Contribution of the Activated mTOR-STAT3 Pathway to the Pathogenesis of Focal Cortical Dysplasia Type IIIa in Pediatric Patients through Astrocyte Proliferation Mediation.

OBJECTIVE: The aim of this study was to detect the association between the mTOR-STAT3 pathway and focal cortical dysplasia type IIIa (FCD IIIa) in children. METHODS: A retrospective review was conducted based on 26 pediatric patients diagnosed with FCD IIIa who underwent surgical intervention. These patients were selected from a cohort of 157 individuals presenting with temporal lobe epilepsy. For comparative analysis, a control group consisting of 5 children who underwent intracranial decompression was established. Immunohistochemistry, immunofluorescence, and western blot techniques were used to assess the expression levels of mTOR, P-mTOR, P-70s6k, STAT3, P-STAT3, and GFAP in brain tissue specimens obtained from the two groups. RESULTS: The mTOR-STAT3 pathway exhibited activation in the FCD IIIa group (all P < 0.01). Additionally, immunofluorescence analysis revealed that cells positive for PSTAT3 were identified as astrocytes. Moreover, within the FCD IIIa group, there was a marked elevation in the expression of the mTOR-STAT3 pathway in the hippocampus compared to the brain cortex tissue. CONCLUSION: The mTOR-STAT3 pathway was demonstrated to be substantially associated with FCD IIIa in pediatric patients. The activation of the mTOR-STAT3 signaling pathway may contribute to the pathogenesis of FCD IIIa in pediatric patients by modulating the proliferation of astrocytes.

Glial Fibrillary Acidic Protein Astrocytopathy - An Autoimmune Mimicker of CNS Tuberculosis.

Glial Fibrillary Acidic Protein (GFAP) Astrocytopathy is a relatively new and poorly recognized autoimmune cause of meningoencephalomyelitis. Our case highlights the challenging nature of diagnosing this rare condition as its broad constellation of radiographic findings and spectrum of presentation may mimic many other etiologies of encephalopathy, particularly infectious causes such as Tuberculosis (TB) meningitis.

Clinicopathological differences between classical schwannomas and cellular schwannomas in the retroperitoneum.

This study aimed to compare clinical and pathological features of retroperitoneal classical schwannomas and cellular schwannomas. A total of 64 cases of retroperitoneal classical schwannoma and 48 cases of cellular schwannoma were studied. Histopathological analysis was performed using hematoxylin and eosin staining and immunohistochemistry. Retroperitoneal cellular schwannomas exhibited 100% (48/48) and 75% (36/48) positive expression for glial fibrillary acidic protein (GFAP) and cytokeratins (CK), respectively. Classical schwannomas showed rates of 6.25% (4/64) and 15.63% (10/64), respectively (P < .05). In classic schwannomas, 85.9% (55/64) showed a reticular pattern of positive anti-CD34 staining around tumor margins and subcapsular areas vs 52.1% (25/48) in cellular schwannomas (P < .05). Cellular schwannomas exhibited more mitotic figures than classical schwannoma (P < .05). The recurrence rate of cellular schwannomas was 10.42% (5/48), while that of classical schwannomas was 1.56% (1/64) (P < .05). Retroperitoneal cellular schwannomas commonly express GFAP and CK compared to classical schwannomas, suggesting that cellular schwannoma may originate from unmyelinated Schwann cells, while classical schwannoma may originate from myelinated Schwann cells. Anti-CD34 staining patterns may be used to distinguish between the 2 types. Retroperitoneal cellular schwannomas also show higher mitotic activity and are more prone to recurrence.

From Nature to Treatment: The Impact of Pterostilbene on Mitigating Retinal Ischemia-Reperfusion Damage by Reducing Oxidative Stress, Inflammation, and Apoptosis.

