An Efficient Epilepsy Prediction Model on European Dataset with Model Evaluation Considering Seizure Types.

This paper develops a computationally efficient model for automatic patient-specific seizure prediction using a two-layer LSTM from multichannel intracranial electroencephalogram time-series data. We decrease the number of parameters by employing a smaller input size and fewer electrodes, thereby making the model a viable option for wearable and implantable devices. We test the proposed prediction model on 26 patients from the European iEEG dataset, which is the largest epileptic seizure dataset. We also apply an automatic preprocessing technique based on a common average reference to remove artifacts from this dataset. The simulation results show that the model with its simple structure in conjunction with the mean post-processing procedure performed the best, with an average AUC of 0.885. This study is the first that utilizes the European database for epilepsy prediction application and the first that analyzes the effect of the seizure type on the system performance and demonstrates that the seizure type has a considerable impact.

Prevalence and risk factors for atypical femoral fracture among Lebanese patients with hip and shaft fractures.

This retrospective study investigates the prevalence of atypical femoral fractures (AFFs) among patients admitted with hip and shaft fractures at a tertiary referral center in Beirut, Lebanon. We analyzed electronic medical records and radiology studies of patients aged above 40 admitted with hip and shaft fractures between January 2006 and December 2019. Fractures were confirmed by ICD9 or ICD10 codes. All cases were reviewed by radiologists, and AFFs were identified according to the 2013 revised ASBMR criteria. We identified 1366 hip and shaft fracture patients, of which 14 female patients had 19 AFFs. This represents a prevalence of 1.0% among all hip and shaft fractures patients and 1.7% among all female hip and shaft fracture patients. Bilateral AFFs were found in 5 of the 14 patients. Patients with AFF tended to be younger, with a mean age of 74.3 (±8.6) yr compared to 78.0 (±10.6) for patients with non-AFF fractures. A total of 36% of AFF patients had a prior history of non-traumatic fracture at first admission. A high percentage of patients with AFFs reported intake of proton pump inhibitors (42.9%) and glucocorticoids (21.4%). Bisphosphonate exposure was noted in 64.3% of AFF patients. None of the AFF patients were active smokers or consumed alcohol regularly. BMD assessments were available for 7 AFF patients, indicating osteoporosis in 4 and osteopenia in 3 cases. Hip axis length measurements showed no significant difference between AFF patients (N = 7) and sex and age-matched controls (N = 21). The study underlines the prevalence and characteristics of AFFs in Lebanon, which is consistent with the numbers reported in the literature (0.32%-5%). A larger prospective study that includes hospitals across the nation is needed to gain a more comprehensive view of the prevalence of AFFs in the Lebanese population.

Metabolomics of repetitive myocardial stunning in chronic multivessel coronary artery stenosis: Effect of non-selective and selective ß1-receptor blockers.

