Serum Glial Fibrillary Acidic Protein Levels Research Articles

Serum Glial Fibrillary Acidic Protein and S100B Profiles in Severity and Outcome Assessment of Moderate and Severe Head Injury Patients in India

Abstract Background: Traumatic brain injury (TBI) is a significant global health issue, with India witnessing approximately 150,000 deaths and 50,000 TBI-related fatalities annually. Severity is classified as mild, moderate, or severe using the Glasgow Coma Scale (GCS). Imaging and blood biomarkers such as serum glial fibrillary acidic protein (GFAP) and S100B aid in diagnosis and outcome prediction, yet imaging facilities are scarce in India. This highlights the necessity for dependable biomarkers. GFAP indicates astroglial injury, while S100B suggests neuronal injury, both in TBI patients’ blood. However, their associations and utility in the Indian population require further exploration. Our study addresses this gap by examining serum GFAP and S100B levels in moderate and severe TBI patients, correlating them with radiological findings and clinical outcomes. Methodology: This prospective observational study was conducted in a tertiary care hospital on 212 patients (106 each for moderate and severely injured groups). Initial disease severity was assessed by GCS score. Outcome assessments were required of surgical intervention and mortality within 5 days. Results: S100B superseded GFAP in assessing disease severity. Receiver operating characteristic analysis showed that S100B was successful with 66% sensitivity and specificity for a cutoff value of 78.77 pg/ml. For early mortality prediction, sensitivity (S100B = 81%–87%, GFAP = 64.1%–78.6%), specificity (S100B = 60.2%–99.2%, GFAP = 54.5%–74.6%), and area under the curve-wise (S100B = 0.721–0.909, GFAP = 0.614–0.763) S100B model performed better than the GFAP model for all corresponding cutoffs (ranged S100B = 86.53–118.56 pg/ml, GFAP = 30.87–34.5 ng/ml). Conclusion: Taken together, our study provides strong evidence that S100B is a better marker of severity and outcome assessment than GFAP.

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

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

Serum Glial Fibrillary Acidic Protein as a Blood Biomarker in Relapsing Remitting Multiple Sclerosis Egyptian Patients

Abstract Background Multiple sclerosis (MS) is a neurodegenerative disease with various clinical subtypes. Glial fibrillary acidic protein (GFAP) is significantly elevated in the cerebrospinal fluid (CSF) of MS patients compared with that of healthy controls and serum concentrations have been shown to reflect CSF levels. Objectives The aim of this study was to evaluate serum levels of GFAP in relation to disease activity in relapsing-remitting MS patients and to compare them with those of healthy controls. Subjects and Methods This case-control study involved 45 RRMS patients; 21 in relapse and 24 in remission, and 45 healthy individuals as age- and sex-matched controls. Blood samples were taken from the patients at inpatient ward and outpatient clinic of Neurology Department of Ain Shams University hospitals and the serum levels of GFAP were determined using the enzyme-linked immunosorbent assay (ELISA) technique. Results Patients in relapse showed higher serum concentration of GFAP than that of patients in remission and this result was highly significantly different (p = 0.000). ROC curve of serum GFAP demonstrated at cut off point >200 pg/ml, it yielded a sensitivity of 76% being in relapse and specificity of 82%. Conclusion GFAP biomarker is an indicator of disease activity in RRMS patients and its serum level may correlate with the state of disease activity.

Moderate intensity aerobic exercise alleviates motor deficits in 6-OHDA lesioned rats and reduces serum levels of biomarkers of Parkinson's disease severity without recovery of striatal dopamine or tyrosine hydroxylase

Alleviation of motor impairment by aerobic exercise (AE) in Parkinson's disease (PD) patients points to activation of neurobiological mechanisms that may be targetable by therapeutic approaches. However, evidence for AE-related recovery of striatal dopamine (DA) signaling or tyrosine hydroxylase (TH) loss has been inconsistent in rodent studies. This ambiguity may be related to the timing of AE intervention in relation to the status of nigrostriatal neuron loss. Here, we replicated human PD at diagnosis by establishing motor impairment with >80% striatal DA and TH loss prior to initiating AE, and assessed its potential to alleviate motor decline and restore DA and TH loss. We also evaluated if serum levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), biomarkers of human PD severity, changed in response to AE. 6-hydroxydopamine (6-OHDA) was infused unilaterally into rat medial forebrain bundle to induce progressive nigrostriatal neuron loss over 28 days. Moderate intensity AE (3× per week, 40 min/session), began 8–10 days post-lesion following establishment of impaired forelimb use. Striatal tissue DA, TH protein and mRNA, and serum levels of NfL/GFAP were determined 3-wks after AE began. Despite severe striatal DA depletion at AE initiation, forelimb use deficits and hypokinesia onset were alleviated by AE, without recovery of striatal DA or TH protein loss, but reduced NfL and GFAP serum levels. This proof-of-concept study shows AE alleviates motor impairment when initiated with >80% striatal DA loss without obligate recovery of striatal DA or TH protein. Moreover, the AE-related reduction of NfL and GFAP serum levels may serve as objective blood-based biomarkers of AE efficacy.

