Higher Glial Fibrillary Acidic Protein Levels Research Articles

NCOG-28. SERUM PROTEIN BIOMARKERS LINKED TO NEURODEGENERATIVE PROCESSES ARE ELEVATED IN GLIOMA PATIENTS AND ASSOCIATED WITH SEVERITY OF NEUROLOGIC SYMPTOMS

Abstract BACKGROUND Glioma patients frequently report neurologic symptoms, adding to the complexity of cancer management and negatively impacting quality of life. However, mechanisms associated with the development of neurologic symptoms in glioma patients remain unclear. Pathological changes in the brain of glioma patients might result in elevated peripheral blood levels of proteins previously linked to central nervous system (CNS) damage and neurodegeneration, including neurofilament light chain (NfL), tau, and glial fibrillary acidic protein (GFAP). Here, we tested the hypothesis that the circulating levels of these proteins in blood are elevated in glioma patients and associated with the severity of neurologic symptoms. METHODS Patients (n=73) were enrolled in a natural history study (NCT02851706, PI T. Armstrong). Healthy subjects (n=39) were recruited by the National Institutes of Health Clinical Center Blood Bank. Neurologic symptom severity and walking interference were assessed using MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT). Serum proteins were analyzed using ultrasensitive assays (Meso Scale Discovery). RESULTS Participants were predominantly white (patients 74%, healthy subjects 67%) and male (patients 58%, healthy subjects 54%). The median age was 44 (range=24,74) for patients and 49 (range=19,78) for healthy volunteers. No significant differences in age, sex, or race were observed between patients and healthy subjects. Serum levels of NfL (p<0.0001), GFAP (p<0.0001), and tau (p<0.0001) were higher in glioma patients when compared to healthy subjects. Patients with walking interference had higher levels of GFAP (p=0.003), NfL (p=0.003), and tau (p=0.004), and those who reported numbness had higher levels of GFAP (p=0.012). CONCLUSIONS These findings suggest that serum levels of protein markers of neurodegeneration are elevated in glioma patients and associated with the presence of neurologic symptoms. Blood-based biomarkers have the potential to shed light on the mechanisms underlying symptoms and offer a non-invasive alternative for monitoring CNS damage that impact patient outcomes.

Alzheimer disease-related biomarkers and cancer-related cognitive decline: the Thinking and Living with Cancer study.

We evaluated whether plasma Alzheimer disease (AD)-related biomarkers were associated with cancer-related cognitive decline among older breast cancer survivors. We included survivors aged 60-90 years with primary stage 0-III breast cancers (n = 236) and frequency-matched noncancer control paricipant (n = 154) who passed a cognitive screen and had banked plasma specimens. Participants were assessed at baseline (presystemic therapy) and annually for up to 60 months. Cognition was measured using tests of attention, processing speed, and executive function and learning and memory; perceived cognition was measured by the Functional Assessment of Cancer Therapy-Cognitive Function v3 Perceived Cognitive Impairments. Baseline plasma neurofilament light, glial fibrillary acidic protein, β-amyloid 42 and 40 and phosphorylated tau 181 were assayed using single molecule arrays. Mixed models tested associations between cognition and baseline AD biomarkers, time, group (survivor vs control participant), and their 2- and 3-way interactions, controlling for age, race, Wide Range 4 Achievement Test Word Reading score, comorbidity, and body mass index; 2-sided P values of .05 were considered statistically significant. There were no group differences in baseline AD-related biomarkers except survivors had higher baseline neurofilament light levels than control participants (P = .013). Survivors had lower adjusted longitudinal attention, processing speed, and executive function than control participants starting from baseline and continuing over time (P ≤ .002). However, baseline AD-related biomarker levels were not independently associated with adjusted cognition over time, except control participants had lower attention, processing speed, and executive function scores with higher glial fibrillary acidic protein levels (P = .008). The results do not support a relationship between baseline AD-related biomarkers and cancer-related cognitive decline. Further investigation is warranted to confirm the findings, test effects of longitudinal changes in AD-related biomarkers, and examine other mechanisms and factors affecting cognition presystemic therapy.

Plasma Markers of Alzheimer's Disease Pathology, Neuronal Injury, and Astrocytic Activation and MRI Load of Vascular Pathology and Neurodegeneration: TheSMART-MR Study.