Retinal ischemia-reperfusion (I/R) injury is a critical pathogenic mechanism in various eye diseases, and an effective therapeutic strategy remains unresolved. Natural derivatives have recently reemerged; therefore, in our present study, we examined the potential therapeutic effects of a stilbenoid that is chemically related to resveratrol. Pterostilbene, recognized for its anti-inflammatory, anti-carcinogenic, anti-diabetic, and neuroprotective properties, counteracts oxidative stress during I/R injury through various mechanisms. This study explored pterostilbene as a retinoprotective agent. Male Sprague Dawley rats underwent retinal I/R injury and one-week reperfusion and were treated with either vehicle or pterostilbene. After this functional electroretinographical (ERG) measurement, Western blot and histological analyses were performed. Pterostilbene treatment significantly improved retinal function, as evidenced by increased b-wave amplitude on ERG. Histological studies showed reduced retinal thinning and preserved the retinal structure in the pterostilbene-treated groups. Moreover, Western blot analysis revealed a decreased expression of glial fibrillary acidic protein (GFAP) and heat shock protein 70 (HSP70), indicating reduced glial activation and cellular stress. Additionally, the expression of pro-apoptotic and inflammatory markers, poly(ADP-ribose) polymerase 1 (PARP1) and nuclear factor kappa B (NFκB) was significantly reduced in the pterostilbene-treated group. These findings suggest that pterostilbene offers protective effects on the retina by diminishing oxidative stress, inflammation, and apoptosis, thus preserving retinal function and structure following I/R injury. This study underscores pterostilbene's potential as a neuroprotective therapeutic agent for treating retinal ischemic injury and related disorders.

Expression of Acidic Fibrillar Protein and Neuroglobin in Thrombolytic Patients in Ischemic Stroke.

Purpose: Glial fibrillary acidic protein (GFAP) and neuroglobin (NGB) are important biomarkers of cerebral hypoxia. For this reason, an attempt was made to assess their concentrations in various time intervals and their impact on the severity of neurological symptoms and functional prognosis of thrombolytic ischemic stroke patients. Patients and Methods: The study involved 94 patients reporting to the emergency department of the Collegium Medicum University Hospital in Bydgoszcz within < 4.5 hours of the onset of stroke symptoms. GFAP and neuroglobin levels were measured in plasma at indicated times using a commercial ELISA kit. Results: Based on the data gathered, statistically significant differences were found between the concentration of biomarkers in stroke patients and the control group. The concentrations of both biomarkers, GFAP and NGB, were elevated in patients after ischemic stroke and the changes in their concentrations in the subsequent stages of stroke may suggest their prognostic value strictly dependent on time. NGB was determined on the 7th day, and mRS - after a year (0.35). GFAP measured after 24 h and on day 7 could be a promising biomarker of functional outcome after one year (cut-off point ≤ 0.231 ng/mL, sensitivity 75.0%, specificity 61.2%, cut off point ≤ 0.235 ng/mL, sensitivity 75.0%, specificity 73.9%, respectively) and the severity of the patient's neurological condition. At GFAP concentrations above 0.25 ng/mL, measured within 24 hours, a sharp increase in mortality was observed in stroke patients. In the case of NGB, at the time of stroke occurrence (14 ng/mL) and after 24 hours (10-60 ng/mL). Differences in the concentrations of these biomarkers have been demonstrated in different stroke subtypes. Conclusion: NGB and GFAP are important biomarkers of ischemic brain injury and may also participate in predicting neurological outcomes.

Elevated cerebrospinal fluid neuronal injury biomarkers within 24 hours of onset in infection-triggered acute encephalopathy compared to complex febrile seizures.

OBJECTIVE: This study aimed to measure and compare cerebrospinal fluid neuronal injury biomarkers in the acute phase of complex febrile seizure (CFS) and infection-triggered acute encephalopathy (AE). Furthermore, we determined the pathogenesis of AE with biphasic seizures and late reduced diffusion (AESD). METHODS: Pediatric patients with febrile status epilepticus who visited Hyogo Prefectural Kobe Children's Hospital from November 1, 2016, to December 31, 2022, and whose cerebrospinal fluid samples were collected within 24 h of neurological symptom onset were included. Patients were classified as having CFS or infection-triggered AE according to their definitions. Patients with AE were further categorized into AESD or unclassified AE. Cerebrospinal fluid biomarkers (neuron-specific enolase, growth differentiation factor 15 [GDF-15], S100 calcium-binding protein B [S100B], glial fibrillary acidic protein, and tau protein were measured and compared among the groups. RESULTS: Total of 63 patients (45 with CFS and 18 with AE) were included. Among the AE patients, nine were classified as having AESD and nine as having unclassified AE. S100B levels were significantly higher in patients with AESD than in patients with CFS (485 pg/ml vs. 175.3 pg/ml) and were even higher in patients with AESD and neurological sequelae (702.4 pg/ml). GDF-15 levels were significantly elevated in patients with AE compared to patients with CFS (85.8 pg/ml vs. 23.6 pg/ml). CONCLUSIONS: The elevation of S100B suggests that activated astrocytes may be closely associated with the early pathology of AESD. Elevated GDF-15 levels in infection-triggered AE suggest the activation of defense mechanisms caused by stronger neurological injury.

