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Background: This study investigated trajectory profiles and the association of concentrations of the biomarkers neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in ventricular cerebrospinal fluid (CSF) with clinical outcome at 1 year and 10–15 years after a severe traumatic brain injury (sTBI). Methods: This study included patients with sTBI at the Neurointensive Care Unit at Sahlgrenska University Hospital, Gothenburg, Sweden. The injury was regarded as severe if patients had a Glasgow Coma Scale ≤ 8 corresponding to Reaction Level Scale ≥ 4. CSF was collected from a ventricular catheter during a 2-week period. Concentrations of NfL and GFAP in CSF were analyzed with enzyme-linked immunosorbent assay. The Glasgow Outcome Scale (GOS) was used to assess the 1-year and 10–15-year outcomes. After adjustment for age and previous neurological diseases, logistic regression was performed for the outcomes GOS 1 (dead) or GOS 2–5 (alive) and GOS 1–3 (poor) or GOS 4–5 (good) versus the independent continuous variables (NfL and GFAP). Results: Fifty-three patients with sTBI were investigated; forty-seven adults are presented in the article, and six children (aged 7–18 years) are described in Supplement 1. The CSF concentrations of NfL gradually increased over 2 weeks post trauma, whereas GFAP concentrations peaked on days 3–4. Increasing NfL and GFAP CSF concentrations increased the odds of GOS 1–3 outcome 1 year after trauma (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.07–2.80, p = 0.025; and OR 1.61, 95% CI 1.09–2.37, p = 0.016, respectively). Similarly, increasing CSF concentrations of NfL and GFAP increased the odds for GOS 1–3 outcome 10–15 years after trauma (OR 2.04, 95% CI 1.05–3.96, p = 0.035; and OR 1.60, 95% CI 1.02–2.00, p = 0.040). Conclusions: This study shows that initial high concentrations of NfL and GFAP in CSF are both associated with higher odds for GOS 1–3 outcome 1 year and 10–15 years after an sTBI, implicating its potential usage as a prognostic marker in the future. [ABSTRACT FROM AUTHOR]

Physical activity is a promising preventative strategy for Alzheimer's disease: it is associated with lower dementia risk, better cognition, greater brain volume and lower brain beta-amyloid. Blood-based biomarkers have emerged as a low-cost, non-invasive strategy for detecting preclinical Alzheimer's disease, however, there is limited literature examining the effect of exercise (a structured form of physical activity) on blood-based biomarkers. The current study investigated the influence of a 6-month exercise intervention on levels of plasma beta-amyloid (Aβ42, Aβ40, Aβ42/40), phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) chain in cognitively unimpaired older adults, and as a secondary aim, whether blood-based biomarkers related to cognition. Ninety-nine community-dwelling older adults (69.1 ± 5.2) were allocated to an inactive control, or to moderate or high intensity exercise groups where they cycled twice weekly for six months. At baseline and six months (post-intervention), fasted blood was collected and analysed using single molecule array (SIMOA) assays, and cognition was assessed. Results demonstrated no change in levels of any plasma biomarker from pre- to post-intervention. At baseline, higher NfL was associated with poorer cognition (β = -0.33, SE = 0.13, adjusted p =.042). Exploratory analyses indicated higher cardiorespiratory fitness was associated with higher NfL and GFAP levels in apolipoprotein E (APOE) ε4 non-carriers compared to ε4 carriers (NfL, β = -0.43, SE = 0.19, p =.029; GFAP, β = -0.41, SE = 0.20, p =.044), though this association was mediated by body mass index (BMI). These results highlight the importance of considering BMI in analysis of blood-based biomarkers, especially when investigating differences between APOE ε4 carriers and non-carriers. Our results also indicate that longer follow-up periods may be required to observe exercise-induced change in blood-based biomarkers. [ABSTRACT FROM AUTHOR]

Objective: To ascertain the changes of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) values in relapsing–remitting multiple sclerosis (RRMS) patients treated with ocrelizumab and their association with treatment response. Methods: Multicenter prospective study including 115 RRMS patients initiating ocrelizumab treatment between February 2020 and March 2022 followed during a year. Serum samples were collected at baseline and every 3 months to measure sNfL and sGFAP levels using single-molecule array (SIMOA) technology. Based on age and body mass index, sNfL values were standardized using z-score. NEDA (non-evidence of disease activity)-3 status was defined for patients free of disease activity after a year of follow-up. Inflammation (INFL) was considered when new relapses occurred during follow-up or new MRI lesions were found at 1-year exploration. PIRA (progression independent of relapse activity) was defined as disability progression occurring in the absence of relapses or new MRI activity. Results: After a year on ocrelizumab, 85 patients (73.9%) achieved NEDA-3. Thirty patients did not achieve NEDA: 20 (17.4%) because of INFL and 10 (8.7%) because of PIRA. Of INFL patients, 6 (30.0%) had relapses, and 17 (85.0%) had at least one new MRI lesion at the 12-month examination. At baseline, INFL patients had higher sNfL (p = 0.0003) and sGFAP (p = 0.03) than the NEDA-3 group. PIRA patients mostly exhibited low sNfL and heterogeneous sGFAP levels. After a year, NEDA-3 and INFL patients showed similar decreases in sNfL (p < 0.0001) and sGFAP (p < 0.0001 for NEDA-3 and p = 0.001 for INFL ones). However, the decrease occurred earlier in NEDA-3 patients. Accordingly, sNfL > 1.5 z-score 3 months after ocrelizumab initiation indicated a higher risk of inflammation (OR = 13.6; p < 0.0001). Decrease in sGFAP values occurred later in both groups, with significant reductions observed at 12 months for INFL and 6 and 12 months for NEDA-3. No significant changes in sNfL or sGFAP were observed in PIRA patients. Conclusion: Ocrelizumab induced normalization of sNfL and sGFAP in the majority of NEDA-3 and inflammatory patients but did not cause changes in the PIRA group. Our data suggest that normalization of sNfL and sGFAP is associated with the lack of inflammatory-associated disease progression but it may not affect non-inflammatory PIRA. [ABSTRACT FROM AUTHOR]

Background: To establish simple screening tests to suspect Alzheimer's disease (AD) pathology, the clinical sign "head-turning sign" (HTS), which is a patient's behavior of turning their head towards their partner to seek assistance with questions posed by the examiner during the interview, and the simple screening questionnaire for dementia named "Neucop-Q" were validated in participants diagnosed with amyloid and tau positron emission tomography (PET). Methods: We enrolled 155 patients: 47 cognitive normal, 36 with mild cognitive impairment, 64 with dementia, and 8 with psychiatric disorders. All participants underwent Neucop-Q [three questions: Consciousness/self-awareness of cognitive disabilities (C) normal/impaired (nor/imp), Pleasure/pastime (P) nor/imp, and News/knowledge on current topics (N) nor/imp] and amyloid/tau PET. Additionally, we measured plasma amyloid β (Aβ) 42/40 ratio, phosphorylated tau 181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NFL) levels and compared with HTS and Neucop-Q results. Results: The specificity and positive predictive value (PPV) of HTS positivity (HTSpos) were the highest (amyloid PET: 0.930 and 0.870, tau PET: 0.944 and 0.957, respectively), while Cimp and Nimp had a high negative predictive value (NPV) for amyloid PET (negativity) (0.750 and 0.725). Pimp showed high specificity for predicting non-AD tau positivity among non-AD participants without amyloid PET positivity (0.854). To validate these findings with PET results, we examined the correlation between well-established AD blood biomarkers and results obtained from these screening tests. HTSpos, Cimp, and Nimp were strongly associated with Aβ42/40 ratio (P < 0.0001, P = 0.0022, and P = 0.001), pTau181 (P < 0.0001, P = 0.0095, and P = 0.001), GFAP (P = 0.0372, P = 0.0088, and P = 0.0002), and amyloid PET Centiloid (P < 0.0001, P = 0.0210, and P = 0.0006), whereas Pimp increased neuroinflammation (GFAP; P = 0.0061) and was associated with non-AD tauopathy. The combination of Neucop-Q questions showed that Cimp/Pnor/Nimp subjects have the highest specificity and PPV (0.972 and 0.833) and were strongly associated with Aβ42/40 ratio (P = 0.0006), pTau181 (P = 0.0006), and amyloid PET Centiloid (P < 0.0001). Conclusion: HTSpos, Cimp, and Nimp have diagnostic utility in suspecting MCI due to AD and AD, and Pimp has diagnostic value in non-AD tauopathy. HTSpos, Cimp, and Nimp were associated with biomarkers of Aβ pathology. HTS and Neucop-Q may serve as powerful first-line screening in memory clinics. Trial registration: UMIN Clinical Trials Registry (UMIN-CTR) under registration numbers 000032027 (Registration date: 2018/03/31) and 000030248 (Registration date: 2018/01/01). [ABSTRACT FROM AUTHOR]

