Biomarker Of Neuroinflammation Research Articles

Demystifying the Role of Neuroinflammatory Mediators as Biomarkers for Diagnosis, Prognosis, and Treatment of Alzheimer's Disease: A Review.

Neuroinflammatory mediators play a pivotal role in the pathogenesis of Alzheimer's Disease (AD), influencing its onset, progression, and severity. The precise mechanisms behind AD are still not fully understood, leading current treatments to focus mainly on managing symptoms rather than preventing or curing the condition. The amyloid and tau hypotheses are the most widely accepted explanations for AD pathology; however, they do not completely account for the neuronal degeneration observed in AD. Growing evidence underscores the crucial role of neuroinflammation in the pathology of AD. The neuroinflammatory hypothesis presents a promising new approach to understanding the mechanisms driving AD. This review examines the importance of neuroinflammatory biomarkers in the diagnosis, prognosis, and treatment of AD. It delves into the mechanisms underlying neuroinflammation in AD, highlighting the involvement of various mediators such as cytokines, chemokines, and ROS. Additionally, this review discusses the potential of neuroinflammatory biomarkers as diagnostic tools, prognostic indicators, and therapeutic targets for AD management. By understanding the intricate interplay between neuroinflammation and AD pathology, this review aims to help in the development of efficient diagnostic and treatment plans to fight this debilitating neurological condition. Furthermore, it elaborates recent advancements in neuroimaging techniques and biofluid analysis for the identification and monitoring of neuroinflammatory biomarkers in AD patients.

Profiling neuroinflammatory markers and response to nusinersen in paediatric spinal muscular atrophy.

Neuroinflammation is an emerging clinical feature in spinal muscular atrophy (SMA). Characterizing neuroinflammatory cytokines in cerebrospinal fluid (CSF) in SMA and their response to nusinersen is important for identifying new biomarkers and understanding the pathophysiology of SMA. We measured twenty-seven neuroinflammatory markers in CSF from twenty SMA children at different time points, and correlated the findings with motor function improvement. At baseline, MCP-1, IL-7 and IL-8 were significantly increased in SMA1 patients compared to SMA2, and were significantly correlated with disease severity. After six months of nusinersen treatment, CSF levels of eotaxin and MIP-1β were markedly reduced, while IL-2, IL-4 and VEGF-A were increased. The decreases in eotaxin and MIP-1β were associated with changes in motor scores in SMA1. We also detected a transient increase in MCP-1, MDC, MIP-1α, IL-12/IL-23p40 and IL-8 after the first or second injection of nusinersen, followed by a steady return to baseline levels within six months. Our study provides a detailed profile of neuroinflammatory markers in SMA CSF. Our data confirms the potential of MCP-1, eotaxin and MIP-1β as new neuroinflammatory biomarkers in SMA1 and indicates the presence of a subtle inflammatory response to nusinersen during the early phase of treatment.

CSF complement proteins are elevated in prodromal to moderate Alzheimer's disease patients and are not altered by the anti-tau antibody semorinemab.

Growing evidence suggests a role for neuroinflammation in Alzheimer's disease (AD). We investigated complement pathway activity in AD patient cerebrospinal fluid (CSF) and evaluated its modulation by the anti-tau antibody semorinemab. Immunoassays were applied to measure CSF complement proteins C4, factor B (FB), C3 and their cleavage fragments C4a, C3a, and factor Bb (Bb) in AD patients and a separate cognitively unimpaired (CU) cohort. All measured CSF complement proteins were increased in AD versus CU subjects, with C4a displaying the most robust increase. Finally, semorinemab did not have a significant pharmacodynamic effect on CSF complement proteins. Elevated levels of CSF C4a, C4, C3a, C3, Bb, and FB are consistent with complement activation in AD brains. Despite showing a reduction in CSF soluble tau species, semorinemab did not impact complement protein levels or activity. Further studies are needed to determine the value of complement proteins as neuroinflammation biomarkers in AD. Cerebrospinal fluid (CSF) complement proteins C4a, C3a, Bb, C4, C3, and factor B levels were increased in Alzheimer's disease (AD) patients compared to a separate cognitively unimpaired (CU) cohort. Baseline CSF complement protein levels were correlated with neuro-axonal degeneration and glial activation biomarkers in AD patients. The investigational anti-tau antibody semorinemab did not impact CSF complement protein levels or activity relative to the placebo arm.