The GFAP proteoform puzzle: How to advance GFAP as a fluid biomarker in neurological diseases.

Glial fibrillary acidic protein (GFAP) is a well-established biomarker of reactive astrogliosis in the central nervous system because of its elevated levels following brain injury and various neurological disorders. The advent of ultra-sensitive methods for measuring low-abundant proteins has significantly enhanced our understanding of GFAP levels in the serum or plasma of patients with diverse neurological diseases. Clinical studies have demonstrated that GFAP holds promise both as a diagnostic and prognostic biomarker, including but not limited to individuals with Alzheimer's disease. GFAP exhibits diverse forms and structures, herein referred to as its proteoform complexity, encompassing conformational dynamics, isoforms and post-translational modifications (PTMs). In this review, we explore how the proteoform complexity of GFAP influences its detection, which may affect the differential diagnostic performance of GFAP in different biological fluids and can provide valuable insights into underlying biological processes. Additionally, proteoforms are often disease-specific, and our review provides suggestions and highlights areas to focus on for the development of new assays for measuring GFAP, including isoforms, PTMs, discharge mechanisms, breakdown products, higher-order species and interacting partners. By addressing the knowledge gaps highlighted in this review, we aim to support the clinical translation and interpretation of GFAP in both CSF and blood and the development of reliable, reproducible and specific prognostic and diagnostic tests. To enhance disease pathology comprehension and optimise GFAP as a biomarker, a thorough understanding of detected proteoforms in biofluids is essential.

Retrospective Analysis of Blood Biomarkers of Neurological Injury in Human Cases of Viral Infection and Bacterial Sepsis.

BACKGROUND: Blood biomarkers of neurological injury could provide a rapid diagnosis of central nervous system (CNS) injury caused by infections. An FDA-approved assay for mild traumatic brain injury (TBI) measures glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which signal astrocyte and neuronal injury, respectively. Here, we assessed the applicability of this biomarker assay for determining infection-induced brain injury. METHODS: We measured serum levels of GFAP and UCH-L1 retrospectively in serum samples from three study populations: 1) human cases infected with Venezuelan equine encephalitis virus (VEEV) and Madariaga virus (MADV) (n = 73), 2) human sepsis patients who were severely ill or diagnosed with encephalitis (n = 66), and 3) sepsis cases that were subsequently evaluated for cognitive impairment (n = 64). RESULTS: In the virus infection group, we found elevated GFAP for VEEV (p = 0.014) and MADV (p = 0.011) infections, which correlated with seizures (p = 0.006). In the bacterial sepsis group, GFAP was elevated in cases diagnosed with encephalitis (p = 0.0007) and correlated with headaches (p = 0.0002). In the bacterial sepsis cases with a later cognitive assessment, elevated GFAP (p = 0.0057) at study enrollment was associated with cognitive impairment six months later with a positive prognostic capacity of 79% (CI: 66-95%; p = 0.0068). CONCLUSIONS: GFAP and UCH-L1 levels measured using an FDA-approved assay for TBI may indicate brain injury resulting from viral or bacterial infections and could predict the development of neurological sequelae.

A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV-C9ORF72 (G4C2)66 mouse model.

The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. Despite displaying key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis, the AAV-(G4C2)66 mouse model in this study exhibits negligible neuronal loss, no motor deficits, and functionally unimpaired TAR DNA-binding protein-43 (TDP-43). While our findings indicate and support that this is a robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease associated neurodegeneration, TDP-43 dysfunction, gliosis, and motor performance. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.

Can Selected Parameters of Brain Injury Reflect Neuronal Damage in Smoldering Multiple Sclerosis?

