Glial Fibrillary Acidic Protein Research Articles

Establishment and Use of Primary Cultured Astrocytes from Alexander Disease Model Mice

Alexander disease (AxD) is an intractable neurodegenerative disease caused by mutations in glial fibrillary acidic protein (GFAP), which is predominantly expressed in astrocytes. Thus, AxD is a primary astrocyte disease. However, it remains unclear how GFAP mutations affect astrocytes and cause AxD pathology. Three features are characteristic of AxD astrocytes in vivo: (1) Rosenthal fibers (RFs), the hallmark of AxD; (2) aberrant Ca2+ signals (AxCa); and (3) upregulation of disease-associated genes (AxGen). We established a primary culture system for astrocytes from an AxD transgenic mouse model, and used it to analyze the above features of AxD pathogenesis in astrocytes in vitro. We observed the formation of RFs in AxD primary cultures. The abundance of RFs was greater in AxD-transgene-homozygous compared with -hemizygous astrocytes, indicating a gene dosage effect, and this abundance increased with time in culture, indicating a developmental process effect. However, cultured AxD astrocytes did not exhibit changes in either AxCa or AxGen. We therefore conclude that RFs in astrocytes form via a cell-autonomous mechanism, whereas AxCa and AxGen are likely to occur via a non-cell-autonomous mechanism through interactions with other cells, such as neurons, microglia, and vascular cells. Although primary cultured AxD astrocytes are suitable for elucidating the mechanisms of RFs formation and for intervention studies, it should be noted that they cannot reflect the pathophysiology of non-cell-autonomous events in astrocytes.

CNSC-50. PRIMARY INTRACRANIAL CONGENITAL GLIOBLASTOMA (PICG): A SYSTEMATIC REVIEW OF CASE REPORTS FROM 2000 TO 2023

Abstract BACKGROUND AND OBJECTIVE The most commonly reported congenital intracranial space occupying lesions are teratoma, glioma and neuroblastoma. Primary intracranial congenital glioblastoma (PICG) is one of the most lethal and extremely rare neoplasms. Most pediatricians and gynecologists are unable to detect it congenitally, posing an ominous risk of spread and disease severity. We aim to determine the clinical manifestations, number of reported cases, radiological findings and neuro-oncological management of PICG. MATERIALS AND METHODS A comprehensive literature search using PubMed Central and Google Scholar was done, retrieving 17 case reports and five case series of 31 patients with PICG and included using the Preferred Reporting items for Systematic Reviews and Meta-Analyses guidelines, published between 2000 and 2023. RESULTS The mean age at presentation was 86.00 ± 88.36 days, with both genders affected equally, i.e. 45.16%. The most common symptoms and signs at presentation were seizures (38.70%) and hydrocephalus (51.61%), respectively. Left hemispheric (48.38%), with frontoparietal involvement (16.12%) was the frequently affected site. MRI findings were suggestive of low intensity signal significant of hemorrhage or calcification and a heterogenous mass in 35.58% and 32.25% cases, respectively. Gross total resection (GTR) was achievable in 48.38% patients. Glial fibrillary acid protein and vimentin were positive in 45.16% and 29.03% cases, respectively. Intraoperative mortality and recurrence were noted in 25.80% and 9.68% of patients, respectively. The average follow up duration was 20.57 months. CONCLUSION PICG has an extremely aggressive course of natural progression. Congenital presentation and its lack of awareness among clinicians is itself a challenge for disease management. Adjuvant chemo-radiotherapy has proven fruitful along with GTR. Post-operative CSF diversion is warranted.

NCOG-27. HIGHER LEVELS OF SERUM ICAM-1 AND IL-10 ARE ASSOCIATED WITH COGNITIVE DYSFUNCTION IN BOTH IDH-WILDTYPE AND IDH-MUTANT GLIOMA