Biomarkers of Neurobiologic Recovery in Adults With Sport-Related Concussion

ImportanceSport-related concussion (SRC), a form of mild traumatic brain injury, is a prevalent occurrence in collision sports. There are no well-established approaches for tracking neurobiologic recovery after SRC.ObjectiveTo examine the levels of serum glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) in Australian football athletes who experience SRC.Design, Setting, and ParticipantsA cohort study recruiting from April 10, 2021, to September 17, 2022, was conducted through the Victorian Amateur Football Association, Melbourne, Australia. Participants included adult Australian football players with or without SRC. Data analysis was performed from May 26, 2023, to March 27, 2024.ExposureSport-related concussion, defined as at least 1 observable sign and/or 2 or more symptoms.Main Outcomes and MeasuresPrimary outcomes were serum GFAP and NfL levels at 24 hours, and 1, 2, 4, 6, 8, 12, and 26 weeks. Secondary outcomes were symptoms, cognitive performance, and return to training times.ResultsEighty-one individuals with SRC (median age, 22.8 [IQR, 21.3-26.0] years; 89% male) and 56 control individuals (median age, 24.6 [IQR, 22.4-27.3] years; 96% male) completed a total of 945 of 1057 eligible testing sessions. Compared with control participants, those with SRC exhibited higher GFAP levels at 24 hours (mean difference [MD] in natural log, pg/mL, 0.66 [95% CI, 0.50-0.82]) and 4 weeks (MD, 0.17 [95% CI, 0.02-0.32]), and NfL from 1 to 12 weeks (1-week MD, 0.31 [95% CI, 0.12-0.51]; 2-week MD, 0.38 [95% CI, 0.19-0.58]; 4-week MD, 0.31 [95% CI, 0.12-0.51]; 6-week MD, 0.27 [95% CI, 0.07-0.47]; 8-week MD, 0.36 [95% CI, 0.15-0.56]; and 12-week MD, 0.25 [95% CI, 0.04-0.46]). Growth mixture modeling identified 2 GFAP subgroups: extreme prolonged (16%) and moderate transient (84%). For NfL, 3 subgroups were identified: extreme prolonged (7%), moderate prolonged (15%), and minimal or no change (78%). Individuals with SRC who reported loss of consciousness (LOC) (33% of SRC cases) had higher GFAP at 24 hours (MD, 1.01 [95% CI, 0.77-1.24]), 1 week (MD, 0.27 [95% CI, 0.06-0.49]), 2 weeks (MD, 0.21 [95% CI, 0.004-0.42]) and 4 weeks (MD, 0.34 [95% CI, 0.13-0.55]), and higher NfL from 1 week to 12 weeks (1-week MD, 0.73 [95% CI, 0.42-1.03]; 2-week MD, 0.91 [95% CI, 0.61-1.21]; 4-week MD, 0.90 [95% CI, 0.59-1.20]; 6-week MD, 0.81 [95% CI, 0.50-1.13]; 8-week MD, 0.73 [95% CI, 0.42-1.04]; and 12-week MD, 0.54 [95% CI, 0.22-0.85]) compared with SRC participants without LOC. Return to training times were longer in the GFAP extreme compared with moderate subgroup (incident rate ratio [IRR], 1.99 [95% CI, 1.69-2.34]; NfL extreme (IRR, 3.24 [95% CI, 2.63-3.97]) and moderate (IRR, 1.43 [95% CI, 1.18-1.72]) subgroups compared with the minimal subgroup, and for individuals with LOC compared with those without LOC (IRR, 1.65 [95% CI, 1.41-1.93]).Conclusions and RelevanceIn this cohort study, a subset of SRC cases, particularly those with LOC, showed heightened and prolonged increases in GFAP and NfL levels, that persisted for at least 4 weeks. These findings suggest that serial biomarker measurement could identify such cases, guiding return to play decisions based on neurobiologic recovery. While further investigation is warranted, the association between prolonged biomarker elevations and LOC may support the use of more conservative return to play timelines for athletes with this clinical feature.

The role of serum C-Fos and glial fibriller acidic protein levels in detecting the severity of obstructive sleep apnea.