BACKGROUND: Inflammatory demyelination and impaired recovery processes result in permanent neurodegeneration and neurological disability in patients with multiple sclerosis (MS). In terms of smoldering MS, chronic neuroinflammation develops in the early period of the disease and leads to confirmed disability accumulation. There is a great need to identify biomarkers of neurodegeneration and disease progression. METHODS: A single-center prospective observational study was performed. The median age of the patients was 40 (31-52) years. Women comprised 64% of the study population. We evaluated the concentrations of the parameters of brain injury (NF-H, GFAP, S100B and UCHL1) in the cerebrospinal fluid (CSF) and the selected interleukins (ILs) in serum of 123 relapsing-remitting MS (RRMS) and 88 progressive MS (PMS) patients. RESULTS: The levels of GFAP, S100B and UCHL were higher in the PMS group than the RRMS group, in contrast to the levels of NF-H. We observed a positive correlation between the selected pro-inflammatory cytokines and the parameters of brain injury. The Expanded Disability Status Scale (EDSS) score increased with GFAP and NF-H levels and was correlated with the selected ILs. The concentrations of S100B, UCHL1 and NF-H reflected the duration of MS symptoms. CONCLUSIONS: The levels of brain injury parameters in the CSF and the selected serum ILs in MS patients seem to be promising biomarkers to determine neurodegeneration and neuroinflammation in smoldering MS. Further studies are warranted in this respect.

A Rare Case of a Heterotopic Sacrococcygeal Glial Nodule.

Heterotopic glial nodule is a rare congenital non-neoplastic lesion that is characterized by ectopic brain tissue. It has occasionally been reported to affect areas such as the nose and face. The report presents a rare case of sacrococcygeal heterotopic glial nodule. Although teratomas are the most common neoplasms in this region, clinicians and radiologists should consider heterotopic glial nodule as a differential diagnosis, despite rarity and nonspecific imaging findings. Histopathology plays a crucial role in diagnosis, which intensely stains with glial fibrillary acidic protein and S-100.

Age and duration of obesity modulate the inflammatory response and expression of neuroprotective factors in mammalian female brain.

Obesity has become a global epidemic and is associated with comorbidities, including diabetes, cardiovascular, and neurodegenerative diseases, among others. While appreciable insight has been gained into the mechanisms of obesity-associated comorbidities, effects of age, and duration of obesity on the female brain remain obscure. To address this gap, adolescent and mature adult female mice were subjected to a high-fat diet (HFD) for 13 or 26 weeks, whereas age-matched controls were fed a standard diet. Subsequently, the expression of inflammatory cytokines, neurotrophic/neuroprotective factors, and markers of microgliosis and astrogliosis were analyzed in the hypothalamus, hippocampus, and cerebral cortex, along with inflammation in visceral adipose tissue. HFD led to a typical obese phenotype in all groups independent of age and duration of HFD. However, the intermediate duration of obesity induced a limited inflammatory response in adolescent females' hypothalamus while the hippocampus, cerebral cortex, and visceral adipose tissue remained unaffected. In contrast, the prolonged duration of obesity resulted in inflammation in all three brain regions and visceral adipose tissue along with upregulation of microgliosis/astrogliosis and suppression of neurotrophic/neuroprotective factors in all brain regions, denoting the duration of obesity as a critical risk factor for neurodegenerative diseases. Importantly, when female mice were older (i.e., mature adult), even the intermediate duration of obesity induced similar adverse effects in all brain regions. Taken together, our findings suggest that (1) both age and duration of obesity have a significant impact on obesity-associated comorbidities and (2) early interventions to end obesity are critical to preserving brain health.