Two of the main causes for dementia are Alzheimer's disease (AD) and vascular pathology, with most patients showing mixed pathology. Plasma biomarkers for Alzheimer's disease-related pathology have recently emerged, including Aβ (amyloid-beta), p-tau (phosphorylated tau), NfL (neurofilament light), and GFAP (glial fibrillary acidic protein). There is a current gap in the literature regarding whether there is an association between these plasma biomarkers with vascular pathology and neurodegeneration. Cross-sectional data from 594 individuals (mean [SD] age: 64 [8] years; 17% female) were included from the SMART-MR (Second Manifestations of Arterial Disease-Magnetic Resonance) study, a prospective cohort study of individuals with a history of arterial disease. Plasma markers were assessed using single molecular array assays (Quanterix). Magnetic resonance imaging markers included white matter hyperintensity volume, presence of infarcts (yes/no), total brain volume, and hippocampal volume assessed on 1.5T magnetic resonance imaging. Linear regressions were performed for each standardized plasma marker with white matter hyperintensity volume, total brain volume, and hippocampal volume as separate outcomes, correcting for age, sex, education, and intracranial volume. Logistic regressions were performed for the presence of lacunar and cortical infarcts. Higher p-tau181 was associated with larger white matter hyperintensity volume (b per SD increase=0.16 [95% CI, 0.06-0.26], P=0.015). Higher NfL (b=-5.63, [95% CI, -8.95 to -2.31], P=0.015) was associated with lower total brain volume and the presence of infarcts (odds ratio [OR], 1.42 [95% CI, 1.13-1.78], P=0.039). Higher GFAP levels were associated with cortical infarcts (OR, 1.45 [95% CI, 1.09-1.92], P=0.010). Plasma biomarkers that have been associated with tau pathology, axonal injury, and astrocytic activation are related to magnetic resonance imagingmarkers of vascular pathology and neurodegeneration in patients with manifest arterial disease.

Abstract 57: Rapid Prehospital Diagnosis of Intracerebral Hemorrhage by Measuring GFAP on a Point-of-Care Platform

Background: The rapid differentiation between intracerebral hemorrhage (ICH) and ischemic stroke (IS) in patients with symptoms of acute stroke is decisive for triage and initiation of targeted therapies. Glial fibrillary acidic protein (GFAP) is a highly promising blood biomarker indicating acute ICH. In this study we investigated the potential of a new GFAP plasma test on a point-of-care (POC) platform for rapidly distinguishing ICH from IS in the prehospital phase. Methods: Patients with symptoms of acute stroke admitted within 6 hours of symptom onset were enrolled. Blood samples were collected already in the prehospital phase in most patients. Plasma GFAP measurements were performed on the i-STAT Alinity® (Abbott) device (duration of analysis 15 min). The primary endpoint was the final diagnosis at hospital discharge categorized as ICH, IS or stroke mimics. Results: 155 patients were enrolled (mean age 75±13, 49% females; final diagnosis 33 ICH, 115 IS, 7 stroke mimics). Prehospital GFAP serum concentrations were strongly elevated in ICH patients compared to IS patients (mean 2283±3821 pg/mL, median 144 [IQR 52.5-2562] vs. mean 45±25 pg/mL, median 29 [IQR 29-53]; p<0.001). In patients with a moderate to severe neurological deficit (NIHSS > 7), GFAP values below 30 pg/mL were associated with a negative predictive value of 100% (i.e. ruling out ICH). The probability of ICH increased in parallel with higher GFAP levels. GFAP concentrations above 120 pg/mL indicated ICH with a positive predictive value of 94%. Conclusion: Rapid prehospital GFAP measurements on a point-of-care platform allow a reliable differentiation between patients with IS and ICH. This opens the potential for optimized triage and for the administration of antidots in severely affected patients with suspected anticoagulation-associated ICH.

Association of plasma biomarkers with imaging markers of brain atrophy and white matter disease across three neurodegenerative diseases and cerebrovascular disease

