Glial Fibrillary Acidic Protein Levels Research Articles

Lestaurtinib (CEP-701) reduces the duration of limbic status epilepticus in periadolescent rats

BackgroundThe timely abortion of status epilepticus (SE) is essential to avoid brain damage and long-term neurodevelopmental sequalae. However, available anti-seizure treatments fail to abort SE in 30% of children. Given the role of the tropomyosin-related kinase B (TrkB) receptor in hyperexcitability, we investigated if TrkB blockade with lestaurtinib (CEP-701) enhances the response of SE to a standard treatment protocol and reduces SE-related brain injury. MethodsSE was induced with intra-amygdalar kainic acid in postnatal day 45 rats under continuous electroencephalogram (EEG). Fifteen min post-SE onset, rats received intraperitoneal (i.p.) CEP-701 (KCEP group) or its vehicle (KV group). Controls received CEP-701 or its vehicle following intra-amygdalar saline. All groups received two i.p. doses of diazepam, followed by i.p. levetiracetam at 15 min intervals post-SE onset. Hippocampal TrkB dimer to monomer ratios were assessed by immunoblot 24 hr post-SE, along with neuronal densities and glial fibrillary acid protein (GFAP) levels. ResultsSE duration was 50% shorter in the KCEP group compared to KV (p < 0.05). Compared to controls, SE induced a 1.5-fold increase in TrkB dimerization in KV rats (p < 0.05), but not in KCEP rats which were comparable to controls (p > 0.05). The KCEP group had lower GFAP levels than KV (p < 0.05), and both were higher than controls (p < 0.05). KCEP and KV rats had comparable hippocampal neuronal densities (p > 0.05), and both were lower than controls (p < 0.05). ConclusionsGiven its established human safety, CEP-701 is a promising adjuvant drug for the timely abortion of SE and the attenuation of SE-related brain injury.

Bloodletting Acupuncture at Jing-Well Points on Hand Induced Autophagy to Alleviate Brain Injury in Acute Altitude Hypoxic Rats by Activating PINK1/Parkin Pathway.

To explore the protective effect of bloodletting acupuncture at twelve Jing-well points on hand (BAJP) on acute hypobaric hypoxia (AHH)-induced brain injury in rats and its possible mechanisms. Seventy-five Sprague Dawley rats were divided into 5 groups by a random number table (n=15), including control, model, BAJP, BAJP+3-methyladenine (3-MA), and bloodletting acupuncture at non-acupoint (BANA, tail tip blooding) groups. After 7-day pre-treatment, AHH models were established using hypobaric oxygen chambers. The levels of S100B, glial fibrillary acidic protein (GFAP), superoxide dismutase (SOD), and malondialdehyde (MDA) in serum were measured by enzyme-linked immunosorbent assay. Hematoxylin-eosin staining and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling method were used to assess hippocampal histopathology and apoptosis. Transmission electron microscopy assay was used to observe mitochondrial damage and autophagosomes in hippocampal tissues. Flow cytometry was used to detect mitochondrial membrane potential (MMP). The mitochondrial respiratory chain complexes I, III and IV activities and ATPase in hippocampal tissue were evaluated, respectively. Western blot analysis was used to detect the protein expressions of Beclin1, autophagy protein 5 (ATG5), microtubule-associated protein 1 light chain 3 beta (LC3B), phosphatase and tensin homolog induced kinase 1 (PINK1), and Parkin in hippocampal tissues. The mRNA expressions of Beclin1, ATG5 and LC3-II were analyzed by quantitative real-time polymerase chain reaction. BAJP treatment reduced hippocampal tissue injury and inhibited hippocampal cell apoptosis in AHH rats. BAJP reduced oxidative stress by decreasing S100B, GFAP and MDA levels and increasing SOD level in the serum of AHH rats (P<0.05 or P<0.01). Then, BAJP increased MMP, the mitochondrial respiratory chain complexes I, III and IV activities, and the mitochondrial ATPase activity in AHH rats (all P<0.01). BAJP improved mitochondrial swelling and increased the autophagosome number in hippocampal tissue of AHH rats. Moreover, BAJP treatment increased the protein and mRNA expressions of Beclin1 and ATG5 and LC3-II/LC3-I ratio in AHH rats (all P<0.01) and activated the PINK1/Parkin pathway (P<0.01). Finally, 3-MA attenuated the therapeutic effect of BAJP on AHH rats (P<0.05 or P<0.01). BAJP was an effective treatment for AHH-induced brain injury, and the mechanism might be through reducing hippocampal tissue injury via increasing the PINK1/Parkin pathway and enhancement of mitochondrial autophagy.

