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BACKGROUND/OBJECTIVES: The aim of this study was to estimate the effect of a 6 months treatment course of the innate immune modulator NP001 (a pH-adjusted intravenous formulation of purified sodium chlorite), on disease progression, as measured by overall survival (OS) in patients with amyotrophic lateral sclerosis. METHODS: Blinded survival data were retrospectively collected for 268 of the 273 patients who had participated in two phase 2 placebo-controlled clinical trials of NP001 (ClinicalTrials.gov: NCT01281631 and NCT02794857) and received at least one dose of either 1 mg/kg or 2 mg/kg of NP001 as chlorite based on actual body weight, or placebo. Kaplan-Meier methods were used on the intent-to-treat population to estimate survival probabilities. RESULTS: In the overall population, the median OS was 4.8 months (2.7 years [95% CI: 2.3, 3.5] in the 2 mg/kg NP001group and 2.3 years [95% CI: 1.8, 2.9] in the placebo group). Hazard ratio (HR): 0.77 (95% CI: 0.57, 1.03), p = 0.073. Among patients aged ≤ 65 years, the median OS for the 2 mg/kg NP001 group was 10.8 months (3.3 years [95% CI: 2.4, 3.8] in the 2 mg/kg NP001 group and 2.4 years [95% CI: 1.7, 3.3] in the placebo group). HR: 0.69 (95% CI: 0.50, 0.95). No differences were observed in the 1 mg/kg NP001 group or in patients aged > 65 years. CONCLUSIONS: The findings from this study suggest that a 6 months treatment course of NP001 resulted in a 4.8-month increase in overall survival in patients with ALS. The findings from this study indicate that targeting inflammation associated with the innate immune system may provide a pathway for new therapeutic options for the treatment of ALS.

Glaucoma, an optic neuropathy with the loss of retinal ganglion cells (RGCs), is a leading cause of irreversible vision loss. Oxidative stress and mitochondrial dysfunction have a significant role in triggering glia-driven neuroinflammation and subsequent glaucomatous RGC degeneration in the context of glaucoma. It has previously been shown that apolipoprotein A-I binding protein (APOA1BP or AIBP) has an anti-inflammatory function. Moreover, Apoa1bp-/- mice are characterized by retinal neuroinflammation and RGC loss. In this study, we found that AIBP deficiency exacerbated the oxidative stress-induced disruption of mitochondrial dynamics and function in the retina, leading to a further decline in visual function. Mechanistically, AIBP deficiency-induced oxidative stress triggered a reduction in glycogen synthase kinase 3β and dynamin-related protein 1 phosphorylation, optic atrophy type 1 and mitofusin 1 and 2 expression, and oxidative phosphorylation, as well as the activation of mitogen-activated protein kinase (MAPK) in Müller glia dysfunction, leading to cell death and inflammatory responses. In vivo, the administration of recombinant AIBP (rAIBP) effectively protected the structural and functional integrity of retinal mitochondria under oxidative stress conditions and prevented vision loss. In vitro, incubation with rAIBP safeguarded the structural integrity and bioenergetic performance of mitochondria and concurrently suppressed MAPK activation, apoptotic cell death, and inflammatory response in Müller glia. These findings support the possibility that AIBP promotes RGC survival and restores visual function in glaucomatous mice by ameliorating glia-driven mitochondrial dysfunction and neuroinflammation.

Microglia-driven neuroinflammation plays an important role in the development of Alzheimers disease. Microglia activation is accompanied by the formation and chronic expression of TLR4 inflammarafts, defined as enlarged and cholesterol-rich lipid rafts serving as an assembly platform for TLR4 dimers and complexes of other inflammatory receptors. The secreted apoA-I binding protein (APOA1BP or AIBP) binds TLR4 and selectively targets cholesterol depletion machinery to TLR4 inflammaraft-expressing inflammatory, but not homeostatic microglia. Here we demonstrated that amyloid-beta (Aβ) induced formation of TLR4 inflammarafts in microglia in vitro and in the brain of APP/PS1 mice. Mitochondria in Apoa1bp-/- APP/PS1 microglia were hyperbranched and cupped, which was accompanied by increased reactive oxygen species and the dilated endoplasmic reticulum. The size and number of Aβ plaques and neuronal cell death were significantly increased, and the animal survival was decreased in Apoa1bp-/-APP/PS1 compared to APP/PS1 female mice. These results suggest that AIBP exerts control of TLR4 inflammarafts and mitochondrial dynamics in microglia and plays a protective role in Alzheimers disease associated oxidative stress and neurodegeneration.

Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in neuroinflammation and HIV-associated neurocognitive impairment (NCI). People with HIV (PWH) using cannabis exhibit lower inflammation and neurological disorders. We hypothesized that TREM2 dysfunction mediates HIV neuropathogenesis and can be reversed by cannabinoids. EcoHIV-infected wildtype (WT) and TREM2R47H mutant mice were used to study HIVs impact on TREM2 and behavior. TREM2 and related gene expressions were examined in monocyte-derived macrophages (MDMs) from PWH (n = 42) and people without HIV (PWoH; n = 19) with varying cannabis use via RNA sequencing and qPCR. Differences in membrane-bound and soluble TREM2 (sTREM2) were evaluated using immunocytochemistry (ICC) and ELISA. EcoHIV increased immature and C-terminal fragment forms of TREM2 in WT mice but not in TREM2R47H mice, with increased IBA1 protein in TREM2R47H hippocampi, correlating with worse memory test performance. TREM2 mRNA levels increased with age in PWoH but not in PWH. Cannabidiol (CBD) treatment increased TREM2 mRNA alone and with IL1β. RNA-seq showed the upregulation of TREM2-related transcripts in cannabis-using PWH compared to naïve controls. IL1β increased sTREM2 and reduced membrane-bound TREM2, effects partially reversed by CBD. These findings suggest HIV affects TREM2 expression modulated by cannabis and CBD, offering insights for therapeutic strategies.

INTRODUCTION: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimers disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research. METHODS: In 2023, the Alzheimers Association convened multidisciplinary researchers at the AAIC Advancements: APOE conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function. RESULTS: This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field. DISCUSSION: Understanding apoEs multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine. HIGHLIGHTS: APOE is a central player in the pathogenesis of Alzheimers disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.

BackgroundObesity and consumption of high-fat diets (HFD) are associated with intestinal permeabilization and increased paracellular transport of endotoxins, which can promote neuroinflammation. Inflammation can affect the hypothalamic pituitary adrenal (HPA) axis, which controls responses to stress and downregulates the brain-derived neurotrophic factor (BDNF), which can promote anxiety and depression, conditions frequently found in obesity. We previously showed that consumption of anthocyanins (AC) mitigate HFD-induced insulin resistance, intestinal permeability, and inflammation.ObjectivesThis study investigated if a dietary supplementation with a cyanidin- and delphinidin-rich extract (CDRE) could counteract HFD/obesity-induced hippocampal inflammation in mice.MethodsC57BL/6J male mice were fed for 14 wk on one of the following diets: 1) a control diet containing 10% total calories from fat (C), 2) a control diet supplemented with 40 mg AC/kg body weight (BW) (CAC), 3) a HFD containing 60% total calories from fat (lard) (HF), or 4) the HFD supplemented with 2, 20, or 40 mg AC/kg BW (HFA2, HFA20, and HFA40, respectively). In plasma and in the hippocampus, parameters of neuroinflammation and the underlying cause (endotoxemia) and consequences (alterations to the HPA and BDNF downregulation) were measured.ResultsConsumption of the HFD caused endotoxemia. Accordingly, hippocampal Tlr4 mRNA levels were 110% higher in the HF group, which were both prevented by CDRE supplementation. Consumption of the HFD also caused: 1) microgliosis and increased expression of genes involved in neuroinflammation, that is, Iba-1, Nox4, Tnfα, and Il-1β, 2) alterations of HPA axis regulation, that is, with low expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors; and 3) decreased Bdnf expression. Supplementation of HFD-fed mice with CDRE mitigated neuroinflammation, microgliosis, and MR and BDNF decreases.ConclusionsCDRE supplementation mitigates the negative effects associated with HFD consumption and obesity in mouse hippocampus, in part by decreasing inflammation, improving glucocorticoid metabolism, and upregulating BDNF.