AbstractBackgroundIt is necessary to better understand the value of plasma biomarkers in reflecting ongoing neurodegenerative processes before widespread use as diagnostic and prognostic tools in specialized clinics and as markers of disease progression in trials. Herein, we investigate their association with imaging markers of brain atrophy and white matter disease across three common neurodegenerative diseases and cerebrovascular disease.MethodPatients from the curated multi‐site Ontario Neurodegenerative Disease Research Initiative (ONDRI) were included in this study, classified by diagnostic group: Alzheimer’s disease/Mild cognitive impairment (AD/MCI, n = 126, age = 71.0±8.2, 55%M), frontotemporal dementia (FTD, n = 53, age = 67.8±7.1, 64%M), Parkinson’s disease (PD, n = 140, age = 67.9±6.3, 78%M) and cerebrovascular disease (CVD, n = 161, age = 69.2±7.4, 68%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using high‐sensitivity Simoa assays. Volumes of regional grey matter, ventricular cerebrospinal fluid, white matter hyperintensities, perivascular spaces, lacunes and strokes were extracted using the semi‐automated SABRE pipeline on 3T structural MRI sequences harmonized across sites. Fractions of supratentorial total intracranial volume were used when appropriate. Linear regression models controlling for age and sex were used to test the association between plasma biomarkers and MRI variables in each group separately.ResultIn AD/MCI, higher levels of GFAP, NfL and p‐tau181 were all associated with extensive grey matter atrophy, ventricular expansion and, excluding p‐tau181, with increased white matter hyperintensities. In FTD, increased Aβ42/40 ratio was associated with frontal grey matter atrophy, and higher levels of NfL were associated with ventricular expansion. In PD, higher levels of NfL were associated with frontal, temporal and hippocampal grey matter atrophy. In CVD, higher levels of GFAP and NfL were associated with temporal and subcortical grey matter atrophy and ventricular expansion. Higher levels of GFAP were also associated with enlarged perivascular spaces, while higher levels of NfL were associated with increased lacunes. Finally, still in CVD, higher levels of GFAP and p‐tau181 were associated with increased stroke volumes.ConclusionExcluding Aβ42/40, plasma biomarkers appear to reflect various levels of brain atrophy in all neurodegenerative diseases studied, but reflect markers of white matter disease only in AD/MCI and CVD.

Association of plasma biomarkers with cognitive domains across three neurodegenerative diseases and cerebrovascular disease

AbstractBackgroundIt is critical to better understand the value of plasma biomarkers in predicting cognitive deficits before widespread use as diagnostic and prognostic tools in specialized clinics and as markers of neurodegenerative disease progression in trials. Herein, we investigate their association with five cognitive domains across three common neurodegenerative diseases and cerebrovascular disease.MethodPatients from the curated multi‐site Ontario Neurodegenerative Disease Research Initiative (ONDRI) were included in this study, classified by diagnostic group: Alzheimer’s disease/Mild cognitive impairment (AD/MCI, n = 126, age = 71.0±8.2, 55%M), frontotemporal dementia spectrum disorders (FTD, n = 53, age = 67.8±7.1, 64%M), Parkinson’s disease (PD, n = 140, age = 67.9±6.3, 78%M) and cerebrovascular disease (CVD, n = 161, age = 69.2±7.4, 68%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using high‐sensitivity Simoa assays. Scores from a 26‐test comprehensive neuropsychological assessment were used to compute composite z‐scores for five cognitive domains: attention & working memory, executive function, language, memory, and visuospatial function. Linear regression models controlling for age, sex, education and APOE E4 allele were used to test the association between plasma biomarkers and cognitive domains in each group separately.ResultIn AD/MCI, higher levels of GFAP, NfL and p‐tau181 were all associated with worse attention & working memory, executive function, and memory. In PD, higher levels of NfL were associated with worse attention & working memory, executive function, and visuospatial function; higher levels of GFAP were also associated with worse executive function. In CVD, higher levels of GFAP were associated with worse executive function, memory and visuospatial function; higher levels of p‐tau181 were also associated with worse memory. In FTD, no associations were found.ConclusionPlasma biomarkers indicative of neuronal and glial pathology are useful to predict the severity of widespread cognitive deficits in AD/MCI, PD, and CVD. Interestingly, p‐tau181 predicted memory deficits in both AD/MCI and CVD, suggesting potential mixed disease or pathological overlap. Plasma Aβ42/40 does not appear to predict any cognitive deficits in any of the neurodegenerative diseases studied. As FTD is highly heterogeneous and had the least number of patients, we are possibly lacking power to detect effects in this group.