Hypoxia and sleep fragmentations that develop during sleep cause central nervous system damage in patients with obstructive sleep apnea (OSA). This study investigates the relationship between OSA severity and glial fibrillary acidic protein (GFAP) and c-Fos, which are considered indicators of neuronal damage. The study included 84 participants (70 patients with OSA and 14 healthy individuals). All participants were evaluated with the Epworth Sleepiness Scale (ESS) before polysomnography (PSG), and serum GFAP and c-Fos values were measured after PSG. All participants were grouped according to the apnea-hypopnea index (AHI) score (control: AHI < 5, Mild OSA: 5 ≤ AHI < 15; moderate OSA: 15 ≤ AHI < 30; severe OSA: AHI ≥ 30). The average age of the participants was 48.5 ± 11.4 years. According to AHI scoring, 14 healthy individuals (16.7%) were in the control group, and 70 patients (83.3%) were in OSA groups. The serum GFAP levels and c-Fos levels were increased in the OSA groups (7.1 ± 5.7 ng/mL and 7.9 ± 7.5 pg/mL respectively) compared to the control group (1.3 ± 0.4 ng/mL and 2.7 ± 1.4 pg/mL p < 0.001 and p < 0.01, respectively). There was a significant positive correlation between AHI and oxygen desaturation index (ODI) values, which indicate disease severity, and serum c-Fos (r: 0.381 and r:0.931, p < 0.01, respectively) and GFAP (r: 0.793 and r:0.745, p < 0.01, respectively) values. Serum GFAP and c-Fos values, which are considered indicators of neuronal damage, can be used as a serum marker to determine disease severity in OSA.

Distinct Serum Glial Fibrillary Acidic Protein and Neurofilament Light Time-Courses After Rapid Head Rotations.

Traumatic brain injury (TBI) causes significant neurophysiological deficits and is typically associated with rapid head accelerations common in sports-related incidents and automobile accidents. There are over 1.5 million TBIs in the United States each year, with children aged 0-4 being particularly vulnerable. TBI diagnosis is currently achieved through interpretation of clinical signs and symptoms and neuroimaging; however, there is increasing interest in minimally invasive fluid biomarkers to detect TBI objectively across all ages. Pre-clinical porcine models offer controlled conditions to evaluate TBI with known biomechanical conditions and without comorbidities. The objective of the current study was to establish pediatric porcine healthy reference ranges (RRs) of common human serum TBI biomarkers and to report their acute time-course after nonimpact rotational head injury. A retrospective analysis was completed to quantify biomarker concentrations in porcine serum samples collected from 4-week-old female (n = 215) and uncastrated male (n = 6) Yorkshire piglets. Subjects were assigned to one of three experimental groups (sham, sagittal-single, sagittal-multiple) or to a baseline only group. A rapid nonimpact rotational head injury model was used to produce mild-to-moderate TBI in piglets following a single rotation and moderate-to-severe TBI following multiple rotations. The Quanterix Simoa Human Neurology 4-Plex A assay was used to quantify glial fibrillary acidic protein (GFAP), neurofilament light (Nf-L), tau, and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1). The 95% healthy RRs for females were calculated and validated for GFAP (6.3-69.4 pg/mL), Nf-L (9.5-67.2 pg/mL), and UCH-L1 (3.8-533.7 pg/mL). Rising early, GFAP increased significantly above the healthy RRs for sagittal-single (to 164 and 243 pg/mL) and increased significantly higher in sagittal-multiple (to 494 and 413 pg/mL) groups at 30 min and 1 h postinjury, respectively, returning to healthy RRs by 1-week postinjury. Rising later, Nf-L increased significantly above the healthy RRs by 1 day in sagittal-single (to 69 pg/mL) and sagittal-multiple groups (to 140 pg/mL) and rising further at 1 week (single = 231 pg/mL, multiple = 481 pg/mL). Sagittal-single and sagittal-multiple UCH-L1 serum samples did not differ from shams or the healthy RRs. Sex differences were observed but inconsistent. Serum GFAP and Nf-L levels had distinct time-courses following head rotations in piglets, and both corresponded to load exposure. We conclude that serum GFAP and Nf-L offer promise for early TBI diagnosis and intervention decisions for TBI and other neurological trauma.

Therapeutic effect and psychological impact of aspirin plus edaravone on patients with cerebral infarction.

Cerebral infarction (CI) is characterized by a high prevalence, disability, and mortality. Timely or improper treatment greatly affects patient prognosis. To explore the drug efficacy of aspirin plus edaravone and to explore their effect on quality of life (QOL), anxiety and depression in CI patients. We retrospectively analyzed the records of 124 CI patients treated between June 2019 and February 2021 who were assigned to an observation group (OG) (combination therapy of aspirin and edaravone, 65 patients) or a control group (CG) (aspirin monotherapy, 59 patients). The therapeutic effects, pre- and posttreatment National Institutes of Health Stroke Scale (NIHSS) scores, activities of daily living, degree of cognitive impairment, protein levels of glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE) and S-100B, occurrence of adverse reactions, and serum high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6 and tumor necrosis factor (TNF)-α were evaluated, detected and compared between the two groups. Finally, posttreatment QOL, anxiety, and depression were assessed by the Medical Outcomes Study 36- Item Short Form Health Survey Scale, Self-rating Depression Scale (SDS), and Self-rating Anxiety Scale (SAS), respectively. Compared with the CG, the OG had markedly better therapeutic effects, greater improvements in activities of daily living, and better alleviation in cognitive dysfunction after treatment, as well as lower posttreatment NIHSS scores and serum NSE, GFAP, S-100B, hs-CRP, IL-6, and TNF-α levels; the OG was similar to the CG in terms of adverse reactions but was better than the CG in terms of posttreatment QOL; and the OG also had lower SDS and SAS scores than the CG after treatment. Aspirin plus edaravone had a good curative effect on CI. It can reverse cranial nerve damage in patients, improve neurological function and prognosis, and alleviate inflammation, anxiety, and depression; thus, it is considered safe and worthy of clinical application.