Elevated cerebrospinal fluid glial fibrillary acidic protein levels in Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a rare, multiple malformation/intellectual disability disorder caused by pathogenic variants of DHCR7. DHCR7 catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol in the final step of cholesterol biosynthesis. This results in accumulation of 7DHC and a cholesterol deficiency. Although the biochemical defect is well delineated and multiple mechanisms underlying developmental defects have been explored, the post developmental neuropathological consequences of altered central nervous system sterol composition have not been studied. Preclinical studies suggest that astroglial activation may occur in SLOS. To determine if astroglial activation is present in individuals with SLOS, we quantified cerebrospinal fluid (CSF) glial fibrillary acidic protein using a Quanterix Simoa® GFAP Discovery Kit for SR-X™. Relative to an age-appropriate comparison group, we found that CSF GFAP levels were elevated 3.9-fold in SLOS (3980 ± 3732 versus 1010 ± 577 pg/ml, p = 0.0184). Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, has previously been shown to increase expression of hypomorphic DHCR7 alleles and in a placebo-controlled trial improved serum sterol levels and decreased irritability. Using archived CSF samples from that prior study, we observed a significant decrease (p = 0.0119) in CSF GFAP levels in response to treatment with simvastatin. Although further work needs to be done to understand the potential contribution of neuroinflammation to SLOS neuropathology and cognitive dysfunction, these data confirm astroglial activation in SLOS and suggest that CSF GFAP may be a useful biomarker to monitor therapeutic responses.

Plasma NfL, GFAP, amyloid, and p-tau species as Prognostic biomarkers in Parkinson's disease.

INTRODUCTION: The prognostic role of plasma neurofilament light chain (NfL), phospho-tau, beta-amyloid, and GFAP is still debated in Parkinson's disease (PD). METHODS: Plasma p-tau181, p-tau231, Aß1-40, Aß1-42, GFAP, and NfL were measured by SIMOA in 136 PD with 2.9 + 1.7 years of follow-up and 76 controls. Differences in plasma levels between controls and PD and their correlation with clinical severity and progression rates were evaluated using linear regression analyses. RESULTS: Patients exhibited similar distribution of plasma biomarkers but higher P-tau181, P-tau231 and lower Aß1-42 compared with controls. NfL and GFAP correlated with baseline motor and non-motor severity measures. At follow-up, NfL emerged as the best predictor of progression with marginal effect of GFAP and p-tau181 adjusting for age, sex, disease duration, and baseline motor severity. CONCLUSION: The present findings confirmed plasma NfL as best predictor of progression in PD, with a marginal role of p-tau181 and GFAP.

Environmental enrichment and sex, but not n-acetylcysteine, alter extended-access amphetamine self-administration and cue-seeking.

There are no approved therapeutics for psychostimulant use and recurrence of psychostimulant use. However, in preclinical rodent models environmental enrichment can decrease psychostimulant self-administration of low unit doses and cue-induced amphetamine seeking. We have previously demonstrated that glutamate-dependent therapeutics are able to alter amphetamine seeking to amphetamine-associated cues only in enriched rats. In the current experiment, we will determine if enrichment can attenuate responding and cue-induced amphetamine seeking during extended access to a high dose of intravenous amphetamine. We will also determine if N-acetylcysteine (NAC), a glutamate dependent therapeutic, can attenuate amphetamine seeking in differentially reared rats. Female and male Sprague-Dawley rats were reared in enriched, isolated, or standard conditions from postnatal day 21-51. Rats were trained to self-administer intravenous amphetamine (0.1 mg/kg/infusion) during twelve 6-hour sessions. During the abstinence period, NAC (100 mg/kg) or saline was administered daily. Following a cue-induced amphetamine-seeking test, astrocyte densities within regions of the medial prefrontal cortex (mPFC) and nucleus accumbens (ACb) were quantified using immunohistochemistry. Environmental enrichment decreased responding for amphetamine and during the cue-induced amphetamine-seeking test. NAC did not attenuate cue-induced amphetamine seeking or alter astrocyte density. Across all groups, female rats self-administered less amphetamine but responded more during cue-induced amphetamine seeking than male rats. While amphetamine increased astrocyte densities within the ACb and mPFC, it did not alter mPFC astrocyte densities in female rats. The results suggest that enrichment can attenuate responding during extended access to a high dose of amphetamine and the associated cues. Sex alters amphetamine-induced changes to astrocyte densities in a regionally specific matter.

Choroid plexus enlargement correlates with periventricular pathology but not with disease activity in radiologically isolated syndrome.