Chronic coronary artery stenosis can lead to regional myocardial dysfunction in the absence of myocardial infarction by repetitive stunning, hibernation or both. The molecular mechanisms underlying repetitive stunning-associated myocardial dysfunction are not clear. We used non-targeted metabolomics to elucidate responses to chronically stunned myocardium in a canine model with and without ß-adrenergic blockade treatment. After development of left ventricular systolic dysfunction induced by ameroid constrictors on the coronary arteries, animals were randomized to 3 months of placebo, metoprolol or carvedilol. We compared these two ß-blockers with their different ß-adrenergic selectivities on myocardial function, perfusion and metabolic pathways involved in tissue undergoing chronic stunning. Control animals underwent sham surgery. Dysfunction in stunned myocardium was associated with reduced fatty acid oxidation and enhanced ketogenic amino acid metabolism, together with alterations in mitochondrial membrane phospholipid composition. These changes were consistent with impaired mitochondrial function and were linked to reduced nitric oxide and peroxisome proliferator-activated receptor signalling, resulting in a decline in adenosine monophosphate-activated protein kinase. Mitochondrial changes were ameliorated by carvedilol more than metoprolol, and improvement was linked to nitric oxide and possibly hydrogen sulphide signalling. In summary, repetitive myocardial stunning commonly seen in chronic multivessel coronary artery disease is associated with adverse metabolic remodelling linked to mitochondrial dysfunction and specific signalling pathways. These changes are reversed by ß-blockers, with the non-selective inhibitor having a more favourable impact. This is the first investigation to demonstrate that ß-blockade-associated improvement of ventricular function in chronic myocardial stunning is associated with restoration of mitochondrial function. KEY POINTS: The mechanisms responsible for the metabolic changes associated with repetitive myocardial stunning seen in chronic multivessel coronary artery disease have not been fully investigated. In a canine model of repetitive myocardial stunning, we showed that carvedilol, a non-selective ß-receptor blocker, ameliorated adverse metabolic remodelling compared to metoprolol, a selective ß1-receptor blocker, by improving nitric oxide synthase and adenosine monophosphate protein kinase function, enhancing calcium/calmodulin-dependent protein kinase, probably increasing hydrogen sulphide, and suppressing cyclic-adenosine monophosphate signalling. Mitochondrial fatty acid oxidation alterations were ameliorated by carvedilol to a larger extent than metoprolol; this improvement was linked to nitric oxide and possibly hydrogen sulphide signalling. Both ß-blockers improved the cardiac energy imbalance by reducing metabolites in ketogenic amino acid and nucleotide metabolism. These results elucidated why metabolic remodelling with carvedilol is preferable to metoprolol when treating chronic ischaemic left ventricular systolic dysfunction caused by repetitive myocardial stunning.

Soluble epoxide hydrolase inhibition reverses cognitive dysfunction in a mouse model of metabolic syndrome by modulating inflammation.

Midlife metabolic syndrome (MetS) is associated with cognitive impairment in late life. The mechanism of delayed MetS-related cognitive dysfunction (MetSCD) is not clear, but it has been linked to systemic inflammation and chronic cerebral microangiopathy. Currently there is no treatment for late life MetSCD other than early risk factor modification. We investigated the effect of soluble epoxide hydrolase (sEH) inhibitor 4-[[trans-4-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]cyclohexyl]oxy]-benzoic acid (t-AUCB) on cognitive performance, cerebral blood flow (CBF), and central and peripheral inflammation in the high-fat diet (HFD) model of MetS in mice. At 6 weeks of age, male mice were randomly assigned to receive either HFD or standard chow (STD) for 6 months. Mice received either t-AUCB or vehicle for 4 weeks. Cognitive performance was evaluated, followed by CBF measurement using magnetic resonance imaging (MRI). At the end of the study, blood was collected for measurement of eicosanoids and inflammatory cytokines. The brains were then analyzed by immunohistochemistry for glial activation markers. The HFD caused a significant impairment in novel object recognition. Treatment with t-AUCB increased plasma levels of 14,15-EET, prevented this cognitive impairment and modified hippocampal glial activation and plasma cytokine levels, without affecting CBF in mice on HFD. In conclusion, sEH inhibition for four weeks prevents cognitive deficits in mice on chronic HFD by modulating inflammatory processes without affecting CBF.

BASET scoring: A novel simple biometric score for screening and grading obstructive sleep apnea.