Association between serum neurofilament light chain levels and sleep disorders in patients with Parkinson’s disease

ObjectivesThis study aimed to investigate the levels of serum neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) in patients with Parkinson's disease (PD) and PD patients with sleep disorders (PD-SD), as well as the relationship between these proteins and sleep disorders in PD patients. MethodsA total of 96 PD patients and 38 healthy controls (HC) were included in this study, of which 70 PD patients experienced sleep disorders. Both motor symptoms and sleep conditions were assessed in all PD patients. The ultrasensitive single molecule array (SIMOA) technique was used to quantify NFL and GFAP in the serum. All data were statistically analyzed using SPSS 23.0. ResultsSerum NFL and GFAP levels were significantly higher in PD patients than in HC. Similarly, PD-SD patients exhibited higher levels of these two proteins than PD patients without sleep disorders (PD-NSD). In addition, both serum GFAP and NFL were significantly associated with sleep-related scales in PD patients. After covariate-adjusted binary logistic regression analysis, NFL remained statistically significant in PD patients with or without sleep disorders, unlike GFAP. ConclusionsOur findings substantiate that serum NFL and GFAP levels are elevated in PD and PD-SD, suggesting neurological axon damage in PD patients, which may be more severe in PD-SD than in PD-NSD. These findings may affect disease diagnosis and provide the foothold for future studies on the underlying mechanisms.

Blood-based biomarkers for Alzheimer’s disease: a multicenter-based cross-sectional and longitudinal study in China

Discrepancies in diagnostic biomarkers for Alzheimer’s Disease (AD) may arise from racial disparities, risk factors, or lifestyle differences. Moreover, there has been a lack of systematic and multicenter studies to evaluate baselines of the AD biomarkers in Chinese populations. Thus, there is an urgent need for research to investigate the effectiveness of blood biomarkers for AD, specifically in the Chinese Han population, using a multicenter approach. In the present multicenter-based cross-sectional and longitudinal study, we evaluated 817 blood samples from 6 different clinical centers. We measured plasma amyloid beta (Aβ)-40, Aβ42, phosphorylated tau 181 (pTau), total tau (tTau), serum neurofilament light (NFL), and glial fibrillary acidic protein (GFAP). Additionally, 18F-florbetapir positron electron tomography and magnetic resonance imaging were also performed. A combination of the APOE genotype with plasma pTau and serum GFAP demonstrated exceptional performance in distinguishing Aβ status. Furthermore, baseline GFAP levels exhibited a strong association with cognitive decline over time and brain atrophy, with higher GFAP levels predicting a faster rate of neurodegeneration. In summary, these results validate the practicality of blood biomarkers in the Chinese Han population, encompassing various regions within China. Additionally, they emphasize the potential of pTau and GFAP as non-invasive methods for detecting and screening AD at an early stage.

Metformin restores cognitive dysfunction and histopathological deficits in an animal model of sporadic Alzheimer's disease

BackgroundMetformin has been introduced as a neuroprotective agent in recent years. Here we evaluate the therapeutic effects of metformin in sporadic mouse model of Alzheimer's disease (SAD). MethodsAD was induced by streptozotocin (STZ, 0.5 mg/kg) on days 1 and 3. Metformin (MET, 200 mg/kg per day) was used for two weeks. Novel objective recognition (NOR) and Barnes Maze test were used to test the learning and memory. Nissl staining was used as s histological method for counting the dying neurons in different regions of hippocampus. Immunofluorescence staining against glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba1) and NeuN were used to visualize reactive astrocytes, microglia and neurons, respectively. ResultsIn NOR test, the discrimination indices in the STZ group were significantly lower than the control and treatment groups. Goal sector/non-goal sector (GS/NGS) ratio index in Barnes maze was increased in metformin group compared to other groups. The number of dying neurons was increased by SAD and metformin reduced it. GFAP level was increased in CA1, CA3 and cortex of STZ group and reversed following the treatment. Iba1 level was significantly higher in STZ group in CA3 and cortex regions compared to Control and decreased by metformin in CA3 and cortex. Counting NeuN+ cells demonstrated significant reduction of neurons in DG+CA1 and CA3 after SAD induction. SignificanceMetformin decreased inflammatory cells and reactive astrocytes as well as the dying neurons in the hippocampus region and the cortex in SAD, and improved the cognitive performance.

Low-Field Magnetic Stimulation Alleviates MPTP-Induced Alterations in Motor Function and Dopaminergic Neurons in Male Mice.