Childhood overweight/obesity is associated with stress-related psychopathology, yet the pathways connecting childhood obesity to stress susceptibility are poorly understood. We employed a systems biology approach with 62 adolescent Lewis rats fed a Western-like high-saturated fat diet (WD, 41% kcal from fat) or a control diet (CD, 13% kcal from fat). A subset of rats underwent a 31-day model of predator exposures and social instability (PSS). Effects were assessed using behavioral tests, DTI (diffusion tensor imaging), NODDI (neurite orientation dispersion and density imaging), 16S rRNA gene sequencing for gut microbiome profiling, hippocampal microglia analysis, and targeted gene methylation. Parallel experiments on human microglia cells (HMC3) examined how palmitic acid influences cortisol-related inflammatory responses. Rats exposed to WD and PSS exhibited deficits in sociability, increased fear/anxiety-like behaviors, food consumption, and body weight. WD/PSS altered hippocampal microstructure (subiculum, CA1, dentate gyrus), and microbiome analysis showed a reduced abundance of members of the phylum Firmicutes. WD/PSS synergistically promoted neuroinflammatory changes in hippocampal microglia, linked with microbiome shifts and altered Fkbp5 expression/methylation. In HMC3, palmitate disrupted cortisol responses, affecting morphology, phagocytic markers, and cytokine release, partially mediated by FKBP5. This study identifies gene-environment interactions that influence microglia biology and may contribute to the connection between childhood obesity and stress-related psychopathology later in life.

Astrocytes respond and contribute to neuroinflammation by adopting inflammatory reactive states. Although recent efforts have characterized the gene expression signatures associated with these reactive states, the cell biology underlying inflammatory reactive astrocyte phenotypes remains under-explored. Here, we used CRISPR-based screening in human iPSC-derived astrocytes to identify mTOR activation a driver of cytokine-induced endolysosomal system remodeling, manifesting as alkalinization of endolysosomal compartments, decreased autophagic flux, and increased exocytosis of certain endolysosomal cargos. Through endolysosomal proteomics, we identified and focused on one such cargo-IL-32, a disease-associated pro-inflammatory cytokine not present in rodents, whose secretion mechanism is not well understood. We found that IL-32 was partially secreted in extracellular vesicles likely to be exosomes. Furthermore, we found that IL-32 was involved in the polarization of inflammatory reactive astrocyte states and was upregulated in astrocytes in multiple sclerosis lesions. We believe that our results advance our understanding of cell biological pathways underlying inflammatory reactive astrocyte phenotypes and identify potential therapeutic targets.

BackgroundVariants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD).MethodsCRISPR-Cas9 was used to generate an Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed.ResultsAbca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aβ) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aβ-associated inflammation, gliosis, and neuronal damage.DiscussionOverall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aβ pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology.HighlightsABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice.

OBJECTIVES: People with HIV (PWH) have high rates of depression and neurocognitive impairment (NCI) despite viral suppression on antiretroviral therapy (ART). Mounting evidence suggests that immunometabolic disruptions may contribute to these conditions in some PWH. We hypothesized that metabolic dysfunction in astrocytes is associated with depressive symptoms and cognitive function in PWH. METHODS: Human astrocytes were exposed to sera from PWH (n=40) with varying degrees of depressive symptomatology and cognitive function. MitoTrackerTM Deep Red FM (MT) was used to visualize mitochondrial activity and glial fibrillary acidic protein (GFAP) as an indicator of astrocyte reactivity using the high-throughput fluorescent microscopy and image analyses platform, CellInsight CX5 (CX5). The Seahorse platform was used to assess glycolytic and mitochondrial metabolism. RESULTS: More severe depression, as indexed by higher Becks Depression Inventory (BDI-II) scores, was associated with lower MT signal measures. Better cognitive function, as assessed by neuropsychiatric testing t-scores, was associated with increased MT signal measures. GFAP intensity negatively correlated with several cognitive t-scores. Age positively correlated with (higher) MT signal measures and GFAP intensity. Worse depressive symptoms (higher BDI-II scores) were associated with decreased oxygen consumption rate and spare respiratory capacity, concomitant with increased extracellular acidification rate in astrocytes. CONCLUSIONS: These findings show that factors in the sera of PWH alter mitochondrial activity in cultured human astrocytes, suggesting that mechanisms that alter mitochondrial and astrocyte homeostasis can be detected peripherally. Thus, in vitro cultures may provide a model to identify neuropathogenic mechanisms of depression or neurocognitive impairment in PWH and test personalized therapeutics for neurologic and psychiatric disorders.

Senicapoc, a small molecule inhibitor of the calcium-activated potassium channel KCa3.1, was safe and well-tolerated in clinical trials for sickle cell anemia. We previously reported proof-of-concept data suggesting that both pharmacological inhibition and genetic deletion of KCa3.1 reduces infarction and improves neurologic recovery in rodents by attenuating neuroinflammation. Here we evaluated the potential of repurposing senicapoc for ischemic stroke. In cultured microglia, senicapoc inhibited KCa3.1 currents with an IC50 of 7 nM, reduced Ca2+ signaling induced by the purinergic agonist ATP, suppressed expression of pro-inflammatory cytokines and enzymes (iNOS and COX-2), and prevented induction of the inflammasome component NLRP3. When transient middle cerebral artery occlusion (tMCAO, 60 min) was induced in male C57BL/6 J mice, twice daily administration of senicapoc at 10 and 40 mg/kg starting 12 h after reperfusion dose-dependently reduced infarct area determined by T2-weighted magnetic resonance imaging (MRI) and improved neurological deficit on day 8. Ultra-high-performance liquid chromatography/mass spectrometry analysis of total and free brain concentrations demonstrated sufficient KCa3.1 target engagement. Senicapoc treatment significantly reduced microglia/macrophage and T cell infiltration and activation and attenuated neuronal death. A different treatment paradigm with senicapoc started at 3 h and MRI on day 3 and day 8 revealed that senicapoc reduces secondary infarct growth and suppresses expression of inflammation markers, including T cell cytokines in the brain. Lastly, we demonstrated that senicapoc does not impair the proteolytic activity of tissue plasminogen activator (tPA) in vitro. We suggest that senicapoc could be repurposed as an adjunctive immunocytoprotective agent for combination with reperfusion therapy for ischemic stroke.

Acute poisoning with organophosphorus cholinesterase inhibitors (OPs), such as OP nerve agents and pesticides, can cause life threatening cholinergic crisis and status epilepticus (SE). Survivors often experience significant morbidity, including brain injury, acquired epilepsy, and cognitive deficits. Current medical countermeasures for acute OP poisoning include a benzodiazepine to mitigate seizures. Diazepam was long the benzodiazepine included in autoinjectors used to treat OP-induced seizures, but it is now being replaced in many guidelines by midazolam, which terminates seizures more quickly, particularly when administered intramuscularly. While a direct correlation between seizure duration and the extent of brain injury has been widely reported, there are limited data comparing the neuroprotective efficacy of diazepam versus midazolam following acute OP intoxication. To address this data gap, we used non-invasive imaging techniques to longitudinally quantify neuropathology in a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP) with and without post-exposure intervention with diazepam or midazolam. Magnetic resonance imaging (MRI) was used to monitor neuropathology and brain atrophy, while positron emission tomography (PET) with a radiotracer targeting translocator protein (TSPO) was utilized to assess neuroinflammation. Animals were scanned at 3, 7, 28, 65, 91, and 168 days post-DFP and imaging metrics were quantitated for the hippocampus, amygdala, piriform cortex, thalamus, cerebral cortex and lateral ventricles. In the DFP-intoxicated rat, neuroinflammation persisted for the duration of the study coincident with progressive atrophy and ongoing tissue remodeling. Benzodiazepines attenuated neuropathology in a region-dependent manner, but neither benzodiazepine was effective in attenuating long-term neuroinflammation as detected by TSPO PET. Diffusion MRI and TSPO PET metrics were highly correlated with seizure severity, and early MRI and PET metrics were positively correlated with long-term brain atrophy. Collectively, these results suggest that anti-seizure therapy alone is insufficient to prevent long-lasting neuroinflammation and tissue remodeling.

While an association between Parkinsons disease (PD) and viral infections has been recognized, the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on PD progression remains unclear. Here, we demonstrate that SARS-CoV-2 infection heightens the risk of PD using human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons and a human angiotensin-converting enzyme 2 (hACE2) transgenic (Tg) mouse model. Our findings reveal that SARS-CoV-2 infection exacerbates PD susceptibility and cellular toxicity in DA neurons pre-treated with human preformed fibrils (hPFFs). Additionally, nasally delivered SARS-CoV-2 infects DA neurons in hACE2 Tg mice, aggravating the damage initiated by hPFFs. Mice infected with SARS-CoV-2 display persisting neuroinflammation even after the virus is no longer detectable in the brain. A comprehensive analysis suggests that the inflammatory response mediated by astrocytes and microglia could contribute to increased PD susceptibility associated with SARS-CoV-2. These findings advance our understanding of the potential long-term effects of SARS-CoV-2 infection on the progression of PD.

