p = 0.046). CONCLUSIONS: Cataract surgery significantly increases cognitive test scores in older patients with MCI. After cataract surgery, the likelihood of improvement in cognitive function may be highly dependent on a patient's preoperative cognitive state.

Effects of intravascular photobiomodulation on cognitive impairment and crossed cerebellar diaschisis in patients with traumatic brain injury: a longitudinal study.

The association between intravascular photobiomodulation (iPBM) and crossed cerebellar diaschisis (CCD) and cognitive dysfunction in patients with traumatic brain injury (TBI) remains unknown. We postulate that iPBM might enable greater neurologic improvements. The objective of this study was to evaluate the clinical impact of iPBM on the prognosis of patients with TBI. In this longitudinal study, patients who were diagnosed with TBI were recruited. CCD was identified from brain perfusion images when the uptake difference of both cerebella was > 20%. Thus, two groups were identified: CCD( +) and CCD( -). All patients received general traditional physical therapy and three courses of iPBM (helium-neon laser illuminator, 632.8 nm). Treatment assemblies were conducted on weekdays for 2 consecutive weeks as a solitary treatment course. Three courses of iPBM were performed over 2-3 months, with 1-3 weeks of rest between each course. The outcomes were measured using the Rancho Los Amigos Levels of Cognitive Functioning (LCF) tool. The chi-square test was used to compare categorical variables. Generalized estimating equations were used to verify the associations of various effects between the two groups. p < 0.05 indicated a statistically significant difference. Thirty patients were included and classified into the CCD( +) and CCD( -) groups (n = 15, each group). Statistics showed that before iPBM, CCD in the CCD( +) group was 2.74 (exp 1.0081) times higher than that of CCD( -) group (p = 0.1632). After iPBM, the CCD was 0.64 (exp-0.4436) times lower in the CCD( +) group than in the CCD( -) group (p < 0.0001). Cognitive assessment revealed that, before iPBM, the CCD( +) group had a non-significantly 0.1030 lower LCF score than that of CCD( -) group (p = 0.1632). Similarly, the CCD( +) group had a non-significantly 0.0013 higher score than that of CCD( -) after iPBM treatment (p = 0.7041), indicating no significant differences between the CCD( +) or CCD( -) following iPBM and general physical therapy. CCD was less likely to appear in iPBM-treated patients. Additionally, iPBM was not associated with LCF score. Administration of iPBM could be applied in TBI patients to reduce the occurrence of CCD. The study failed to show differences in cognitive function after iPBM, which still serves as an alternative non-pharmacological intervention.

Cerebrospinal fluid biomarkers that reflect clinical symptoms in idiopathic normal pressure hydrocephalus patients.

BACKGROUND: The relationship between cerebrospinal fluid (CSF) biomarkers and the clinical features of idiopathic normal pressure hydrocephalus (iNPH) has been inconclusive. We aimed to evaluate CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid ß (Aß) aggregation, tau pathology, neuroinflammation and axonal degeneration in relation to the clinical features of pre- and post-shunt surgery in iNPH patients. METHODS: Mini Mental State Examination (MMSE) scores and gait velocity were evaluated pre- and postoperatively in cohorts of 65 Finnish (FIN) and 82 Swedish (SWE) iNPH patients. Lumbar CSF samples were obtained prior to shunt surgery and analysed for soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPß); amyloid-ß isoforms of 42, 40 and 38 (Aß42, Aß40, Aß38); total tau (T-tau); phosphorylated tau (P-tau181); neurofilament light (NfL) and monocyte chemoattractant protein 1 (MCP1). RESULTS: Preoperative patient characteristics showed no significant differences between patients in the FIN and SWE cohorts. Patients in both cohorts had significantly improved gait velocity after shunt surgery (p < 0.0001). Low CSF T-tau and absence of apolipoprotein E ε4 predicted over 20% gait improvement postoperatively (p = 0.043 and p = 0.008). Preoperative CSF T-tau, P-tau181 and NfL correlated negatively with MMSE scores both pre- (p < 0.01) and post-surgery (p < 0.01). Furthermore, T-tau, NfL and Aß42 correlated with MMSE outcomes (p < 0.05). Low preoperative CSF P-tau181 (p = 0.001) and T-tau with NfL (p < 0.001 and p = 0.049) best predicted pre- and postoperative MMSE scores greater than or equal to 26. CONCLUSIONS: CSF biomarkers of neurodegeneration appeared to correlate with pre- and postoperative cognition, providing a window into neuropathological processes. In addition, preoperative CSF neurodegeneration biomarkers may have potential in the prediction of gait and cognitive outcomes after shunt surgery.

Neuropsychological performance after carotid endarterectomy.

Background: Internal carotid endarterectomy (CEA) is a method of stroke prevention in patients with severe internal carotid artery (ICA) stenosis. Patients with significant carotid stenosis tend to have lower cognitive performance than those without significant stenosis. This is believed to be due to hypoperfusion or ongoing microembolization to the brain. Methods: We evaluated 60 patients with at least 70% ICA stenosis with the RBANS test (Repeatable Battery for the Assessment of Neuropsychological Status, Czech research version), preoperatively and one month after endarterectomy. Results: Neuropsychological follow-up was completed by N = 57 patients one month after the procedure. At the group level, there was a significant improvement in Language, Attention, Delayed Memory and Total Scale Index Scores (p < 0.05). Conclusions: CEA not only decreases the long-term risk of ischemic stroke, but may also improve cognitive performance. In a small percentage of cases, there is higher risk of embolic stroke and silent microembolization due to surgery, which may have a negative impact on cognitive function. However, we did not detect any cognitive impairment after CEA in our patients.