Recent studies show that repetitive transcranial magnetic stimulation (rTMS) improves cognitive and motor functions in patients with Parkinson's Disease (PD). Gamma rhythm low-field magnetic stimulation (LFMS) is a new non-invasive rTMS technique that generates diffused and low-intensity magnetic stimulation to the deep cortical and subcortical areas. To investigate the potential therapeutic effects of LFMS in PD, we subjected an experimental mouse model to LFMS (as an early treatment). We examined the LFMS effect on motor functions as well as neuronal and glial activities in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated male C57BL/6J mice. Mice received MPTP injection (30 mg/kg, i.p., once daily for 5 days) followed by LFMS treatment, 20 min each day for 7 days. LFMS treatment improved motor functions compared with the sham-treated MPTP mice. Further, LFMS significantly improved tyrosine hydroxylase (TH) and decreased glial fibrillary acidic protein (GFAP) levels in substantia nigra pars compacta (SNpc) and non-significantly in striatal (ST) regions. LFMS treatment improved neuronal nuclei (NeuN) levels in SNpc. Our findings suggest that early LFMS treatment improves neuronal survival and, in turn, motor functions in MPTP-treated mice. Further investigation is required to clearly define the molecular mechanisms by which LFMS improves motor and cognitive function in PD patients.

Serum glial fibrillary acidic protein and neurofilament light chain in treatment-naïve patients with unipolar depression

BackgroundUnipolar depression has been associated with increased levels of glial dysfunction and neurodegeneration biomarkers, such as Glial Fibrillary Acidic Protein (GFAP) and Neurofilament light chain (NfL). However, previous studies were conducted on patients taking psychotropic medication and did not monitor longitudinal associations between disease status and GFAP/NfL. MethodsTreatment-naïve patients with unipolar depression (n = 110) and healthy controls (n = 33) were included. GFAP/NfL serum levels were analyzed by Single Molecule Array at baseline and 3-month follow-up. The primary endpoint was GFAP/NfL levels in patients with depression compared with healthy controls. The secondary endpoint was the associations between GFAP/NfL with depression severity and cognitive function. ResultsThe patients' mean HAM-D17 score was 18.9 (SD 3.9) at baseline and improved by 7.9 (SD 6.8) points during follow-up. GFAP/NfL was quantified in all individuals. At baseline, the adjusted GFAP levels were −16.8 % (95 % CI: −28.8 to −1.9, p = 0.03) lower among patients with depression compared to healthy controls, while NfL levels were comparable between the groups (p = 0.57). In patients with depression, mean NfL levels increased from baseline to follow-up (0.68 pg/ml, p = 0.03), while GFAP levels were unchanged (p = 0.24). We did not find consistent associations between NfL/GFAP with depression scores or cognitive function. ConclusionThis largest study of serum NfL/GFAP levels in patients with depression did not support previous findings of elevated GFAP/NfL in patients with depression or positive associations with depression severity. Although limited by a small control group, our study may support the presence of glial dysfunction but not damage to neurons in depression.

The endothelin receptor antagonist macitentan ameliorates endothelin-mediated vasoconstriction and promotes the survival of retinal ganglion cells in rats.

Glaucoma is a chronic and progressive eye disease, commonly associated with elevated intraocular pressure (IOP) and characterized by optic nerve degeneration, cupping of the optic disc, and loss of retinal ganglion cells (RGCs). The pathological changes in glaucoma are triggered by multiple mechanisms and both mechanical effects and vascular factors are thought to contribute to the etiology of glaucoma. Various studies have shown that endothelin-1 (ET-1), a vasoactive peptide, acting through its G protein coupled receptors, ETA and ETB, plays a pathophysiologic role in glaucoma. However, the mechanisms by which ET-1 contribute to neurodegeneration remain to be completely understood. Our laboratory and others demonstrated that macitentan (MAC), a pan endothelin receptor antagonist, has neuroprotective effects in rodent models of IOP elevation. The current study aimed to determine if oral administration of a dual endothelin antagonist, macitentan, could promote neuroprotection in an acute model of intravitreal administration of ET-1. We demonstrate that vasoconstriction following the intravitreal administration of ET-1 was attenuated by dietary administration of the ETA/ETB dual receptor antagonist, macitentan (5 mg/kg body weight) in retired breeder Brown Norway rats. ET-1 intravitreal injection produced a 40% loss of RGCs, which was significantly lower in macitentan-treated rats. We also evaluated the expression levels of glial fibrillary acidic protein (GFAP) at 24 h and 7 days post intravitreal administration of ET-1 in Brown Norway rats as well as following ET-1 treatment in cultured human optic nerve head astrocytes. We observed that at the 24 h time point the expression levels of GFAP was upregulated (indicative of glial activation) following intravitreal ET-1 administration in both retina and optic nerve head regions. However, following macitentan administration for 7 days after intravitreal ET-1 administration, we observed an upregulation of GFAP expression, compared to untreated rats injected intravitreally with ET-1 alone. Macitentan treatment in ET-1 administered rats showed protection of RGC somas but was not able to preserve axonal integrity and functionality. The endothelin receptor antagonist, macitentan, has neuroprotective effects in the retinas of Brown Norway rats acting through different mechanisms, including enhancement of RGC survival and reduction of ET-1 mediated vasoconstriction.