Background: Polysomnography (PSG) is the gold-standard diagnostic tool for Obstructive Sleep Apnea (OSA). However, the availability of PSG is limited, and OSA is widely underdiagnosed; more than 80% of most developed nations undiagnosed. There is no diagnostic validated simple tool with clear cutoff point for predicting and roll out patient with OSA in primary care clinics significantly alters clinical outcomes. Objectives: Our study aimed to assess the validity of BASET scoring as a new potential tool for screening and grading the severity of OSA patients. Methods: After institution review board approval and formal patient consent, 144 subjects for suspected OSA and their relatives were enrolled. All subjects were subjected to a full night PSG study after history taking, sleep questionnaires, and physical examination, including BASET score components: B= Body Mass Index (BMI), A= Abdominal circumference (AC), S = Snoring, E= Epworth Sleepiness Scale, and T= Tongue teeth imprint. ROC analysis that used to assess the optimal cutoff point of the BASET score and to compare its accuracy for predicting OSA with Berlin and STOP-Bang scores. Results: This study included 63 OSAS patients, 33 (52.38%) males and 30 (47.62%) females, and 81 controls; 22 (27.16%) males and 50 (72.84%) females. The Cronbach's alpha for the 5 BASET score components was 0.846, indicating the internal consistency reliability of the scale. Moreover, BASET score has a moderately strong positive significant correlation (r = 0.778, p<0.001) with AHI. By ROC analysis, the accuracy of the three measures was generally high, with BASET score predicting OSA most accurately (AUC=0.984, 95%CI: 0.956-0.999), followed by STOP-Bang (AUC=0.939, 95%CI: (0.887-0.972) and Berlin (AUC=0.901, 95%CI: 0.841-0.945). The AUC of BASET score was significantly higher compared to the Berlin score (difference= 0.0825, 95%CI: 0.039-0.125) and STOP-Bang score (difference= 0.0447, 95%CI: 0.011-0.078). On the other hand, there was no difference between the AUC of Berlin and STOP-Bang scores (difference=0.0378, 95%CI: 0.006 - 0.081 4). BASET score was significantly (p<0.001) associated with OSA grades. Conclusion: BASET score is a convenient, reliable, and valid tool for diagnosing OSA. BASET score is more accurate for predicting OSA than Berlin and STOP-Bang scores, while there is no difference between Berlin and STOP-Bang scores. BASET score indicates OSA grades. Registration of clinical trials by number: NCT05511974. Name of the registry: ClinicalTrials.gov URL: https://clinicaltrials.gov/.

Cytochrome P450-derived eicosanoids in brain: From basic discovery to clinical translation.

Cytochrome P450 metabolism of arachidonic acid produces epoxyeicosatrienoates (EETs) and hydroxyeicosatetraenoates (HETEs). Both classes of eicosanoids play important and opposing roles in brain function and disease. EETs promote vasodilation and exhibit antiinflammatory and cytoprotective properties; their biological action is blunted by metabolism to less active diols by the enzyme soluble epoxide hydrolase (sEH). EETs levels are dysregulated in disease states, primarily due to increased activity of sEH. Inhibition of sEH is a promising therapeutic approach for multiple brain disorders including stroke, dementia, subarachnoid hemorrhage and epilepsy. In this chapter, we summarize evidence implicating P450 eicosanoids and their synthetic and metabolizing enzymes in brain health and disease, and experimental and clinical studies targeting these pathways for brain disorders. We also discuss the diagnostic utility of quantifying P450 eicosanoids and their enzymes as disease biomarkers. Remarkable progress has been achieved in translating basic science discoveries in this field clinically.

Low-Intensity Ultrasound Reduces Brain Infarct Size by Upregulating Phosphorylated Endothelial Nitric Oxide in Mouse Model of Middle Cerebral Artery Occlusion.

OBJECTIVE: There have been attempts to use therapeutic ultrasound (US) for the treatment of both experimental and clinical stroke. We hypothesized that low-intensity US has direct beneficial effects on the brain independent of cerebral blood flow (CBF) during middle cerebral artery occlusion (MCAO). METHODS: Three groups of mice were studied. Group I included 84 mice with MCAO undergoing US treatment/no treatment at two US frequencies (0.25 and 1.05 MHz) with three different acoustic pressures at each frequency in which infarct size (IS) was measured 24 h later. Group II included 11 mice undergoing treatment based on best US results from group I animals in which the IS/risk area (RA) ratio was measured 24 h later. Group III included 38 normal mice undergoing US treatment/no treatment for assessment of CBF, tissue metabolite and protein expression and histopathology. DISCUSSION: Ultrasound at both frequencies and most acoustic pressures resulted in reduction in IS in group I animals, with the best results obtained with 0.25 MHz at 2.0 MPa: IS was reduced 4-fold in the cerebral cortex, 1.5-fold in the caudate putamen and 3.5-fold in the cerebral hemisphere compared with control. US application in group III animals elicited only a marginal increase in CBF despite a 2.6-fold increase in phosphorylated endothelial nitric oxide synthase (p-eNOS)-S1177 and a corresponding decrease in p-eNOS-T494. Histopathology revealed no evidence of hemorrhage, inflammation or necrosis. CONCLUSION: Low-intensity US at specific frequencies and acoustic pressures results in marked neuroprotection in a mouse model of stroke by modulation of p-eNOS independent of its effect on CBF.