Microglial neuroinflammation appears to be neuroprotective in the early pathological stage, yet neurotoxic, which often precedes neurodegeneration in Alzheimer's disease (AD). However, it remains unclear how the microglial activities transit to the neurotoxic state during AD progression, due to complex neuron-glia interactions. Here, the mechanism of detrimental microgliosis in AD by employing 3D human AD mini-brains, brain tissues of AD patients, and 5XFAD mice is explored. In the human and animal AD models, amyloid-beta (Aβ)-overexpressing neurons and reactive astrocytes produce interferon-gamma (IFNγ) and excessive oxidative stress. IFNγ results in the downregulation of mitogen-activated protein kinase (MAPK) and the upregulation of Kelch-like ECH-associated Protein 1 (Keap1) in microglia, which inactivate nuclear factor erythroid-2-related factor 2 (Nrf2) and sensitize microglia to the oxidative stress and induces a proinflammatory microglia via nuclear factor kappa B (NFκB)-axis. The proinflammatory microglia in turn produce neurotoxic nitric oxide and proinflammatory mediators exacerbating synaptic impairment, phosphorylated-tau accumulation, and discernable neuronal loss. Interestingly, recovering Nrf2 in the microglia prevents the activation of proinflammatory microglia and significantly blocks the tauopathy in AD minibrains. Taken together, it is envisioned that IFNγ-driven Nrf2 downregulation in microglia as a key target to ameliorate AD pathology.

It has recently become well-established that there is a connection between Alzheimers disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aβ amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis.Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each others experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aβ burden was detectable upto 12 weeks of age when Aβ burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aβ burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-β deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice.Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses.Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimers disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aβ deposition or when given after Aβ deposition is already at higher levels.

This review explores the application of the conservative management model for pain to sports-related concussions (SRCs), framing concussions as a distinct form of pain syndrome with a pathophysiological foundation in central sensitization. Drawing parallels with proven pain management models, we underscore the significance of a proactive approach to concussion management. Recognizing concussions as a pain syndrome allows for the tailoring of interventions in alignment with conservative principles. This review first covers the epidemiology and controversies surrounding prolonged concussion recovery and persistent post-concussion symptoms (PPCS). Next, the pathophysiology of concussions is presented within the central sensitization framework, emphasizing the need for early intervention to mitigate the neuroplastic changes that lead to heightened pain sensitivity. Five components of the central sensitization process specific to concussion injuries are highlighted as targets for conservative interventions in the acute period: peripheral sensitization, cerebral metabolic dysfunction, neuroinflammation, glymphatic system dysfunction, and pain catastrophizing. These proactive interventions are emphasized as pivotal in accelerating concussion recovery and reducing the risk of prolonged symptoms and PPCS, in line with the philosophy of conservative management.

Glaucoma is a group of ocular diseases that cause irreversible blindness. It is characterized by multifactorial degeneration of the optic nerve axons and retinal ganglion cells (RGCs), resulting in the loss of vision. Major components of glaucoma pathogenesis include glia-driven neuroinflammation and impairment of mitochondrial dynamics and bioenergetics, leading to retinal neurodegeneration. In this review article, we summarize current evidence for the emerging role of apolipoprotein A-I binding protein (AIBP) as an important anti-inflammatory and neuroprotective factor in the retina. Due to its association with toll-like receptor 4 (TLR4), extracellular AIBP selectively removes excess cholesterol from the plasma membrane of inflammatory and activated cells. This results in the reduced expression of TLR4-associated, cholesterol-rich lipid rafts and the inhibition of downstream inflammatory signaling. Intracellular AIBP is localized to mitochondria and modulates mitophagy through the ubiquitination of mitofusins 1 and 2. Importantly, elevated intraocular pressure induces AIBP deficiency in mouse models and in human glaucomatous retina. AIBP deficiency leads to the activation of TLR4 in Müller glia, triggering mitochondrial dysfunction in both RGCs and Müller glia, and compromising visual function in a mouse model. Conversely, restoring AIBP expression in the retina reduces neuroinflammation, prevents RGCs death, and protects visual function. These results provide new insight into the mechanism of AIBP function in the retina and suggest a therapeutic potential for restoring retinal AIBP expression in the treatment of glaucoma.

Age-related macular degeneration (AMD) is invariably associated with the chronic accumulation of activated mononuclear phagocytes in the subretinal space. The mononuclear phagocytes are composed of microglial cells but also of monocyte-derived cells, which promote photoreceptor degeneration and choroidal neovascularization. Infiltrating blood monocytes can originate directly from bone marrow, but also from a splenic reservoir, where bone marrow monocytes develop into angiotensin II receptor (ATR1)+ splenic monocytes. The involvement of splenic monocytes in neurodegenerative diseases such as AMD is not well understood. Using acute inflammatory and well-phenotyped AMD models, we demonstrate that angiotensin II mobilizes ATR1+ splenic monocytes, which we show are defined by a transcriptional signature using single-cell RNA sequencing and differ functionally from bone marrow monocytes. Splenic monocytes participate in the chorio-retinal infiltration and their inhibition by ATR1 antagonist and splenectomy reduces the subretinal mononuclear phagocyte accumulation and pathological choroidal neovascularization formation. In aged AMD-risk ApoE2-expressing mice, a chronic AMD model, ATR1 antagonist and splenectomy also inhibit the chronic retinal inflammation and associated cone degeneration that characterizes these mice. Our observation of elevated levels of plasma angiotensin II in AMD patients, suggests that similar events take place in clinical disease and argue for the therapeutic potential of ATR1 antagonists to inhibit splenic monocytes for the treatment of blinding AMD.

Infection during the perinatal period can adversely affect brain development, predispose infants to ischemic stroke and have lifelong consequences. We previously demonstrated that diet enriched in n-3 polyunsaturated fatty acids (n-3 PUFA) transforms brain lipid composition in the offspring and protects the neonatal brain from stroke, in part by blunting injurious immune responses. Critical to the interface between the brain and systemic circulation is the vasculature, endothelial cells in particular, that support brain homeostasis and provide a barrier to systemic infection. Here, we examined whether maternal PUFA-enriched diets exert reprograming of endothelial cell signalling in postnatal day 9 mice after modeling aspects of infection using LPS. Transcriptome analysis was performed on microvessels isolated from brains of pups from dams maintained on 3 different maternal diets from gestation day 1: standard, n-3 enriched or n-6 enriched diets. Depending on the diet, in endothelial cells LPS produced distinct regulation of pathways related to immune response, cell cycle, extracellular matrix, and angiogenesis. N-3 PUFA diet enabled higher immune reactivity in brain vasculature, while preventing imbalance of cell cycle regulation and extracellular matrix cascades that accompanied inflammatory response in standard diet. Cytokine analysis revealed a blunted LPS response in blood and brain of offspring from dams on n-3 enriched diet. Analysis of cerebral vasculature in offspring in vivo revealed no differences in vessel density. However, vessel complexity was decreased in response to LPS at 72 h in standard and n-6 diets. Thus, LPS modulates specific transcriptomic changes in brain vessels of offspring rather than major structural vessel characteristics during early life. N-3 PUFA-enriched maternal diet in part prevents an imbalance in homeostatic processes, alters inflammation and ultimately mitigates changes to the complexity of surface vessel networks that result from infection. Importantly, maternal diet may presage offspring neurovascular outcomes later in life.

Disease-associated microglia (DAM) are a subset of microglia that appear at various stages of central nervous system neurodegenerative diseases. DAM were identified using single-cell RNA sequencing within Alzheimer's Disease (AD) where they were characterized by their unique localization near amyloid-β plaques and their phagocytic and lipid-metabolizing features. Unfortunately, activation and etiology of DAM are only understood within the context of AD where Triggering Receptor Expressed On Myeloid Cells 2 (TREM2), a receptor for amyloid-β, appears to be the key regulator in microglial transition to a DAM state. Despite this reliance on TREM2 in AD, DAM appear across other neurodegenerative diseases in which TREM2 may not be a critical player. This begs the question of if DAM are truly the same across all neurodegenerative diseases or if there exists a heterogeneity to DAM across neurodegenerative pathologies. Investigation into this critical gap in the field regarding DAM etiology and activation, as well as DAM function, could be delineated utilizing models of Parkinson's disease (PD) to complement studies in models of AD. Though highly underexplored regarding DAM, PD with its pattern of protein aggregation-associated pathology like AD could serve as the spatiotemporal comparison against AD findings to ascertain the nature of DAM. The experimental vehicle that could guide the future of such investigation is the multi-omics model. With a compound approach focusing on exploring triggers for DAM at the chromatin or mRNA level and related protein output, it becomes possible to strongly characterize and firmly answer the question of what is a DAM. [ABSTRACT FROM AUTHOR]