Angiocentric glioma (AG) is a supratentorial diffuse low‐grade glioma characterized by the MYB::QKI fusion gene, showing angiocentric growth of monomorphous spindle cells with astrocytic and ependymal immunophenotypes. We describe a rare case of MYB::QKI fusion‐positive diffuse cerebellar glioma in a 54‐year‐old male. The patient initially presented with a T2/FLAIR hyperintense lesion in the left cerebellar hemisphere and slowly progressive neurological symptoms. Histopathological evaluation revealed a diffuse glioma characterized by spindle‐shaped and small epithelioid cells with perivascular infiltration. Immunohistochemistry showed positivity for glial fibrillary acidic protein and only occasionally positive for Olig2. No dot‐ or ring‐like epithelial membrane antigen immunoreactivity was observed. In this case, the proliferative activity was higher than that in typical AG cases, as manifested by multiple mitoses (four mitoses/slide) and a Ki‐67 labeling index of 5%. The tumor cells were negative for IDH1 p.R132H and H3 p.K28M mutation‐specific antibodies. Fluorescence in situ hybridization showed a MYB break‐apart signal, and reverse transcription‐polymerase chain reaction analysis confirmed an in‐frame MYB (6q23.3, exon 11, NM_001161659.2)::QKI (6q26, exon 5, NM_006775.3) fusion. IDH1 p.R132, IDH2 p.R172, H3‐3A p.K28, H3C2 p.K28, and BRAF p.V600 were all wild type. DNA methylome profiling did not match any of the established methylation classes, including the four subtypes of diffuse glioma, MYB‐ or MYBL1‐altered. Considering the results of DNA methylome profiling, the question remains as to whether this case represents a subset of AG (diffuse glioma, MYB/MYBL1‐altered) or a distinct subtype. Although the morphological findings and the presence of fusion indicated that the tumor was a cerebellar AG, the DNA methylome profile did not match that of AG. An accumulation of more cases is needed to determine the precise nature of the tumor, which may lead to an expansion of the tumor concept. [ABSTRACT FROM AUTHOR]

Background: Glial fibrillary acidic protein (GFAP) is an important biomarker for neuroinflammatory conditions. Recently, advancements in the treatment of neurological diseases have highlighted the increasing importance of biomarkers, creating a demand for accurate and simple measurement systems for GFAP levels, which are essential for both research and clinical applications. This study presents the development and validation of a novel fully automated immunoassay for the quantitative determination of GFAP levels in biological samples. Methods: We examined the analytical performance of the GFAP assay on the LUMIPULSE platform. The assay's parameters, including antibody concentrations, incubation times, and detection methods, were optimized to enhance sensitivity and specificity. GFAP levels were measured in 396 serum or plasma samples, comprising both healthy controls and patients with neurodegenerative diseases. Results: In the analytical performance studies, intra- and inter-assay coefficients of variation (CV) were below 5%, indicating high reproducibility. Additionally, the assay demonstrated good linearity over the measurement range. The limit of quantification (LoQ) for this assay was 6.0 pg/mL, which is sufficient for measuring specimens from healthy controls. In clinical validation studies, GFAP levels were significantly elevated in patients with neurodegenerative diseases compared to healthy controls. Conclusions: This automated GFAP assay provides a robust and reliable tool for GFAP measurement, facilitating further research into GFAP's role in neurological disorders and potentially aiding in the diagnosis and monitoring of these conditions. [ABSTRACT FROM AUTHOR]

The article discusses the role of biomarkers in Alzheimer's disease diagnosis and staging, emphasizing the shift towards a biological definition of the disease. Biomarkers such as Aβ plaques and tau aggregates are crucial in understanding disease progression and are now routinely used in clinical settings. The article also highlights the importance of integrating diagnostic biomarkers with clinical and biological staging to make meaningful diagnoses consistent with the evolving understanding of Alzheimer's disease. [Extracted from the article]

Introduction Materials and Methods Results Conclusion Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions and repetitive behaviors. This study examines the effects of fenofibrate on a propionic acid (PPA)‐induced rat model of ASD, focusing on behavioral changes, inflammatory markers, and histological findings.Thirty male Wistar rats were divided into three groups: a control group, a group receiving PPA and saline, and a group treated with PPA and fenofibrate for 15 days. Behavioral assessments, including the three‐chamber sociability test, open‐field test, and passive avoidance learning, were conducted. Biochemical analyses measured TNF‐α, NGF, IL‐17, IL‐2, and galectin‐3 levels in brain tissues. Histological evaluations focused on Purkinje neuron counts in the cerebellum and neuronal changes in the CA1 and CA3 regions of the hippocampus, along with glial fibrillary acidic protein (GFAP) levels.Fenofibrate treatment significantly improved behavioral outcomes, reducing autism‐like behaviors compared to the PPA/saline group. Biochemically, the PPA/saline group showed elevated levels of malondialdehyde, TNF‐α, IL‐2, IL‐17, and galectin‐3, which were reduced following fenofibrate treatment. Histologically, the PPA/saline group exhibited fewer, dysmorphic Purkinje neurons and increased glial activity in the CA1 region, both of which were ameliorated by fenofibrate treatment.Fenofibrate shows promise in mitigating autism‐like behaviors in a rat model of ASD, likely due to its antioxidative and neuroprotective properties, which contribute to preserving neuronal integrity and reducing inflammation. [ABSTRACT FROM AUTHOR]

Objective: Cerebrospinal fluid biomarkers are challenging to use for diagnosing mild cognitive impairment (MCI) in large populations, and there is an urgent need for new blood biomarkers. The aim of this study is to investigate whether astrocyte activation is correlated with hippocampal atrophy, and to assess the potential of glial fibrillary acidic protein (GFAP) as a biomarker for diagnosing MCI among community-dwelling older individuals. Methods: This cross-sectional study included 107 older adults. The levels of GFAP in serum were measured, and the volumetric assessment of gray matter within hippocampal subregions was conducted using Voxel-Based Morphometry (VBM). The relationship between hippocampal subregion volume and blood biomarkers were analyzed using partial correlation. The effectiveness of blood biomarkers in differentiating MCI was assessed using a receiver operating characteristic (ROC) curve. Results: We found that serum GFAP levels were significantly elevated in the MCI group compared to the cognitively normal (CN) group. Additionally, individuals with MCI exhibited a reduction gray matter volume in specific hippocampal subregions. Notably, the right dentate gyrus (DG) and right cornu ammonis (CA) subregions were found to be effective for distinguishing MCI patients from CN individuals. Serum levels of GFAP demonstrate a sensitivity of 65.9% and a specificity of 75.6% in differentiating patients with MCI from CN individuals. Conclusion: Specific atrophy within hippocampal subregions has been observed in the brains of community-dwelling elderly individuals. Elevated levels of circulating GFAP may serve as a sensitive peripheral biomarker indicative of hippocampal-specific cognitive alterations in patients with MCI. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance 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. [ABSTRACT FROM AUTHOR]

Neurovascular unit (NVU) inflammation via activation of glial cells and neuronal damage plays a critical role in neurodegenerative diseases. Though the exact mechanism of disease pathogenesis is not understood, certain biomarkers provide valuable insight into the disease pathogenesis, severity, progression and therapeutic efficacy. These markers can be used to assess pathophysiological status of brain cells including neurons, astrocytes, microglia, oligodendrocytes, specialized microvascular endothelial cells, pericytes, NVU, and blood-brain barrier (BBB) disruption. Damage or derangements in tight junction (TJ), adherens junction (AdJ), and gap junction (GJ) components of the BBB lead to increased permeability and neuroinflammation in various brain disorders including neurodegenerative disorders. Thus, neuroinflammatory markers can be evaluated in blood, cerebrospinal fluid (CSF), or brain tissues to determine neurological disease severity, progression, and therapeutic responsiveness. Chronic inflammation is common in age-related neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and dementia. Neurotrauma/traumatic brain injury (TBI) also leads to acute and chronic neuroinflammatory responses. The expression of some markers may also be altered many years or even decades before the onset of neurodegenerative disorders. In this review, we discuss markers of neuroinflammation, and neurodegeneration associated with acute and chronic brain disorders, especially those associated with neurovascular pathologies. These biomarkers can be evaluated in CSF, or brain tissues. Neurofilament light (NfL), ubiquitin C-terminal hydrolase-L1 (UCHL1), glial fibrillary acidic protein (GFAP), Ionized calcium-binding adaptor molecule 1 (Iba-1), transmembrane protein 119 (TMEM119), aquaporin, endothelin-1, and platelet-derived growth factor receptor beta (PDGFRβ) are some important neuroinflammatory markers. Recent BBB-on-a-chip modeling offers promising potential for providing an in-depth understanding of brain disorders and neurotherapeutics. Integration of these markers in clinical practice could potentially enhance early diagnosis, monitor disease progression, and improve therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is associated with diffuse axonal injury (DAI), a primary pathology linked to progressive neurodegeneration and neuroinflammation, including chronic astrogliosis, which influences long-term post-TBI recovery and morbidity. Sex-based differences in blood-brain barrier (BBB) permeability increases the risk of accelerated brain aging and early-onset neurodegeneration. However, few studies have evaluated chronic time course of astrocytic responses around cerebrovascular in the context of aging after TBI and sex dependence. We observed increased glial fibrillary acidic protein (GFAP)-labeled accessory processes branching near and connecting with GFAP-ensheathed cortical vessels, suggesting a critical nuance in astrocyte-vessel interactions after TBI. To quantify this observation, male and female Sprague Dawley rats (∼3 months old, n = 5–6/group) underwent either sham surgery or midline fluid percussion injury. Using immunohistochemical analysis, we quantified GFAP-labeled astrocyte primary and accessory processes that contacted GFAP-ensheathed vessels in the somatosensory barrel cortex at 7, 56, and 168 days post-injury (DPI). TBI significantly increased GFAP-positive primary processes at 7 DPI (P < 0.01) in both sexes. At 56 DPI, these vessel-process interactions remained significantly increased exclusively in males (P < 0.05). At 168 DPI, both sexes showed a significant reduction in vessel-process interactions compared to 7 DPI (P < 0.05); however, a modest but significant injury effect reemerged in females (P < 0.05). A similar sex-dependent pattern in the number of accessory processes provides novel evidence of long-term temporal changes in astrocyte-vessel interactions. TBI-induced changes in astrocyte-vessel interactions may indicate chronic BBB vulnerability and processes responsible for early onset vascular and neurodegenerative pathology. [ABSTRACT FROM AUTHOR]