NEUROINFLAMMATION IN PARKINSON’S DISEASE: A STUDY WITH [11C]PBR28 PET AND CEREBROSPINAL FLUID MARKERS

ObjectiveTo investigate neuroinflammation in Parkinson’s disease (PD) with [11C]PBR28 positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers, and the relationship to dopaminergic functioning measured with 6-[18F]-fluoro-L-dopa ([18F]FDOPA) PET. MethodsThe clinical cohort consisted of 20 subjects with PD and 51 healthy controls (HC). All HC and 15 PD participants underwent [11C]PBR28 High Resolution Research Tomograph (HRRT) PET for the quantitative assessment of cerebral binding to the translocator protein (TSPO), a neuroinflammation marker. CSF samples were available from 17 subjects with PD and 21 HC and were examined for soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), neurogranin (NG), alpha-synuclein (aSyn) and oligo-alpha-synuclein. All subjects with PD underwent [18F]FDOPA HRRT PET. ResultsWhile the subjects with PD and HC did not differ in the total volume of distribution (VT) of [11C]PBR28 in any studied brain regions, higher levels of neuroinflammation and neurodegeneration CSF biomarkers sTREM2 and NG, respectively were associated with more severe motor symptoms evaluated by The Unified Parkinson’s Disease Rating Scale motor part (UPDRS-III) (r = 0.52, p=0.041 and r = 0.59, p=0.016 respectively). Additionally, in the PD group increased [11C]PBR28 VT in the basal ganglia and substantia nigra (SN) was related to higher levels of neuroinflammation biomarker YKL-40 (p <0.01). ConclusionAssociations between CSF biomarkers, motor disability and [11C]PBR28 VT in the striatum and SN may support a role for neuroinflammation in PD.

Effects of Cannabidiol (CBD) on Doxorubicin-Induced Anxiety and Depression-like Behaviors and mRNA Expression of Inflammatory Markers in Rats.

Background: Post-treatment side effects of chemotherapy can include cognitive deficits commonly known as Chemo-brain. The treatment of patients with Doxorubicin (DOX), one of the most widely used chemotherapeutic drugs in the treatment of cancer, can induce depression, anxiety, and impaired cognitive function. Cannabidiol (CBD) is a non-psychoactive component of Cannabis sativa that has been identified as a possible therapeutic agent against many neurodegenerative disorders, including traumatic brain injury, spinal cord injury, Tau-protein-induced neurodegeneration, and neuropathic pain. Therefore, this study aimed to assess whether oral CBD administration could reduce DOX-induced anxiety and depression-like behaviors and alter the expression of mRNA associated with neuroinflammation. Methods: Female Long Evans Hooded rats received intraperitoneal injections of DOX (6 mg/kg) or the vehicle (0.9% saline) once a week for four weeks, followed by oral administration of CBD (10 mg/kg) three times a week for the same period. Results: CBD was significantly protective against DOX-induced anxiety and depression-like behaviors, as measured by several behavioral tests. Furthermore, CBD improved DOX-induced alterations in the gene expression of biomarkers of neuroinflammation in the hippocampus and prefrontal cortex. Conclusions: This provides insights into future studies on possible mechanisms by which DOX-induced cognitive dysfunction could be alleviated by CBD.

Caregiving-Related Depression Increases Neuroinflammation in Spousal Caregivers to Individuals with Cognitive Impairment: A Longitudinal Study