The mechanisms underlying pathological changes in the central nervous system (CNS) following Coxsackievirus A16 (CV-A16) infection have not yet been elucidated. IFN-γ-inducible protein-10 (IP-10) is often used as a predictive factor to monitor early virus infection. It has also been reported that IP-10 plays a pivotal role in neuroinflammation. In this study, we aimed to explore the role of IP-10 in the neuropathogenesis of CV-A16 infection. We observed that the level of IP-10, as well as the TLR3-TRIF-TRAF3-TBK1-NF-κB and RIG-I/MDA5-MAVS-TRAFS-TBK1-NF-κB pathways, which are the upstream of IP-10, were significantly elevated during the course of CV-A16 infection. This increase was accompanied by an increase in a series of inflammatory cytokines at different time-points during CV-A16 infection. To determine whether IP-10 influences BBB integrity, we examined junctional complexes. Our results revealed that the expression levels of Claudin5, Occludin, ZO-1 and VE-Cadherin were notably decreased in CV-A16-infected HUVECs, but these indicators were restored in CV-A16-infected HUVECs with Eldelumab treatment. Nevertheless, IP-10 is only a chemokine that primarily traffics CXCR3-positive immune cells to inflammatory sites or promotes the production of inflammatory cytokines. Therefore, the interactions between IP-10 and inflammatory cytokines were evaluated. Our data revealed that IP-10 mediated the production of TNF-α, which was also observed to change the junctional complexes. Moreover, in a suckling mouse model, IP-10 and TNF-α treatments exacerbated clinical symptoms, mortality and pathological changes in the brain of CV-A16-infected mice, but Anti-IP-10 and Anti-TNF-α treatments alleviated these changes. Our data also revealed that IP-10 may be detected early in CV-A16 infection, whereas TNF-α was detected late in CV-A16 infection, and the production of TNF-α was also found to be positively correlated with IP-10. In addition, IP-10 and TNF-α were observed to reduce junctional complexes and enhance virus entry into the CNS. Taken together, this study provides the first evidence that CV-A16 activates the IP-10/TNF-α regulatory axis to cause BBB damage and accelerate the formation of neuroinflammation in infected hosts, which not only provides a new understanding of the neuropathogenesis caused by CV-A16, but also offers a promising target for the development of CV-A16 antiviral drugs. [ABSTRACT FROM AUTHOR]

Background and purpose: The immune response following aneurysmal subarachnoid hemorrhage (aSAH) can exacerbate secondary brain injury and impact clinical outcomes. As the immune response after aSAH is a dynamic process, we aim to track and characterize immune cell trajectories over time to identify patterns associated with various clinical outcomes. Methods: In this retrospective single-center study of patients with aSAH, we analyzed immune cell count trajectories, including neutrophil, monocyte, and lymphocyte counts, collected from day 1 to day 14. These trajectories were classified into four distinct clusters utilizing the k-means longitudinal clustering method. A comprehensive multivariable analysis was performed to explore the associations of these immune cell clusters with various clinical outcomes. These outcomes included a Modified Rankin Scale score (mRS) of 3 to 6, indicative of poor functional outcomes, along with complications including shunt dependency, vasospasm, and secondary cerebral infarction. Results: In this study, 304 patients with aSAH were analyzed. The trajectories of immune cell counts, including neutrophils, monocytes, and lymphocytes, were successfully categorized into four distinct clusters for each immune cell type. Within neutrophil clusters, both persistent neutrophilia and progressive neutrophilia were associated with poor functional outcomes, shunt dependency, and vasospasm, with resolving neutrophilia showing a lesser degree of these associations. Within monocyte clusters, early monocytosis was associated with vasospasm, whereas delayed monocytosis was associated with shunt dependency. Within lymphocyte clusters, both early transient lymphopenia and early prolonged lymphopenia were associated with poor functional outcomes. Conclusion: Our study demonstrates that distinct immune cell trajectories post-aSAH, identified through unsupervised clustering, are significantly associated with specific clinical outcomes. Understanding these dynamic immune responses may provide key insights with potential for future therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Pericytes play a crucial role in controlling inflammation and vascular functions in the central nervous system, which are disrupted in Parkinson's disease (PD). Still, there is a lack of studies on the impact of pericytes on neurodegenerative diseases, and their involvement in the pathology of PD is unclear. Our objective was to investigate the molecular and functional differences between healthy pericytes and pericytes with the LRRK2 G2019S mutation, which is one of the most common mutations associated with PD. Methods: Our study employed pericyte-like cells obtained from induced pluripotent stem cells produced from PD patients with the LRRK2 G2019S mutation as well as from healthy individuals. We examined the gene expression profiles of the cells and analyzed how the alterations reflect on their functionality. Results: We have shown differences in the expression of genes related to inflammation and angiogenesis. Furthermore, we observe modified migration speed in PD pericyte-like cells as well as enhanced secretion of inflammatory mediators, such as soluble VCAM-1 and MCP-1, in these pericyte-like cells following exposure to proinflammatory stimuli. Conclusions: In summary, our findings support the notion that pericytes play a role in the inflammatory and vascular changes observed in PD. Further investigation of pericytes could provide valuable insight into understanding the pathogenesis of PD. [ABSTRACT FROM AUTHOR]

CNS Drug discovery has been challenging due to the lack of clarity on CNS diseases' basic biological and pathological mechanisms. Despite the difficulty, some CNS drugs have been developed based on phenotypic effects. Herein, we propose a phenotype-structure relationship model, which predicts an anti-neuroinflammatory potency based on 3D molecular structures of the phenotype-active or inactive compounds without specifying targets. For this chemo-centric study, a predictive model of the nitric oxide (NO) inhibitory potency in hyper-activated microglia is built from the 548 agents, which were collected from 95 research articles (28 substructures consisting of natural products and synthetic scaffolds) and doubly externally validated by the agents of 9 research articles as third set. 3D Structures (multi-conformer ensemble) of every agent were encoded into the E3FP molecular fingerprint of the Keiser group as a 3D molecular representation. The location information of the molecular fingerprints could be learned and validated to classify the inhibitory potency of compounds (IC50 cut-off between the active and inactive: 37.1 µM): (1) multi-layer perceptron (MLP) (AUC-CV: 0.997, AUC-Test: 0.992), (2) recurrent neural network (RNN) (AUC-CV: 0.999, AUC-Test: 0.995), and (3) convolutional neural network (CNN) (AUC-CV: 0.998, AUC-Test: 0.994). The high performance of these models was compared with that of four classical machine classification models (Logistic, Ridge, Lasso, and Naïve Bayes). We named the binary classification models NO-Classifier. Independent test set validation and decision region analysis of the independent test set doubly demonstrated NO-Classifier effectively discerned the anti-inflammatory potency of testing compounds in inflammatory cell phenotype with the webserver in https://no-classifier.onrender.com. [ABSTRACT FROM AUTHOR]

Microglia, the resident immune cells of the central nervous system, emerge in the brain during early embryonic development and persist throughout life. They play essential roles in brain homeostasis, and their dysfunction contributes to neuroinflammation and the progression of neurodegenerative diseases. Recent studies have uncovered an intricate relationship between microglia functions and metabolic processes, offering fresh perspectives on disease mechanisms and possible treatments. Despite these advancements, there are still significant gaps in our understanding of how metabolic dysregulation affects microglial phenotypes in these disorders. This review aims to address these gaps, laying the groundwork for future research on the topic. We specifically examine how metabolic shifts in microglia, such as the transition from oxidative phosphorylation and mitochondrial metabolism to heightened glycolysis during proinflammatory states, impact the disease progression in Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Additionally, we explore the role of iron, fatty and amino acid metabolism in microglial homeostasis and repair. Identifying both distinct and shared metabolic adaptations in microglia across neurodegenerative diseases could reveal common therapeutic targets and provide a deeper understanding of disease-specific mechanisms underlying multiple CNS disorders. [ABSTRACT FROM AUTHOR]

Background: The global demographic shift towards an aging population is generating a rise in neurodegenerative conditions, with Alzheimer's disease (AD) as the most prominent problem. In this landscape, the use of natural supplements has garnered attention for their potential in dementia prevention. Curcumin (Cur), derived from Curcuma longa, has demonstrated promising pharmacological effects against AD by reducing the levels of inflammatory mediators. However, its clinical efficacy is hindered by poor solubility and bioavailability. Our study introduces the use of H-Ferritin nanocages (HFn) as a nanoformulation vehicle for Cur, aiming to enhance its therapeutic potential for AD. In this work, we characterized a nanoformulation of Cur in HFn (HFn-CUR) by evaluating its safety, stability, and its transport across the blood-brain barrier (BBB) in vitro. Moreover, we evaluated the efficacy of HFn-CUR by transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from both AD patients and healthy controls (HC), and by using the well-established 5xFAD mouse model of AD. Results: Our data show that HFn-CUR exhibits improved water dispersibility, is non-toxic, and can traverse the BBB. Regarding its activity on PBMCs from AD patients, HFn-CUR enhances cellular responses to inflammation and reduces RAGE-mediated stress. Studies on an AD mouse model demonstrate that HFn-CUR exhibits mild beneficial effects on cognitive performance. Moreover, it effectively reduces microgliosis and astrogliosis and in vivo in mouse, suggesting potential neuroprotective benefits. Conclusions: Our data suggest that HFn-CUR is safe and effective in reducing inflammation in both in vitro and in vivo models of AD, supporting the need for further experiments to define its optimal use. [ABSTRACT FROM AUTHOR]