The case of a 75‐year‐old man with a glioblastoma of the right frontal lobe showing features of adenoid glioblastoma is reported. The tumor consisted of two components: the adenoid component, in which large, cohesive, polygonal cells with vesicular nuclei and abundant basophilic cytoplasm showed nest‐like, trabecular, or tubular growth on the myxoid matrix and formed a multinodular configuration; and the subsidiary component, in which short spindle cells showed compact fascicular growth. The features of ordinary glioblastoma were also found in a small area. Tumor cells were immunoreactive for S‐100 protein, glial fibrillary acidic protein, and Olig2, and some tumor cells in the adenoid component showed immunoreactivity for cytokeratins and E‐cadherin. A marked regional decrease in microvascular density, approaching almost complete absence of microvessels, was demonstrated in the adenoid component. In contrast, microvascular density was well preserved in the spindle cell component and the area of ordinary glioblastoma. Tumor cells in the adenoid component showed cytoplasmic expression of chondromodulin‐I, one of the cytokines that strongly inhibit angiogenesis, whereas the expression of this protein was very weak or only faint in the spindle cell component and the area of ordinary glioblastoma. A marked regional decrease in microvascular density was associated with myxoid change of the stroma and considered to be caused by the secretion of chondromodulin‐I by tumor cells. Stromal hypovascularity with myxoid change might play an important role in the morphogenesis of adenoid features. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore the effect of moxibustion at Governor Vessel (GV) acupoints, including Baihui (GV 20), Shenting (GV 24) and Dazhui (GV 14) for 14 days on glial vascular unit (GVU) in rats with multiple microinfarctions (MMI), and to explore its action mechanism. Methods: The effect and mechanism of moxibustion on vascular dementia (VD) were studied in MMI rats by means of behavioral and molecular biology experiments. Results: Rats receiving MMI showed impairment of memory function, reduction of cerebral blood flow, damage of blood-brain barrier (BBB) integrity and increased brain mass. MMI also increased neuronal degeneration in the hippocampus. Notably, levels of glial fibrillary acidic protein (GFAP) and complement component 3 significantly increased, but those of Connexin43 (CX43) and platelet derived growth factor receptor β (PDGFRβ) significantly decreased in the hippocampus of the rats receiving MMI. Moxibustion, as well as oxiracetam (ORC) treatment improved memory function and neuronal degeneration, ameliorated BBB integrity, increased cerebral blood flow and decreased brain mass. In addition, moxibustion as well as oxiracetam (ORC) treatment reduced the decrease of CX43 protein and increased PDGFRβ protein level in the hippocampus of MMI rats. Moreover, moxibustion treatment reversed MMI-induced increase of the GFAP/CX43 ratio in vascular structural units. Importantly, after PDGFRβ inhibition, VD rats treated with moxibustion had impaired learning and memory, decreased cerebral blood flow, and BBB disruption. Conclusion: Moxibustion treatment at various GV acupoints improved cerebral blood flow and repaired BBB function in rats with MMI, likely through protecting GVU. [ABSTRACT FROM AUTHOR]

Background: Stroke is one of the leading causes of death and disability worldwide. The diagnosis of stroke remains largely clinical, yet widely used stroke scoring systems and brain imaging do not satisfactorily allow the distinction of ischaemic stroke (IS) patients from stroke mimics (SMs). Blood biomarkers are promising tools that could facilitate clinical triage. Methods: This study recruited 66 patients with IS and 24 SMs. The levels of Glial fibrillary acidic protein (GFAP), Neuron-specific enolase (NSE), Neurofilament light chain (NfL) and blood-brain barrier (BBB) proteins [Occludin (OCLN), Zonula occludens 1 (ZO-1), Claudin-5] in blood serum were measured by enzyme-linked immunosorbent assay technique. Biomarker levels in IS patients and SMs were compared using the Mann–Whitney U test. Multivariable logistic regression analysis was used to evaluate the diagnostic performance of biomarkers in combination with the National Institutes of Health Stroke Scale (NIHSS) score. Results: More significant differences in circulating GFAP, NfL, OCLN, ZO-1, and Claudin-5 but not NSE were found in IS patients compared to SMs. A combination of circulating ZO-1, Claudin-5, and OCLN with NIHSS score gives the highest diagnostic accuracy, sensitivity, and specificity. Conclusions: A prediction model with circulating BBB proteins in combination with NIHSS score differentiates between IS patients and SMs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI)-induced intracerebral hematoma is a major driver of secondary injury pathology such as neuroinflammation, cerebral edema, neurotoxicity, and blood–brain barrier dysfunction, which contribute to neuronal loss, motor deficits, and cognitive impairment. Cluster of differentiation 47 (CD47) is an antiphagocytic cell surface protein inhibiting hematoma clearance. This study was designed to evaluate the safety and efficacy of blockade of CD47 via intravenous (i.v.) administration of anti-CD47 antibodies following penetrating ballistic-like brain injury (PBBI) with significant traumatic intracerebral hemorrhage (tICH). The pharmacokinetic (PK) profile of the anti-CD47 antibody elicited that antibody concentration decayed over 7 days post-administration. Blood tests and necropsy analysis indicated no severe adverse events following treatment. Cerebral hemoglobin levels were significantly increased after injury, however, anti-CD47 antibody administration at 0.1 mg/kg resulted in a significant reduction in cerebral hemoglobin levels at 72 h post-administration, indicating augmentation of hematoma clearance. Immunohistochemistry assessment of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (IBA1) demonstrated a significant reduction of GFAP levels in the lesion core and peri-lesional area. Based on these analyses, the optimal dose was identified as 0.1 mg/kg. Lesion volume showed a reduction following treatment. Rotarod testing revealed significant motor deficits in all injured groups but no significant therapeutic benefits. Spatial learning performance revealed significant deficits in all injured groups, which were significantly improved by the last testing day. Anti-CD47 antibody treated rats showed significantly improved attention deficits, but not retention scores. These results provide preliminary evidence that blockade of CD47 using i.v. administration of anti-CD47 antibodies may serve as a potential therapeutic for TBI with ICH. [ABSTRACT FROM AUTHOR]

Blood biomarkers are an emerging diagnostic and prognostic tool that reflect a range of neuropathological processes following traumatic brain injury (TBI). Their effectiveness in identifying long-term neuropathological processes after TBI is unclear. Studying biomarkers in the chronic phase is vital because elevated levels in TBI might result from distinct neuropathological mechanisms during acute and chronic phases. Here, we examine plasma biomarkers in the chronic period following TBI and their association with amyloid and tau PET, white matter microarchitecture, brain age and cognition. We recruited participants ≥40 years of age who had suffered a single moderate–severe TBI ≥10 years previously between January 2018 and March 2021. We measured plasma biomarkers using single molecule array technology [ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light (NfL), tau, glial fibrillary acidic protein (GFAP) and phosphorylated tau (P-tau181)]; PET tracers to measure amyloid-β (18F-NAV4694) and tau neurofibrillary tangles (18F-MK6240); MRI to assess white matter microstructure and brain age; and the Rey Auditory Verbal Learning Test to measure verbal-episodic memory. A total of 90 post-TBI participants (73% male; mean = 58.2 years) were recruited on average 22 years (range = 10–33 years) post-injury, and 32 non-TBI control participants (66% male; mean = 57.9 years) were recruited. Plasma UCH-L1 levels were 67% higher {exp(b) = 1.67, P = 0.018, adjusted P = 0.044, 95% confidence interval (CI) [10% to 155%], area under the curve = 0.616} and P-tau181 were 27% higher {exp(b) = 1.24, P = 0.011, adjusted P = 0.044, 95% CI [5% to 46%], area under the curve = 0.632} in TBI participants compared with controls. Amyloid and tau PET were not elevated in TBI participants. Higher concentrations of plasma P-tau181, UCH-L1, GFAP and NfL were significantly associated with worse white matter microstructure but not brain age in TBI participants. For TBI participants, poorer verbal-episodic memory was associated with higher concentration of P-tau181 {short delay: b = −2.17, SE = 1.06, P = 0.043, 95% CI [−4.28, −0.07]; long delay: b P-tau = −2.56, SE = 1.08, P = 0.020, 95% CI [−4.71, −0.41]}, tau {immediate memory: b Tau = −6.22, SE = 2.47, P = 0.014, 95% CI [−11.14, −1.30]} and UCH-L1 {immediate memory: b UCH-L1 = −2.14, SE = 1.07, P = 0.048, 95% CI [−4.26, −0.01]}, but was not associated with functional outcome. Elevated plasma markers related to neuronal damage and accumulation of phosphorylated tau suggest the presence of ongoing neuropathology in the chronic phase following a single moderate–severe TBI. Plasma biomarkers were associated with measures of microstructural brain disruption on MRI and disordered cognition, further highlighting their utility as potential objective tools to monitor evolving neuropathology post-TBI. [ABSTRACT FROM AUTHOR]