Abstract Background The caregiving burden of the spousal caregivers (SCGs) to individuals with cognitive impairment poses public health challenges with adverse psychosocial and physiological effects. However, few studies have investigated the neurobiological impact of caregiving, particularly through the investigation of neuroinflammation and neurodegeneration. Methods Using data from a longitudinal cohort at Chungnam National University Hospital, the relationship between caregiving burden, neuroinflammation and neurodegeneration was examined in 38 older adult couples over a 16-month period. Caregiving burden was assessed through a multifaceted approach. For factors related to the care recipient, we assessed cognitive function and neuropsychiatric symptoms. Factors regarding the SCGs included the measurement of perceived depression. Glial fibrillary acidic protein (GFAP) was used as a plasma biomarker for neuroinflammation and neurofilament light chain (NfL) for neurodegeneration. Regression analyses were adjusted for age, sex, apolipoprotein E status, follow-up interval, vascular risk factors, and physical activity. Results Changes in depression among SCGs were significantly correlated with increased GFAP levels (p = 0.003), indicating that greater depressive symptoms during caregiving are associated with increased neuroinflammation. In contrast, no significant correlations were found between changes in cognitive function or neuropsychiatric symptoms in care recipients and the plasma biomarker levels of SCGs. Additionally, there was no significant association between changes in depression and NfL levels in SCGs. Conclusions The psychological stress experienced by SCGs while caring for partners with cognitive impairment actively contributes to neuroinflammation, a well-known risk factor for various diseases. This study emphasizes the need to address psychological stress experienced by older adult caregivers.

DNL343 is an investigational CNS penetrant eukaryotic initiation factor 2B activator that prevents and reverses the effects of neurodegeneration caused by the integrated stress response.

The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that is activated in response to multiple sources of cellular stress. Although acute activation of this pathway restores cellular homeostasis, intense or prolonged ISR activation perturbs cell function and may contribute to neurodegeneration. DNL343 is an investigational CNS-penetrant small-molecule ISR inhibitor designed to activate the eukaryotic initiation factor 2B (eIF2B) and suppress aberrant ISR activation. DNL343 reduced CNS ISR activity and neurodegeneration in a dose-dependent manner in two established in vivo models - the optic nerve crush injury and an eIF2B loss of function (LOF) mutant - demonstrating neuroprotection in both and preventing motor dysfunction in the LOF mutant mouse. Treatment with DNL343 at a late stage of disease in the LOF model reversed elevation in plasma biomarkers of neuroinflammation and neurodegeneration and prevented premature mortality. Several proteins and metabolites that are dysregulated in the LOF mouse brains were normalized by DNL343 treatment, and this response is detectable in human biofluids. Several of these biomarkers show differential levels in CSF and plasma from patients with vanishing white matter disease (VWMD), a neurodegenerative disease that is driven by eIF2B LOF and chronic ISR activation, supporting their potential translational relevance. This study demonstrates that DNL343 is a brain-penetrant ISR inhibitor capable of attenuating neurodegeneration in mouse models and identifies several biomarker candidates that may be used to assess treatment responses in the clinic.

Targeting leptin/CCL3-CCL4 axes in NAFLD/MAFLD: A novel role for BPF in counteracting thalamic inflammation and white matter degeneration

Non-alcoholic fatty liver disease (NAFLD), redefined as Metabolic Associated Fatty Liver Disease (MAFLD), is characterized by an extensive multi-organ involvement. MAFLD-induced systemic inflammatory status and peripheral metabolic alteration lead to an impairment of cerebral function. Herein, we investigated a panel of leptin-related inflammatory mediators as predictive biomarkers of neuroinflammation and evaluated the possible role of Bergamot Polyphenolic Fraction (BPF) in counteracting this MAFLD-induced inflammatory cascade. Male DIAMOND mice were randomly assigned to fed chow diet and tap water or high fat diet with sugar water. Starting from week 16, mice were further divided and treated with vehicle or BPF (50 mg/kg/day), via gavage, until week 30. Magnetic resonance imaging was performed at the baseline and at week 30. Correlation and regression analyses were performed to discriminate the altered lipid metabolism in the onset of cerebral alterations. Steatohepatitis led to an increase in leptin levels, resulting in a higher expression of proinflammatory mediators. The inflammatory biomarkers involved in leptin/CCL3-CCL4 axes were correlated with the altered thalamus energetic metabolism and the white matter degeneration. BPF administration restored leptin level, improved glucose and lipid metabolism, and reduced chronic low-grade inflammatory mediators, resulting in a prevention of white matter degeneration, alterations of thalamus metabolism and brain atrophy. The highlighted positive effect of BPF, mediated by the downregulation of the inflammatory biomarkers involved in leptin/CCL3-CCL4 axes, affording novel elements to candidate BPF for the development of a therapeutic strategy aimed at counteracting MAFLD-related brain inflammation.