Role of Inflammatory Processes in Hemorrhagic Stroke.

Hemorrhagic stroke is the deadliest form of stroke and includes the subtypes of intracerebral hemorrhage and subarachnoid hemorrhage. A common cause of hemorrhagic stroke in older individuals is cerebral amyloid angiopathy. Intracerebral hemorrhage and subarachnoid hemorrhage both lead to the rapid collection of blood in the central nervous system and generate inflammatory immune responses that involve both brain resident and infiltrating immune cells. These responses are complex and can contribute to both tissue recovery and tissue injury. Despite the interconnectedness of these major subtypes of hemorrhagic stroke, few reviews have discussed them collectively. The present review provides an update on inflammatory processes that occur in response to intracerebral hemorrhage and subarachnoid hemorrhage, and the role of inflammation in the pathophysiology of cerebral amyloid angiopathy-related hemorrhage. The goal is to highlight inflammatory processes that underlie disease pathology and recovery. We aim to discuss recent advances in our understanding of these conditions and identify gaps in knowledge with the potential to develop effective therapeutic strategies.

Fluid dynamics in aging-related dementias.

Recent human and animal model experimental studies revealed novel pathways for fluid movement, immune cell trafficking and metabolic waste clearance in CNS. These studies raise the intriguing possibility that the newly discovered pathways, including the glymphatic system, lymphatic meningeal vessels and skull-brain communication channels, are impaired in aging and neurovascular and neurodegenerative diseases associated with dementia, including Alzheimer's disease (AD) and AD-related dementia. We provide an overview of the glymphatic and dural meningeal lymphatic systems, review current methods and approaches used to study glymphatic flow in humans and animals, and discuss current evidence and controversies related to its role in CNS flow homeostasis under physiological and pathophysiological conditions. Non-invasive imaging approaches are needed to fully understand the mechanisms and pathways driving fluid movement in CNS and their roles across lifespan including healthy aging and aging-related dementia.

Sex Difference in Capillary Reperfusion After Transient Middle Cerebral Artery Occlusion in Diabetic Mice.

BACKGROUND: Type 2 diabetes (DM2) exacerbates stroke injury, reduces efficacy of endovascular therapy, and worsens long-term functional outcome. Sex differences exist in stroke incidence, response to therapy, poststroke microvascular dysfunction, and functional recovery. In this study, we tested the hypotheses that poor outcome after stroke in the setting of DM2 is linked to impaired microvascular tissue reperfusion and that male and female DM2 mice exhibit different microvascular reperfusion response after transient middle cerebral artery occlusion (MCAO). METHODS: Transient MCAO was induced for 60 minutes using an intraluminal filament in young adult DM2 and nondiabetic control male and female mice. Capillary flux in deep cortical layers was assessed using optical coherence tomography-based optical microangiography (OMAG), and associated regional brain infarct size was evaluated by hematoxylin and eosin staining. RESULTS: Compared to baseline, MCAO reduced absolute capillary red blood cell flux by 84% at 24 hours post-MCAO in male DM2 (P<0.001) but not male control mice. When normalized to pre-MCAO baseline, red blood cell flux 24 hours after stroke was 64% lower in male DM2 mice than male nondiabetic controls (P<0.01). In females, MCAO decreased capillary flux by 48% at 24 hours post-MCAO compared with baseline in DM2 (P<0.05) but not in control mice. Red blood cell flux of female DM2 mice did not differ from that of nondiabetic controls either before or 24 hours after MCAO. Furthermore, normalized capillary flux 24 hours after MCAO failed to differ between female DM2 mice and nondiabetic controls. Concomitantly, male but not female DM2 mice experienced 25% larger infarct in caudate-putamen versus respective nondiabetic controls (P<0.05). CONCLUSIONS: DM2 impairs capillary perfusion and exacerbates ischemic deep brain injury in male but not female young adult mice. Premenopausal females appear to be protected against DM2-related capillary dysfunction and brain injury.