Varenicline improves cognitive impairment in a mouse model of mPFC ischemia: The possible roles of inflammation, apoptosis, and synaptic factors.

Ischemia in the medial prefrontal cortex (mPFC) causes cognitive impairment in stroke cases. This study aimed to examine the effects of varenicline as α7 and α4ß2 nicotine acetylcholine receptors (nAChRs) agonist, on cognitive impairment, inflammation, apoptosis, and synaptic dysfunction in mPFC ischemia. Mice were divided to three groups of control, sham, or photothrombotic mPFC ischemia model. The control and sham groups received 2 ml/kg of normal saline for a 14-day period. As well, the animals in the ischemia groups received normal saline (2 ml/kg) or varenicline at 0.1, 1, and 3 mg/kg doses for a 14-day period. Anxiety-like behaviors were then assessed by open field (OFT) and elevated plus-maze (EPM) tests. Memory was also evaluated using Morris water maze (MWM) and novel object recognition (NOR) tests. The levels of inflammatory (IL-1ß, TNF-α), apoptotic (Bax, caspase3, BCL-2), and synaptic (SYP, PSD-95, and GAP-43) proteins were examined using the western blot method. In addition, the histological evaluation was performed to assess tissue damage. The administration of Varenicline at the dose of 3 mg/kg reduced the IL-1ß, TNF-α, Bax, and caspase3 levels. Moreover, it increased BCL-2, SYP, PSD-95, and GAP-43 levels at the same dose and ameliorated memory impairment and anxiety-like behaviors in mPFC ischemic mice. Varenicline improved cognitive impairment by blocking inflammation and apoptosis, improving synaptic factors, and diminishing tissue damage in the mPFC ischemic mice.

Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome.

Dravet syndrome is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. Repetitive seizures can lead to endurable and untreatable neurological deficits. Whether this severe pathology is reversible after symptom onset remains unknown. To address this question, we generated a Scn1a conditional knock-in mouse model (Scn1a Stop/+) in which Scn1a expression can be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with sudden unexpected death in epilepsy (SUDEP) and behavioral alterations including hyperactivity, social interaction deficits and cognitive impairment starting from the second/third week of age. However, we showed that Scn1a gene re-activation when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures, marked amelioration of behavioral abnormalities and normalization of hippocampal fast-spiking interneuron firing. We also identified dramatic gene expression alterations, including those associated with astrogliosis in Dravet syndrome mice, that, accordingly, were rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Nav1.1 physiological level rescued seizures also in adult Dravet syndrome mice (P90) after months of repetitive attacks. Overall, these findings represent a solid proof-of-concept highlighting that disease phenotype reversibility can be achieved when Scn1a gene activity is efficiently reconstituted in brain cells.

Cognitive impairment persists at least 1 year after juvenile rats are treated with methotrexate.

Methotrexate (MTX) is widely employed for children with cancer, but is also associated with persistent cognitive deficits among survivors. The present study investigated the mechanisms behind long-term cognitive dysfunction after juvenile animals are treated with MTX. Male and female Long-Evans rats were treated with a combination of 6 systemic doses (0.5 mg/kg/dose intraperitoneally) and 4 intrathecal doses (1 mg/kg) beginning at post-natal age 3 weeks, a schedule designed to mimic repeated exposure given to children with leukemia. Behavioral testing was conducted at 60-61 weeks of age, followed by analysis of brain histolopathology. This MTX regimen had no acute toxicity and no effect on growth. The spatial memory and visual memory deficits observed at 13 and 17 weeks of age persisted 1 year after MTX exposure in both females and males. Significantly decreased cell proliferation and increased hippocampal microglial activation were observed in MTX-treated females when compared to the controls, with a similar trend in the male groups. In addition, MTX treatment significantly increased the number of TUNEL positive cells in the periventricular area. Our study demonstrates that a clinically relevant regimen of systemic and intrathecal MTX induces persistent deficits in cognition, lasting approximately 1 year after the last injection. The mechanisms behind MTX-induced deficits are likely multifactorial, including suppression of neurogenesis, microglial activation, and increased brain cell apoptosis. Our study suggests female and male animals differ in susceptibility to MTX-induced neurotoxicity and provides insights for developing therapeutic approaches to prevent treatment related cognitive impairment among children with ALL.

The role of neutrophil gelatinase-associated lipocalin and iron homeostasis in object recognition impairment in aged sepsis-survivor rats.

Older adult patients with sepsis frequently experience cognitive impairment. The roles of brain neutrophil gelatinase-associated lipocalin (NGAL) and iron in older sepsis patients remain unknown. We investigated the effects of lipopolysaccharide-induced sepsis on novel object recognition test, NGAL levels, an inflammatory mediator tumor necrosis factor-α (TNFα) levels, and iron ion levels in the hippocampus and cortex of young and aged rats. The effect of an iron chelator deferoxamine pretreatment on aged sepsis rats was also examined. Young sepsis-survivor rats did not show impaired novel object recognition, TNFα responses, or a Fe2+/Fe3+ imbalance. They showed hippocampal and cortical NGAL level elevations. Aged sepsis-survivor rats displayed a decreased object discrimination index, elevation of NGAL levels and Fe2+/Fe3+ ratio, and no TNFα responses. Pretreatment with deferoxamine prevented the reduction in the object recognition of aged sepsis-survivor rats. The elevation in hippocampal and cortical NGAL levels caused by lipopolysaccharide was not influenced by deferoxamine pretreatment. The lipopolysaccharide-induced Fe2+/Fe3+ ratio elevation was blocked by deferoxamine pretreatment. In conclusion, our findings suggest that iron homeostasis in the cortex and hippocampus contributes to the maintenance of object recognition ability in older sepsis survivors.