Abstract BACKGROUND Cognitive dysfunction is common among glioma patients, but the contribution of specific mechanisms to the development of cognitive symptoms is unclear. Circulating levels of proteins linked to neurodegeneration, inflammation, and vascular damage have been associated with cognitive symptoms in neurological diseases and aging, but their prognostic value in glioma is unknown. Here, we examined associations between cognitive symptoms and serum levels of protein biomarkers in glioma patients. METHODS Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA, scores ≤ 25 = cognitive dysfunction). Cytokines (interleukin-1β [IL-1β], IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ [IFN-γ], tumor necrosis factor-α [TNF-α]), and neurodegeneration (neurofilament light chain [NfL], tau, glial fibrillary acidic protein [GFAP]), and vascular damage markers (Serum amyloid A [SAA], C-reactive protein [CRP], vascular cell adhesion molecule 1 [VCAM-1], and intercellular adhesion molecule 1 [ICAM-1]) were measured using ultrasensitive assays (Meso Scale Discovery). RESULTS Patients (n=73) were predominantly male (58%), white (74%), with a median age of 44 (range=24,74). Cognitive dysfunction was found in 53% of the patients. Levels of NfL (p=0.035), IL-6 (p=0.006), IL-10 (p=0.007), TNF-α (p=0.035), IFN-γ (p=0.011), CRP (p=0.016), VCAM-1 (p=0.012), and ICAM-1 (p<0.001) were higher in patients with cognitive dysfunction when compared to those with normal cognition. After adjusting for isocitrate dehydrogenase (IDH) tumor mutation status, age, tumor grade, and number of surgeries, higher levels of ICAM-1 and IL-10, but not other markers, remained associated with cognitive dysfunction. MoCA scores were negatively correlated with GFAP (r=-0.24, p=0.038), IFN-γ (r=-0.31, p=0.008), IL-6 (r=-0.29, p=0.014), IL-10 (r=-0.24, p=0.039), and ICAM-1 (r=-0.39, p<0.001). CONCLUSIONS ICAM-1 and IL-10 levels were higher in patients with MOCA determined cognitive dysfunction, suggesting an association between cognitive symptoms and inflammation and vascular impairment in glioma patients. Future analyses in larger longitudinal cohorts are warranted to assess the predictive value of protein biomarkers.

TMIC-70. CORRELATION OF LLT-1 AND NLRC4 INFLAMMASOME AND ITS EFFECT ON GLIOBLASTOMA PROGNOSIS

Abstract PURPOSE LLT-1 is a well-known ligand for the natural killer (NK) cell inhibitory receptor NKRP1A. Here, we examined NLRC4 inflammasome components and LLT-1 expression in glioblastoma (GBM) tissues to elucidate potential associations and interactions between these factors. METHODS Nine GBM tissues were collected for experiments and RNA sequencing, while fifty-two tumor core tissues were collected for RNA sequencing. Expression of LLT-1 and other proteins was assessed by immunofluorescence. Computational analyses utilized RNA-seq data from 296 and 52 patients from the Chinese Glioma Genome Atlas and CHA medical records, respectively, using survival, non-negative matrix factorization clustering, Gene Ontology enrichment, and protein-protein interaction analyses. Receptor-ligand interactions between tumor and immune cells were confirmed by single cell RNA sequencing analysis. RESULTS In GBM tissues, LLT-1 was predominantly colocalized with Glial fibrillary acidic protein (GFAP) -expressing astrocytes, but not with microglial markers like Iba-1. Additionally, LLT-1 and activated NLRC4 inflammasomes were co-expressed mainly in intratumoral astrocytes, suggesting an association between LLT-1, NLRC4, and glioma malignancy. High LLT-1 expression correlates with poor prognosis, particularly in the mesenchymal subtype, and is associated with TNF and NOD-like receptor signaling pathway enrichment, indicating a potential role in tumor inflammation and progression. At the single-cell level, mesenchymal-like malignant cells were highly enriched in the TNF, NLR, and IL-1 signaling pathways compared to other malignant cell types. CONCLUSION We revealed an association between NLRC4 inflammasome activity and LLT-1 expression, suggesting a novel regulatory pathway involving TNF, inflammasomes, and IL-1, potentially offering new anti-glioma approaches by enhancing NK cell-based treatments.

BIOM-40. BLOOD AND NASAL BIOMARKERS OF BRAIN MICROENVIRONMENT BLOOD–BRAIN BARRIER PERMEABILITY: CLINICAL AND APPLIED CONCEPTS