GPR39 Knockout Worsens Microcirculatory Response to Experimental Stroke in a Sex-Dependent Manner.

No current treatments target microvascular reperfusion after stroke, which can contribute to poor outcomes even after successful clot retrieval. The G protein-coupled receptor GPR39 is expressed in brain peri-capillary pericytes, and has been implicated in microvascular regulation, but its role in stroke is unknown. We tested the hypothesis that GPR39 plays a protective role after stroke, in part due to preservation of microvascular perfusion. We generated GPR39 knockout (KO) mice and tested whether GPR39 gene deletion worsens capillary blood flow and exacerbates brain injury and functional deficit after focal cerebral ischemia. Stroke was induced in male and female GPR39 KO and WT littermates by 60-min middle cerebral artery occlusion (MCAO). Microvascular perfusion was assessed via capillary red blood cell (RBC) flux in deep cortical layers in vivo using optical microangiography (OMAG). Brain injury was assessed by measuring infarct size by 2,3,5-triphenyltetrazolium chloride staining at 24 h or brain atrophy at 3 weeks after ischemia. Pole and cylinder behavior tests were conducted to assess neurological function deficit at 1 and 3 weeks post-stroke. Male but not female GPR39 KO mice exhibited larger infarcts and lower capillary RBC flux than WT controls after stroke. Male GPR39 KO mice also exhibited worse neurologic deficit at 1 week post-stroke, though functional deficit disappeared in both groups by 3 weeks. GPR39 deletion worsens brain injury, microvascular perfusion, and neurological function after experimental stroke. Results indicate that GPR39 plays a sex-dependent role in re-establishing microvascular flow and limiting ischemic brain damage after stroke.

Role of Endothelial STAT3 in Cerebrovascular Function and Protection from Ischemic Brain Injury.

STAT3 plays a protective role against ischemic brain injury; however, it is not clear which brain cell type mediates this effect, and by which mechanism. We tested the hypothesis that endothelial STAT3 contributes to protection from cerebral ischemia, by preserving cerebrovascular endothelial function and blood-brain barrier (BBB) integrity. The objective of this study was to determine the role of STAT3 in cerebrovascular endothelial cell (EC) survival and function, and its role in tissue outcome after cerebral ischemia. We found that in primary mouse brain microvascular ECs, STAT3 was constitutively active, and its phosphorylation was reduced by oxygen-glucose deprivation (OGD), recovering after re-oxygenation. STAT3 inhibition, using two mechanistically different pharmacological inhibitors, increased EC injury after OGD. The sub-lethal inhibition of STAT3 caused endothelial dysfunction, demonstrated by reduced nitric oxide release in response to acetylcholine and reduced barrier function of the endothelial monolayer. Finally, mice with reduced endothelial STAT3 (Tie2-Cre; STAT3flox/wt) sustained larger brain infarcts after middle cerebral artery occlusion (MCAO) compared to wild-type (WT) littermates. We conclude that STAT3 is vital to maintaining cerebrovascular integrity, playing a role in EC survival and function, and protection against cerebral ischemia. Endothelial STAT3 may serve as a potential target in preventing endothelial dysfunction after stroke.

Specific aeroallergen sensitization associated with current rhinitis among adults in southwestern Saudi Arabia.