It is debated whether CNS involvement begins during acute human immunodeficiency virus (HIV) infection in persons without meningitis/encephalitis and whether specific antiretroviral drugs or combinations would be beneficial. Neurologically asymptomatic participants enrolled in a randomized and controlled study comparing three combination antiretroviral regimens (tenofovir alafenamide/emtricitabine plus dolutegravir; darunavir; or both) during primary HIV infection were enrolled. Serum and CSF were collected at baseline and at 12 and 48 (serum only) weeks after treatment initiation. Single molecule array was used to measure neurofilament light chain (NFL), total tau protein (Tau), brain-derived neurotrophic factor, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase. We assessed the longitudinal change in biomarkers over time, in addition to the change in the prevalence of serum NFL concentrations above previously published age-adjusted cut-offs (7 pg/ml if 5–18 years, 10 pg/ml if 18–51 years, 15 pg/ml if 51–61 years, 20 pg/ml if 61–70 years and 35 pg/ml if >70 years). Serum was available from 47 participants at all time points, and CSF was available from 13 participants at baseline and 7 at Week 12. We observed a significant direct serum-to-CSF correlation for NFL (ρ = 0.692, P = 0.009), GFAP (ρ = 0.659, P = 0.014) and brain-derived neurotrophic factor (ρ = 0.587, P = 0.045). Serum (ρ = 0.560, P = 0.046) and CSF NFL (ρ = 0.582, P = 0.037) concentrations were directly associated with CSF HIV RNA levels. We observed a significant decrease over time in serum NFL (P = 0.006) and GFAP (P = 0.006) but not in the other biomarkers. No significant difference was observed among the treatment arms. At baseline, serum and CSF age-adjusted NFL levels were above age-adjusted cut-offs in 23 (48.9%) and four participants (30.8%), respectively; considering serum NFL, this proportion was lower at Weeks 12 (31.9%, P = 0.057) and 48 (27.7%, P = 0.13). A relevant proportion of neurologically asymptomatic participants had abnormal CSF and serum NFL levels during primary HIV infection. NFL and GFAP decreased in serum following combination antiretroviral therapy without significant differences among the treatment arms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Environmental concerns have consistently been a focal point for the scientific community. Pollution is a critical ecological issue that poses significant threats to human health and agricultural production. Contamination with heavy metals and pesticides is a considerable concern, a threat to the environment, and warrants special attention. In this study, we investigated the significant issues arising from sub-chronic exposure to imidacloprid (IMI), mercury (Hg), and cadmium (Cd), either alone or in combination, using zebrafish (Danio rerio) as an animal model. Additionally, we assessed the potential protective effects of polyfloral honey enriched with natural ingredients, also called honey formulation (HF), against the combined sub-chronic toxic effects of the three contaminants. The effects of IMI (0.5 mg·L−1), Hg (15 μg·L−1), and Cd (5 μg·L−1), both individually and in combination with HF (500 mg·L−1), on zebrafish were evaluated by quantifying acetylcholinesterase (AChE) activity, lipid peroxidation (MDA), various antioxidant enzyme activities like superoxide dismutase and glutathione peroxidase (SOD and GPx), 2D locomotor activity, social behavior, histological and immunohistochemical factors, and changes in body element concentrations. Our findings revealed that all concentrations of pollutants may disrupt social behavior, diminish swimming performances (measured by total distance traveled, inactivity, and swimming speed), and elevate oxidative stress (OS) biomarkers of SOD, GPx, and MDA in zebrafish over the 21-day administration period. Fish exposed to IMI and Hg + Cd + IMI displayed severe lesions and increased GFAP (Glial fibrillary acidic protein) and S100B (S100 calcium-binding protein B) protein expression in the optic tectum and cerebellum, conclusively indicating astrocyte activation and neurotoxic effects. Furthermore, PCNA (Proliferating cell nuclear antigen) staining revealed reduced cell proliferation in the IMI-exposed group, contrasting with intensified proliferation in the Hg + Cd group. The nervous system exhibited significant damage across all studied concentrations, confirming the observed behavioral changes. Moreover, HF supplementation significantly mitigated the toxicity induced by contaminants and reduced OS. Therefore, the exposure to chemical mixtures offers a more complete picture of adverse impacts on aquatic ecosystems and the supplementation with bioactive compounds can help to reduce the toxicity induced by exposure to environmental pollutants. [ABSTRACT FROM AUTHOR]

The document delves into pre-clinical therapeutic strategies for amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD), focusing on targeting specific proteins like Atxn2, TDP-43, and FUS for potential gene therapies and small molecules. It also examines the role of sphingolipids, mitochondrial dysfunction, and immune responses in ALS pathogenesis, offering potential therapeutic interventions. Additionally, the document explores the impact of ketogenic diets, regulatory T cells, and HERV-K ENV protein on ALS progression, providing a comprehensive overview of diverse therapeutic approaches for ALS and FTD. Various research studies in the document explore treatments for ALS, including antibodies targeting TDP-43, gene silencing approaches, AAV-mediated gene therapies, and the therapeutic effects of probiotics and remote ischemic conditioning in ALS models. Other studies investigate neuronal excitability modulation through transcranial magnetic stimulation and the potential neuroprotective effects of Lactocaseibacillus rhamnosus HA-114, aiming to offer novel therapeutic strategies for ALS. [Extracted from the article]

The article provides an overview of studies and experiments on Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Degeneration, focusing on topics such as endogenous retrovirus-K (ERVK), alternative polyadenylation, TARDBP mutations, TDP-43 proteinopathy, and RNA aptamers in ALS neuropathology. It also discusses the impact of miRNAs, SOD1 aggregates, and different mechanisms of ALS spread, as well as the potential of direct neuronal reprogramming for ALS therapy. The research utilizes animal models like mice, zebrafish, and C. elegans to investigate the therapeutic potential of compounds and probiotics, aiming to understand disease progression and evaluate novel treatments for ALS. Clinical trials are proposed to assess probiotic supplementation effects on ALS patients. [Extracted from the article]

Purpose: [18F]-D3FSP is a new β-amyloid (Aβ) PET imaging tracer designed to decrease nonspecific signals in the brain by reducing the formation of the N-demethylated product. However, its optimal reference region for calculating the standardized uptake value ratio (SUVR) and its relation to the well-established biomarkers of Alzheimer's disease (AD) are still unclear. Methods: We recruited 203 participants from the Greater Bay Area Healthy Aging Brain Study (GHABS) to undergo [18F]-D3FSP Aβ PET imaging. We analyzed plasma Aβ42/Aβ40, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform. We compared the standardized uptake value (SUV) of five reference regions (cerebellum, cerebellum cortex, brainstem/PONs, white matter, composite of the four regions above) and AD typical cortical region (COMPOSITE) SUVR among different clinical groups. The association of D3FSP SUVR with plasma biomarkers, imaging biomarkers, and cognition was also investigated. Results: Brainstem/PONs SUV showed the lowest fluctuation across diagnostic groups, and COMPOSITE D3FSP SUVR had an enormous effect distinguishing cognitively impaired (CI) individuals from cognitively unimpaired (CU) individuals. COMPOSITE SUVR (Referred to brainstem/PONs) was positively correlated with p-Tau181 (p < 0.001), GFAP (p < 0.001), NfL (p = 0.014) in plasma and temporal-metaROI tau deposition (p < 0.001), and negatively related to plasma Aβ42/Aβ40 (p < 0.001), temporal-metaROI cortical thickness (p < 0.01), residual hippocampal volume (p < 0.001) and cognition (p < 0.001). The voxel-wise analysis replicated these findings. Conclusion: This study suggests brainstem/PONs as an optimal reference region for calculating D3FSP SUVR to quantify cortical Aβ plaques in the brain. [18F]-D3FSP could distinguish CI from CU and strongly correlates with well-established plasma biomarkers, tau PET, neurodegeneration, and cognitive decline. However, future head-to-head comparisons of [18F]-D3FSP PET images with other validated Aβ PET tracers or postmortem results are crucial. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a leading cause of long-term disability across the world. Evidence for the usefulness of imaging and fluid biomarkers to predict outcomes and screen for the need to monitor complications in the acute stage is steadily increasing. Still, many people experience symptoms such as fatigue and cognitive and motor dysfunction in the chronic phase of TBI, where objective assessments for brain injury are lacking. Consensus criteria for traumatic encephalopathy syndrome, a clinical syndrome possibly associated with the neurodegenerative disease chronic traumatic encephalopathy, which is commonly associated with sports concussion, have been defined only recently. However, these criteria do not fit all individuals living with chronic consequences of TBI. The pathophysiology of chronic TBI shares many similarities with other neurodegenerative and neuroinflammatory conditions, such as Alzheimer disease. As with Alzheimer disease, advancements in fluid biomarkers represent one of the most promising paths for unravelling the chain of pathophysiological events to enable discrimination between these conditions and, with time, provide prediction modelling and therapeutic end points. This Review summarizes fluid biomarker findings in the chronic phase of TBI (≥6 months after injury) that demonstrate the involvement of inflammation, glial biology and neurodegeneration in the long-term complications of TBI. We explore how the biomarkers associate with outcome and imaging findings and aim to establish mechanistic differences in biomarker patterns between types of chronic TBI and other neurodegenerative conditions. Finally, current limitations and areas of priority for future fluid biomarker research are highlighted. Traumatic brain injury can result in long-lasting symptoms and is associated with progressive neurodegenerative and neuroinflammatory pathology, but biomarkers to diagnose and monitor these chronic effects are lacking. Here, Thelin and co-workers summarize the available evidence for fluid biomarker use in chronic traumatic brain injury. Key points: Many people live with chronic symptoms following traumatic brain injury (TBI), with an increased risk of developing neurodegenerative conditions. The current definitions of chronic TBI do not cover all aspects of the disease, and biomarkers of neurodegeneration and neuroinflammation have not been included in the diagnostic criteria. Neurofilament light and glial fibrillary acidic protein remain elevated in blood years after brain injury, and elevated tau protein is seen in people with chronic TBI who are developing neurodegenerative conditions. Autoantibodies towards brain-enriched proteins are elevated in blood in both the acute and chronic phases of TBI and are associated with levels of neurodegenerative proteins. Considering the heterogeneity of the existing literature, improved grading of chronic TBI symptomatology and better biomarker sampling strategies are warranted to advance current criteria and guidelines. [ABSTRACT FROM AUTHOR]