Thermal cycling-hyperthermia ameliorates Aβ25-35-induced cognitive impairment in C57BL/6 mice

Despite continuation of some controversies, Alzheimer’s disease (AD), the most common cause of dementia nowadays, has been widely believed to derive mainly from excessive β-amyloid (Aβ) aggregation, that would increase reactive oxygen species (ROS) and induce neuroinflammation, leading to neuron loss and cognitive impairment. Existing drugs on Aβ have been ineffective or offer only temporary relief at best, due to blood–brain barrier or severe side effects. The study employed thermal cycling-hyperthermia (TC-HT) to ease the Aβ-induced cognitive impairments and compared its effect with continuous hyperthermia (HT) in vivo. It established an AD mice model via intracerebroventricular (i.c.v.) injection of Aβ25-35, proving that TC-HT is much more effective in alleviating its performance decline in Y-maze and novel object recognition (NOR) tests, in comparison with HT. In addition, TC-HT also exhibits a better performance in decreasing the hippocampal Aβ and β-secretase (BACE1) expressions as well as the neuroinflammation markers–ionized calcium-binding adapter molecule 1 (Iba-1) and glial fibrillary acidic protein (GFAP) levels. Furthermore, the study finds that TC-HT can elevate more protein expressions of insulin degrading enzyme (IDE) and antioxidative enzyme superoxide dismutase 2 (SOD2) than HT. In sum, the study proves the potential of TC-HT in AD treatment, which can be put into application with the use of focused ultrasound (FUS).

Tracking reactive astrocytes in autosomal dominant Alzheimer disease with plasma GFAP and multi‐modal PET imaging

AbstractBackgroundWe have proposed astrogliosis as a “first wave” of response to AD pathology with diverging longitudinal changes of reactive astrocytes and amyloid‐β positron emission tomography (PET) retention in pre‐symptomatic autosomal dominant AD (ADAD). It has been suggested that plasma glial fibrillary acidic protein (GFAP) could be a marker of neuroinflammation in AD brain, although this hypothesis remains unproven. We therefore compared plasma GFAP levels with 11C‐deprenyl (DED) with a multi‐modal PET design in ADAD mutation carriers (MC) and non‐carriers (NC).MethodTwenty‐three individuals from families with known ADAD mutations were included (MC = 9; NC = 14). All individuals underwent PET imaging with 11C‐DED, 11C‐PIB and 18F‐FDG, for assessing monoamine oxidase B as a marker of reactive astrocytes, amyloid‐beta deposition, and glucose metabolism, respectively. Plasma sampling was performed after a median of 3 (interquartile range 1.5‐5.5) months. GFAP levels were measured using single molecule array technology. Eleven individuals had follow‐up imaging investigations and plasma sampling after a median of 2.7 (interquartile range 2.5‐2.9) years.ResultPlasma GFAP levels and 11C‐PIB binding increased significantly from pre‐symptomatic to symptomatic stage while 11C‐DED binding and 18F‐FDG uptake significantly decreased towards estimated onset of clinical symptoms in MC. Cross‐sectionally, plasma GFAP showed negative correlations with [18F]FDG uptake in widespread cortical areas, in contrast to no correlations with 11C‐DED or 11C‐PIB binding. 11C‐DED binding showed a positive correlation with 18F‐FDG uptake. Across the follow‐up interval, plasma GFAP levels showed a four‐fold greater intraindividual variation relative to 11C‐DED binding variation (longitudinal Δ variance = 1.67 vs 0.39 z‐scores, respectively). When averaging plasma GFAP values and tracer binding across consecutive time points for the same individual, strong negative correlations were found between plasma GFAP and 11C‐DED binding and 18F‐FDG uptake, but no significant correlation was found between plasma GFAP levels and 11C‐PIB binding in MC.ConclusionDivergent plasma GFAP levels and PET 11C‐DED brain binding in pre‐symptomatic ADAD carriers may reflect different but associated underlying processes, including different types of reactive astrocytes. However, the levels of plasma GFAP show large intraindividual variation over time and the assessment of reactive astrocytes based solely on cross‐sectional plasma GFAP levels poses great challenges and warrants further investigations.