Advanced age increases the risk of severe disease from SARS‐CoV‐2 infection, as well as incidence of long COVID and SARS‐CoV‐2 reinfection. We hypothesized that perturbations in the aged antiviral CD8+ T cell response predisposes elderly individuals to severe coronavirus infection, re‐infection, and postinfectious cognitive sequelae. Using MHV‐A59 as a murine model of respiratory coronavirus, we found that aging increased CNS infection and lethality to MHV infection. This was coupled with increased CD8+ T cells within the aged CNS but reduced antigen specificity. Aged animals also displayed a decreased proportion of CD103+ resident memory cells (TRM), which correlated with increased severity of secondary viral challenge. Using a reciprocal adoptive transfer paradigm, data show that not only were fewer aged CD8+ T cells retained within the adult brain post‐infection, but also that adult CD8+ cells expressed lower levels of TRM marker CD103 when in the aged microenvironment. Furthermore, aged animals demonstrated spatial learning impairment following MHV infection, which worsened in both aged and adult animals following secondary viral challenge. Spatial learning impairment was accompanied by increased TUNEL positivity in hippocampal neurons, suggestive of neuronal apoptosis. Additionally, primary cell coculture showed that activated CD8+ T cells induced TUNEL positivity in neurons, independent of antigen‐specificity. Altogether, these results show that non‐antigen specific CD8+ T cells are recruited to the aged brain and cause broad neuronal death without establishing a TRM phenotype that confers lasting protection against a secondary infection. [ABSTRACT FROM AUTHOR]

Background: Preclinical studies indicate that the systemic application of C1-inhibitor, clinically used to treat hereditary angioedema, reduces secondary brain injury after ischemic stroke. This study assessed the effect of C1-inhibitor on secondary brain injury after hemorrhagic stroke. Methods: We used an established striatal whole-blood injection mouse model to mimic intracerebral hemorrhage-related secondary brain injury. Based on the spatiotemporal dynamics in our model, we calculated the necessary sample size (n = 24) and determined the most sensitive time point to detect potential group differences (48 h) prior to the experiments. The experimental setup, tissue processing and image analysis adhered to our published protocol. We randomized mice into three groups: C1-inhibitor treatment, placebo, and sham. Histology was standardized by taking eight anatomically predefined slices across the entire lesion. Lesion size, vascular leakage, and inflammatory responses were assessed using automated thresholding and dextran/ICAM1/CD45 intensity mapping. Investigators were blinded to group allocation during the experiment, tissue processing, and image analysis. Results: Whole blood injection resulted in significantly larger lesion size and more pronounced vascular leakage and cellular inflammation compared to the sham group. However, there was no difference in lesion size or inflammatory markers between the C1-inhibitor and placebo groups. In addition, there was no difference in the inflammatory response of the choroid plexus, which has been identified as a central organ orchestrating inflammation after intracerebral hemorrhage. Conclusion: The protective effect of C1-inhibitor might be isolated to pathophysiological processes with a predominant thromboinflammatory component, as in ischemia-reperfusion, but less so in permanent ischemia or intracerebral hemorrhage. [ABSTRACT FROM AUTHOR]

Glia–neuron interaction is a crucial feature in aged hippocampus during the occurrence of postoperative cognitive impairment. However, the regulatory effects of microglia, astrocytes, and oligodendrocytes in this glia–neuron interaction, the potential mechanisms and gene targets are still to be elucidated. Here, single‐cell RNA sequencing was performed to detect the perioperative genomic expression characteristics of neuroglial system in the hippocampus of aged mice, and to investigate the potential cross‐cellular mechanisms and valuable treatment options for glia–neuron interaction‐related cognitive impairment. We found that postoperative neurons and glia cells exhibited protein dysmetabolism and mitochondrial electron misrouting. Impaired autophagy and circadian rhythm worsened microglia activation/neuroinflammation, and exacerbated these metabolic alterations. Reactive microglia also aggravated astrocyte and oligodendrocyte cytotoxicity through the PGD2/DP and complement pathways, altering glutamate level and synaptic function via the “tripartite synapses” model, and affecting neuronal myelination. Ligand‐receptor communication also indicated these synaptic and axonal dysfunctions via enhanced MDK and PTN pathways. Additionally, we found that anesthetic dexmedetomidine hold therapeutic potential within the disrupted neuroglial system. It enhanced neuronal metabolic rebalance (Atf3‐related) and reduced neuroinflammation from a multicellular perspective, therefore improving postoperative cognitive impairment. Together, our study proposes an aged hippocampal cell atlas and provides insights into the role of disrupted glia–neuron cycle in postoperative cognitive impairment. Our findings also elucidate the therapeutic potential and mechanism of dexmedetomidine intervention. [ABSTRACT FROM AUTHOR]

The role of nonneuronal cells in the resolution of cerebral ischemia remains to be fully understood. To decode key molecular and cellular processes that occur after ischemia, we performed spatial and single-cell transcriptomic profiling of the male mouse brain during the first week of injury. Cortical gene expression was severely disrupted, defined by inflammation and cell death in the lesion core, and glial scar formation orchestrated by multiple cell types on the periphery. The glial scar was identified as a zone with intense cell-cell communication, with prominent ApoE-Trem2 signaling pathway modulating microglial activation. For each of the three major glial populations, an inflammatory-responsive state, resembling the reactive states observed in neurodegenerative contexts, was observed. The recovered spectrum of ischemia-induced oligodendrocyte states supports the emerging hypothesis that oligodendrocytes actively respond to and modulate the neuroinflammatory stimulus. The findings are further supported by analysis of other spatial transcriptomic datasets from different mouse models of ischemic brain injury. Collectively, we present a landmark transcriptomic dataset accompanied by interactive visualization that provides a comprehensive view of spatiotemporal organization of processes in the postischemic mouse brain. [ABSTRACT FROM AUTHOR]

Background: Defects in the ataxin-2 (ATXN-2) protein and CAG trinucleotide repeat expansion in its coding gene, Atxn-2, cause the neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2). While clinical studies suggest potential benefits of human-derived mesenchymal stem cells (hMSCs) for treating various ataxias, the exact mechanisms underlying their therapeutic effects and interaction with host tissue to stimulate neurotrophin expression remain unclear specifically in the context of SCA2. Methods: Human bone marrow-derived MSCs (hMSCs) were injected into the cisterna magna of 26-week-old wild-type and SCA2 mice. Mice were assessed for impaired motor coordination using the accelerating rotarod, open field test, and composite phenotype scoring. At 50 weeks, the cerebellum vermis was harvested for protein assessment and immunohistochemical analysis. Results: Significant loss of NeuN and calbindin was observed in 25-week-old SCA2 mice. However, after receiving multiple injections of hMSCs starting at 26 weeks of age, these mice exhibited a significant improvement in abnormal motor performance and a protective effect on Purkinje cells. This beneficial effect persisted until the mice reached 50 weeks of age, at which point they were sacrificed to study further mechanistic events triggered by the administration of hMSCs. Calbindin-positive cells in the Purkinje cell layer expressed bone-derived neurotrophic factor after hMSC administration, contributing to the protection of cerebellar neurons from cell death. Conclusion: In conclusion, repeated administration of hMSCs shows promise in alleviating SCA2 symptoms by preserving Purkinje cells, improving neurotrophic support, and reducing inflammation, ultimately leading to the preservation of locomotor function in SCA2 mice. [ABSTRACT FROM AUTHOR]