Serum GFAP levels correlate with astrocyte reactivity, post-mortem brain atrophy and neurofibrillary tangles.

Glial fibrillary acidic protein (GFAP), a proxy of astrocyte reactivity, has been proposed as biomarker of Alzheimer's disease. However, there is limited information about the correlation between blood biomarkers and post-mortem neuropathology. In a single-centre prospective clinicopathological cohort of 139 dementia patients, for which the time-frame between GFAP level determination and neuropathological assessment was exceptionally short (on average 139 days), we analysed this biomarker, measured at three time points, in relation to proxies of disease progression such as cognitive decline and brain weight. Most importantly, we investigated the use of blood GFAP to detect the neuropathological hallmarks of Alzheimer's disease, while accounting for potential influences of the most frequent brain co-pathologies. The main findings demonstrated an association between serum GFAP level and post-mortem tau pathology (β = 12.85; P < 0.001) that was independent of amyloid deposits (β = 13.23; P = 0.02). A mediation analysis provided additional support for the role of astrocytic activation as a link between amyloid and tau pathology in Alzheimer's disease. Furthermore, a negative correlation was observed between pre-mortem serum GFAP and brain weight at post-mortem (r = -0.35; P < 0.001). This finding, together with evidence of a negative correlation with cognitive assessments (r = -0.27; P = 0.005), supports the role of GFAP as a biomarker for disease monitoring, even in the late phases of Alzheimer's disease. Moreover, the diagnostic performance of GFAP in advanced dementia patients was explored, and its discriminative power (area under the receiver operator characteristic curve at baseline = 0.91) in differentiating neuropathologically-confirmed Alzheimer's disease dementias from non-Alzheimer's disease dementias was determined, despite the challenging scenario of advanced age and frequent co-pathologies in these patients. Independently of Alzheimer's disease, serum GFAP levels were shown to be associated with two other pathologies targeting the temporal lobes-hippocampal sclerosis (β = 3.64; P = 0.03) and argyrophilic grain disease (β = -6.11; P = 0.02). Finally, serum GFAP levels were revealed to be correlated with astrocyte reactivity, using the brain GFAP-immunostained area as a proxy (ρ = 0.21; P = 0.02). Our results contribute to increasing evidence suggesting a role for blood GFAP as an Alzheimer's disease biomarker, and the findings offer mechanistic insights into the relationship between blood GFAP and Alzheimer's disease neuropathology, highlighting its ties with tau burden. Moreover, the data highlighting an independent association between serum GFAP levels and other neuropathological lesions provide information for clinicians to consider when interpreting test results. The longitudinal design and correlation with post-mortem data reinforce the robustness of our findings. However, studies correlating blood biomarkers and neuropathological assessments are still scant, and further research is needed to replicate and validate these results in diverse populations.

The Importance of Increased Serum GFAP and UCH-L1 Levels in Distinguishing Large Vessel from Small Vessel Occlusion in Acute Ischemic Stroke.

Acute ischemic stroke (AIS) is one of the leading causes of morbidity worldwide, thus, early recognition is essential to accelerate treatment. The only definite way to diagnose AIS is radiological imaging, which is limited to hospitals. However, two serum neuromarkers, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1), have been proven as indicators of brain trauma and AIS. We aimed to investigate the potential utility of these markers in distinguishing between large vessel occlusion (LVO) and small vessel occlusion (SVO), considering differences in treatment. Sixty-nine AIS patients were included in our study and divided into LVO and SVO groups based on radiological imaging. Control group consisted of 22 participants without history of neurological disorders. Results showed differences in serum levels of both GFAP and UHC-L1 between all groups; control vs. SVO vs. LVO (GFAP: 30.19 pg/mL vs. 58.6 pg/mL vs. 321.3 pg/mL; UCH-L1: 117.7 pg/mL vs. 251.8 pg/mL vs. 573.1 pg/mL; p < 0.0001), with LVO having the highest values. Other prognostic factors of stroke severity were analyzed and did not correlate with serum biomarkers. In conclusion, a combination of GFAP and UCH-L1 could potentially be a valuable diagnostic tool for differentiating LVO and SVO in AIS patients.