High plasma Glial Fibrillary Acidic Protein levels are associated with an increased risk of dementia and Alzheimer’s disease over a 13‐year follow‐up period: Results from a prospective population‐based cohort

AbstractBackgroundReactive astrogliosis, an activation state that includes morphological, metabolic and functional changes of astrocytes, occurs in neurodegenerative diseases, including Alzheimer’s disease (AD). Increased plasma levels of glial fibrillary acidic protein (GFAP), a reactive astrogliosis biomarker, have been recently reported in the preclinical and symptomatic stages of AD. However, very few works have investigated its ability to predict long‐term AD risk. This study aimed to investigate the association between plasma GFAP levels and future risk of dementia and AD.MethodWithin the Bordeaux‐3C prospective population‐based cohort, we quantified plasma GFAP levels using V‐PLEX immunoassay among 1068 non‐demented participants aged 69 years or over. Dementia was screened over a follow‐up of 13 years. Associations of baseline plasma GFAP levels with the risk of incident AD and dementia were investigated using Cox models adjusted for socio‐demographic characteristics, cardio‐vascular comorbidities and APOE4 status.ResultThe mean age of the participants was 77.6 years (std 4.7) and 64% were women. Median GFAP level was 239 pg/ml [IQR 192‐321]. During the follow‐up (median 8.8 years, up to 14.3 years), 281 dementias occurred, including 120 probable AD. In multivariate models, the middle and high tertiles of GFAP were associated with an increased risk of dementia (aHR = 1.8, 95%CI: 1.3 to 2.5 and aHR = 2.0, 95%CI: 1.5 to 2.8 respectively, compared to the lower tertile, global p‐value&lt;.0001). These risks were higher when considering only probable AD (aHR = 2.7, 95%CI: 1.5 to 4.7 and aHR = 3.0, 95%CI: 1.7 to 5.2 for the middle and high tertiles respectively, global p‐value 0.0004). The association was found regardless of the APOE4 status. There was no interaction with time meaning that baseline GFAP was associated with higher risk of AD at short as at long‐term.ConclusionThese results suggest that plasma GFAP levels are increased very early in the process of AD. GFAP could represent a useful means to identify people at high risk of AD for both an objective of prevention or to include them in clinical trials. The interest of such a marker, alone or in combination with other plasmatic biomarkers of AD, should be further studied.

Early neurofilament light and glial fibrillary acidic protein levels improve predictive models of multiple sclerosis outcomes.

Early risk-stratification in multiple sclerosis (MS) may impact treatment decisions. Current predictive models have identified that clinical and imaging characteristics of aggressive disease are associated with worse long-term outcomes. Serum biomarkers, neurofilament (sNfL) and glial fibrillary acidic protein (sGFAP), reflect subclinical disease activity through separate pathological processes and may contribute to predictive models of clinical and MRI outcomes. We conducted a retrospective analysis of the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB study), where patients with multiple sclerosis are seen every 6 months and undergo Expanded Disability Status Scale (EDSS) assessment, have annual brain MRI scans where volumetric analysis is conducted to calculate T2-lesion volume (T2LV) and brain parenchymal fraction (BPF), and donate a yearly blood sample for subsequent analysis. We included patients with newly diagnosed relapsing-remitting MS and serum samples obtained at baseline visit and 1-year follow-up (both within 3 years of onset), and were assessed at 10-year follow-up. We measured sNfL and sGFAP by single molecule array at baseline visit and at 1-year follow-up. A predictive clinical model was developed using age, sex, Expanded Disability Status Scale (EDSS), pyramidal signs, relapse rate, and spinal cord lesions at first visit. The main outcome was odds of developing of secondary progressive (SP)MS at year 10. Secondary outcomes included 10-year EDSS, brain T2LV and BPF. We compared the goodness-of-fit of the predictive clinical model with and without sNfL and sGFAP at baseline and 1-year follow-up, for each outcome by area under the receiver operating characteristic curve (AUC) or R-squared. A total 144 patients with median MS onset at age 37.4 years (interquartile range: 29.4-45.4), 64% female, were included. SPMS developed in 25 (17.4%) patients. The AUC for the predictive clinical model without biomarker data was 0.73, which improved to 0.77 when both sNfL and sGFAP were included in the model (P=0.021). In this model, higher baseline sGFAP associated with developing SPMS (OR=3.3 [95%CI:1.1,10.6], P=0.04). Adding 1-year follow-up biomarker levels further improved the model fit (AUC=0.79) but this change was not statistically significant (P=0.15). Adding baseline biomarker data also improved the R-squared of clinical models for 10-year EDSS from 0.24 to 0.28 (P=0.032), while additional 1-year follow-up levels did not. Baseline sGFAP was associated with 10-year EDSS (ß=0.58 [95%CI:0.00,1.16], P=0.05). For MRI outcomes, baseline biomarker levels improved R-squared for T2LV from 0.12 to 0.27 (P<0.001), and BPF from 0.15 to 0.20 (P=0.042). Adding 1-year follow-up biomarker data further improved T2LV to 0.33 (P=0.0065) and BPF to 0.23 (P=0.048). Baseline sNfL was associated with T2LV (ß=0.34 [95%CI:0.21,0.48], P<0.001) and 1-year follow-up sNfL with BPF (ß=-2.53% [95%CI:-4.18,-0.89], P=0.003). Early biomarker levels modestly improve predictive models containing clinical and MRI variables. Worse clinical outcomes, SPMS and EDSS, are associated with higher sGFAP levels and worse MRI outcomes, T2LV and BPF, are associated with higher sNfL levels. Prospective study implementing these predictive models into clinical practice are needed to determine if early biomarker levels meaningfully impact clinical practice.