Abstract The limiting step to treating glioblastoma (GBM) patients is the close blood-brain barrier (BBB) which protects the brain making it an inaccessible compartment. Although multiple studies have highlighted the presence of circulating tumour cells (CTCs) in glioblastoma multiforme (GBM) patients their relationship with brain microenvironment and BBB permeability was not explored in depth. We studied the development of GBM by transferring tumour cells into the mouse brain and also in a subcutaneous location to verify how the different microenvironment affected the release of circulating tumour and endothelial cells. Glioblastoma U3T3MG IDHwt secondary cell line was transfected to track circulating tumour cells released. Moreover, both U3T3 cells and short-time-expanded CTCs1 from GBM patients were used for intracranial xenografts and patient-derived xenografts (PDX). The in vivo models demonstrated the correspondence between BBB permeability with the release of CTCs and the increment of endothelial progenitor cells in GBM HIFpos >20% compared to subcutaneous xenografts releasing CTCs in GBM HIFpos< 20%. These data were confirmed in HIFpos tissue biopsy of GBM-IDHwt patients with CTCs >30 cells/ml. Both in PDXs and in the GBM patient demonstrated that the release of CTCs was intermittent, related to BBB opening induced by HIF-dependent cytokines release (IL8, TNFa)2. In parallel, the analysis of structural Glial fibrillary acidic protein (GFAP)3, on nasal secretion and interstitial fluid, collected in surgical treated GBM patients, demonstrated that the recognition of the two GFAP isoforms (p150 and p50 kDa) were the result of inflammatory microenvironment enriched for proteases induced by IL8, TNFa. Overall data indicate at least two different ways of monitoring the BBB and the brain microenvironment, one distal (blood) and one proximal (nasal secretion) useful to perform precision treatments in patients with GBM. REFERENCES 1) Malara, N. et al. Mol Cancer 23, 32 (2024). doi.org/10.1186/s12943-024-01951-x2) Coluccio ML. et al Cancers (2020) doi: 10.3390/cancers12061362.3) Malara, N. et al Front. Oncol.(2021) doi.org/10.3389/fonc.2021.737730

Inhibition of IRAP Enhances the Expression of Pro-Cognitive Markers Drebrin and MAP2 in Rat Primary Neuronal Cells

The insulin-regulated aminopeptidase (IRAP; oxytocinase) is part of the M1 aminopeptidase family and is highly expressed in many tissues, including the neocortex and hippocampus of the brain. IRAP is involved in various physiological functions and has been identified as a receptor for the endogenous hexapeptide Angiotensin IV (Ang IV). The binding of Ang IV inhibits the enzymatic activity of IRAP and has been proven to enhance learning and memory in animal models. The macrocyclic compound 9 (C9) is a potent synthetic IRAP inhibitor developed from the previously reported inhibitor HA08. In this study, we have examined compound C9 and its effects on cognitive markers drebrin, microtubule-associated protein 2 (MAP2), and glial fibrillary acidic protein (GFAP) in primary hippocampal and cortical cultures. Cells from Sprague Dawley rats were cultured for 14 days before treatment with C9 for 4 consecutive days. The cells were analysed for protein expression of drebrin, MAP2, GFAP, glucose transporter type 4 (GLUT4), vesicular glutamate transporter 1 (vGluT1), and synapsin I using immunocytochemistry. The gene expression of related proteins was determined using qPCR, and viability assays were performed to evaluate toxicity. The results showed that protein expression of drebrin and MAP2 was increased, and the corresponding mRNA levels were decreased after treatment with C9 in the hippocampal cultures. The ratio of MAP2-positive neurons and GFAP-positive astrocytes was altered and there were no toxic effects observed. In conclusion, the IRAP inhibitor compound C9 enhances the expression of the pro-cognitive markers drebrin and MAP2, which further confirms IRAP as a relevant pharmaceutical target and C9 as a promising candidate for further investigation.

Case report: Polymorphous low-grade neuroepithelial tumor of the young and supratentorial ependymoma diagnosed in an adult male

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a rare central nervous system (CNS) pathology predominantly observed in the pediatric population. Ependymomas also exhibit a peak incidence in early childhood, with rare presentations after early adulthood. In this report, we describe a rare case of a 41-year-old man diagnosed sequentially with a polymorphous low-grade neuroepithelial tumor of the young, followed by a supratentorial ependymoma within a year. He underwent tumor resection for both tumors, as well as adjuvant radiation therapy for the ependymoma. Despite these interventions, he ultimately succumbed to tumor progression and postoperative complications. Currently, no genetic syndromes are known to link these two primary CNS tumors. Two commonalities at the chromosomal and cellular level include histone gene H3F3A mutations and positive glial fibrillary acidic protein staining on immunohistochemistry. To the best of our knowledge, this unique dual pathology has not been previously described in the literature, making this case an avenue for further investigation and research into connections between these two distinct CNS pathologies.