Cognitive decline in post-COVID-19 syndrome does not correspond with persisting neuronal or astrocytic damage

Cognitive impairment is the most frequent symptom reported in post-COVID-19 syndrome (PCS). Aetiology of cognitive impairment in PCS is still to be determined. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are increased in acute COVID-19. Their role as biomarkers in other neurological disorders is under debate. We analysed serum levels of NfL and GFAP as markers for neuronal and astrocytic damage in 53 patients presenting to a PCS Neurology outpatient clinic. Only individuals with self-reported cognitive complaints were included. In these individuals, cognitive complaints were further assessed by comprehensive neuropsychological assessment (NPA). Patients were categorized into subgroups of subjective cognitive decline, single domain impairment, or multi-domain impairment. Serum NfL was in normal range, however an increase of serum GFAP was detected in 4% of patients. Serum NfL and GFAP levels correlated with each other, even when adjusting for patient age (r = 0.347, p = 0.012). NPA showed deficits in 70%; 40% showing impairment in several tested domains. No significant differences were found between serum NfL- and GFAP-levels comparing patients with subjective cognitive decline, single domain impairment, or multi-domain impairment. Persistent neuronal or astrocytic damage did not correlate with cognitive impairment in PCS.

Value of serum brain-derived neurotrophic factor and glial fibrillary acidic protein for detecting depression in patients with Helicobacter pylori infection

ObjectiveInfection with helicobacter pylori (H. pylori) is associated with depression, and depression can affect the outcome of H. pylori treatment. This study aimed to evaluate the value of serum brain-derived neurotrophic factor (BDNF) and glial fibrillary acidic protein (GFAP) for predicting depression in H. pylori-positive patients. MethodA total of 82H. pylori-positive and 82H. pylori-negative patients were recruited for this study. All patients underwent neuropsychological and gastrointestinal assessments and blood sampling. BDNF and GFAP levels were measured in serum. The least absolute shrinkage and selection operator (LASSO) model was used to determine a composite marker. ResultsH. pylori-positive patients showed significantly increased serum GFAP levels and significantly decreased serum BDNF levels compared to H. pylori-negative patients. Among H. pylori-positive patients, serum levels of gastrin 17 (G-17), pepsinogen (PG) I/PGII, BDNF, and GFAP, as well as Gastrointestinal Symptom Rating Scale (GSRS) scores, were significantly correlated with Hamilton Depression Scale (HAMD-24) overall scores and factor scores. Interactions between serum BDNF/GFAP and gastrointestinal serum indices or GSRS scores were significantly associated with HAMD-24 scores in H. pylori-positive patients. The LASSO model indicated that the combination of serum BDNF, GFAP, and G-17 and GSRS scores could identify H. pylori-positive patients with depression with an area under the curve of 0.879. ConclusionCirculating changes in BDNF and GFAP were associated with the occurrence of depression in H. pylori-positive patients. A composite marker including neural and gastrointestinal function-related indices may be of value for identifying depression among H. pylori-positive patients.

Relationship between increased serum neurofilament light chain and glial fibrillary acidic protein levels with non-motor symptoms in patients with Parkinson's disease.

This study set out to investigate the relationship between serum neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and various non-motor symptoms (NMSs) in patients with Parkinson's disease (PD). The study included 37 healthy controls (HCs) and 51 PD patients. Clinical assessments of PD symptoms were conducted for all PD patients. The NMSS was utilised to evaluate the NMS burden (NMSB) in individuals. Based on the severity of NMSB, we further categorised the PD group into two subgroups: mild-moderate NMSB group and severe-very severe NMSB group. The amounts of NFL and GFAP in the serum were measured using an extremely sensitive single molecule array (Simoa) method. Statistical analyses were performed on the collected data using SPSS 26.0 and R (version 3.6.3). Serum GFAP and NFL levels in the PD group with severe-very severe NMSB were significantly higher than those in the mild-moderate NMSB group (GFAP: P < 0.007; NFL: P < 0.009). Serum NFL and GFAP levels had positive correlations with NMSS total scores (GFAP: r = 0.326, P = 0.020; NFL: r = 0.318, P = 0.023) and multiple subdomains. The relationship between the attention/memory domains of NMSS and NFL levels is significantly positive (r = 0.283, P = 0.044). Similarly, the mood/apathy domains of NMSS are also significantly positively correlated with GFAP levels (r = 0.441, P = 0.001). Patients with emotional problems or cognitive impairment had higher GFAP or NFL levels, respectively. Furthermore, it has been demonstrated that NMSs play a mediating role in the quality of life of patients with PD. Moreover, the combination of NFL and GFAP has proven to be more effective than using a single component in identifying PD patients with severe-very severe NMSB. The severity of NMSs in PD patients, particularly cognitive and emotional symptoms, was found to be associated with the levels of serum NFL and GFAP. This study marks the first attempt to examine the connection between NMSs of PD and the simultaneous identification of NFL and GFAP levels.