The moderating effect of APOE E4 on the association of plasma biomarkers with markers of cognition and brain health in Alzheimer’s disease

AbstractBackgroundDue to low success rates in clinical trials for Alzheimer’s disease (AD), there is a need to apply precision medicine approaches, such as stratifying based on APOE genotype, in order to assess its effects on outcome measures. Herein, we aim to better understand how plasma biomarkers of AD and neurodegenerative pathology are associated with cognition and neurodegeneration in APOE E4 carriers compared to non‐carriers.MethodPatients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) diagnosed with AD were included (n = 126, age = 71.0±8.2, 55%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using Simoa assays. Composite cognitive domain scores (attention & working memory, executive function, language, memory, and visuospatial function) were computed from a comprehensive neuropsychological assessment. Volumes of regional grey matter, ventricular cerebrospinal fluid, white matter hyperintensities, perivascular spaces, lacunes and strokes were extracted from 3T structural MRI sequences using the SABRE pipeline. Linear regression models with an interaction term, controlling for age, sex and education were used to test the moderating effect of the APOE E4 allele on the association of plasma biomarkers with cognitive and MRI variables. When interaction effects were significant, post‐hoc models stratified by APOE E4 carrier status and controlling for age, sex and education were assessed.ResultThe APOE E4 allele moderated the association of GFAP, NfL and p‐tau181 with memory. Further stratification revealed that higher levels of GFAP, NfL and p‐tau181 were all associated with worse memory only in APOE E4 carriers. APOE E4 was also found to moderate the association of GFAP and p‐tau181 with many imaging markers. Further stratification revealed that higher levels of GFAP were associated with increased white matter hyperintensities, ventricular expansion and grey matter atrophy (temporal lobe, occipital lobe, hippocampus, basal ganglia and thalamus) only in APOE E4 carriers. Higher levels of p‐tau181 were also associated with increased temporal, parietal, and hippocampal atrophy only in APOE E4 carriers.ConclusionPlasma biomarkers, especially GFAP and p‐tau181, appear to be significantly more predictive of memory deficits and brain neurodegeneration in APOE E4 carriers compared to non‐carriers in AD.

Blood‐based markers of neurodegeneration linked with brain atrophy and cognition in aging

AbstractBackgroundNeurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have been linked to aging‐related brain tissue loss and cognitive decline, both related to neurodegeneration. Recently, NfL and GFAP have become quantifiable in blood; little is known about their association with brain structure in aging adults.MethodSingle‐Molecule Array (SIMOA) technology was used for ultra‐sensitive detection and quantification of NfL and GFAP in blood plasma at baseline in healthy volunteers (N = 102, 52 female, 52‐79 years old). These individuals also underwent magnetic resonance imaging twice, 3 years apart (N = 72 at follow‐up), and cognitive testing. We examined the relationships among NfL, GFAP, age, brain atrophy parameters (gray‐matter volume ‐ GMV, cortical thickness ‐ CT) and cognitive performance (composite score of episodic and working memory, executive functions and perceptual speed). The relationships between blood markers, GMV and CT were assessed using voxel‐ and surface‐based morphometry, cross‐sectionally and longitudinally, adjusting for age, sex and education.ResultOlder age was related to higher levels of NfL and GFAP (ps < .001; Figure 1). Cross‐sectionally, older age was related to lower GMV in the hippocampi and lateral middle temporal regions, and lower CT in lateral frontoparietal areas. Longitudinally, atrophy was located in fronto‐parieto‐temporal regions, more strongly in the left hemisphere (all ps < .05 Family‐Wise Error corrected). Controlling for age, sex, education and total intracranial volume, higher NfL levels were associated with lower volume in inferior temporal regions (cross‐sectionally), and with atrophy in right hippocampus (longitudinally) (p < .001 uncorrected; Figure 2). Higher GFAP levels were associated with lower volume and thinner cortex in frontoparietal regions, and atrophy in right frontal cortex (p < .001; Figure 2). After splitting the individuals as decliners and non‐decliners based on their cognitive‐performance changes, it was found that the negative associations between NfL and inferior‐temporal volume, and between GFAP and fronto‐temporal volume, were driven by the decliners (Figure 3).ConclusionHigher NfL or GFAP levels are related to atrophy, beyond age, in key regions known to be affected in neurodegenerative disorders, possibly indicating early neuropathological changes.