Objective(s): Most individuals who suffer from spinal cord injury (SCI) experience neuropathic pain, which currently has no effective treatment. In this study, we examined how testosterone affects neuropathic pain resulting from SCI. Materials and Methods: We administered three different doses of testosterone (4, 8, 16 mg/kg, intraperitoneal) to male rats after an electrolytic lesion of the spinothalamic tract. We then conducted behavioral tests, including open field and von Frey tests, within 28 days post-SCI. On day 28 after SCI, we analyzed spinal tissue using western blot to measure the levels of ionized calcium binding adaptor molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), phospho-extracellular signal-regulated kinase (p-ERK1/2), and p-P38 at the injury site. Results: The results showed that testosterone significantly improved both motor activity and mechanical allodynia compared to the SCI-only group. Testosterone also inhibited microglia and astrocyte activation. Furthermore, testosterone significantly decreased p-P38 and p-ERK levels. Conclusion: The findings indicate that testosterone may alleviate SCI-induced neuropathic pain by inhibiting the activation of astrocytes and microglia, as well as suppressing MAPK signaling pathways. [ABSTRACT FROM AUTHOR]

Estrone and estradiol differentially modulate neuroplasticity and cognition. How they influence the maturation of new neurons in the adult hippocampus, however, is not known. The present study assessed the effects of estrone and estradiol on the maturation timeline of neurogenesis in the dentate gyrus (DG) of ovariectomized (a model of surgical menopause) young adult Sprague–Dawley rats using daily subcutaneous injections of 17β‐estradiol, estrone or vehicle. Rats were injected with a DNA synthesis marker, 5‐bromo‐2‐deoxyuridine (BrdU), and were perfused 1, 2, or 3 weeks after BrdU injection and daily hormone treatment. Brains were sectioned and processed for various markers including: sex‐determining region Y‐box 2 (Sox2), glial fibrillary acidic protein (GFAP), antigen kiel 67 (Ki67), doublecortin (DCX), and neuronal nuclei (NeuN). Immunofluorescent labeling or co‐labelling of BrdU with Sox2 (progenitor cells), Sox2/GFAP (neural progenitor cells), Ki67 (cell proliferation), DCX (immature neurons), NeuN (mature neurons) was used to examine the trajectory and maturation of adult‐born neurons over time. Estrogens had early (1 week of exposure) effects on different stages of neurogenesis (neural progenitor cells, cell proliferation and early maturation of new cells into neurons) but these effects were less pronounced after prolonged treatment. Estradiol enhanced, whereas estrone reduced cell proliferation after 1 week but not after longer exposure to either estrogen. Both estrogens increased the density of immature neurons (BrdU/DCX‐ir) after 1 week of exposure compared to vehicle treatment but this increased density was not sustained over longer durations of treatments to estrogens, suggesting that the enhancing effects of estrogens on neurogenesis were short‐lived. Longer duration post‐ovariectomy, without treatments with either of the estrogens, was associated with reduced neural progenitor cells in the DG. These results demonstrate that estrogens modulate several aspects of adult hippocampal neurogenesis differently in the short term, but may lose their ability to influence neurogenesis after long‐term exposure. These findings have potential implications for treatments involving estrogens after surgical menopause. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to explore the potential of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) as biomarkers for diagnosis and prognosis in mild and severe TBI cases, including TBI-related deaths. Methods: This prospective cohort study includes 40 cases each of mild, severe, fatal TBI cases, and 40 healthy controls. Serum samples were collected from live patients at 8 and 20 h post injury for UCH-L1 and GFAP respectively, and from deceased patients within 6 h of death. Results: Elevated levels of both GFAP and UCH-L1 were observed in patients with severe and fatal TBI cases. These biomarkers exhibited promising potential for predicting various Glasgow Outcome Scale Extended (GOSE) categories. Combining GFAP and UCH-L1 yielded higher predictive accuracy both for diagnosis and prognosis in TBI cases. The study additionally established specific cut-off levels for GFAP and UCH-L1 stratified according to the severity and prognosis. Conclusion: GFAP and UCH-L1 individually demonstrated moderate to good discrimination capacity in predicting TBI severity and functional outcomes. However, combining these biomarkers is recommended for improved diagnostic and prognostic utility. This precision tool can enhance patient care, enabling tailored treatment plans, ultimately reducing morbidity and mortality rates in TBI cases. [ABSTRACT FROM AUTHOR]

Epithelioid glioblastoma (eGB) is a rare and aggressive brain tumor that primarily affects children and young adults. This article presents a case study of a young adult male with eGB, describing the characteristics of the tumor and the genetic alterations commonly found in eGB. The patient had a poor prognosis and died four months after diagnosis. The article emphasizes the importance of recognizing and studying this rare subtype of glioblastoma to improve patient care and prognosis. Treatment options for eGB include BRAF and MEK inhibitor combination therapy. [Extracted from the article]

Autism spectrum disorder (ASD) is known as a group of neurodevelopmental conditions including stereotyped and repetitive behaviors, besides social and sensorimotor deficits. Anatomical and functional evidence indicates atypical maturation of the striatum. Astrocytes regulate the maturation and plasticity of synaptic circuits, and impaired calcium signaling is associated with repetitive behaviors and atypical social interaction. Spontaneous calcium transients (SCT) recorded in the striatal astrocytes of the rat were investigated in the preclinical model of ASD by prenatal exposure to valproic acid (VPA). Our results showed sensorimotor delay, augmented glial fibrillary acidic protein -a typical intermediate filament protein expressed by astrocytes- and diminished expression of GABAA-ρ3 through development, and increased frequency of SCT with a reduced latency that resulted in a diminished amplitude in the VPA model. The convulsant picrotoxin, a GABAA (γ-aminobutyric acid type A) receptor antagonist, reduced the frequency of SCT in both experimental groups but rescued this parameter to control levels in the preclinical ASD model. The amplitude and latency of SCT were decreased by picrotoxin in both experimental groups. Nipecotic acid, a GABA uptake inhibitor, reduced the mean amplitude only for the control group. Nevertheless, nipecotic acid increased the frequency but diminished the latency in both experimental groups. Thus, we conclude that striatal astrocytes exhibit SCT modulated by GABAA-mediated signaling, and prenatal exposure to VPA disturbs this tuning. [ABSTRACT FROM AUTHOR]

Somatostatin (SST) is a peptide expressed in the peripheral and central nervous systems, as well as in endocrine and immune cells. The aim of the current study is to determine the percentage of SST immunoreactive (IR) neurons and their colocalization with choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS), neuropeptide Y (NPY), and glial fibrillary acidic protein (GFAP) in the myenteric plexus (MP) and submucous plexus (SP) of the small intestine (SI) and large intestine (LI) of rats across different age groups from newborn to senescence using immunohistochemistry. In the MP of the SI and LI, the percentage of SST-IR neurons significantly increased during early postnatal development from 12 ± 2.4 (SI) and 13 ± 3.0 (LI) in newborn rats to 23 ± 1.5 (SI) and 18 ± 1.6 (LI) in 20-day-old animals, remaining stable until 60 days of age. The proportion of SST-IR cells then decreased in aged 2-year-old animals to 14 ± 2.0 (SI) and 10 ± 2.6 (LI). In the SP, the percentage of SST-IR neurons significantly rose from 22 ± 3.2 (SI) and 23 ± 1.7 (LI) in newborn rats to 42 ± 4.0 in 20-day-old animals (SI) and 32 ± 4.9 in 30-day-old animals (LI), before declining in aged 2-year-old animals to 21 ± 2.6 (SI) and 28 ± 7.4 (LI). Between birth and 60 days of age, 97–98% of SST-IR neurons in the MP and SP colocalized with ChAT in both plexuses of the SI and LI. The percentage of SST/ChAT neurons decreased in old rats to 85 ± 5.0 (SI) and 90 ± 3.8 (LI) in the MP and 89 ± 3.2 (SI) and 89 ± 1.6 (LI) in the SP. Conversely, in young rats, only a few SST-IR neurons colocalized with nNOS, but this percentage significantly increased in 2-year-old rats. The percentage of SST/NPY-IR neurons exhibited considerable variation throughout postnatal development, with no significant differences across different age groups in both the MP and SP of both intestines. No colocalization of SST with GFAP was observed in any of the studied animals. In conclusion, the expression of SST in enteric neurons increases in young rats and decreases in senescence, accompanied by changes in SST colocalization with ChAT and nNOS. [ABSTRACT FROM AUTHOR]