Relationship between Serum Glial Fibrillary Acidic Protein and Neurogranin Levels and Cognition in Multiple Sclerosis

Multiple sclerosis is an inflammatory neurodegenerative disorder, and cognitive problems occur in the early and late phases of the disease. The purpose of this study was to investigate the relationship between serum glial fibrillary acidic protein and neurogranin levels and cognition in patients with multiple sclerosis (MS). Twenty-three patients and 25 healthy controls were included in the study. Serum glial fibrillary acidic protein (GFAP) and neurogranin (NRGN) levels were determined on blood samples from patients and controls. Disease duration and EDSS scores of patients were recorded, and the Montreal Cognitive Assessment (MOCA) scale was used for cognitive assessment. There was no statistically significant difference between the two groups in terms of serum NRGN and GFAP levels. MOCA scores were lower in the patient group than in the healthy control group. No statistically significant correlation was found between NRGN and GFAP serum levels and MOCA scores. Our study showed that there was no statistically significant association between serum NRGN and GFAP levels and cognition in MS patients. This study is the first to examine serum GFAP and NRGN levels in the context of cognition in MS.

Serum Biomarker Profiles Discriminate AQP4 Seropositive and Double Seronegative Neuromyelitis Optica Spectrum Disorder.

Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) serum levels are useful to define disease activity in different neurologic conditions. These biomarkers are increased in patients with aquaporin-4 antibody-positive NMOSD (AQP4+NMOSD) during clinical attacks suggesting a concomitant axonal and glial damage. However, there are contradictory results in double seronegative NMOSD (DS-NMOSD). The aim of this study was to characterize the neuronal, axonal, and glial damage of DS-NMOSD in comparison with AQP4+NMOSD. Patients with DS-NMOSD (i.e., for AQP4 and myelin oligodendrocyte glycoprotein antibodies-MOG-Abs) and age-matched AQP4+NMOSD diagnosed according to the latest diagnostic criteria and with available serum samples obtained within 3 months from onset/relapse were retrospectively enrolled from 14 international centers. Clinical and radiologic data were collected. Serum NfL, GFAP, tau, and UCH-L1 levels were determined using an ultrasensitive paramagnetic bead-based ELISA (SIMOA). Statistical analysis was performed using nonparametric tests and receiver-operating characteristic (ROC) curve analysis. We included 25 patients with AQP4+NMOSD and 26 with DS-NMOSD. The median age at disease onset (p = 0.611) and female sex predominance (p = 0.072) were similar in the 2 groups. The most common syndromes at sampling in both AQP4+NMOSD and DS-NMOSD were myelitis (56% vs 38.5%) and optic neuritis (34.6% vs 32%), with no statistical differences (p = 0.716). Median EDSS at sampling was 3.2 (interquartile range [IQR] 2-7.7) in the AQP4+NMOSD group and 4 (IQR [3-6]) in the DS-NMOSD group (p = 0.974). Serum GFAP, tau, and UCH-L1 levels were higher in patients with AQP4+NMOSD compared with those with DS-NMOSD (median 308.3 vs 103.4 pg/mL p = 0.001; median 1.2 vs 0.5 pg/mL, p = 0.001; and median 61.4 vs 35 pg/mL, p = 0.006, respectively). The ROC curve analysis showed that GFAP, tau, and UCH-L1, but not NfL, values were able to discriminate between AQP4+ and DS-NMOSD (area under the curve (AUC) tau: 0.782, p = 0.001, AUC GFAP: 0.762, p = 0.001, AUC UCH-L1: 0.723, p = 0.006). NfL levels were associated with EDSS at nadir only in patients with AQP4+NMOSD. Serum GFAP, tau, and UCH-L1 levels discriminate between AQP4+NMOSD and DS-NMOSD. The different biomarker profile of AQP4+NMOSD vs DS-NMOSD suggests heterogeneity of diseases within the latter category and provides useful data to improve our understanding of this disease.

Baseline serum neurofilament light chain levels differentiate aggressive from benign forms of relapsing–remitting multiple sclerosis: a 20-year follow-up cohort