Data about allergic sensitization to rhinitis among adults are limited. The objectives were to explore the prevalence of current rhinitis (CR) and associated specific allergen sensitizations in southwestern Saudi Arabia. A cross-sectional study was conducted on 969 adults in southwestern regions of Saudi Arabia, namely Aseer, Jazan, and Al Baha. From each region, 5 primary health care centers were chosen. The validated Arabic Version of the International Study of Asthma and Allergies in Childhood questionnaire was used. Total immunoglobulin E (IgE) enzyme-linked immunosorbent assay, cytokine enzyme-linked immunosorbent assay (interleukin [IL]-4, IL-10, IL-13, and interferon-γ), aeroallergen-specific IgE immunoassay (a panel of 30 common aeroallergens; 9 indoor and 21 outdoors), and eosinophilic count were assessed. A prevalence of CR of 35.8% (95% confidence interval: 32.8%-38.9%) was found. Regarding outdoor aeroallergens, Mesquite-positive IgE antibodies were higher among CR adults (odds ratio = 1.52, 95% confidence interval: 1.02-2.21) compared to those without CR. The same significant pattern was found with Chenopodium, Ragweed, Pigweed, Russian thistle, Bermuda grass, Timothy grass, and Rye. All indoor aeroallergens were not significantly associated with CR. Total IgE and eosinophil count were significantly higher among adults with CR. In conclusion, CR in southwestern regions of Saudi Arabia is common and of significant public health importance. Aeroallergens that associate with adult sensitization to CR tend to be of the outdoor variety particularly the herbaceous grass and their pollens. The magnitude of CR and its association with exposure to outdoor aeroallergens should be taken into account by health policy decision makers, clinicians, and medical practitioners when diagnosing and treating related conditions.

Increased mental stress among undergraduate medical students in south-western Saudi Arabia during the COVID-19 pandemic.

Background: The COVID-19 pandemic has disrupted the daily life and academic trajectory of many students. The objectives of this study were to evaluate the effect of the pandemic on perceived stress levels among medical students. Methods: Comparative pre-pandemic and pandemic surveys were conducted among samples of undergraduate medical students. Students responded to a questionnaire including personal and academic data, and Cohen's Perceived Stress Scale (PSS). Results: Overall, the prevalence of high perceived stress during the pandemic (20.6%) was significantly higher (p = 0.001) than pre-pandemic (11.6%). A multivariable analysis revealed that the independent factors associated with high perceived stress were: participation in the study during the pandemic (aOR = 1.79, 95% CI: 1.22-2.63), female sex (aOR = 1.74, 95% CI: 1.23-2.47), younger age (aOR = 1.62, 95% CI: 1.04-2.55) and lower family income (aOR = 1.50, 95% CI: 1.12-2.03). PSS score was negatively correlated with increasing age, family income, and academic level. PSS score was positively correlated with: worries about the possible disruption of education or exams, excessive news exposure, worries about the possibility of COVID-19 infection, and the effects of mandatory isolation and social distancing. Conclusion: The COVID-19 pandemic increased the level of stress among medical students. Female students, younger students, and those in lower academic grades are the most at risk of having high stress. Worries about possible academic disruptions due to the pandemic are significant stressors. The implementation of online stress management programs is recommended.

Age-dependent cognitive impairment, hydrocephalus and leukocyte infiltration in transgenic mice with endothelial expression of human EPHX2.

Soluble epoxide hydrolase (sEH) is upregulated in microvascular endothelium of human brain with vascular cognitive impairment (VCI). Transgenic endothelial expression of human sEH in mice (Tie2hsEH) induces endothelial dysfunction (ED), a pathogenetic mechanism of VCI. We sought to determine if endothelial upregulation of sEH is sufficient to cause cognitive impairment, and if cognitive impairment due to chronic hypoperfusion induced by unilateral common carotid artery occlusion (CCAO) is exacerbated in Tie2hsEH mice. Behavioral performance was assessed by the open field, rotarod, novel object, Morris water maze and fear conditioning tests. Cerebral blood flow and brain morphology were evaluated by MRI, and inflammatory changes investigated using immunohistochemistry and flow cytometry. We demonstrate that transgenic endothelial expression of sEH is sufficient to induce cognitive impairment, associated with leukocyte infiltration, brain atrophy and accelerated, age-dependent ventriculomegaly, identifying ED and sEH upregulation as potential underlying mechanisms and therapeutic targets for VCI.