Postoperative cognitive dysfunction (POCD) is a frequent neurological complication encountered during the perioperative period with unclear mechanisms and no effective treatments. Recent research into the pathogenesis of POCD has primarily focused on neuroinflammation, oxidative stress, changes in neural synaptic plasticity and neurotransmitter imbalances. Given the high-energy metabolism of neurons and their critical dependency on mitochondria, mitochondrial dysfunction directly affects neuronal function. Additionally, as the primary organelles generating reactive oxygen species, mitochondria are closely linked to the pathological processes of neuroinflammation. Surgery and anesthesia can induce mitochondrial dysfunction, increase mitochondrial oxidative stress, and disrupt mitochondrial quality-control mechanisms via various pathways, hence serving as key initiators of the POCD pathological process. We conducted a review on the role and potential mechanisms of mitochondria in postoperative cognitive dysfunction by consulting relevant literature from the PubMed and EMBASE databases spanning the past 25 years. Our findings indicate that surgery and anesthesia can inhibit mitochondrial respiration, thereby reducing ATP production, decreasing mitochondrial membrane potential, promoting mitochondrial fission, inducing mitochondrial calcium buffering abnormalities and iron accumulation, inhibiting mitophagy, and increasing mitochondrial oxidative stress. Mitochondrial dysfunction and damage can ultimately lead to impaired neuronal function, abnormal synaptic transmission, impaired synthesis and release of neurotransmitters, and even neuronal death, resulting in cognitive dysfunction. Targeted mitochondrial therapies have shown positive outcomes, holding promise as a novel treatment for POCD. [ABSTRACT FROM AUTHOR]

Aims: We aimed to investigate the anxiolytic effect of darbepoetin alpha (DEPO), an erythropoietin derivative, in a neuroinflammation model regarding different behaviors and biological pathways. Methods: Forty adult male Wistar albino rats were divided into four groups (control, LPS, DEPO, and DEPO + LPS). The rats were treated with 5 µg /kg DEPO once a week for four weeks, after which neuroinflammation was induced with 2 mg/kg lipopolysaccharide (LPS). The elevated plus maze, open-field, and light‒dark box tests were conducted to assess anxiety levels. Harderian gland secretions were scored via observation. Tumor necrosis factor alpha (TNF-α), Interleukin-1-beta (IL-1β), brain-derived growth factor (BDNF), serotonin, cortisol, total antioxidant/oxidant (TAS/TOS), and total/free thiol levels were measured in the prefrontal cortex, striatum, and serum. Results: DEPO had a potent anxiolytic effect on both DEPO and DEPO + LPS groups. Compared to the control group, DEPO administration caused an increase in serotonin and BDNF levels and decreased basal cortisol and TNF-α levels in naive rats. IL-1β did not alter after DEPO administration in naive rats. Prophylactic DEPO treatment remarkably downregulated cortisol, IL-1β, and TNF-α in the DEPO + LPS group. In addition, prophylactic DEPO administration significantly attenuated the decrease in serotonin and BDNF levels in the DEPO + LPS group. Furthermore, DEPO ameliorated excessive harderian gland secretion in the DEPO + LPS group. Compared with those in the control group, the free thiol content in the serum increased after DEPO administration. No similar effect was seen in the DEPO + LPS group receiving prophylactic DEPO. TAS showed no difference among all experimental groups. DEPO administration increased TOS and OSI in the serum and prefrontal cortex but not in the striatum. This effect was not seen in the DEPO + LPS group. Conclusion: Darbepoetin alpha had an anxiolytic effect on many physiological mechanisms in a neuroinflammation model and naive rats. [ABSTRACT FROM AUTHOR]

The prevalence of neurodegenerative disorders such as Parkinson's disease are increasing as world populations age. Despite this growing public health concern, the precise molecular and cellular mechanisms that culminate in neurodegeneration remain unclear. Effective treatment options for Parkinson's disease and other neurodegenerative disorders remain very limited, due in part to this uncertain disease etiology. One commonality across neurodegenerative diseases is sustained neuroinflammation, mediated in large part by microglia, the innate immune cells of the brain. Initially thought to simply react to neuron-derived pathology, genetic and functional studies in recent years suggest that microglia play a more active role in the neurodegenerative process than previously appreciated. Here, we review evidence for the roles of microglia in Parkinson's disease pathogenesis and progression, with a particular focus on microglial functions that are perturbed by disease associated genes and mutations. [ABSTRACT FROM AUTHOR]

The role of myeloid cells (granulocytes and monocytes) in neurodegeneration and neurodegenerative disorders (NDD) is indisputable. Here we discuss the roles of myeloid cells in neurodegenerative diseases, and the recent advances in biofluid and imaging myeloid biomarker research with a focus on methods that can be used in the clinic. For this review, evidence from three neurodegenerative diseases will be included, Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). We discuss the potential for these biomarkers to be used in humans with suspected NDD as prognostic, diagnostic, or monitoring tools, identify knowledge gaps in literature, and propose potential approaches to further elucidate the role of myeloid cells in neurodegeneration and better utilize myeloid biomarkers in the understanding and treatment of NDD. [ABSTRACT FROM AUTHOR]

Dementia encompasses a spectrum of neurodegenerative disorders significantly impacting global health, with environmental factors increasingly recognized as crucial in their etiology. Among these, ozone, has been identified as a potential exacerbator of neurodegenerative processes, particularly in Alzheimer's disease (AD). Ozone exposure induces the production of reactive oxygen species (ROS), which penetrate the BBB, leading to oxidative damage in neuronal cells. This oxidative stress is closely linked with mitochondrial dysfunction and lipid peroxidation, processes that are foundational to the pathology observed in dementia, such as neuronal death and protein aggregation. Furthermore, ozone triggers chronic neuroinflammation, exacerbating these neurodegenerative processes and perpetuating a cycle of CNS damage. Recent studies highlight the role of peripheral biomarkers like High Mobility Group Box 1 (HMGB1) and Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in mediating ozone's effects. Disruption of these and other identified proteins by ozone exposure impairs microglial function and response to amyloid plaques, suggesting a novel pathway through which ozone may influence AD pathology via immune dysregulation. This review discusses the concept of a bidirectional lung-brain axis, illustrating that systemic responses to air pollutants like ozone may reflect and contribute to neurodegenerative processes in the CNS. By delineating these mechanisms, we emphasize the critical need for integrating environmental health management into strategies for the prevention and treatment of dementia. [ABSTRACT FROM AUTHOR]

Mg-Li alloys can be promising candidates as bioresorbable Li-releasing implants for bipolar disorder and other neurodegenerative disorders. In order to compare the therapeutic efficacy of conventional Li salts and Li delivered through Mg-Li alloy extracts, we tested an in vitro model based on the neuroinflammation hypothesis of mood disorders (peripheral inflammation inducing neuroinflammation) wherein, a coculture of microglia and astrocytes was treated with conditioned medium from pro-inflammatory macrophages. Two alloys, Mg-1.6Li and Mg-9.5Li, were tested in the form of material extracts and well-known outcomes of Li treatment such as GSK3β phosphorylation (indirect flow cytometry) and influence on inflammation-related gene expression (qPCR) were compared against Li salts. This is the first study demonstrating that Li can increase the phosphorylation of GSK3β in glial cells in the presence of excess Mg. Furthermore, Mg-Li alloys were more effective than Li salts in downregulating IL6 and upregulating the neurotrophin GDNF. Mg had no antagonistic effects toward Li-driven downregulation of astrogliosis markers. Overall, the results provide evidence to support further studies employing Mg-Li alloys for neurological applications. [ABSTRACT FROM AUTHOR]

Background: Epilepsy, a common neurological disorder, has been increasingly associated with neuroinflammation, especially microglia activation. To gain insights into the research trends and patterns in this intersection, we conducted a bibliometric analysis of studies published between 2005 and 2024. Using the Web of Science Core Collection, we identified 1,229 relevant articles and reviews, focusing on the relationship between epilepsy and microglia. Methods: We employed the Bibliometrix R package and VOSviewer to analyze the data. Our search strategy combined epilepsy-related terms with microglia and microglial cell keywords. The analysis encompassed publication trends, country and institutional contributions, journal sources, authors, keywords, and thematic evolution. Results: The number of publications has steadily increased, particularly after 2019, indicating growing research interest. The United States, China, and Germany emerged as the most productive countries, with extensive collaboration between China and the United States. Epilepsia and Journal of Neuroinflammation were the most influential journals. Aronica E, Vezzani A, and Engel T were the most prolific authors. Thematic analysis revealed clusters focused on temporal lobe epilepsy, epilepsy-related disorders, and microglia activation. Over the past several years, research has shifted from fundamental brain function studies to in-vivo investigations of specific molecular mechanisms. The CSTB (−) mouse model and NF-κB signaling pathway both merit further in-depth investigation. Conclusion: In conclusion, this bibliometric study reveals a surge in epilepsy-microglia research, led by key countries, journals, and researchers. Temporal lobe epilepsy, epilepsy-related disorders, and microglia activation are focal themes. Future directions include exploring microglia activation mechanisms, utilizing animal models, and interdisciplinary approaches. [ABSTRACT FROM AUTHOR]