Glial fibrillary acidic protein in Alzheimer’s disease: a narrative review

Abstract Astrocytes are fundamental in neural functioning and homeostasis in the Central Nervous System. These cells respond to injuries and pathological conditions through astrogliosis, a reactive process associated with neurodegenerative diseases such as Alzheimer’s disease. This process is thought to begin in the early stages of these conditions. Glial Fibrillary Acidic Protein (GFAP), a type III intermediate filament protein predominantly expressed in astrocytes, has emerged as a key biomarker for monitoring this response. During astrogliosis, GFAP is released into biofluids, making it a candidate for non-invasive diagnosis and tracking of neurodegenerative diseases. Growing evidence positions GFAP as a biomarker for Alzheimer’s disease with specificity and disease-correlation characteristics comparable to established clinical markers, such as Aβ peptides and phosphorylated tau protein. To improve diagnostic accuracy, particularly in the presence of confounders and comorbidities, incorporating a panel of biomarkers may be advantageous. This review will explore the potential of GFAP within such a panel, examining its role in early diagnosis, disease progression monitoring, and its integration into clinical practice for Alzheimer’s disease management.

Bcl2l12, a novel protein interacting with Arf6, triggers Schwann cell differentiation program.

Schwann cells are glial cells in the peripheral nervous system (PNS); they wrap neuronal axons with their differentiated plasma membranes called myelin sheaths. Although the physiological functions, such as generating saltatory conduction, have been well studied in the PNS, the molecular mechanisms by which Schwann cells undergo their differentiation program without apparent morphological changes before dynamic myelin sheath formation remain unclear. Here, for the first time, we report that Arf6, a small GTP/GDP-binding protein controlling morphological differentiation, and the guanine-nucleotide exchange factors cytohesin proteins are involved in the regulation of Schwann cell differentiation marker expression in primary Schwann cells. Specific inhibition of Arf6 and cytohesins by NAV-2729 and SecinH3, respectively, decreased expression of marker proteins 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and glial fibrillary acidic protein (GFAP). Similar results using promoter assays were observed using the IMS32 Schwann cell line. Furthermore, using an affinity-precipitation technique, we identified Bcl2-like 12 (Bcl2l12) as a novel GTP-bound Arf6-interacting protein. Knockdown of Bcl2l12 using a specific artificial miRNA decreased expression of marker proteins. The knockdown also led to decreased filamentous actin extents. These results suggest that Arf6 and Bcl2l12 can trigger Schwann cell differentiation, providing evidence for a molecular relay that underlies how Schwann cells differentiate.

Assessing polyomic risk to predict Alzheimer's disease using a machine learning model.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Given that AD neuropathology begins decades before symptoms, there is a dire need for effective screening tools for early detection of AD to facilitate early intervention. Here, we used tree-based and deep learning methods to train polyomic prediction models for AD affection status and age at onset, employing genomic, proteomic, metabolomic, and drug use data from UK Biobank. We used SHAP to determine the feature's importance. Our best-performing polyomic model achieved an area under the receiver operating characteristics curve (AUROC) of 0.87. We identified GFAP and CXCL17 proteins to be the strongest predictors of AD, besides apolipoprotein E (APOE) alleles. Increasing the number of cases by including "AD-by-proxy" cases did not improve AD prediction. Among the four modalities, genomics, and proteomics were the most informative modality based on AUROC (area under the receiver operating characteristic curve). Our data suggest that two blood-based biomarkers (glial fibrillary acidic protein [GFAP] and CXCL17) may be effective for early presymptomatic prediction of AD. We developed a polyomic model to predict AD and age-at-onset using omics and medication use data from EHR. We identified GFAP and CXCL17 proteins to be the strongest predictors of AD, besides APOE alleles. "AD-by-proxy" cases, if used in training, do not improve AD prediction. Proteomics was the most informative modality overall for affection status and AAO prediction.

Response to amoxicillin and perampanel in infantile Alexander disease.