Background: Rheum tanguticum root, cataloged as "Daehwang" in the Korean Pharmacopeia, is rich in various anthraquinones known for their anti-inflammatory and antioxidant properties. Formulations containing Daehwang are traditionally employed for treating neurological conditions. This study aimed to substantiate the antiepileptic and neuroprotective efficacy of R. tanguticum root extract (RTE) against trimethyltin (TMT)-induced epileptic seizures and hippocampal neurodegeneration. Methods: The constituents of RTE were identified by ultra-performance liquid chromatography (UPLC). Experimental animals were grouped into the following five categories: control, TMT, and three TMT+RTE groups with dosages of 10, 30, and 100 mg/kg. Seizure severity was assessed daily for comparison between the groups. Brain tissue samples were examined to determine the extent of neurodegeneration and neuroinflammation using histological and molecular biology techniques. Network pharmacology analysis involved extracting herbal targets for Daehwang and disease targets for epilepsy from multiple databases. A protein-protein interaction network was built using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, and pivotal targets were determined by topological analysis. Enrichment analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool to elucidate the underlying mechanisms. Results: The RTE formulation was found to contain sennoside A, sennoside B, chrysophanol, emodin, physcion, (+)-catechin, and quercetin-3-O-glucuronoid. RTE effectively inhibited TMT-induced seizures at 10, 30, and 100 mg/kg dosages and attenuated hippocampal neuronal decay and neuroinflammation at 30 and 100 mg/kg dosages. Furthermore, RTE significantly reduced mRNA levels of tumor necrosis factor (TNF-α), glial fibrillary acidic protein (GFAP), and c-fos in hippocampal tissues. Network analysis revealed TNF, Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Protein c-fos (FOS), RAC-alpha serine/threonine-protein kinase (AKT1), and Mammalian target of rapamycin (mTOR) as the core targets. Enrichment analysis demonstrated significant involvement of R. tanguticum components in neurodegeneration (p = 4.35 x 10-5) and TNF signaling pathway (p = 9.94 x 10-5). Conclusions: The in vivo and in silico analyses performed in this study suggests that RTE can potentially modulate TMT-induced epileptic seizures and neurodegeneration. Therefore, R. tanguticum root is a promising herbal treatment option for antiepileptic and neuroprotective applications. [ABSTRACT FROM AUTHOR]

Objectives: The majority of neuromyelitis optica spectrum disorders (NMOSD) patients are seropositive for aquaporin-4 (AQP4)-specific antibodies [also named neuromyelitis optica immunoglobulin G antibodies (NMO-IgG)]. Although NMO-IgG can induce pathological changes in the central nervous system (CNS), the immunological changes in the CNS and peripheral tissue remain largely unknown. We investigated whether NMO-IgG binds to tissue expressing AQP4 and induces immunological changes in the peripheral tissue and CNS. Methods: C57BL/6 female mice were assigned into an NMOSD or control group. Pathological and immunological changes in peripheral tissue and CNS were measured by immunostaining and flow cytometry, respectively. Motor impairment was measured by open-field test. Results: We found that NMO-IgG did bind to astrocyte- and AQP4-expressing peripheral tissue, but induced glial fibrillary acidic protein and AQP4 loss only in the CNS. NMO-IgG induced the activation of microglia and modulated microglia polarization toward the classical (M1) phenotype, but did not affect innate or adaptive immune cells in the peripheral immune system, such as macrophages, neutrophils, Th17/Th1, or IL-10-producing B cells. In addition, NMOSD mice showed significantly less total distance traveled and higher immobility time in the open field. Conclusions: We found that injection of human NMO-IgG led to astrocytopathic lesions with microglial activation in the CNS. However, there were no significant pathological or immunological changes in the peripheral tissues. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Blood tests have the potential to improve the accuracy of Alzheimer's disease (AD) clinical diagnosis, which will enable greater access to AD‐specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD‐related outcomes. METHODS: Plasma samples from the Alzheimer's Disease Neuroimaging Initiative were assayed with AD blood tests from C2N Diagnostics, Fujirebio Diagnostics, ALZPath, Janssen, Roche Diagnostics, and Quanterix. Outcomes measures were amyloid positron emission tomography (PET), tau PET, cortical thickness, and dementia severity. Logistic regression models assessed the classification accuracies of individual or combined plasma biomarkers for binarized outcomes, and Spearman correlations evaluated continuous relationships between individual plasma biomarkers and continuous outcomes. RESULTS: Measures of plasma p‐tau217, either individually or in combination with other plasma biomarkers, had the strongest relationships with all AD outcomes. DISCUSSION: This study identified the plasma biomarker analytes and assays that most accurately classified amyloid pathology and other AD‐related outcomes. Highlights: Plasma p‐tau217 measures most accurately classified amyloid and tau status.Plasma Aβ42/Aβ40 had relatively low accuracy in classification of amyloid status.Plasma p‐tau217 measures had higher correlations with cortical thickness than NfL.Correlations of plasma biomarkers with dementia symptoms were relatively low. [ABSTRACT FROM AUTHOR]

Neuromuscular and vascular hamartoma (NMVH) is an infrequent gastrointestinal lesion described in human and veterinary medical literature. The histologic features of this entity are haphazardly arranged fascicles of smooth muscle, nerve fibers, scattered ganglion cells, and hemangiomatous blood vessels. Here we describe 2 putative cases of NMVH in a 1.7-y-old, intact female Anatolian mixed-breed dog and a 4-mo-old intact male Akita dog. Both animals had gastrointestinal clinical signs, including hematochezia, and on exploratory laparotomy, intussusception was confirmed. Histologic examination confirmed NMVH within the cecal wall in both cases using a panel of immunohistochemical (IHC) markers for vascular structures (CD31), smooth muscle (alpha–smooth muscle actin [α-SMA]), and nerves (glial fibrillary acidic protein [GFAP] and S100). The complete surgical excision of the lesion in both animals was considered curative without persistent clinical signs 14 mo and 12 mo, respectively, after surgery. [ABSTRACT FROM AUTHOR]

A growing number of studies link dysfunction of macroautophagy/autophagy to the pathogenesis of diseases such as Alzheimer disease (AD). Given the global importance of autophagy for homeostasis, how its dysfunction can lead to specific neurological changes is puzzling. To examine this further, we compared the global deactivation of autophagy in the adult mouse using the atg7iKO with the impact of AD-associated pathogenic changes in autophagic processing of synaptic proteins. Isolated forebrain synaptosomes, rather than total homogenates, from atg7iKO mice demonstrated accumulation of synaptic proteins, suggesting that the synapse might be a vulnerable site for protein homeostasis disruption. Moreover, the deactivation of autophagy resulted in impaired cognitive performance over time, whereas gross locomotor skills remained intact. Despite deactivation of autophagy for 6.5 weeks, changes in cognition were in the absence of cell death or synapse loss. In the symptomatic APP PSEN1 double-transgenic mouse model of AD, we found that the impairment in autophagosome maturation coupled with diminished presence of discrete synaptic proteins in autophagosomes isolated from these mice, leading to the accumulation of one of these proteins in the detergent insoluble protein fraction. This protein, SLC17A7/Vglut, also accumulated in atg7iKO mouse synaptosomes. Taken together, we conclude that synaptic autophagy plays a role in maintaining protein homeostasis, and that while decreasing autophagy interrupts normal cognitive function, the preservation of locomotion suggests that not all circuits are affected similarly. Our data suggest that the disruption of autophagic activity in AD may have relevance for the cognitive impairment in this adult-onset neurodegenerative disease. Abbreviations: 2dRAWM: 2-day radial arm water maze; AD: Alzheimer disease; Aβ: amyloid-beta; AIF1/Iba1: allograft inflammatory factor 1; APP: amyloid beta precursor protein; ATG7: autophagy related 7; AV: autophagic vacuole; CCV: cargo capture value; Ctrl: control; DLG4/PSD-95: discs large MAGUK scaffold protein 4; GFAP: glial fibrillary acidic protein; GRIN2B/NMDAR2b: glutamate ionotropic receptor NMDA type subunit 2B; LTD: long-term depression; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; m/o: months-old; PNS: post-nuclear supernatant; PSEN1/PS1: presenilin 1; SHB: sucrose homogenization buffer; SLC32A1/Vgat: solute carrier family 32 member 1; SLC17A7/Vglut1: solute carrier family 17 member 7; SNAP25: synaptosome associated protein 25; SQSTM1/p62: sequestosome 1; SYN1: synapsin I; SYP: synaptophysin ; SYT1: synaptotagmin 1; Tam: tamoxifen; VAMP2: vesicle associated membrane protein 2; VCL: vinculin; wks: weeks. [ABSTRACT FROM AUTHOR]

Introduction: The pathophysiological mechanism of Alzheimer’s disease (AD) has not been clearly identified, and effective treatment methods have not yet been established. Scopolamine causes cholinergic dysfunction in the brain, including the accumulation of amyloid-beta plaques, thereby increasing oxidative stress and neuroinflammation, mimicking AD. Glial cells such as astrocytes have recently been identified as possible biomarkers for AD. Photobiomodulation (PBM) elicits a beneficial biological response in cells and tissues. PBM effects on the central nervous system (CNS) have been widely researched, including effects on astrocyte activity. Methods: In the present study, PBM was performed using light at the nearinfrared wavelength of 825 nm. The Morris water maze and Y-maze tests were employed to evaluate cognitive function decline in a scopolamineinduced memory dysfunction model and its improvement with PBM. In addition, alteration of the mitogen-activated protein kinase (MAPK) pathway and immunofluorescence expression levels of active astrocytes were observed in the hippocampus, which is one of the areas affected by AD, to evaluate the mechanism of action of PBM. Results: A reduction in the neuronal cell death in the hippocampus caused by scopolamine was observed with PBM. Moreover, alteration of a MAPK pathwayrelated marker and changes in glial fibrillary acidic protein (an active astrocyte marker) expression were observed in the PBM-treated group. Finally, significant correlations between functional and histological results were found, validating the results. Discussion: These findings indicate the possibility of behavioral and histological improvement due to PBM in scopolamine-induced CNS alteration, which mimics AD. This improvement could be related to neuroinflammatory modulation and altered astrocyte activity. [ABSTRACT FROM AUTHOR]