Neuroinflammation is a central feature in the pathophysiology of several neurodegenerative diseases, including MS, AD, and PD. This review aims to synthesize current research on the role of inflammation in these conditions, emphasizing the potential of inflammatory biomarkers for diagnosis and treatment. We highlight recent findings on the mechanisms of neuroinflammation, the utility of biomarkers in disease differentiation, and the implications for therapeutic strategies. Advances in understanding inflammatory pathways offer promising avenues for developing targeted interventions to improve patient outcomes. Future research should focus on validating these biomarkers in larger cohorts and integrating them into clinical practice to enhance diagnostic accuracy and therapeutic efficacy. [ABSTRACT FROM AUTHOR]

In neurodegenerative diseases, the activation of microglia and the ensuing neuroinflammation are pivotal in regulating disease progression. Attenuating inflammation induced by microglial cells is considered a key strategy for slowing the progression of neurodegenerative diseases. γ‐glutamylcysteine (γ‐GC) has exhibited significant antioxidative and anti‐inflammatory effects; nevertheless, its potential role in modulating neuroinflammatory responses remains incompletely explored. The current investigation aimed to establish a neuroinflammation model by stimulating BV2 microglia cells with lipopolysaccharide (LPS) and to explore the protective effect of γ‐GC on neuroinflammation in BV2 microglia cells. The results demonstrated that γ‐GC significantly attenuated LPS‐induced oxidative damage in BV2 cells, reduced the levels of tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β), inhibited the cytoplasmic translocation of high‐mobility group box 1 protein (HMGB1), and effectively mitigated the LPS‐induced inflammatory response in BV2 cells. We further investigated the regulatory mechanism of γ‐GC on LPS‐induced BV2 neuroinflammation and found that γ‐GC significantly enhances autophagy in BV2 cells, resulting in a marked reduction in mammalian target of rapamycin (mTOR) phosphorylation levels and an increase in AMP‐activated protein kinase (AMPK) phosphorylation levels. The use of autophagy inhibitors 3‐methyladenine (3‐MA) and AMPK inhibitors further corroborates the proposition that γ‐GC promotes autophagy in BV2 cells while suppressing the LPS‐induced inflammatory response of BV2 microglia through the activation of the AMPK‐mTOR pathway. The findings indicate that γ‐GC exerts a substantial inhibitory impact on neuroinflammation, making it a promising candidate for the development of therapeutic strategies against neuroinflammatory disorders and related conditions. [ABSTRACT FROM AUTHOR]

Background: In mucopolysaccharidosis type III (MPS III, also known as Sanfilippo syndrome), a pediatric neurodegenerative disorder, accumulation of abnormal glycosaminoglycans (GAGs) induces severe neuroinflammation by triggering the microglial pro-inflammatory cytokines production via a TLR4-dependent pathway. But the extent of the microglia contribution to the MPS III neuropathology remains unclear. Extracellular vesicles (EVs) mediate intercellular communication and are known to participate in the pathogenesis of adult neurodegenerative diseases. However, characterization of the molecular profiles of EVs released by MPS III microglia and their effects on neuronal functions have not been described. Methods: Here, we isolated EVs secreted by the microglial cells after treatment with GAGs purified from urines of Sanfilippo patients (sfGAGs-EVs) or from age-matched healthy subjects (nGAGs-EVs) to explore the EVs' proteins and small RNA profiles using LC–MS/MS and RNA sequencing. We next performed a functional assay by immunofluorescence following nGAGs- or sfGAGs-EVs uptake by WT primary cortical neurons and analyzed their extensions metrics after staining of βIII-tubulin and MAP2 by confocal microscopy. Results: Functional enrichment analysis for both proteomics and RNA sequencing data from sfGAGs-EVs revealed a specific content involved in neuroinflammation and neurodevelopment pathways. Treatment of cortical neurons with sfGAGs-EVs induced a disease-associated phenotype demonstrated by a lower total neurite surface area, an impaired somatodendritic compartment, and a higher number of immature dendritic spines. Conclusions: This study shows, for the first time, that GAGs from patients with Sanfilippo syndrome can induce microglial secretion of EVs that deliver a specific molecular message to recipient naive neurons, while promoting the neuroinflammation, and depriving neurons of neurodevelopmental factors. This work provides a framework for further studies of biomarkers to evaluate efficiency of emerging therapies. [ABSTRACT FROM AUTHOR]

Neurodegeneration and neuroinflammation are key components in the pathogenesis of Japanese Encephalitis caused by Japanese Encephalitis Virus (JEV) infection. The N-methyl-D-aspartate (NMDA)-type glutamate receptor displays excitatory neurotoxic and pro-inflammatory properties in a cell context-dependent manner. Herein, potential roles of the NMDA receptor in excitatory neurotoxicity and neuroinflammation and effects of NMDA receptor blockade against JEV pathogenesis were investigated in rat microglia, neuron/glia, neuron cultures, and C57BL/6 mice. In microglia, JEV infection induced glutamate release and activated post-receptor NMDA signaling, leading to activation of Ca2+ mobilization and Calcium/Calmodulin-dependent Protein Kinase II (CaMKII), accompanied by pro-inflammatory NF-κB and AP-1 activation and cytokine expression. Additionally, increased Dynamin-Related Protein-1 protein phosphorylation, NAPDH Oxidase-2/4 expression, free radical generation, and Endoplasmic Reticulum stress paralleled with the reactive changes of microglia after JEV infection. JEV infection-induced biochemical and molecular changes contributed to microglia reactivity and pro-inflammatory cytokine expression. NMDA receptor antagonists MK801 and memantine alleviated intracellular signaling and pro-inflammatory cytokine expression in JEV-infected microglia. JEV infection induced neuronal cell death in neuron/glia culture associated with the concurrent production of pro-inflammatory cytokines. Conditioned media of JEV-infected microglia compromised neuron viability in neuron culture. JEV infection-associated neuronal cell death was alleviated by MK801 and memantine. Activation of NMDA receptor-related inflammatory changes, microglia activation, and neurodegeneration as well as reversal effects of memantine were revealed in the brains of JEV-infected mice. The current findings highlight a crucial role of the glutamate/NMDA receptor axis in linking excitotoxicity and neuroinflammation during the course of JEV pathogenesis, and proposes the anti-inflammatory and neuroprotective potential of NMDA receptor blockade. [ABSTRACT FROM AUTHOR]

Background: Chronic ethanol exposure (CEE) is recognized as an important risk factor for depression, and the gut-brain axis has emerged as a key mechanism underlying chronic ethanol exposure-induced anxiety and depression-like behaviors. Short-chain fatty acids (SCFAs), which are the key metabolites generated by gut microbiota from insoluble dietary fiber, exert protective roles on the central nervous system, including the reduction of neuroinflammation. However, the link between gut microbial disturbances caused by chronic ethanol exposure, production of SCFAs, and anxiety and depression-like behaviors remains unclear. Methods: Initially, a 90-day chronic ethanol exposure model was established, followed by fecal microbiota transplantation model, which was supplemented with SCFAs via gavage. Anxiety and depression-like behaviors were determined by open field test, forced swim test, and elevated plus-maze. Serum and intestinal SCFAs levels were quantified using GC-MS. Changes in related indicators, including the intestinal barrier, intestinal inflammation, neuroinflammation, neurotrophy, and nerve damage, were detected using Western blotting, immunofluorescence, and Nissl staining. Results: Chronic ethanol exposure disrupted with gut microbial homeostasis, reduced the production of SCFAs, and led to anxiety and depression-like behaviors. Recipient mice transplanted with fecal microbiota that had been affected by chronic ethanol exposure exhibited impaired intestinal structure and function, low levels of SCFAs, intestinal inflammation, activation of neuroinflammation, a compromised blood-brain barrier, neurotrophic defects, alterations in the GABA system, anxiety and depression-like behaviors. Notably, the negative effects observed in these recipient mice were significantly alleviated through the supplementation of SCFAs. Conclusion: SCFAs not only mitigate damage to intestinal structure and function but also alleviate various lesions in the central nervous system, such as neuroinflammation, and reduce anxiety and depression-like behaviors, which were triggered by transplantation with fecal microbiota that had been affected by chronic ethanol exposure, adding more support that SCFAs serve as a bridge between the gut and the brain. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular events secondary to stroke–collectively classified as stroke-heart syndrome–greatly impair the patient's prognosis, however its underlying mechanism has yet to be determined. To investigate the mechanism of central neuroinflammation and its effects on stroke-heart syndrome, a temperature-ultrasound responsive brain-targeted drug delivery system, DATS/MION-LPE, was synthesized to specifically study neuroinflammation in the mouse middle cerebral artery occlusion (MCAO) model. Results: The specific polymer of DATS/MION-LPE can close the nanoparticle pores at 37 °C, restricting drug release in the circulation. After the nanoparticles were targeted to brains, the polymer can be cleaved under external ultrasound irradiation, reopening the nanoparticle pores and allowing drug release, therefore directly managing the neuroinflammation. After a stroke, a significant cerebral inflammation occurred, with elevated IL-1β and pyrin domain-containing 3 (NLRP3) inflammasome. Accordingly, significantly increased histone deacetylase 6 (HDAC6) and decreased sirtuin 1 (SIRT1) were observed. An antagonistic relationship between HDAC6 and SIRT1 was found, which can jointly regulate the cerebral NLRP3 expression. The systemic IL-1β and ATP levels were increased after the stroke, accompanied by a significant heart injury including contractile dysfunction, elevated IL-1β levels, and oxidative stress. Meanwhile, neuroinflammation can trigger sympathetic nervous overexcitation with associated heart damage. DATS/MION-LPE can targetedly effect on ischemic brain, exhibiting cerebral and cardiac protective effects including downregulated cerebral NLRP3 and HDAC6 expressions, upregulated SIRT1 expressions in brain, reduced IL-1β and ATP in circulation, and alleviated cardiac impairment. Conclusion: This study introduced the key role of neuroinflammation in stroke-heart syndrome and first investigated the crucial HDAC6/SIRT1-NLRP3 circuit in this process. Heart injury secondary to stroke is mediated by neuroinflammation induced systemic inflammatory responses and sympathoexcitation. DATS/MION-LPE is a unique tool and effective therapeutic agent, which provides new insights into combinational heart and cardiac protection. [ABSTRACT FROM AUTHOR]