The association between Alzheimer’s disease blood‐based biomarkers and cognitive impairment and probable dementia in Look AHEAD MIND

AbstractBackgroundThe effect of an intensive lifestyle intervention (ILI) on Alzheimer’s disease (AD) blood‐based biomarker levels and cognitive outcomes among individuals with type 2 diabetes (T2D) is unknown. We examined AD biomarkers and cognitive outcomes in the Look AHEAD Study.MethodParticipants aged 45‐76 years were randomized at baseline to a 10‐year ILI or a diabetes support and education (DSE) condition. Cognitive assessments at years 8‐18 included measures of attention, executive function, global function, and memory. Mild cognitive impairment (MCI) and probable dementia were adjudicated by an expert panel. Stored baseline and end‐of‐intervention plasma samples were analyzed with the Quanterix Simoa HD‐X Analyzer. Changes in Aβ42/Aβ40, ptau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were evaluated in relation to randomization status, demographic characteristics, and cognitive outcomes. Cognitive scores and biomarker levels were converted to z‐scores. Cognitive trajectories were evaluated using mixed models to account for repeated measures; logistic regression was used for a composite outcome of MCI/dementia. Models were adjusted for baseline characteristics (age, sex, education, race/ethnicity, body mass index (BMI), CVD history, hypertension, diabetes duration, eGFR), APOE‐ε4, randomization arm, time from randomization, and time between blood draw and cognitive testing.ResultThe mean age of 779 participants was 61.4 years; 56% = female, 22.8% = APOE ε4+, mean BMI = 34.8, baseline diabetes duration &gt;5 years = 57%, 16.7% Black, 12.5% Hispanic, 66.2% White, and 4.7% other racial and ethnic groups. There were no associations between the intervention and biomarker levels at baseline or biomarker change over time. Increases in NfL levels significantly predicted lower memory (‐0.04 ±0.01; p = 0.002), global cognition scores (‐0.05 ±0.02; p = 0.011), executive function (‐0.04 ±0.01; p = 0.01), as well as increased risk of MCI/probable dementia (odds ratio [OR] 1.10, 95% CI 1.02‐1.19). Increases in GFAP predicted lower memory (‐0.10 ±0.03; p = 0.0001), global cognition (‐0.09 ±0.03; p = 0.009), executive function scores (‐0.12 ±0.03; p&lt;0.0001), and increased risk of MCI/probable dementia (OR 1.24, 95% CI 1.09‐1.41).ConclusionThere was no association between the intervention and changes in biomarker levels. Increasing levels of NfL and GFAP over the ∼10 year period were associated with reduced cognitive performance and increased risk of MCI/probable dementia.

Melatonin reduces β-amyloid accumulation and improves short-term memory in streptozotocin-induced sporadic Alzheimer's disease model.