Type I Alexander disease (AxD) presents with paroxysmal neurodegeneration, refractory epilepsy, and encephalopathy in the first years of life and is associated with a poor prognosis. Although there is no treatment, mild symptomatic improvement has been reported in one case of adult Alexander treated with ceftriaxone, given its interaction with the mutant glial fibrillary acid protein (GFAP) responsible for the disease's pathogenesis. We describe a patient presenting with irritability starting at 2 months of age, initially attributed to gastroesophageal reflux. A ventriculoperitoneal shunt was placed at 3 months of age due to hydrocephalus secondary to aqueduct stenosis detected through an MRI scan, but the irritability persisted. At 5 months, a new brain MRI was performed due to irritability worsening, onset of abnormal ocular movements and seizures. In addition genetic testing was performed. AxD was diagnosed due to the mutation c.716G>A (p.Arg239His) in GFAP. Since irritability had worsened and had not responded to levomepromazine, treatment with amoxicillin (80 mg/kg/day) was attempted to modulate glutamate levels. The patient showed a striking improvement of irritability in 48 h that persisted over the next months. The patient had frequent daily seizures which did not respond to valproate, clonazepam, or phenobarbital. Perampanel, a postsynaptic AMPA receptor antagonist, was added to phenobarbital and he was seizure free for more than 3 months. Drugs modulating glutamate levels in the central nervous system, including β-lactam antibiotics and perampanel, may have an important role in the symptomatic treatment of AxD and other neurodegenerative diseases where glutamatergic excitotoxicity is a pathogenic determinant. PLAIN LANGUAGE SUMMARY: Alexander disease is a rare and serious condition that affects the brain, often leading to neurodegeneration (brain damage), seizures, and other problems in early childhood. The disease is caused by a mutation in a gene called GFAP. There is no cure, and current treatments mainly focus on relieving symptoms. This article discusses the case of a baby who showed signs of irritability and seizures from a young age. The baby was diagnosed with Alexander disease after brain scans and genetic testing. Despite treatment with various drugs, the baby continued to experience seizures and irritability. The doctors decided to try amoxicillin, a common antibiotic, because of its potential to help control the disease by affecting a brain chemical called glutamate. Surprisingly, the baby's irritability improved within 2 days of starting amoxicillin, and the improvement lasted for several months. However, the seizures persisted until another medication, perampanel, was added. This combination controlled the baby's seizures for over 3 months. Unfortunately, the baby passed away at 13 months due to complications from the disease. However, doctors believe that drugs like amoxicillin and perampanel could be promising treatments for managing symptoms of Alexander disease and other similar brain conditions in the future, especially where excess glutamate plays a role in the damage. This case suggests that these treatments may help control irritability and seizures, offering hope for better management of this challenging disease.

Histopathological substrate of increased T2 signal in the anterior temporal lobe white matter in temporal lobe epilepsy associated with hippocampal sclerosis.

This study was undertaken to analyze the histology underlying increased T2 signal intensity (iT2SI) in anterior temporal lobe white matter (aTLWM) epilepsy due to hippocampal sclerosis (TLE/HS). Twenty-three patients were included: 16 with increased T2 signal in the aTLWM and seven with HS only. Magnetic resonance imaging (MRI) findings were consistent across two neuroradiologists (kappa = .89, p < .001). Quantification of neuronal cells, astrocytes, oligodendrocytes, and vacuolization in the white matter of temporal lobe specimens was performed by immunohistochemistry (neuronal nuclear antigen, glial fibrillary acidic protein, oligodendrocyte transcription factor, and basic myelin protein, respectively). Surgical specimens from TLE/HS patients with and without iT2SI in the aTLWM were compared. Samples of aTLWM were divided into three groups, according to MRI features: G1 = samples of iT2SI, G2 = samples with normal T2 signal intensity from patients without white matter imaging abnormalities, and G3 = samples with normal T2 signal intensity adjacent to areas with iT2SI. Patients with increased T2 signal had a significantly younger age at epilepsy onset (p < .035). Histological analysis revealed a higher percentage of vacuolar area in these patients (p < .004) along with a lower number of ectopic neurons (p = .042). No significant differences were found in astrocyte or oligodendrocyte counts among groups. A higher proportion of vacuoles in regions with iT2SI may be the histopathologic substrate of this signal alteration in the white matter of the temporal lobe in patients with TLE/HS. This method of quantifying vacuoles using digital image analysis proved reliable and cost-effective.

Blood-Based Biomarkers in Frontotemporal Dementia: A Narrative Review.