Background and objectivesSerum biomarkers are emerging as useful prognostic tools for multiple sclerosis (MS); however, long-term studies are lacking. We aimed to evaluate the long-term prognostic value of the serum levels of neurofilament light chain (NfL), total tau, glial fibrillary acidic protein (GFAP), and chitinase 3-like-1 (CHI3L1) measured close to the time of MS onset.MethodsIn this retrospective, exploratory, observational, case and controls study, patients with relapsing–remitting MS (RRMS) with available baseline serum samples and prospectively follow-up in our MS unit for a long time were selected based on their clinical evolution to form two groups: (1) a benign RRMS (bRRMS) group, defined as patients with an Expanded Disability Status Scale (EDSS) score of ≤ 3 at ≥ 10 years of follow-up; (2) an aggressive RRMS (aRRMS) group, defined as patients with an EDSS score of ≥ 6 at ≤ 15 years of follow-up. An age-matched healthy control (HC) group was selected. NfL, total tau, and GFAP serum levels were quantified using a single-molecule array (SIMOA), and CHI3L1 was quantified using ELISA.ResultsThirty-one patients with bRRMS, 19 with aRRMS, and 10 HC were included. The median follow-up time from sample collection was 17.74 years (interquartile range, 14.60–20.37). Bivariate and multivariate analyses revealed significantly higher NfL and GFAP levels in the aRRMS group than in the bRRMS group. A receiver operating characteristic curve analysis identified serum NfL level as the most efficient marker for distinguishing aRRMS from bRRMS.DiscussionThis proof-of-concept study comparing benign and aggressive RRMS groups reinforces the potential role of baseline NfL serum levels as a promising long-term disability prognostic marker. In contrast, serum GFAP, total tau, and CHI3L1 levels demonstrated a lower or no ability to differentiate between the long-term outcomes of RRMS.

Associations between neuropsychiatric symptoms and ADRD serum biomarkers in Mexican American and non‐Hispanic white adults with mild cognitive impairment

AbstractBackgroundMild cognitive impairment (MCI) is a heterogenous diagnostic category with trajectories ranging from reversion to unimpaired cognition to progression to dementia. Neuropsychiatric symptoms such as depression and irritability are common and influence quality of life of patients and caregivers. The role of neuropsychiatric symptoms on disease biology, presentation, and course remains poorly understood. The goal of this study was to evaluate the associations between neuropsychiatric symptoms and serum ADRD biomarkers in Mexican American and non‐Hispanic white participants diagnosed with MCI.MethodParticipants from the Texas Alzheimer’s Research and Care Consortium underwent a blood draw and clinical evaluation, including psychopathological and cognitive assessments. Diagnoses of MCI were adjudicated in consensus reviews. The presence and severity of neuropsychiatric symptoms were assessed by informant report using the Neuropsychiatric Inventory (NPI). Serum levels of total tau, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were assessed using Simoa HD‐X Analyzer. Associations between NPI total score and individual items with serum biomarker levels were assessed using linear regression adjusted for age and sex.ResultA total of 425 participants (mean age: 71 ± 9 years, 62% female, 74% Mexican American) had a diagnosis of MCI and serum ADRD biomarkers (Table 1). Total NPI score was not associated with total tau (ß = 0.002, p = 0.609), NfL (ß = 0.001, p = 0.658), or GFAP (ß = 0.001, p = 0.777). However, endorsement of appetite changes was associated with higher NfL (ß = 0.077, p = 0.006) and GFAP (ß = 0.088, p = 0.002) levels. Stratified analyses indicated associations of appetite changes with serum NfL (ß = 0.108, p = 0.002) and GFAP (ß = 0.095, p = 0.003) in Mexican Americans, but not in non‐Hispanic whites (NfL: ß = 0.022, p = 0.633, GFAP: ß = 0.102, p = 0.066).There were no other significant associations between individual items on the NPI with serum biomarkers (p&gt;0.05, Bonferroni adjustment p±0.003).ConclusionWithin Mexican American adults with MCI, changes in appetite were associated with higher serum NFL and GFAP levels. As elevations in circulating NfL and GFAP levels are associated with ADRD pathology and accelerated disease progression, appetite changes, a non‐invasive and easily discernible behavioral phenotype, may predict higher likelihood of worsening cognitive course. Future longitudinal studies will be necessary to confirm predictive utility of appetite changes for disease progression.

A novel automated multiplex immunoassay for the ultrasensitive detection of blood‐based biomarkers for neurodegenerative diseases