Associations of plasma GFAP, NfL, and p‐tau231 with early‐onset Alzheimer’s Disease pathology

AbstractBackgroundIncreased levels of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau 231 (p‐tau231) in plasma have been associated with late‐onset Alzheimer’s Disease (AD). The impact of these biomarkers in early‐onset AD (EOAD) is unclear and the novel plasma biomarker, p‐tau231, has not been studied in this population. We aimed to demonstrate the effect of each biomarker on EOAD pathology by investigating their associations with amyloid burden, tau burden, and gray matter density (GMD).Method183 EOAD participants from the Longitudinal EOAD study with available baseline plasma GFAP, NfL, p‐tau231, MRI, amyloid PET, and tau PET data were included (mean age = 58.7, 55.2% female, 54.1% APOE‐e4 carrier, mean MMSE = 21.9). Voxel‐wise multiple linear regression models of amyloid PET, tau PET, and T1‐weighted MRI images yielded statistical maps with GFAP, NfL, or p‐tau231 as predictors. Covariates were hierarchically added: Model 1: age, sex; Model 2: age, sex and APOE‐e4; Model 3: age, sex, APOE‐e4 and MMSE. All models are displayed at a family‐wise error adjustment of p<.05.ResultHigher levels of GFAP, NfL, and p‐tau231 were significantly associated with greater amyloid burden and tau burden. Higher levels of GFAP and NfL were also significantly associated with lower GMD. No significant associations were found for p‐tau231 and GMD (Figures 1, 2 & 3). When controlling for APOE‐e4 carrier status, the effect of GFAP on amyloid burden was no longer significant (Figure 1). After additionally controlling for MMSE, the effects of NfL and p‐tau231 on amyloid burden were no longer significant, while the effects of all three biomarkers on tau burden were reduced but remained significant. In terms in of GMD, the effect of NfL survived correction for dementia severity, while the effect of GFAP did not.ConclusionThese results suggest that all three plasma biomarkers show stronger associations with neurodegeneration (cortical atrophy and/or tau burden) than with amyloid burden. Furthermore, this study highlights the importance of plasma biomarkers for AD diagnosis and monitoring. Future work should investigate longitudinal associations and the mediational role of APOE‐e4 and dementia severity.

Recalling Biobank Participants to Clinical Study of Alzheimer’s Disease – FinnGen Pilot Study

AbstractBackgroundPopulation‐based biobanks that comprehensively ascertain health and genetic data hold promise to facilitate identification of Alzheimer’s disease (AD) trial participants. We conducted a pilot study in individuals with mild impairment in cognition or AD to assess the feasibility of recalling biobank participants. We also tested the utility of computer‐ and telephone‐based cognitive assessments as cost‐effective alternatives to in‐person neuropsychological testing and investigated plasma‐based biomarkers.MethodsWe utilized FinnGen, a large population‐based biobank study of up to 500,000 participants representing almost 10% of the Finnish population. Single‐center cross‐sectional study included individuals with ICD‐10 codes for AD (G30) and mild cognitive disorder (MCD; F06.7). Dementia screening instruments were in‐person Mini‐Mental State Examination (MMSE) and telephone interview for dementia (TELE). Episodic memory was assessed with three trial word list tasks in three formats; in‐person, with web‐based tool and with the modified Telephone Interview for Cognitive Status including three learning trials. Each of these yielded immediate and delayed free recall measures. Blood samples were collected to determine plasma‐based biomarkers: amyloid beta (Aβ)1‐40 to Aβ1‐42 ratio, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and phosphorylated‐tau181 (pTau‐181).ResultsA total of 78% (110/140) of a pre‐specified FinnGen sub‐cohort were successfully reached. Of those, 39% (43/110) were willing to participate and 19% (N = 27, mean age = 72y, 13 women) completed the study. FinnGen and hospital records largely matched. For 8/12, MCD was due to other reasons than early AD. MMSE and TELE correlated .818 (p< .001). Immediate and delayed recall measures correlated across three formats: from .584 to .679 (p’s<.003) and from .250 to .424 (p’s: .031 ‐ .218), respectively. AD group had higher levels of GFAP (p = .002) and pTau‐181 (p = .020). TELE was negatively correlated with GFAP (p = .011), NfL (p = .001) and pTau‐181 (p = .006). Moreover, p‐Tau181 had negative correlations with episodic memory measures (all r’s< ‐.202) with telephone‐administered immediate recall reaching statistical significance (r = ‐.394, p = .042).ConclusionsInformative, customized clinical recall studies from FinnGen are feasible. Remote testing is a cost‐effective approach in recall studies. Next phase of our study aims to invite cognitively unimpaired FinnGen participants for screening of high AD risk individuals.