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a rare autoimmune disease, which is characterized by the immune system attacking astrocytes in the central nervous system, resulting in inflammation and damage to the nervous system. We reported a 41-year-old female patient with only drowsiness for 3 months, who was, otherwise, healthy with no other signs of meningoencephalitis or myelitis. There were no obvious abnormalities in her neurological and ophthalmic tests. Brain magnetic resonance imaging (MRI) plain scan + enhancement with the gadolinium contrast agent revealed patchy hypointensity on T1-weighted imaging, hyperintensity on T2-weighted imaging, hyperintensity on T2-weighted fluid-attenuated inversion recovery in the left basal ganglia, corona radiata, and local septum pellucida, with no enhancement in the enhanced lesions. Cerebrospinal fluid (CSF) revealed white blood cell count of 5.00 × 106/L, CSF protein of 828.53 mg/L, and glucose of 2.83 mmol/L. Aquaporin-4 (AQP4) antibody, N-methyl-D-aspartate receptor (NMDAR) antibody and GFAP antibody were all positive, whereas the remaining autoimmune encephalitis antibody tests were negative. Oncology screening [including head, chest, and whole-abdomen (involving the pelvic cavity) CT and tumor markers] did not reveal any obvious evidence of tumor presence. The patient received systemic treatment with high-dose intravenous injection of steroids combined with immunosuppressive agents, and the clinical and imaging features of the patients improved. To the best of our knowledge, reports on overlapping positivity of AQP4 antibody and NMDAR antibody in patients with GFAP astrocytopathy were still very rare. We hope to supplement the existing literature on this topic, review the relevant literature, and strive to increase the understanding toward GFAP astrocytopathy with overlapping autoimmune syndrome so as to enable early diagnosis and early treatment and to improve the clinical outcome of patients. [ABSTRACT FROM AUTHOR]

The neurotoxicant trimethyltin (TMT) triggers cognitive impairment and hippocampal neurodegeneration. TMT is a useful research tool for the study of Alzheimer's disease (AD) pathogenesis and treatment. Although the antidiabetic agent metformin has shown promising neuroprotective effects, however, its precise modes of action in neurodegenerative disorders need to be further elucidated. In this study, we investigated whether metformin can mitigate TMT cognition impairment and hippocampal neurodegeneration. To induce an AD-like phenotype, TMT was injected i.p. (8 mg/kg) and metformin was administered daily p.o. for 3 weeks at 200 mg/kg. Our results showed that metformin administration to the TMT group mitigated learning and memory impairment in Barnes maze, novel object recognition (NOR) task, and Y maze, attenuated hippocampal oxidative, inflammatory, and cell death/pyroptotic factors, and also reversed neurodegeneration-related proteins such as presenilin 1 and p-Tau. Hippocampal level of AMP-activated protein kinase (AMPK) as a key regulator of energy homeostasis was also improved following metformin treatment. Additionally, metformin reduced hippocampal acetylcholinesterase (AChE) activity, glial fibrillary acidic protein (GFAP)-positive reactivity, and prevented the loss of CA1 pyramidal neurons. This study showed that metformin mitigated TMT-induced neurodegeneration and this may pave the way to develop new therapeutics to combat against cognitive deficits under neurotoxic conditions. [ABSTRACT FROM AUTHOR]

Mutations in the human granulin (GRN) gene are associated with multiple diseases, including dementia disorders such as frontotemporal dementia (FTD) and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). We studied a Grn knockout (Grn‐KO) mouse model in order to evaluate a potential therapeutic strategy for these diseases using nicorandil, a commercially available agonist for the ABCC9/Abcc9‐encoded regulatory subunit of the “K+ATP” channel that is well‐tolerated in humans. Aged (13 months) Grn‐KO and wild‐type (WT) mice were treated as controls or with nicorandil (15 mg/kg/day) in drinking water for 7 months, then tested for neurobehavioral performance, neuropathology, and gene expression. Mortality was significantly higher for aged Grn‐KO mice (particularly females), but there was a conspicuous improvement in survival for both sexes treated with nicorandil. Grn‐KO mice performed worse on some cognitive tests than WT mice, but Morris Water Maze performance was improved with nicorandil treatment. Neuropathologically, Grn‐KO mice had significantly increased levels of glial fibrillary acidic protein (GFAP)‐immunoreactive astrocytosis but not ionized calcium binding adaptor molecule 1 (IBA‐1)‐immunoreactive microgliosis, indicating cell‐specific inflammation in the brain. Expression of several astrocyte‐enriched genes, including Gfap, were also elevated in the Grn‐KO brain. Nicorandil treatment was associated with a subtle shift in a subset of detected brain transcript levels, mostly related to attenuated inflammatory markers. Nicorandil treatment improved survival outcomes, cognition, and inflammation in aged Grn‐KO mice. [ABSTRACT FROM AUTHOR]

Postmortem human brain tissue is a critical resource for studying neurodegenerative disease, providing critical insights into cellular morphology, pathology, and network connectivity. To improve standard microscopy and enable high-resolution, threedimensional (3D) images of tissues at the subcellular level, tissue-clearing methods have been developed. These 3D images allow for the analysis of large regions of interest and can be used to study structural and spatial changes that occur during neurodegeneration. Additionally, 3D imaging facilitates the visualization of whole-cell morphology, especially in cells with long processes that would otherwise be truncated in single-plane images. Human brain tissue is especially challenging for tissue clearing due to the abundance of lipids in myelin and the need for optimal fixation and low postmortem intervals. Formaldehydebased fixatives, commonly used in preserving tissue, hinder antibody binding by crosslinking important antibody epitopes, and fluorescent microscopy requires the incorporation of fluorescent labels through passive diffusion or electrophoresis. Recent studies have focused on optimally fixed human brain tissue with short postmortem intervals, limiting the general applicability of these methods. To address these challenges, we developed SHARD (SHIELD, antigen retrieval, and delipidation), a simple and widely applicable method for clearing and labeling human brain tissue, which can be applied to long-term banked human brain tissue preserved in formaldehyde. SHARD is a novel addition to the SHIELD tissue clarification method, combining antigen retrieval, tissue clearing, and staining of 200-μm sections from long-term banked human brain tissue. The SHARD method is effective for postmortem intervals (PMIs) ranging from 10 to 72 h in multiple neurodegenerative diseases and control samples. In this study, we demonstrate that the SHARD method significantly enhances the immunostaining of glial fibrillary acidic protein (GFAP), an astrocytic cytoskeletal marker. Overall, the combination of antigen retrieval and tissue delipidation holds great potential for achieving detailed 3D immunostaining in long-term formaldehyde-fixed postmortem human brain tissue, opening new avenues for research and discovery. [ABSTRACT FROM AUTHOR]

Petunidin-3-O-(trans-p-coumaroylrutinoside)-5-O-glucoside (PtCG), the primary anthocyanin ingredient in Lycium ruthenicum Murr., possesses a range of biological activities, including antioxidative properties and melanin inhibition. This study aimed to investigate the protective effect of PtCG on D-galactose (D-gal)-induced aging in female mice and elucidate the underlying molecular pathways. Behavioral experiments, including the MWW and Y-maze tests, revealed that PtCG significantly ameliorated cognitive decline and enhanced learning and memory abilities in aging mice. Regarding biochemical indicators, PtCG considerably improved superoxide dismutase (SOD) and glutathione (GSH) activity while reducing malondialdehyde (MDA) and acetylcholinesterase (AChE) levels in the hippocampus and serum. Furthermore, PtCG ingestion alleviated liver injury by decreasing alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (AKP) levels, and attenuated renal damage by reducing blood urea nitrogen (BUN) and uric acid (UA) levels. Transmission electron microscopy (TEM) results demonstrated that PtCG restored the function and quantity of synapses in the hippocampus. Hematoxylin and eosin (H&E), Masson's trichrome, and Nissl staining revealed that PtCG significantly improved the relevant pathological characteristics of liver and hippocampal tissues in aging mice. The molecular mechanism investigation showed that PtCG downregulated the protein expression of microglial marker ionized calcium-binding adapter molecule 1 (Iba1), astrocytic marker glial fibrillary acidic protein (GFAP), β-secretase 1 (BACE-1), and amyloid-beta1–42 (Aβ1–42) in the hippocampus of aging mice. The protein expression of inflammatory pathway components, including nuclear factor-kappa B (NF-κB), cyclooxygenase-2 (COX2), inducible nitric oxide synthase (iNOS), and interleukin-1 beta (IL-1β), was also suppressed. These findings suggest that PtCG may possess anti-aging properties, with its mechanism of action potentially linked to the attenuation of neuroinflammation, oxidative stress, and liver and kidney damage. PtCG may have future applications as a functional food for the treatment of aging-related disorders. [ABSTRACT FROM AUTHOR]

Environmental noise is associated with various health outcomes. However, the mechanisms through which these outcomes influence behavior and metabolism remain unclear. This study investigated how environmental noise affects the liver, adipose tissue, and brain metabolic functions, leading to behavioral and body weight changes. Mice were divided into a noise group exposed to construction noise and an unexposed (control) group. Behavior and body weight changes were monitored over 50 days. Early changes in response to noise exposure were assessed by measuring plasma cortisol and glial fibrillary acidic protein expression in brain tissues on days 1, 15, and 30. Chronic responses, including changes in lipoprotein and fat metabolism and neurotransmitters, were investigated by analyzing serum lipoprotein levels and body fat mass and evaluating liver, fat, and brain tissue after 50 days. The noise group showed higher locomotor activity and reduced anxiety in the open-field and Y-maze tests. Noise exposure caused an initial weight loss; however, chronic noise increased fat mass and induced adipocyte hypertrophy. Our findings underscore the role of environmental noise-induced stress in augmenting locomotor activity and reducing anxiety in mice through neurotransmitter modulation while increasing the risk of obesity by decreasing HDL cholesterol levels and promoting adipocyte hypertrophy. [ABSTRACT FROM AUTHOR]