Assessment of Mannitol-Induced Chronic Blood-Brain Barrier Dysfunction In Vivo Using Magnetic Resonance.

The blood-brain barrier (BBB) is essential for protection and plays a crucial role in chronic neurological disorders like small-vessel disease and Alzheimer's disease. Its complexity poses significant challenges for effective diagnostics and treatments, highlighting the need for novel animal models and comprehensive BBB dysfunction studies. This study investigates chronic BBB dysfunction induction using osmotic disruption via mannitol in healthy adult male Sprague Dawley rats over 12 weeks. Group 1 received 1 bolus/week (2.0 g/kg), Group 2 received 3 boluses/week (1.5 g/kg), and Group 3 received 3 boluses/week (2.5 g/kg). BBB dysfunction was assessed using gadolinium (Gd) infusion and MRI to evaluate location, severity, evolution, and persistence. MR spectroscopy (MRS) examined the brain metabolism changes due to intravenous mannitol, with T2-weighted MRI assessing brain lesions. Biomarkers of neuroinflammation were analyzed in the highest mannitol dose group. Our data show chronic BBB dysfunction primarily in the cortex, hippocampus, and striatum, but not in the corpus callosum of rats under periodic mannitol dosing in groups 1 and 2. MRS identified a distinctive metabolite signature, including changes in alanine, choline, and N-acetyl aspartate in the striatum of Group 1. No significant differences were found in the serum levels of all pro- and anti-inflammatory cytokines analyzed in the high-dose Group 3. This study underscores the feasibility and implications of using osmotic disruption to model chronic BBB dysfunction, offering insights for future neuroprotection and therapeutic strategies research.

Neuroinflammatory Biomarkers and Their Associations With Cognitive, Affective, and Functional Outcomes 3 to 12 Months After a Traumatic Brain Injury: A Pilot Study.

Neuroinflammation is an important feature of traumatic brain injury (TBI) that remains poorly understood in the 3- to 12-month period post-TBI. The purpose of our pilot study was to examine the relationships between biomarkers of neuroinflammation and functional outcomes in TBI patients 3 to 12months postinjury. TBI patients (n =36) 3 to 12months post-TBI were recruited from a South Florida TBI clinic from May 2022 to June 2023. The Disability Rating Scale, Satisfaction with Life Scale, NIH Toolbox Sorting Working Memory, Neuro-Quality of Life Cognitive Function, Anxiety, Depression, and Sleep assessments were performed. Multiple plasma biomarkers were assayed. Analysis of variance was used to compare between-group results. Linear regression was performed to analyze relationships between biomarkers and outcomes. Brain-derived neurotrophic factor concentrations were higher as postinjury time interval increased and were associated with cognitive battery outcomes. S-100β and glial fibrillary acidic protein were associated with anxiety score and hospital length of stay; S-100β was also associated with depression. Interleukin 6 was associated with cognitive function score and time since injury. We found S-100β, glial fibrillary acidic protein, Interleukin 6, and brain-derived neurotrophic factor to play a larger role in the TBI recovery period than other biomarkers examined. Clinicians should continue to monitor for symptoms post-TBI, as the neuroinflammatory process continues to persist even into the later rehabilitation stage.

Cerebrospinal fluid soluble CD27 is a sensitive biomarker of inflammation in autoimmune encephalitis