Melatonin is a hormone secreted by the pineal gland, it can be associated with circadian rhythms, aging and neuroprotection. Melatonin levels are decreased in sporadic Alzheimer's disease (sAD) patients, which suggests a relationship between the melatonergic system and sAD. Melatonin may reduce inflammation, oxidative stress, TAU protein hyperphosphorylation, and the formation of β-amyloid (Aβ) aggregates. Therefore, the objective of this work was to investigate the impact of treatment with 10mg/kg of melatonin (i.p) in the animal model of sAD induced by the intracerebroventricular (ICV) infusion of 3mg/kg of streptozotocin (STZ). ICV-STZ causes changes in the brain of rats similar to those found in patients with sAD. These changes include; progressive memory decline, the formation of neurofibrillary tangles, senile plaques, disturbances in glucose metabolism, insulin resistance and even reactive astrogliosis characterized by the upregulation of glucose levels and glial fibrillary acidic protein (GFAP). The results show that ICV-STZ caused short-term spatial memory impairment in rats after 30 days of STZ infusion without locomotor impairment which was evaluated on day 27 post-injury. Furthermore, we observed that a prolonged 30-day treatment with melatonin can improve the cognitive impairment of animals in the Y-maze test, but not in the object location test. Finally, we demonstrated that animals receiving ICV-STZ have high levels of Aβ and GFAP in the hippocampus and that treatment with melatonin reduces Aβ levels but does not reduce GFAP levels, concluding that melatonin may be useful to control the progression of amyloid pathology in the brain.

Association of microbiota‐derived products with astrogliosis and neurodegeneration in patients with Alzheimer’s Disease

AbstractBackgroundMicrobiota‐derived short chain fatty acids (SCFA) and liposaccharide (LPS) could modulate astrocyte and neuronal activity. Glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are markers of astroglial activation and neuronal damage, can be measured in blood samples and have been associated with Alzheimer’s disease (AD) pathology. The aim of the present study was to assess the association of SCFAs and LPS with GFAP and NfL in 13 amyloid‐β‐negative cognitively unimpaired individuals (CU), 38 patients with cognitive impairment and no brain amyloidosis (CI‐NAD) and 34 patients with cognitive impairment and amyloid‐β positivity (CI‐AD).MethodBlood levels of 4 SCFAs (acetate, propionate, valerate and butyrate) were measured by GC‐FID gaschromatography, LPS by ELISA, and GFAP and NfL by single‐molecule array technology.ResultPlasma valerate, LPS and GFAP concentrations were increased in CI‐AD compared with CI‐NAD and CU (p&lt;0.034), acetate was increased in CI‐AD as well as decreased in CI‐NAD as compared with CU (p&lt;0.018) and NfL was increased in both CI groups (p&lt;0.023). In the pooled group of CI‐AD and CU, there were significant associations between plasma LPS and valerate with higher GFAP and NfL (p&lt;0.032). Conversely, in the pooled group of CI‐NAD and CU, there were associations between plasma acetate with lower level of GFAP and NfL (p&lt;0.026).ConclusionValerate and LPS were associated with astrogliosis and neuronal damage only in patients with AD. These results suggest that microbiota‐derived molecules might be mediators along the gut‐brain axis and contribute to AD pathology by modulating microglial and neuronal activity.

Long-Term Capsaicin Administration Ameliorates the Dysfunction and Astrogliosis of the Brain in Aged Mice with Missing Maxillary Molars.

Tooth loss and decreased masticatory function reportedly affect cognitive function; tooth loss allegedly induces astrogliosis and aging of astrocytes in the hippocampus and hypothalamus, which is a response specific to the central nervous system owing to homeostasis in different brain regions. Capsaicin, a component of red peppers, has positive effects on brain disorders in mice. Decreased expression of transient receptor potential vanilloid 1, a receptor of capsaicin, is associated with the development of dementia. In this study, we investigated the effect of capsaicin administration in aged mice (C57BL/6N mice) with reduced masticatory function owing to the extraction of maxillary molars to investigate preventive/therapeutic methods for cognitive decline attributed to age-related masticatory function loss. The results demonstrated that mice with impaired masticatory function showed decreased motor and cognitive function at the behavioral level. At the genetic level, neuroinflammation, microglial activity, and astrogliosis, such as increased glial fibrillary acidic protein levels, were observed in the mouse brain. The mice with extracted molars fed on a diet containing capsaicin for 3 months demonstrated improved behavioral levels and astrogliosis, which suggest that capsaicin is useful in maintaining brain function in cases of poor oral function and prosthetic difficulties.

Serum neurofilament light chain levels at attack predict post-attack disability worsening and are mitigated by inebilizumab: analysis of four potential biomarkers in neuromyelitis optica spectrum disorder

ObjectiveTo investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum...