AbstractBackgroundEfforts to identify accurate blood biomarkers for neurodegenerative disease hallmarks have been hampered by the lack of a proteomic tool that has the required sensitivity to detect very low concentrations of brain‐derived proteins in plasma or serum and the ability to multiplex many analytes in a single assay. Here we evaluated NULISA™, a recently developed novel immunoassay with attomolar level sensitivity and high multiplex capability1, for its ability to detect serum biomarkers associated with Alzheimer’s disease.MethodSerum samples from 31 Alzheimer’s disease (AD) patients and 31 non‐AD controls were analyzed using NULISA with a 200plex inflammation panel targeting a broad spectrum of inflammation‐related cytokines, chemokines and other proteins. Five samples failed quality control and were excluded from further analysis, resulting in 28 AD and 29 control samples in the final dataset. Linear model analysis, including age and sex as covariates, was performed for each target for differential expression between AD patients and controls.ResultTwo significant proteins were identified. The level of glial fibrillary acidic protein (GFAP) was 1.84‐fold higher in AD patients (adjusted p‐value = 0.00014), whereas the level of S100 calcium‐binding protein A12 (S100A12) was 2‐fold higher in non‐AD controls (adjusted p‐value = 0.031). GFAP serum levels correlated strongly with total tau (Spearman rho = 0.69, p = 1.7e‐09), p‐tau181 (rho = 0.69, p = 1.7e‐09) and amyloid beta 42 (rho = ‐0.71, p = 4.7e‐10) levels in cerebrospinal fluid (CSF). S100A12 levels also correlated significantly with total tau (rho = ‐0.39, p = 0.0031), p‐tau181 (rho = ‐0.36, p = 0.0053) and amyloid beta 42 (rho = 0.38, p = 0.0067) CSF levels. Receiver operating characteristic analysis demonstrated that GFAP strongly discriminated AD from controls with an area under the curve (AUC) of 0.93 (95% CI 0.87‐1.0), and S100A12 also exhibited good discrimination with an AUC of 0.72 (95% CI 0.59‐0.86).ConclusionThis exploratory study identified serum GFAP levels as a strong discriminatory biomarker for AD, consistent with previous studies. S100A12 also demonstrated significant associations with AD and CSF biomarkers and thus warrants further study. NULISA holds great promise for the discovery and validation of blood‐based biomarkers for the early detection and monitoring of neurodegenerative diseases.1. Feng, W. et al. bioRxiv 2023.04.09.536130 (2023) https://doi.org/10.1101/2023.04.09.536130.

Utility of serum neurofilament light chain and glial fibrillary acidic protein as diagnostic biomarkers of freezing of gait in Parkinson’s disease

Freezing of gait (FOG) is one of the most distressing features of Parkinson’s disease (PD), increasing the risks of fractures and seriously affecting patients’ quality of life. We aimed to examine the potential diagnostic roles of serum neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) in PD patients with FOG (PD-FOG). We included 99 patients, comprising 54 PD patients without FOG (PD-NoFOG), 45 PD-FOG and 37 healthy controls (HCs). Our results indicated serum markers were significantly higher in PD-FOG and postural instability and gait difficulty (PIGD) motor subtype patients than in PD-NoFOG and non-PIGD subtype patients (P < 0.05), respectively. Patients with high concentrations of the markers NFL and GFAP had higher PIGD scores and greater FOG severity than those with low concentrations. Moreover, serum levels of both NFL and GFAP were significantly positively associated with age, FOG severity, PD-FOG status, and negatively associated with Mini-Mental State Examination (MMSE) scores. Logistic regression analysis identified serum levels of NFL and GFAP as independent risk factors for PD-FOG. Mediation analysis revealed that MMSE scores fully mediated the relationship between serum GFAP levels and FOG-Q scores, accounting for 33.33% of the total effects (indirect effect = 0.01, 95% CI 0.01–0.02). NFL levels differentiated PD-FOG from PD-NoFOG with reliable diagnostic accuracy (AUC 0.75, 95% CI 0.66–0.84), and the combination of NFL, GFAP, duration and MMSE scores demonstrated high accuracy (AUC 0.84, 95% CI 0.76–0.91). Our findings support the notion that NFL and GFAP may be potential biomarkers for the diagnosis of PD-FOG.

High burdens of phosphorylated tau protein and distinct precuneus atrophy in sporadic early-onset Alzheimer’s disease

Early-onset Alzheimer’s disease (EOAD) is a rare devastating subclassification of Alzheimer’s disease (AD). EOAD affects individuals <65 years old, and accounts for 5%–10% of all AD cases. Previous studies on EOAD primarily focused on familial forms, whereas research on sporadic EOAD (sEOAD), which represents 85%–90% of EOAD cases, is limited. In this prospective cohort study, participants were recruited between 2018 and 2023 and included patients with sEOAD (n = 110), late-onset AD (LOAD, n = 89), young controls (YC, n = 50), and older controls (OC, n = 25). All AD patients fulfilled the diagnostic criteria based on biomarker evidence. Familial EOAD patients or non-AD dementia patients were excluded. Single molecule array technology was used to measure fluid biomarkers, including cerebrospinal fluid (CSF) and plasma amyloid beta (Aβ) 40, Aβ42, phosphorylated tau (P-tau) 181, total tau (T-tau), serum neurofilament light chain and glial fibrillary acidic protein (GFAP). Patients with sEOAD exhibited more severe executive function impairment and bilateral precuneus atrophy (P < 0.05, family-wise error corrected) than patients with LOAD. Patients with sEOAD showed elevated CSF and plasma P-tau181 levels (154.0 ± 81.2 pg/mL, P = 0.002; and 6.1 ± 2.3 pg/mL, P = 0.046). Moreover, precuneus atrophy was significantly correlated with serum GFAP levels in sEOAD (P < 0.001). Serum GFAP levels (area under the curve (AUC) = 96.0%, cutoff value = 154.3 pg/mL) displayed excellent diagnostic value in distinguishing sEOAD patients from the control group. These preliminary findings highlight the crucial role of tau protein phosphorylation in the pathogenesis and progression of sEOAD.