BackgroundAutoimmune encephalitis (AE) comprises a group of rare, severe neuroinflammatory conditions. Current biomarkers of neuroinflammation are often normal in AE which therefore can be difficult to rule out in patients with seizures, cognitive and/or neuropsychiatric symptoms. Cerebrospinal fluid (CSF) soluble CD27 (sCD27) and soluble B-cell maturation antigen (sBCMA) have high sensitivity for neuroinflammation in other neuroinflammatory conditions. In this exploratory study we investigate the potential of sCD27 and sBCMA in CSF as biomarkers of neuroinflammation in AE. MethodsConcentrations of sCD27 and sBCMA were measured in CSF from 40 AE patients (20 patients were untreated (12 with anti-N-Methyl-d-Aspartate receptor antibodies (NMDA) and 8 with anti-Leucine-rich Glioma-Inactivated 1 antibodies (LGI1)), and 37 symptomatic controls (SCs). ResultsCSF concentrations of sCD27 were increased in untreated NMDA AE patients (median 1571 pg/ml; p < 0.001) and untreated LGI1 AE patients (median 551 pg/ml; p < 0.05) compared to SCs (median 250 pg/ml). CSF sBCMA was increased in untreated NMDA AE patients (median 832 pg/ml) compared to SCs (median 429 pg/ml). CSF sCD27 and sBCMA correlated with the CSF cell count. Receiver operating characteristic curve analysis of untreated AE patients versus SCs showed an area under the curve of 0.97 for sCD27 and 0.76 for sBCMA. ConclusionCSF sCD27 is a suitable biomarker of neuroinflammation in AE with an ability to discriminate patients with NMDA AE and LGI1 AE from symptomatic controls. CSF sCD27 may be suited for ruling out AE and other neuroinflammatory conditions in the early phase of the diagnostic work-up.

CYP7B1 deficiency impairs myeloid cell activation in autoimmune disease of the central nervous system.

Dysregulation of cholesterol metabolism underlies neurodegenerative disease and is increasingly implicated in neuroinflammatory diseases, such as multiple sclerosis (MS). Cytochrome P450 family 7 subfamily B member 1 (CYP7B1) is a key enzyme in alternative cholesterol metabolism. A recessive mutation in the gene CYP7B1 is known to cause a neurodegenerative disease, hereditary spastic paraplegia type 5 and oxysterol accumulation. However, the role of CYP7B1 in neuroinflammation has been little revealed. In this study, we induced experimental autoimmune encephalomyelitis (EAE), as a murine model of MS, using CYP7B1 homozygous knockout (KO) mice. We found that CYP7B1 deficiency can significantly attenuate EAE severity. CYP7B1 deficiency is sufficient to reduce leukocyte infiltration into the central nervous system, suppress proliferation of pathogenic CD4+ T cells, and decrease myeloid cell activation during EAE. Additionally, live-animal imaging targeting translocator protein expression, an outer mitochondrial membrane protein biomarker of neuroinflammation, showed that CYP7B1 deficiency results in suppressed neuroinflammation. Using human monocyte-derived microglia-like cellular disease model and primary microglia of CYP7B1 KO mice, we also found that activation of microglia of CYP7B1 deficiency was impaired. These cumulative results suggest that CYP7B1 can regulate neuroinflammation, thus providing potential new targets for therapeutic intervention.

ISMRM Clinical Focus Meeting 2023: "Imaging the Fire in the Brain".

Set during the Annual Meeting of the International Society for Magnetic Resonance in Medicine (ISMRM), the "Clinical Focus Meeting" (CFM) aims to bridge the gap between innovative magnetic resonance imaging (MRI) scientific research and daily patient care. This initiative is dedicated to maximizing the impact of MRI technology on healthcare outcomes for patients. At the 2023 Annual Meeting, clinicians and scientists from across the globe were invited to discuss neuroinflammation from various angles (entitled "Imaging the Fire in the Brain"). Topics ranged from fundamental mechanisms and biomarkers of neuroinflammation to the role of different contrast mechanisms, including both proton and non-proton techniques, in brain tumors, autoimmune disorders, and pediatric neuroinflammatory diseases. Discussions also delved into how systemic inflammation can trigger neuroinflammation and the role of the gut-brain axis in causing brain inflammation. Neuroinflammation arises from various external and internal factors and serves as a vital mechanism to mitigate tissue damage and provide neuroprotection. Nonetheless, excessive neuroinflammatory responses can lead to significant tissue injury and subsequent neurological impairments. Prolonged neuroinflammation can result in cellular apoptosis and neurodegeneration, posing severe consequences. MRI can be used to visualize these consequences, by detecting blood-brain barrier damage, characterizing brain lesions, quantifying edema, and identifying specific metabolites. It also facilitates monitoring of chronic changes in both the brain and spinal cord over time, potentially leading to better patient outcomes. This paper represents a summary of the 2023 CFM, and is intended to guide the enthusiastic MR user to several key and novel sequences that MRI offers to image pathophysiologic processes underlying acute and chronic neuroinflammation. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 3.