This narrative review explores the current landscape of blood biomarkers in Frontotemporal dementia (FTD). Neurofilament light chain (NfL) may be useful in the differentiation of behavioral variant FTD from primary psychiatric disorders (PPDs) or dementia with Lewy bodies (DLB). In prodromal FTD and presymptomatic mutation carriers (GRN, MAPT, C9orf72), elevated NfL may herald pheno-conversion to full-blown dementia. Baseline NfL correlates with steeper neuroanatomical changes and cognitive, behavioral and functional decline, making NfL promising in monitoring disease progression. Phosphorylated neurofilament heavy chain (pNfH) levels have a potential limited role in the demarcation of the conversion stage to full-blown FTD. Combined NfL and pNfH measurements may allow a wider stage stratification. Total tau levels lack applicability in the framework of FTD. p-tau, on the other hand, is of potential value in the discrimination of FTD from Alzheimer's dementia. Progranulin concentrations could serve the identification of GRN mutation carriers. Glial fibrillary acidic protein (GFAP) may assist in the differentiation of PPDs from behavioral variant FTD and the detection of GRN mutation carriers (additional research is warranted). Finally, TAR DNA-binding protein-43 (TDP-43) appears to be a promising diagnostic biomarker for FTD. Its potential in distinguishing TDP-43 pathology from other FTD-related pathologies requires further research.

Neuropathology of Severe Depression in Long COVID-19 Infection; Possible Roles for Astrocytes, Creatine Kinase and Lactate Dehydrogenase Activity

Background: The incidence of depression has increased significantly during the COVID-19 pandemic. Some individuals infected with COVID-19 develop persistent neurological and neuropsychiatric symptoms approximately 12 weeks after the acute infection, a condition known as long COVID-19 syndrome. However, the underlying pathogenesis remains unclear. Glial fibrillary acidic protein (GFAP), creatine kinase (CK), and lactate dehydrogenase (LDH) are enzymes abundant in the central nervous system (CNS), playing important roles in neuronal energy homeostasis. Objectives: This study aimed to investigate the correlation between serum GFAP, CK, and LDH levels and depression in patients with long COVID-19 syndrome. Methods: This cross-sectional study involved 150 patients (75 males and 75 females). The Beck Depression Inventory-II (BDI-II) was used, along with standardized peripheral serum assessments. Serum GFAP, CK, and LDH levels were measured using customized direct ELISA. Data were matched by age and sex, and analyzed using Spearman non-parametric tests to assess the correlation between variables. Results: The serum level of GFAP was significantly higher in both males and females with severe depression compared to those with mild depression (282 ± 3 pg/mL, 280 ± 2.9 pg/mL, P = 0.001). The mean serum CK level was 239 ± 24.05 U/L in males and 142 ± 18.08 U/L in females (P &lt; 0.0001). Furthermore, a significant positive correlation was found between CK serum levels and Beck scores (r = 0.33, 95% CI = 0.176 to 0.469), with a similar pattern observed for LDH (r = 0.22, 95% CI = 0.042 to 0.358). GFAP, CK, and LDH levels were higher in male patients. Conclusions: This study identified potential neurobiological mechanisms in CNS-related long COVID syndrome, suggesting that elevated astrocyte activity, along with increased serum CK and LDH levels, may contribute to the neurobiological issues seen in depressed long COVID survivors. Men appeared to be more susceptible to these changes than women. Further research is essential.

Plasma neurofilament light outperforms glial fibrillary acidic protein in differentiating behavioural variant frontotemporal dementia from primary psychiatric disorders

ObjectiveTimely, accurate distinction between behavioural variant frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD) is a clinical challenge. Blood biomarkers such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have shown promise. Prior work has shown NfL helps distinguish FTD from PPD. Few studies have assessed NfL together with GFAP. MethodsWe investigated plasma GFAP and NfL levels in participants with bvFTD, bipolar affective disorder (BPAD), major depressive disorder (MDD), treatment-resistant schizophrenia (TRS), healthy controls (HC), adjusting for age and sex. We compared ability of GFAP and NfL to distinguish bvFTD from PPD. ResultsPlasma GFAP levels were significantly (all p < 0.001) elevated in bvFTD (n = 22, mean (M) = 273 pg/mL) compared to BPAD (n = 121, M = 96 pg/mL), MDD (n = 42, M = 105 pg/mL), TRS (n = 82, M = 67.9 pg/mL), and HC (n = 120, M = 76.8 pg/mL). GFAP distinguished bvFTD from all PPD with an area under the curve (AUC) of 0.85, 95 % confidence interval [0.76, 0.95]. The optimal cut-off of 105 pg/mL was associated with 73 % specificity and 86 % sensitivity. NfL had AUC 0.95 [0.91, 0.99], 13.3 pg/mL cut-off, 88 % specificity, 86 % sensitivity, and was superior to GFAP (p = 0.02863) and combination of GFAP and NfL (p = 0.04726). ConclusionsThis study found elevated GFAP levels in bvFTD compared to a large cohort of PPD, but NfL levels exhibited better performance in this distinction. These findings extend the literature on GFAP in bvFTD and build evidence for plasma NfL as a useful biomarker to assist with distinguishing bvFTD from PPD. Utilisation of NfL may improve timely and accurate diagnosis of bvFTD.