Key Points: Question: What is the association of plasma biomarker (amyloid-β 42 to amyloid-β 40 [Aβ42:Aβ40] ratio, phosphorylated tau at threonine [p-tau181], neurofilament light [NfL], glial fibrillary acid protein [GFAP]) changes from midlife to late life with all-cause dementia? Findings: In this retrospective analysis of prospectively collected plasma biomarkers from 1525 adults from the Atherosclerosis Risk in Communities study, only Alzheimer disease (AD)–specific (Aβ42:Aβ40, p-Tau181) biomarkers in midlife demonstrated significant long-term associations with late-life dementia. In late life, each of the biomarkers and their change from midlife were significantly associated with incident all-cause dementia. Meaning: AD-specific biomarkers' association with dementia starts in midlife whereas late-life measures of AD, neuronal injury, and astrogliosis biomarkers are all associated with dementia. Importance: Plasma biomarkers show promise for identifying Alzheimer disease (AD) neuropathology and neurodegeneration, but additional examination among diverse populations and throughout the life course is needed. Objective: To assess temporal plasma biomarker changes and their association with all-cause dementia, overall and among subgroups of community-dwelling adults. Design, Setting, and Participants: In 1525 participants from the US-based Atherosclerosis Risk in Communities (ARIC) study, plasma biomarkers were measured using stored specimens collected in midlife (1993-1995, mean age 58.3 years) and late life (2011-2013, mean age 76.0 years; followed up to 2016-2019, mean age 80.7 years). Midlife risk factors (hypertension, diabetes, lipids, coronary heart disease, cigarette use, and physical activity) were assessed for their associations with change in plasma biomarkers over time. The associations of biomarkers with incident all-cause dementia were evaluated in a subpopulation (n = 1339) who were dementia-free in 2011-2013 and had biomarker measurements in 1993-1995 and 2011-2013. Exposure: Plasma biomarkers of amyloid-β 42 to amyloid-β 40 (Aβ42:Aβ40) ratio, phosphorylated tau at threonine 181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured using the Quanterix Simoa platform. Main Outcomes and Measures: Incident all-cause dementia was ascertained from January 1, 2012, through December 31, 2019, from neuropsychological assessments, semiannual participant or informant contact, and medical record surveillance. Results: Among 1525 participants (mean age, 58.3 [SD, 5.1] years), 914 participants (59.9%) were women, and 394 participants (25.8%) were Black. A total of 252 participants (16.5%) developed dementia. Decreasing Aβ42:Aβ40 ratio and increasing p-tau181, NfL, and GFAP were observed from midlife to late life, with more rapid biomarker changes among participants carrying the apolipoprotein E epsilon 4 (APOEε4) allele. Midlife hypertension was associated with a 0.15-SD faster NfL increase and a 0.08-SD faster GFAP increase per decade; estimates for midlife diabetes were a 0.11-SD faster for NfL and 0.15-SD faster for GFAP. Only AD-specific biomarkers in midlife demonstrated long-term associations with late-life dementia (hazard ratio per SD lower Aβ42:Aβ40 ratio, 1.11; 95% CI, 1.02-1.21; per SD higher p-tau181, 1.15; 95% CI, 1.06-1.25). All plasma biomarkers in late life had statistically significant associations with late-life dementia, with NfL demonstrating the largest association (1.92; 95% CI, 1.72-2.14). Conclusions and Relevance: Plasma biomarkers of AD neuropathology, neuronal injury, and astrogliosis increase with age and are associated with known dementia risk factors. AD-specific biomarkers' association with dementia starts in midlife whereas late-life measures of AD, neuronal injury, and astrogliosis biomarkers are all associated with dementia. This cohort study characterizes temporal changes in plasma biomarkers, identifies factors associated with changes in plasma biomarkers over time, and evaluates the prospective associations of plasma biomarkers with late-life all-cause dementia. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation To investigate the longitudinal dynamics of serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) levels in people with multiple sclerosis (pwMS) under B‐cell depleting therapy (BCDT) and their capacity to prognosticate future progression independent of relapse activity (PIRA) events.A total of 362 pwMS (1,480 samples) starting BCDT in the Swiss Multiple Sclerosis (MS) Cohort were included. sGFAP levels in 2,861 control persons (4,943 samples) provided normative data to calculate adjusted Z scores.Elevated sGFAP levels (Z score >1) at 1 year were associated with a higher hazard for PIRA (hazard ratio [HR]: 1.80 [95% CI: 1.17–2.78]; p = 0.0079) than elevated sNfL levels (HR, 1.45 [0.95–2.24], p = 0.0886) in a combined model. Independent of PIRA events, sGFAP levels longitudinally increased by 0.49 Z score units per 10 years follow‐up (estimate, 0.49 [0.29, 0.69], p < 0.0001). In patients experiencing PIRA, sGFAP Z scores were 0.52 Z score units higher versus stable patients (0.52 [0.22, 0.83], p = 0.0009). Different sNfL Z score trajectories were found in pwMS with versus without PIRA (interaction p = 0.0028), with an average decrease of 0.92 Z score units per 10 years observed without PIRA (−0.92 [−1.23, −0.60], p < 0.0001), whereas levels in patients with PIRA remained high.Elevated sGFAP and lack of drop in sNfL after BCDT start are associated with increased risk of future PIRA. These findings provide a rationale for combined monitoring of sNfL and sGFAP in pwMS starting BCDT to predict the risk of PIRA, and to use sGFAP as an outcome in clinical trials aiming to impact on MS progressive disease biology. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Background and purpose: Among patients with solid tumors, those with breast cancer (BC) experience the most severe psychological issues, exhibiting a high global prevalence of depression that negatively impacts prognosis. Depression can be easily missed, and clinical markers for its diagnosis are lacking. Therefore, this study in order to investigate the diagnostic markers for BC patients with depression and anxiety and explore the specific changes of metabolism. Method and results: Thirty-eight BC patients and thirty-six matched healthy controls were included in the study. The anxiety and depression symptoms of the participants were evaluated by the 17-item Hamilton Depression Scale (HAMD-17) and Hamilton Anxiety Scale (HAMA). Plasma levels of glial fibrillary acidic protein (GFAP) and lipocalin-2 (LCN2) were evaluated using enzyme linked immunosorbent assay, and plasma lactate levels and metabolic characteristics were analyzed. Conclusion: This study revealed that GFAP and LCN2 may be good diagnostic markers for anxiety or depression in patients with BC and that plasma lactate levels are also a good diagnostic marker for anxiety. In addition, specific changes in metabolism in patients with BC were preliminarily explored. [ABSTRACT FROM AUTHOR]

Mild traumatic brain injury (mTBI) is a common consequence of head injury but there are no recognized interventions to promote recovery of the brain. We previously showed that photobiomodulation (PBM) significantly reduced the number of apoptotic cells in adult rat hippocampal organotypic slice cultures. In this study, we first optimized PBM delivery parameters for use in mTBI, conducting cadaveric studies to calibrate 660 and 810 nm lasers for transcutaneous delivery of PBM to the cortical surface. We then used an in vivo weight drop mTBI model in adult rats and delivered daily optimized doses of 660, 810 nm, or combined 660/810 nm PBM. Functional recovery was assessed using novel object recognition (NOR) and beam balance tests, whilst histology and immunohistochemistry were used to assess the mTBI neuropathology. We found that PBM at 810, 660 nm, or 810/660 nm all significantly improved both NOR and beam balance performance, with 810 nm PBM having the greatest effects. Histology demonstrated no overt structural damage in the brain after mTBI, however, immunohistochemistry using brain sections showed significantly reduced activation of both CD11b+ microglia and glial fibrillary acidic protein (GFAP)+ astrocytes at 3 days post‐injury. Significantly reduced cortical localization of the apoptosis marker, cleaved caspase‐3, and modest reductions in extracellular matrix deposition after PBM treatment, limited to choroid plexus and periventricular areas were also observed. Our results demonstrate that 810 nm PBM optimally improved functional outcomes after mTBI, reduced markers associated with apoptosis and astrocyte/microglial activation, and thus may be useful as a potential regenerative therapy. [ABSTRACT FROM AUTHOR]

Transmembrane protein 184b (Tmem184b) has been implicated in axon degeneration and neuromuscular junction dysfunction. Notably, Tmem184b exhibits high expression levels in the retina; however, its specific function within this tissue remains poorly understood. To elucidate the role of Tmem184b in the mammalian visual system, we developed a Tmem184b knockout (KO) model for further investigation. Loss of Tmem184b led to significant decreases in both a and b wave amplitudes of scotopic electroretinogram (ERG) and reduced b wave amplitudes of photopic ERG, respectively, reflecting damage to both the photoreceptors and secondary neuronal cells of the retina. Histologic analyses showed a progressive retinal thinning accompanied by the significantly loss of retinal cells including cone, rod, bipolar, horizontal and retinal ganglion cells. The expression levels of photo‐transduction‐related proteins were down‐regulated in KO retina. TUNEL (terminal deoxynucleotidyl transferase‐mediated biotinylated Uridine‐5'‐triphosphate [UTP] nick end labelling) and glial fibrillary acidic protein (GFAP)‐labelling results suggested the increased cell death and inflammation in the KO mice. RNA‐sequencing analysis and GO enrichment analysis revealed that Tmem184b deletion resulted in down‐regulated genes involved in various biological processes such as visual perception, response to hypoxia, regulation of transmembrane transporter activity. Taken together, our study revealed essential roles of Tmem184b in the mammalian retina and confirmed the underlying mechanisms including cell death, inflammation and hypoxia pathway in the absence of Tmem184b, providing a potential target for therapeutic and diagnostic development. [ABSTRACT FROM AUTHOR]