Acute encephalopathy in a 6-year-old child with concurrent COVID-19 infection: a case report from Saudi Arabia.

COVID-19 is a global health crisis that has impacted the world with heavy economic and social losses. In the early days of the pandemic, pediatric COVID-19 was well-known for its low infectivity and mortality rates as well as its benign clinical outcomes. Herein, we report the case of a 6-year-old girl with COVID-19-associated encephalopathy without respiratory symptoms. To the best of our knowledge, this is the first child reported from Saudi Arabia with COVID-19-induced encephalopathy. A 6-year-old patient with COVID-19 was presented to the Abha Maternity and Child Hospital in southeastern Saudi Arabia. Routine clinical and laboratory examinations revealed normal findings. Despite the absence of COVID-19 respiratory manifestations, the patient manifested COVID-19-related encephalopathy. The patient responded well to pulse steroid, favipiravir, and symptomatic seizure therapies. The patient recovered completely without any neurologic morbidities. A COVID-19-related encephalopathy was observed for the first time in Saudi Arabia among pediatric patients. Clinicians should be alert to potential neurologic complications associated with COVID-19. It should be considered in the differential diagnosis of children presenting with acute encephalopathy, even in the absence of respiratory symptoms. To avoid long-term neurologic sequelae, prompt seizure and immunosuppressive therapies are essential.

GPR39 Deficiency Impairs Memory and Alters Oxylipins and Inflammatory Cytokines Without Affecting Cerebral Blood Flow in a High-Fat Diet Mouse Model of Cognitive Impairment.

Vascular cognitive impairment (VCI) is the second most common cause of dementia. There is no treatment for VCI, in part due to a lack of understanding of the underlying mechanisms. The G-protein coupled receptor 39 (GPR39) is regulated by arachidonic acid (AA)-derived oxylipins that have been implicated in VCI. Furthermore, GPR39 is increased in microglia of post mortem human brains with VCI. Carriers of homozygous GPR39 SNPs have a higher burden of white matter hyperintensity, an MRI marker of VCI. We tested the hypothesis that GPR39 plays a protective role against high-fat diet (HFD)-induced cognitive impairment, in part mediated via oxylipins actions on cerebral blood flow (CBF) and neuroinflammation. Homozygous (KO) and heterozygous (Het) GPR39 knockout mice and wild-type (WT) littermates with and without HFD for 8 months were tested for cognitive performance using the novel object recognition (NOR) and the Morris water maze (MWM) tests, followed by CBF measurements using MRI. Brain tissue and plasma oxylipins were quantified with high-performance liquid chromatography coupled to mass spectrometry. Cytokines and chemokines were measured using a multiplex assay. KO mice, regardless of diet, swam further away from platform location in the MWM compared to WT and Het mice. In the NOR test, there were no effects of genotype or diet. Brain and plasma AA-derived oxylipins formed by 11- and 15-lipoxygenase (LOX), cyclooxygenase (COX) and non-enzymatically were increased by HFD and GPR39 deletion. Interleukin-10 (IL-10) was lower in KO mice on HFD than standard diet (STD), whereas IL-4, interferon γ-induced protein-10 (IP-10) and monocyte chemotactic protein-3 (MCP-3) were altered by diet in both WT and KO, but were not affected by genotype. Resting CBF was reduced in WT and KO mice on HFD, with no change in vasoreactivity. The deletion of GPR39 did not change CBF compared to WT mice on either STD or HFD. We conclude that GPR39 plays a role in spatial memory retention and protects against HFD-induced cognitive impairment in part by modulating inflammation and AA-derived oxylipins. The results indicate that GPR39 and oxylipin pathways play a role and may serve as therapeutic targets in VCI.