Changes and significance of serum ubiquitin carboxyl-terminal hydrolase L1 and glial fibrillary acidic protein in patients with glioma

Brain gliomas are malignant tumors with high postoperative recurrence rates. Early prediction of prognosis using specific indicators is of great significance. To assess changes in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) levels in patients with glioma pre-and postoperatively. Between June 2018 and June 2021, 91 patients with gliomas who underwent surgery at our hospital were enrolled in the glioma group. Sixty healthy volunteers were included in the control group. Serum UCH-L1 and GFAP levels were measured in peripheral blood collected from patients with glioma before and 3 d after surgery. UCH-L1 and GFAP levels in patients with glioma with different clinicopathological characteristics were compared before and after surgery. The patients were followed-up until February 2022. Postoperative glioma recurrence was recorded to determine the serum UCH-L1 and GFAP levels, which could assist in predicting postoperative glioma recurrence. UCH-L1 and GFAP levels in patients with glioma decreased significantly 3 d after surgery compared to those before therapy (P < 0.05). However, UCH-L1 and GFAP levels in the glioma group were significantly higher than those in the control group before and after surgery (P < 0.05). There were no statistically significant differences in preoperative serum UCH-L1 and GFAP levels among patients with glioma according to sex, age, pathological type, tumor location, or number of lesions (P > 0.05). Serum UCH-L1 and GFAP levels were significantly lower in the patients with WHO grade I-II tumors than in those with grade III-IV tumors (P < 0.05). Serum UCH-L1 and GFAP levels were lower in the patients with tumor diameter ≤ 5 cm than in those with diameter > 5 cm, in which the differences were statistically significant (P < 0.05). Glioma recurred in 22 patients. The preoperative and 3-d postoperative serum UCH-L1 and GFAP levels were significantly higher in the recurrence group than these in the non-recurrence group (P < 0.05). Receiver operating characteristic curves were plotted. The areas under the curves of preoperative serum UCH-L1 and GFAP levels for predicting postoperative glioma recurrence were 0.785 and 0.775, respectively. However, the efficacy of serum UCH-L1 and GFAP levels 3 d after surgery in predicting postoperative glioma recurrence was slightly lower compared with their preoperative levels. UCH-L1 and GFAP efficiently reflected the development and recurrence of gliomas and could be used as potential indicators for the recurrence and prognosis of glioma.

Glial suppression and post-traumatic stress disorder: A cross-sectional study of 1,520 world trade center responders

BackgroundChronically re-experiencing the memory of a traumatic event might cause a glial response. This study examined whether glial activation would be associated with PTSD in a study of responders present after the 9/11 World Trade Center attacks without comorbid cerebrovascular disease. MethodsPlasma was retrieved from 1,520 WTC responders and stored for a cross-sectional sample of responders of varying levels of exposure and PTSD. Plasma levels (pg/ml) of glial fibrillary acidic protein (GFAP) were assayed. Because stroke and other cerebrovascular diseases cause distributional shifts in GFAP levels, multivariable-adjusted finite mixture models analyzed GFAP distributions in responders with and without possible cerebrovascular disease. ResultsResponders were aged 56.3 years and primarily male; 11.07% (n = 154) had chronic PTSD. Older age was associated with increased GFAP, whereas higher body mass was associated with decreased GFAP. Multivariable-adjusted finite mixture models revealed that severe re-experiencing trauma from 9/11 was associated with lower GFAP (B = −0.558, p = 0.003). ConclusionThis study presents evidence of reduced plasma GFAP levels among WTC responders with PTSD. Results suggest re-experiencing traumatic events might cause glial suppression.

Circulating Brain Injury Biomarkers: A Novel Method for Quantification of the Impact on the Brain After Tumor Surgery.

Clinical methods to quantify brain injury related to neurosurgery are scarce. Circulating brain injury biomarkers have recently gained increased interest as new ultrasensitive measurement techniques have enabled quantification of brain injury through blood sampling. To establish the time profile of the increase in the circulating brain injury biomarkers glial fibrillary acidic protein (GFAP), tau, and neurofilament light (NfL) after glioma surgery and to explore possible relationships between these biomarkers and outcome regarding volume of ischemic injury identified with postoperative MRI and new neurological deficits. In this prospective study, 34 adult patients scheduled for glioma surgery were included. Plasma concentrations of brain injury biomarkers were measured the day before surgery, immediately after surgery, and on postoperative days 1, 3, 5, and 10. Circulating brain injury biomarkers displayed a postoperative increase in the levels of GFAP ( P < .001), tau ( P < .001), and NfL ( P < .001) on Day 1 and a later, even higher, peak of NFL at Day 10 ( P = .028). We found a correlation between the increased levels of GFAP, tau, and NfL on Day 1 after surgery and the volume of ischemic brain tissue on postoperative MRI. Patients with new neurological deficits after surgery had higher levels of GFAP and NfL on Day 1 compared with those without new neurological deficits. Measuring circulating brain injury biomarkers could be a useful method for quantification of the impact on the brain after tumor surgery or neurosurgery in general.