Quercetin ameliorates neuroinflammatory and neurodegenerative biomarkers in the brain and improves neurobehavioral parameters in a repeated intranasal amyloid-beta exposed model of Alzheimer's disease.

Objectives: The aim of the present study was to study the potential therapeutic effects of quercetin in protection against repeated intranasal exposure of an amyloid-beta-induced mouse model. Methods: Mice received intranasal Aβ1-42 (5 μg/10 μL) exposure once daily for seven consecutive days. Quercetin was orally administered to them at 30 mg kg-1 and 100 mg kg-1 doses for one week starting from day five following Aβ1-42 peptide administration. Following this, the animals were evaluated for neurobehavioral parameters using a Morris water maze test and a novel object recognition test. Further to this, the biomarkers for neuroinflammation and neurodegeneration were evaluated in the hippocampus and cortex regions of the brain in these animals. Results: Multiple exposures to intranasal Aβ led to a significant decline in the learning and cognitive memory of the animals, whereas oral treatment with quercetin at dosages of 30 and 100 mg kg-1 alleviated Aβ-induced effects. Quercetin treatment significantly reduced Aβ accumulation, oxidative stress and proinflammatory cytokine biomarkers in the brain. In addition, it also alleviated the activation of astrocytic biomarkers, amyloid precursor protein and phosphorylated-tau proteins in the brain. Conclusion: Quercetin was found to be a potent antioxidant, anti-inflammatory compound with protection against neurodegenerative damage and improved learning and cognitive memory in a repeated Aβ-exposure model of AD.

Optimization of bioactivities of solvent extracts of bark and heartwood of Pterocarpus marsupium and exploration of neuroprotective effect linking to the major Phytoconstituents

The study aims to evaluate the neuroprotective properties of Pterocarpus marsupium Roxb. The bioactive optimized hydroalcohol-extracted fractions of bark (PMBHA) and heartwood (PMHHA) at 300 and 400 mg/kg were examined in rats with scopolamine-induced neurotoxicity to study oxidative, neurochemical, and neuroinflammation biomarkers. Phenol and flavonoid-rich radical scavengers in contributing total antioxidant capacities of PMBHA and PMHHA quenched peroxyl radicals and protected the cellular membrane and lipoproteins from ROS in DPPH, ORAC, and CAP-e tests. In anticholinesterase activities, PMBHA inhibited AChE (IC50: 54.40 ± 0.98 µg/mL) and BChE (IC50: 50.95 ± 0.98 µg/mL) mixed-competitively, while PMHHA inhibited cholinesterase activities (AChE: 42.23 ± 0.54, and BChE: 47.19 ± 0.65 µg/mL) competitively. Dosage at 300 and 400 mg/kg of PMBHA and PMHHA improved serum and brain oxidative indicators (MDA, SOD, CAT, and GSH), and restored proinflammatory cytokines (TNF-α, and IL-6) leading to enhanced brain cholinesterase and β-secretase levels in neurotoxic rats. GC-MS reported antioxidant, anti-inflammatory, and neuroprotective compounds of PMBHA catechol, thiamet-G, d-Gala-l-ido-octonic amide, falcarinol, D-mannose, ribitol, 1,2,4-cyclopentanetrione, 3-(2-pentenyl)-, hexadecanoic acid methyl ester, n-hexadecanoic acid, oleic acid, and 3,5-Dimethoxybenzyl alcohol, α-epi-7-epi-5-Eudesmol, 1 R,4aR,7 R,8aR)-7-(2-Hydroxypropan-2-yl)-1,4a-dimethyldecahydro naphthalen-1-ol, arctiol, 1,1,4,7-tetramethyldecahydro-1 H-cyclopropa[e]azulene-4,7-diol, 2-Propen-1-ol, 3-(2,6,6-trimethyl-1-cyclohexen-1-yl), 4-t-Butyl-2-[4-nitrophenyl]phenol in PMHHA were responsible in neuroprotection in neurotoxic rats. However, heartwood demonstrated better neuroprotective activities than the bark of P. marsupium due to some of the key compounds (1 R,4aR,7 R,8aR)-7-(2-Hydroxypropan-2-yl)-1,4a-dimethyldecahydronaphthalen-1-ol, 2-Propen-1-ol, 3-(2,6,6-trimethyl-1-cyclohexen-1-yl)-, 4-t-Butyl-2-[4-nitrophenyl]phenol, 1,1,4,7-Tetramethyldecahydro-1 H-cyclopropa[e]azulene-4,7-diol.