BACKGROUND: Choroid plexus (ChP) enlargement is an emerging radiological biomarker in multiple sclerosis (MS). OBJECTIVES: This study aims to assess ChP volume in a large cohort of patients with radiologically isolated syndrome (RIS) versus healthy controls (HC) and explore its relationship with other brain volumes, disease activity, and biological markers. METHODS: RIS individuals were included retrospectively and compared with HC. ChPs were automatically segmented using an in-house automated algorithm and manually corrected. RESULTS: A total of 124 patients fulfilled the 2023 RIS criteria, and 55 HCs were included. We confirmed that ChPs are enlarged in RIS versus HC (mean (±SD) normalized ChP volume: 17.24 (±4.95) and 11.61 (±3.58), respectively, p < 0.001). Larger ChPs were associated with more periventricular lesions (ρ = 0.26; r2 = 0.27; p = 0.005 for the correlation with lesion volume, and ρ = 0.2; r2 = 0.21; p = 0.002 for the correlation with lesion number) and lower thalamic volume (ρ = -0.38; r2 = 0.44; p < 0.001), but not with lesions in other brain regions. Conversely, ChP volume did not correlate with biological markers. No significant difference in ChP volume was observed between subjects who presented or did not have a clinical event or between those with or without imaging disease activity. CONCLUSIONS: This study provides evidence that ChP volume is higher in RIS and is associated with measures reflecting periventricular pathology but does not correlate with biological, radiological, or clinical markers of disease activity.

Combined biomaterial scaffold and neuromodulation strategy to promote tissue repair and corticospinal connectivity after spinal cord injury in a rodent model.

Spinal cord injury (SCI) damages the trauma site, leading to progressive and secondary structural defects rostral and caudal to the injury. Interruption of ascending and descending pathways produce motor, sensory, and autonomic impairments, driving the need for effective therapies. In this study, we address lesion site repair and promoting descending projections using a combined biomaterial-neuromodulation strategy in a rat model of cervical contusion SCI. To promote tissue repair, we used Chitosan fragmented physical hydrogel suspension (Cfphs), a biomaterial formulation optimized to mitigate inflammation and support tissue remodeling. To promote descending projections, we targeted the corticospinal motor system with dual motor cortex-trans-spinal direct current neuromodulation to promote spared corticospinal tract (CST) axon sprouting rostral and caudal to SCI. Cfphs, injected into the lesion site acutely, was followed by 10 days of daily neuromodulation. Analysis was made at the chronic phase, 8-weeks post-SCI. Compared with SCI only, Cfphs alone or in combination with neuromodulation prevented cavity formation, by promoting tissue remodeling at the injury site, abrogated astrogliosis surrounding the newly formed tissue, and enabled limited CST axon growth into the remodeled injury site. Cfphs alone significantly reduced CST axon dieback and was accompanied by preserving more CST axon gray matter projections rostral to SCI. Cfphs + neuromodulation produced sprouting rostral and caudal to injury. Our findings show that our novel biomaterial-neuromodulation combinatorial strategy achieves significant injury site tissue remodeling and promoted CST projections rostral and caudal to SCI.

What we've learnt about autoimmune neurological diseases from neuropathology.

Antibody-associated autoimmune neurological diseases are a group of disorders with various immune effector mechanisms that result in significant differences in disease course and prognosis. Paraneoplastic or idiopathic autoimmune encephalitis associated with antibodies against intracellular antigens are mostly characterized by a T-cell-dominated inflammation with neuronal loss, astrogliosis, and microglial nodules. In anti-Yo paraneoplastic cerebellar degeneration CD8+/granzymeB+ T cells were demonstrated in close apposition to neurons along with a nuclear upregulation of the activator of transcription 1, suggesting an important role of interferon-gamma in disease pathogenesis. Early and late disease stages may show different lesion types. For example, tissue samples from patients with temporal lobe epilepsy associated with antiglutamic acid decarboxylase 65 antibodies in early disease stages show numerous infiltrating T cells targeting hippocampal neurons and high numbers of B cells and plasma cells, while in chronic stages inflammation gets less and is followed by hippocampal sclerosis. Similarly, antiglial fibrillary acidic protein meningoencephalomyelitis may show loss of astrocytes only in the very early lesions, whereas in subacute and chronic stages astrocytes can get replenished most likely due to their high regeneration potential. In contrast, neuropathology of autoimmune neurological diseases mediated by surface antibodies is mostly characterized by a dysfunction of neurons in the absence of immune-mediated neuronal damage. The interaction of surface antibodies with their target antigen and the resulting downstream mechanisms are variable and can range from an internalization of the receptor in well-preserved neurons in anti-N-methyl-D-aspartate receptor encephalitis to an irreversible internalization and blocking of the receptor that may be associated with an accumulation of phosphorylated tau in specific brain regions in anti-IgLON5 disease. Interestingly, anti-IgLON5 patients with short disease duration were shown to present prominent deposition of IgG4 in the neuropil and on neuronal membranes in the absence of neuronal tau deposits, suggesting that the immune mechanisms precede neurodegeneration. Knowledge about pathomechanisms and patterns of tissue damage in different disease stages of antibody-associated autoimmune diseases will help to identify novel biomarkers and can give important clues for possible therapeutic interventions.