Microglia are critically involved in post‐stroke inflammation affecting neurological outcomes. Lipid droplet (LD) accumulation in microglia results in a dysfunctional and pro‐inflammatory state in the aged brain and worsens the outcome of neuroinflammatory and neurodegenerative diseases. However, the role of LD‐rich microglia (LDRM) under stroke conditions is unknown. Using in vitro and in vivo stroke models, herein accumulation patterns of microglial LD and their corresponding microglial inflammatory signaling cascades are studied. Interactions between temporal and spatial dynamics of lipid profiles and microglial phenotypes in different post‐stroke brain regions are found. Hence, microglia display enhanced levels of LD accumulation and elevated perilipin 2 (PLIN2) expression patterns when exposed to hypoxia or stroke. Such LDRM exhibit high levels of TNF‐α, IL‐6, and IL‐1β as well as a pro‐inflammatory phenotype and differentially expressed lipid metabolism‐related genes. These post‐ischemic alterations result in distinct lipid profiles with spatial and temporal dynamics, especially with regard to cholesteryl ester and triacylglycerol levels, further exacerbating post‐ischemic inflammation. The present study sheds new light on the dynamic changes of brain lipid profiles and aggregation patterns of LD in microglia exposed to ischemia, demonstrating a mutual mechanism between microglial phenotype and function, which contributes to progression of brain injury. [ABSTRACT FROM AUTHOR]

Age-related decline occurs in most brain structures and sensory systems. An illustrative case is olfaction. The olfactory bulb (OB) undergoes deterioration with age, resulting in reduced olfactory ability. A decline in olfaction is also associated with early symptoms of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). However, the underlying reasons are unclear. The microphthalmia-associated transcription factor (MITF) is expressed in the projection neurons (PNs) of the OB–the mitral and tufted (M/T) cells. Primary M/T cells from Mitf mutant mice show hyperactivity, potentially attributed to the reduced expression of a key potassium channel subunit, Kcnd3 /Kv4.3. This influences intrinsic plasticity, an essential mechanism involving the non-synaptic regulation of neuronal activity. As neuronal hyperactivity often precedes neurodegenerative conditions, the current study aimed to determine whether the absence of Mitf causes degenerative effects during aging. Aged Mitf mutant mice showed reduced olfactory ability without inflammation. However, an increase in the expression of potassium channel subunit genes in the OBs of aged Mitf mi-vga9/mi-vga9 mice suggests that during aging, compensatory mechanisms lead to stabilization. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV-1) remains a persistent global health crisis. Even while successfully virologically suppressed, people with HIV (PWH) experience a higher risk for inflammatory disorders such as HIV-associated neurocognitive disorder (HAND). Tobacco use puts PWH at higher risk for neurocognitive symptoms resulting from HIV-associated neuroinflammation. The NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome has been implicated as a driver of HIV-associated inflammation, including HAND. Nicotine, the psychoactive component of tobacco smoke, has also been shown to signal through the NLRP3 inflammasome and modulate inflammatory signaling in the CNS. Here, we explore the impacts of nicotine and tobacco on the complex neurobiology of HAND, including effects on cognition, inflammation, viral latency, and blood-brain barrier integrity. We outline nicotine's role in the establishment of active and latent infection in the brain and posit the NLRP3 inflammasome as a common pathway by which HIV-1 and nicotine promote neuroinflammation in PWH. [ABSTRACT FROM AUTHOR]

This paper reviews the effects of gut microbiota in regulating neurodegenerative diseases through controlling gut-brain axis. Specific microbial populations and their metabolites (short-chain fatty acids and tryptophan derivatives) regulate neuroinflammation, neurogenesis and neural barrier integrity. We then discuss ways by which these insights lead to possible interventions - probiotics, prebiotics, dietary modification, and fecal microbiota transplantation (FMT). We also describe what epidemiological and clinical studies have related certain microbiota profiles with the courses of neurodegenerative diseases and how these impact the establishment of microbiome-based diagnostics and individualized treatment options. We aim to guide microbial ecology research on this key link to neurodegenerative disorders and also to highlight collaborative approaches to manage neurological health by targeting microbiome-related factors. [ABSTRACT FROM AUTHOR]

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) are broad diagnoses that encompass a range of sudden-onset neuropsychiatric symptoms in children, which can include obsessive-compulsive disorder (OCD), tics, anxiety, emotional instability, and cognitive difficulties. Unlike PANDAS, PANS is not strictly linked to group A streptococcal infections but can be triggered by various infectious or environmental factors. Lights and shadows remain upon the management of children with PANS and PANDAS and there is no clear consensus regarding definition, diagnostic criteria, treatment, and follow-up. The aim of the present study was to evaluate the level of agreement on PANS and PANDAS definition, diagnostic criteria, treatment and follow-up and to assess on the basis of recent studies whether there is a need to modify the current recommendations used by primary care pediatricians and hospital pediatricians in clinical practice in order to improve outcomes. Using the Delphi method, this consensus provides shared indications on PANS and PANDAS management in pediatric age, based on the most updated literature. This work represents, in our opinion, the most complete and up-to-date information on the diagnosis of PANS and PANDAS, as well as consensus statements about several aspects of clinical care. Undoubtedly, more randomized and controlled trials are needed in the pediatric population to better define the best management, also in terms of adequate follow-up examinations and period of observation. [ABSTRACT FROM AUTHOR]

Introduction: Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are tauopathic atypical parkinsonisms. Given their overlap in terms of clinical manifestation, there is growing interest in the mechanisms leading to these entities. Materials and methods: In total, 71 patients were included in the study, 19 of whom were clinically diagnosed with CBS, 37 with PSP, and 15 with Parkinson's disease (PD). The mean ages of the participants were 72.8, 72.9, and 64.0 years, respectively, and the disease duration varied from 3 to 6 years. Each individual underwent blood collection. Morphological and biochemical evaluation of blood samples was performed to analyze the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-high-density lipoprotein ratio (NHR). A single-photon emission computed tomography (SPECT) with technetium-99m hexamethylpropyleneamine oxime (99Tc-HMPAO) tracer was used to assess perfusion in two regions of interest (ROI): the thalamus and insula. Using Pearson correlation to assess the linear relationship between NHR and perfusion in the insula and thalamus for CBS, PSP, and PD patients, the authors intended to verify possible correlations between NLR, PLR, and NHR and perfusion in the indicated ROIs. Results: The study revealed a negative linear correlation between NHR and perfusion of both the left (Insula L; R = −0.59) and right (Insula R; R = −0.58) insula regions. Similar to the insula, a linear correlation between NHR and activity in both the left (Thalamus L) and right (Thalamus R) thalamus regions in CBS subjects with a relatively stronger correlation in the right thalamus (R = −0.64 vs. R = −0.58) was found. These observations were not confirmed in PSP and PD patients. Conclusion: Simultaneously using non-specific parameters for peripheral inflammation (NLR, PLR, and NHR) and perfusion, SPECT may be an interesting beginning point for further analysis of inflammatory disease mechanisms. To the best of our knowledge, this is the first study to address the potential correlation between the peripheral neuroinflammatory markers NLR, PLR, and NHR and perfusion disturbances in particular ROIs. [ABSTRACT FROM AUTHOR]