Plasma glial fibrillary acidic protein as a biomarker of disease progression in Parkinson’s disease: a prospective cohort study

BackgroundReactive astrogliosis has been demonstrated to have a role in Parkinson’s disease (PD); however, astrocyte-specific plasma glial fibrillary acidic protein (GFAP)’s correlation with PD progression remains unknown. We aimed to determine whether plasma GFAP can monitor and predict PD progression.MethodsA total of 184 patients with PD and 95 healthy controls (HCs) were included in this prospective cohort study and followed-up for 5 years. Plasma GFAP, amyloid-beta (Aβ), p-tau181, and neurofilament light chain (NfL) were measured at baseline and at 1- and 2-year follow-ups. Motor and non-motor symptoms, activities of daily living, global cognitive function, executive function, and disease stage were evaluated using the Unified Parkinson’s Disease Rating Scale (UPDRS) part III, UPDRS-I, UPDRS-II, Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), and Hoehn and Yahr (H&Y) scales at each visit, respectively.ResultsPlasma GFAP levels were higher in patients with PD (mean [SD]: 69.80 [36.18], pg/mL) compared to HCs (mean [SD]: 57.89 [23.54], pg/mL). Higher levels of GFAP were observed in female and older PD patients. The adjusted linear mixed-effects models showed that plasma GFAP levels were significantly associated with UPDRS-I scores (β: 0.006, 95% CI [0.001–0.011], p = 0.027). Higher baseline plasma GFAP correlated with faster increase in UPDRS-I (β: 0.237, 95% CI [0.055–0.419], p = 0.011) and UPDRS-III (β: 0.676, 95% CI [0.023–1.330], p = 0.043) scores and H&Y stage (β: 0.098, 95% CI [0.047–0.149], p < 0.001) and faster decrease in MoCA (β: − 0.501, 95% CI [− 0.768 to − 0.234], p < 0.001) and FAB scores (β: − 0.358, 95% CI [− 0.587 to − 0.129], p = 0.002). Higher baseline plasma GFAP predicted a more rapid progression to postural instability (hazard ratio: 1.009, 95% CI [1.001–1.017], p = 0.033).ConclusionsPlasma GFAP might be a potential biomarker for monitoring and predicting disease progression in PD.

4 Evaluating Plasma GFAP for the Detection of Alzheimer’s Disease Dementia

Objective:Blood-based biomarkers represent a scalable and accessible approach for the detection and monitoring of Alzheimer’s disease (AD). Plasma phosphorylated tau (p-tau) and neurofilament light (NfL) are validated biomarkers for the detection of tau and neurodegenerative brain changes in AD, respectively. There is now emphasis to expand beyond these markers to detect and provide insight into the pathophysiological processes of AD. To this end, a reactive astrocytic marker, namely plasma glial fibrillary acidic protein (GFAP), has been of interest. Yet, little is known about the relationship between plasma GFAP and AD. Here, we examined the association between plasma GFAP, diagnostic status, and neuropsychological test performance. Diagnostic accuracy of plasma GFAP was compared with plasma measures of p-tau181 and NfL.Participants and Methods:This sample included 567 participants from the Boston University (BU) Alzheimer’s Disease Research Center (ADRC) Longitudinal Clinical Core Registry, including individuals with normal cognition (n=234), mild cognitive impairment (MCI) (n=180), and AD dementia (n=153). The sample included all participants who had a blood draw. Participants completed a comprehensive neuropsychological battery (sample sizes across tests varied due to missingness). Diagnoses were adjudicated during multidisciplinary diagnostic consensus conferences. Plasma samples were analyzed using the Simoa platform. Binary logistic regression analyses tested the association between GFAP levels and diagnostic status (i.e., cognitively impaired due to AD versus unimpaired), controlling for age, sex, race, education, and APOE e4 status. Area under the curve (AUC) statistics from receiver operating characteristics (ROC) using predicted probabilities from binary logistic regression examined the ability of plasma GFAP to discriminate diagnostic groups compared with plasma p-tau181 and NfL. Linear regression models tested the association between plasma GFAP and neuropsychological test performance, accounting for the above covariates.Results:The mean (SD) age of the sample was 74.34 (7.54), 319 (56.3%) were female, 75 (13.2%) were Black, and 223 (39.3%) were APOE e4 carriers. Higher GFAP concentrations were associated with increased odds for having cognitive impairment (GFAP z-score transformed: OR=2.233, 95% CI [1.609, 3.099], p&lt;0.001; non-z-transformed: OR=1.004, 95% CI [1.002, 1.006], p&lt;0.001). ROC analyses, comprising of GFAP and the above covariates, showed plasma GFAP discriminated the cognitively impaired from unimpaired (AUC=0.75) and was similar, but slightly superior, to plasma p-tau181 (AUC=0.74) and plasma NfL (AUC=0.74). A joint panel of the plasma markers had greatest discrimination accuracy (AUC=0.76). Linear regression analyses showed that higher GFAP levels were associated with worse performance on neuropsychological tests assessing global cognition, attention, executive functioning, episodic memory, and language abilities (ps&lt;0.001) as well as higher CDR Sum of Boxes (p&lt;0.001).Conclusions:Higher plasma GFAP levels differentiated participants with cognitive impairment from those with normal cognition and were associated with worse performance on all neuropsychological tests assessed. GFAP had similar accuracy in detecting those with cognitive impairment compared with p-tau181 and NfL, however, a panel of all three biomarkers was optimal. These results support the utility of plasma GFAP in AD detection and suggest the pathological processes it represents might play an integral role in the pathogenesis of AD.