Serum growth differentiation factor-15, glial fibrillary acidic protein, and neurofilament light chain: Their link and role in Creutzfeldt-Jakob disease

BackgroundCreutzfeldt-Jakob disease (CJD) is a rapidly progressive neurodegenerative disorder characterized by neuronal damage. Emerging biomarkers, such as serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), and growth differentiation factor-15 (sGDF-15), are currently being studied for their potential use in this disease. ObjectivesThis study analyzes the levels of sNfL, sGFAP, and sGDF-15, as well as their relationships, in patients with CJD compared to healthy controls (HC). MethodsA total of 19 CJD patients and 81 age- and sex-matched HCs were enrolled. Serum levels of sNfL and sGFAP were measured using ultrasensitive immunoassays, while sGDF-15 levels were assessed via ELISA. Statistical analyses included correlation analysis and analysis of covariance (ANCOVA) models. ResultsCJD patients showed significantly higher serum levels of sNfL and sGFAP compared to HCs (p 〈0,001). sNfL levels were positively correlated with both sGFAP (Rho = 0,70; p < 0,001) and sGDF-15 (Rho = 0,60; p = 0,004). Interestingly, sGFAP levels were higher in female CJD patients compared to males (p = 0,001), while no significant difference in sNfL levels was observed between sexes. ConclusionsIn conclusion, this study explores the potential of sNfL, sGDF-15, and sGFAP as biomarkers in CJD patients. The higher levels of sNfL and sGFAP in CJD patients compared to healthy controls, along with the observed sex differences in sGFAP, highlight the need for further research into the interaction between astroglia and neurons in CJD, with a focus on sex as a key variable.

Neurofilament light and glial fibrillary acidic protein in mood and anxiety disorders: A systematic review and meta-analysis

Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are biomarkers of neuronal injury measurable in cerebrospinal fluid (CSF) and blood. Despite their potential as diagnostic tests for neurodegenerative disorders, it is unclear how they behave in mood and anxiety disorders. We conducted a systematic review and meta-analysis to investigate whether NfL and GFAP concentrations were altered in adults with mood and anxiety disorders compared to healthy controls. We searched PubMed, Web of Science, PsycINFO, MEDLINE and Embase through August 20, 2024, and assessed relevant studies and their risk of bias. The primary outcome was the standardised mean difference (SMD) and 95 % confidence interval (95 % CI) of NfL and GFAP concentrations. Twenty-nine studies comprising 2,962 individuals (927majordepression,804bipolardisorder,and1,231controls). When we compared individuals with major depression and healthy controls, there was no difference in NfL nor GFAP levels. In individuals with bipolar disorder, NfL was significantly elevated compared to controls (SMD = 0.53; 95 % CI: 0.20, 0.85; p = 0.005). Only one study reported on NfL levels anxiety disorders. Our study informs clinicians about how to interpret these emerging biomarkers in determining whether a person’s symptoms are caused by a neurodegenerative or mood disorder. The mild elevation of NfL in bipolar disorder may suggest underlying neuroaxonal injury, warranting further research into its clinical and prognostic significance.

Hepatoprotective and neuroprotective effects of quinacrine against bile duct ligation-induced hepatic encephalopathy in rats: Role of bone morphogenetic proteins signaling