Cerebral ischemia biomarkers: Their roles in early diagnosis and prognosis with potential clinical applications

Cerebral ischemia, caused by a disruption in blood supply to the brain, remains a significant cause of morbidity and mortality worldwide. Identifying reliable biomarkers for the early diagnosis and prognosis of cerebral ischemia is crucial for timely intervention and improved patient outcomes. This review aims to provide a comprehensive overview of the current knowledge on cerebral ischemia biomarkers, focusing on their potential role in early detection and prediction of clinical outcomes. Specifically, we discuss the current advances in the field of cerebral ischemia biomarkers, which serve as essential tools for early diagnosis and monitoring of ischemic stroke. We examine several promising biomarkers, including omics data, genetic (FOXF2 and ATP5H), physiological and neuroinflammatory biomarkers, neuroimaging markers, blood-based biomarkers (proteins, microRNAs, and metabolites), and newer modalities such as exosomes, microvesicles, and cell-free deoxyribonucleic acid (cfDNA). In addition, we highlight the challenges and future directions in translating these biomarkers into clinical practice. Standardization and reproducibility, methodological limitations, and cost and accessibility are critical challenges in the translation of biomarkers into clinical practice. Addressing these challenges requires multi-stakeholder collaborations and coordinated efforts to establish standardized protocols, improve analytical methods, and develop cost-effective biomarker assays. The use of point-of-care testing devices or miniaturized lab-on-a-chip technologies can reduce costs and improve accessibility, particularly in low-resource settings. Furthermore, collaborations between academia, industry, and regulatory agencies can facilitate the translation of biomarkers by addressing regulatory and reimbursement hurdles that affect the affordability and availability of these tests.

CSF Neopterin Levels Are Elevated in Various Neurological Diseases and Aging.

Background/Objectives: Cerebrospinal fluid (CSF) neopterin reflects inflammation of the central nervous system (CNS) and is a potentially useful biomarker for neuroinflammatory assessment and differential diagnosis. However, its optimal cut-off level in adult patients with neurological disease has not been established and it has not been adequately studied in controls. We aimed to determine its usefulness as a biomarker of neuroinflammation and the effect of age on its level. Methods: In this retrospective study, CSF neopterin was evaluated in 652 patients in 38 disease groups. Its levels were analyzed with high-performance liquid chromatography with fluorometric detection. Results: A receiver operating characteristic analysis revealed that the optimal cut-off value of 33.57 pmol/mL for CSF neopterin distinguished the control and meningitis/encephalitis groups with a sensitivity of 100.0% and specificity of 94.4%. In the control group, which consisted of 170 participants (99 men and 71 women; mean ± standard deviation age, 52.56 ± 17.99 years), age was significantly positively correlated with CSF protein (r = 0.474, p < 0.001) and CSF neopterin (r = 0.476, p < 0.001) levels but not with CSF cell count (r = 0.144, p = 0.061). Both male and female controls exhibited significant increases in CSF neopterin levels with age. Similarly, the CSF neopterin level was significantly positively correlated with age in patients with amyotrophic lateral sclerosis, independently of disease duration and respiratory function. Conclusions: CSF neopterin levels were elevated in patients with various CNS diseases, reflecting CNS inflammation; they were also elevated with age. Prospective studies are required to establish CSF neopterin as a sensitive biomarker of neuroinflammation.

Challenges in the Diagnosis of SARS-CoV-2 Infection in the Nervous System.