Human in vivo evidence of reduced astrocyte activation and neuroinflammation in patients with treatment-resistant depression following electroconvulsive therapy.

This study aimed to investigate the neuroinflammatory hypothesis of depression and the potential anti-inflammatory effect of electroconvulsive therapy (ECT) in vivo, utilizing astrocyte-derived extracellular vesicles (ADEVs) isolated from plasma. A total of 40 patients with treatment-resistant depression (TRD) and 35 matched healthy controls (HCs) were recruited at baseline, and 34 TRD patients completed the post-ECT visits. Blood samples were collected at baseline and post-ECT. Plasma ADEVs were isolated and confirmed, and the concentrations of two astrocyte markers (glial fibrillary acidic protein (GFAP) and S100β), an EV marker cluster of differentiation (CD) 81, and nine inflammatory markers in ADEVs were measured as main analyses. Additionally, correlation analysis was conducted between clinical features and ADEV protein levels as exploratory analysis. At baseline, the TRD group exhibited significantly higher levels of two astrocyte markers GFAP and S100β, as well as CD81 compared to the HCs. Inflammatory markers interferon (IFN)-γ, interleukin (IL)-1β, IL-4, IL-6, tumor necrosis factor (TNF)-α, IL-10, and IL-17A were also significantly higher in the TRD group. After ECTs, there was a significant reduction in the levels of GFAP, S100β, and CD81, along with a significant decrease in the levels of IFN-γ and IL-4. Furthermore, higher levels of GFAP, S100β, CD81 and inflammatory cytokines were associated with more severe depressive symptoms and poorer cognitive function. This study provides direct insight supporting the astrocyte activation and neuroinflammatory hypothesis of depression using ADEVs. ECT may exert anti-inflammatory effect through inhibition of such activation of astrocytes. This article is protected by copyright. All rights reserved.

Glial fibrillary acidic protein as a serum neuromarker of brain injury in pediatric patients with congenital heart defects undergoing cardiac surgery

Abstract Objective: The aim of this study was to assess glial fibrillary acidic protein (GFAP) as a marker of short-term neurodevelopmental delay in pediatric patients with congenital defects (CHD) after cardiovascular surgical intervention. Methods: Included patients were screened by Denver Developmental Screening Test II scale a few days before and then at 4 to 6 months after the surgical intervention. Blood samples were collected preoperatory and at 24 hours after surgery; GFAP levels were assessed by enzyme-linked immunosorbent assay using commercial kit form BioVendor. Results: Forty children were enrolled and dichotomized into two groups based on peripheric oxygen saturation: cyanotic (&lt;95%) and non-cyanotic (&gt;=95%) group. 63% from our population had an abnormal neurodevelopmental outcome. Significant differences between groups were found in language domain scores preoperatory (p=0.03) and in fine motor domain postoperatory (p=0.03). In the postoperatory period, GFAP had significantly higher values (p=0.0248) in the cyanotic CHD group. Association between GFAP and NIRS were analyzed and significant differences were found in both groups with a good predicting model in the non-cyanotic CHD group (aria under curve of 0.7 for receiver operative characteristic). Higher GFAP levels from the postoperatory period correlated with neurodevelopmental impairment (mean value of: 0.66 ± 0.02ng/ml in those with good neurodevelopmental score, 0.69 ± 0.02ng/ml in those with low neurodevelopmental score, p=0.01). Conclusions: GFAP could be a reliable neuromarker in identifying early acute brain injury documented by NIRS monitorization during perioperatory period and it also could identify short term neurodevelopmental impairment documented by lower neurodevelopmental scores.

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.