AimsThis study aimed to assess the potential protective effect of quinacrine, an FDA approved antimalarial drug with reported anti-inflammatory effects, on hepatic encephalopathy (HE) in a bile duct ligation (BDL) experimental model and to investigate the mechanisms responsible for this effect, namely those associated with the liver-brain axis, particularly, bone morphogenetic protein 2 (BMP2) signaling. Materials and methodsFive groups of rats were selected at random: sham, BDL, (BDL+ quinacrine 5), (BDL+ quinacrine 10), and (quinacrine 10 + sham). Daily Intraperitoneal (I.P.) administration of quinacrine was initiated on the surgery day and continued for 28 days. Key findingsResults showed that rats that underwent BDL exhibited marked elevation of serum liver enzymes, ammonia, total bilirubin, together with oxidative stress, inflammation, dysregulated farnesoid x receptor (FXR), dysregulated BMP2 signaling and escalated fibrotic markers indicating hepatotoxicity, cholestasis and fibrosis. Besides, neurotoxicity was detected as manifested by cognitive deficits and dysregulation of hippocampal FXR, BMP2 signaling, WNT3A signaling, brain derived neurotrophic factor (BDNF), phospholipase A2 (PLA2) and glial fibrillary acidic protein (GFAP). In contrast, co-treatment with quinacrine mitigated BDL-induced hepatotoxicity, cholestasis, fibrosis, and neurotoxicity. Notably, quinacrine improved learning and memory and restored FXR, BMP2 signaling in the liver and hippocampus. In addition, quinacrine restored hippocampal WNT3A signaling, BDNF, whereas it downregulated expression of hippocampal PLA2 and GFAP. SignificanceThese findings demonstrated implication of BMP2 signaling in the molecular process of BDL-induced HE and proposed that quinacrine has potential hepatoprotective and neuroprotective properties against HE.

Ambroxol Improves Amyloidogenic, NF-κB, and Nrf2 Pathways in a Scopolamine-Induced Cognitive Impairment Rat Model of Alzheimer's Disease.

Ambroxol (ABX) is used to manage excessive production of mucus in the respiratory system. The present study sought to assess the neuroprotective potential of ambroxol by influencing the amyloidogenic, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways in a rat model of Alzheimer's disease (AD) induced by scopolamine. The AD pathology was induced by chronic administration of scopolamine. The rats were given scopolamine at a dose of 2 mg/kg via intraperitoneal injection daily for 14 days, followed by treatment (ABX 121.5, 135, and 180 mg/kg orally and 5 mg/kg orally of donepezil) for the next 28 days while continuing to receive daily scopolamine injection. The behavior of the rats was evaluated using Modified Y-Maze and Novel object recognition tasks. Analyses were carried out on AD pathological markers [Amyloid beta peptide 1-40, Amyloid beta peptide 1-42, acetylcholinesterase, beta-secretase 1 (BACE1), total tau, and p-tau], inflammatory markers [NF-κB, tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interferon γ], antioxidant markers (Nrf2 and heme Oxygenase 1 (HO-1)], along with synaptophysin and glial fibrillary acidic protein (GFAP) immunohistochemistry and histopathological assessment of the hippocampus. Our findings indicated that ABX reduced impairment in behavior. Levels of Acetylcholinesterase, BACE1, amyloid beta 1-40, amyloid beta 1-42, total tau, p-tau, NF-κB, IFN-γ, IL-6, and TNF-α decreased significantly. There was a significant increase in the levels of HO-1 and Nrf2. It stopped the neuronal degeneration, raised synaptophysin immunoreactivity, and lowered GFAP immunoreactivity. The current research indicates that ambroxol may possess senomorphic properties by impacting the transcription factors NF-κB and senescence-associated secretory phenotype (SASP). Consequently, it could provide neuroprotection through alterations in the Nrf2 and NF-κB signaling pathways in AD.

Serum neurofilament light and glial fibrillary acidic protein levels are not associated with wearing-off symptoms in natalizumab-treated multiple sclerosis patients

Background: Biomarkers of neuronal and axonal damage (serum neurofilament light (sNfL) and serum glial fibrillary acidic protein (sGFAP)) may provide insight into the aetiology of natalizumab wearing-off symptoms (WoSs). Objectives: We investigated the longitudinal association between and predictive value of sNfL and sGFAP and the occurrence of WoS in MS patients treated with natalizumab. Methods: We performed longitudinal measurements of sNfL and sGFAP in NEXT-MS trial participants who completed a questionnaire about WoS. Results: A total of 364 participants were included. In total, 55.5% presented with WoS and 44.5% without WoS during natalizumab treatment. Longitudinal analyses showed no association between sNfL and sGFAP levels and WoS at any timepoint. Biomarker levels at baseline did not predict first-time WoS occurrence. Conclusion: Acute and chronic neuronal and axonal damage are most likely not the underlying cause of WoS.