Neurological involvement has been widely reported in SARS-CoV-2 infection. However, viral identification in the cerebrospinal fluid (CSF) is rarely found. The aim of this study is to evaluate the accuracy of virological and immunological biomarkers in CSF for the diagnosis of neuroCOVID-19. We analyzed 69 CSF samples from patients with neurological manifestations: 14 with suspected/confirmed COVID-19, with 5 additional serial CSF samples (group A), and as a control, 50 non-COVID-19 cases (group B-26 with other neuroinflammatory diseases; group C-24 with non-inflammatory diseases). Real-time reverse-transcription polymerase chain reaction (real-time RT-PCR) was used to determine SARS-CoV-2, and specific IgG, IgM, neopterin, and protein 10 induced by gamma interferon (CXCL-10) were evaluated in the CSF samples. No samples were amplified for SARS-CoV-2 by real-time RT-PCR. The sensitivity levels of anti-SARS-CoV-2 IgG and IgM were 50% and 14.28%, respectively, with 100% specificity for both tests. CXCL-10 showed high sensitivity (95.83%) and specificity (95.83%) for detection of neuroinflammation. Serial CSF analysis showed an association between the neuroinflammatory biomarkers and outcome (death and hospital discharge) in two cases (meningoencephalitis and rhombencephalitis). The detection of SARS-CoV-2 RNA and specific immunoglobulins in the CSF can be used for neuroCOVID-19 confirmation. Additionally, CXCL-10 in the CSF may contribute to the diagnosis and monitoring of neuroCOVID-19.

Gut Microbiota and Autism Spectrum Disorder: A Neuroinflammatory Mediated Mechanism of Pathogenesis?

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication and behavior, frequently accompanied by restricted and repetitive patterns of interests or activities. The gut microbiota has been implicated in the etiology of ASD due to its impact on the bidirectional communication pathway known as the gut-brain axis. However, the precise involvement of the gut microbiota in the causation of ASD is unclear. This study critically examines recent evidence to rationalize a probable mechanism in which gut microbiota symbiosis can induce neuroinflammation through intermediator cytokines and metabolites. To develop ASD, loss of the integrity of the intestinal barrier, activation of microglia, and dysregulation of neurotransmitters are caused by neural inflammatory factors. It has emphasized the potential role of neuroinflammatory intermediates linked to gut microbiota alterations in individuals with ASD. Specifically, cytokines like brain-derived neurotrophic factor, calprotectin, eotaxin, and some metabolites and microRNAs have been considered etiological biomarkers. We have also overviewed how probiotic trials may be used as a therapeutic strategy in ASD to reestablish a healthy balance in the gut microbiota. Evidence indicates neuroinflammation induced by dysregulated gut microbiota in ASD, yet there is little clarity based on analysis of the circulating immune profile. It deems the repair of microbiota load would lower inflammatory chaos in the GI tract, correct neuroinflammatory mediators, and modulate the neurotransmitters to attenuate autism. The interaction between the gut and the brain, along with alterations in microbiota and neuroinflammatory biomarkers, serves as a foundational background for understanding the etiology, diagnosis, prognosis, and treatment of autism spectrum disorder.

Navitoclax safety, tolerability, and effect on biomarkers of senescence and neurodegeneration in aged nonhuman primates

Alzheimer's disease (AD) is the most common global dementia and is universally fatal. Most late-stage AD disease-modifying therapies are intravenous and target amyloid beta (Aβ), with only modest effects on disease progression: there remains a high unmet need for convenient, safe, and effective therapeutics. Senescent cells (SC) and the senescence-associated secretory phenotype (SASP) drive AD pathology and increase with AD severity. Preclinical senolytic studies have shown improvements in neuroinflammation, tau, Aβ, and CNS damage; most were conducted in transgenic rodent models with uncertain human translational relevance. In this study, aged cynomolgus monkeys had significant elevation of biomarkers of senescence, SASP, and neurological damage. Intermittent treatment with the senolytic navitoclax induced modest reversible thrombocytopenia; no serious drug-related toxicity was noted. Navitoclax reduced several senescence and SASP biomarkers, with CSF concentrations sufficient for senolysis. Finally, navitoclax reduced TSPO-PET frontal cortex binding and showed trends of improvement in CSF biomarkers of neuroinflammation, neuronal damage, and synaptic dysfunction. Overall, navitoclax administration was safe and well tolerated in aged monkeys, inducing trends of biomarker changes relevant to human neurodegenerative disease.