Aberrant neurodevelopment in human iPS cell-derived models of Alexander disease.

Alexander disease (AxD) is a rare and severe neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP). While the exact disease mechanism remains unknown, previous studies suggest that mutant GFAP influences many cellular processes, including cytoskeleton stability, mechanosensing, metabolism, and proteasome function. While most studies have primarily focused on GFAP-expressing astrocytes, GFAP is also expressed by radial glia and neural progenitor cells, prompting questions about the impact of GFAP mutations on central nervous system (CNS) development. In this study, we observed impaired differentiation of astrocytes and neurons in co-cultures of astrocytes and neurons, as well as in neural organoids, both generated from AxD patient-derived induced pluripotent stem (iPS) cells with a GFAPR239C mutation. Leveraging single-cell RNA sequencing (scRNA-seq), we identified distinct cell populations and transcriptomic differences between the mutant GFAP cultures and a corrected isogenic control. These findings were supported by results obtained with immunocytochemistry and proteomics. In co-cultures, the GFAPR239C mutation resulted in an increased abundance of immature cells, while in unguided neural organoids and cortical organoids, we observed altered lineage commitment and reduced abundance of astrocytes. Gene expression analysis revealed increased stress susceptibility, cytoskeletal abnormalities, and altered extracellular matrix and cell-cell communication patterns in the AxD cultures, which also exhibited higher cell death after stress. Overall, our results point to altered cell differentiation in AxD patient-derived iPS-cell models, opening new avenues for AxD research.

Synergistic effects of GFAP and Aß42: Implications for white matter integrity and verbal memory across the cognitive spectrum.

Background: Plasma glial fibrillary acidic protein (GFAP), an astrocytic biomarker, has previously been linked with Alzheimer's disease (AD) status, amyloid levels, and memory performance in older adults. The neuroanatomical pathways by which astrogliosis/astrocyte reactivity might impact cognitive outcomes remains unclear. We evaluated whether plasma GFAP and amyloid levels had a synergistic effect on fornix structure, which is critically involved in AD-associated cholinergic pathways. We also examined whether fornix structure mediates associations between GFAP and verbal memory. Methods: In a cohort of both asymptomatic and symptomatic older adults (total n = 99), we assessed plasma GFAP, amyloid-ß42 (Aß42), other AD-related proteins, and vascular markers, and we conducted comprehensive memory testing. Tractography-based methods were used to assess fornix structure with whole brain diffusion metrics to control for diffuse alterations in brain white matter. Results: In individuals in the low plasma amyloid-ß42 (Aß42) group, higher plasma GFAP was associated with lower fractional anisotropy (FA; p = 0.007), higher mean diffusivity (MD; p < 0.001), higher radial diffusivity (RD; p < 0.001), and higher axial diffusivity (DA; p = 0.001) in the left fornix. These associations were independent of APOE gene status, plasma levels of total tau and neurofilament light, plasma vascular biomarkers, and whole brain diffusion metrics. In a sub-analysis of participants in the low plasma Aß42 group (n = 33), fornix structure mediated the association between higher plasma GFAP levels and lower verbal memory performance. Discussion: Higher plasma GFAP was associated with altered fornix microstructure in the setting of greater amyloid deposition. We also expanded on our prior GFAP-verbal memory findings by demonstrating that in the low plasma Aß42 group, left fornix integrity may be a primary white matter conduit for the negative associations between GFAP and verbal memory performance. Overall, these findings suggest that astrogliosis/astrocyte reactivity may play an early, pivotal role in AD pathogenesis, and further demonstrate that high GFAP and low Aß42 in plasma may reflect a particularly detrimental synergistic role in forniceal-memory pathways.