Diagnostic values of glial fibrillary acidic protein, neuron-specific enolase and protein S100β for sepsis-associated encephalopathy

Abstract Background To investigate the expressions of glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE) and protein S100β and their diagnostic values for sepsis-associated encephalopathy (SAE). Methods One hundred patients with sepsis treated from August 2021 to August 2022 were included. They were assigned to a sepsis group (n=65) and an SAE group (n=35), while 50 healthy volunteers physically examined in the same period were enrolled as a control group. The levels of GFAP and NSE were detected by enzyme-linked immunosorbent assay, and that of S100β was determined by transmitted immunoturbidimetric assay. The expressions of GFAP, NSE and S100β in patients with SAE were detected, and their correlations and diagnostic values were analyzed. Results Compared to patients with mild and moderate SAE, those with severe SAE had higher levels of GFAP, NSE and S100β (P&lt;0.05). The levels of GFAP, NSE and S100β were higher in coma patients than those with consciousness disturbance, and they were higher in patients with a poor prognosis than those with a good prognosis (P&lt;0.05). Positive correlations were identified between GFAP and NSE (r=0.573, P=0.001), GFAP and S100β (r=0.468, P=0.005), and NSE and S100β (r=0.540, P=0.001) expression in patients with SAE. Compared with GFAP, NSE and S100β alone, their combination had higher sensitivity and lower specificity for diagnosing SAE (P&lt;0.05). Conclusions There are correlations among GFAP, NSE and S100β, and the combined detection of these three indicators is highly valuable for the diagnosis of SAE.

0320 Sex Differences in Sleep Quality and Biomarker Levels in Service Members and Veterans with Chronic Mild Traumatic Brain Injury

Abstract Introduction Sleep disorders are highly prevalent in military populations and are frequently associated with a history of traumatic brain injury (TBI). Despite the recent increase in female representation in the military, few studies have focused on sex differences in sleep quality in military populations. In this study, we examined biological sex differences in self-reported sleep quality and blood levels of protein biomarkers of TBI in a cohort of service members and veterans with chronic mild TBI (mTBI). Methods Participants (n=1,121) were enrolled in the Chronic Effects of Neurotrauma Consortium (CENC)/Long Term Impact of Military Brain Injury Consortium (LIMBIC) study. Females (n=147) and males (n=974) were classified into control (n=192, no TBI history) or mTBI (n=929, positive history of mTBI) groups. Self-reported sleep quality was assessed using PSQI (Pittsburgh Sleep Quality Index). Plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), Tau, interleukin (IL)-10, IL-6, and tumor necrosis factor-alpha (TNFα) were analyzed using a Simoa HD-X analyzer. Results Regression models revealed higher PSQI scores in females than males (ß(SE)=1.36(0.40), p =0.001) and in the TBI group (ß(SE)=1.97(0.36), p&amp;lt;0.001) in comparison to controls. TBI x sex interaction was not statistically significant. Within the mTBI group, females had higher PSQI scores (p=0.031) and GFAP levels (p&amp;lt;0.001) than males, which remained significant when controlling for demographics, number of mTBIs, and time since last mTBI. No other significant differences in biomarker levels were observed. In men, but not women, higher levels of GFAP were associated with lower PSQI scores (ß(SE)=-1.38(0.43), p=0.001). Conclusion Our findings suggest sex differences in sleep quality after mTBI, providing insights into possible mechanisms underlying the development of chronic symptoms in military populations. Our results support the need for considering biological sex in the development of personalized therapeutic strategies for chronic TBI-related sleep disorders. Support (If Any) This work was supported by grant funding from: The U.S. Army Medical Research and Material Command, from the U.S. Department of Veterans Affairs Long-term Impact of Military-related Brain Injury Consortium/Chronic Effects of Neurotrauma Consortium under Award No.1I01CX002097-01 and the U.S Department of Defense under Award No.W81XWH-18-PH/TBIRP-LIMBIC.

Blood markers of neuronal/axonal and glial injury for clinical progression in a predominately Hispanic cohort: The Texas Alzheimer’s Research and Care Consortium

AbstractBackgroundThe clinical translation of biofluid markers for Alzheimer’s disease and related dementias (ADRDs) requires validation in diverse cohorts. The goal of the study was to evaluate if blood biomarkers of neuronal/axonal and glial injury predict cognitive decline and clinical disease progression in a predominately Hispanic cohort from the Texas Alzheimer’s Research and Care Consortium.MethodParticipants included 745 Hispanic and 274 non‐Hispanic white participants, aged 55‐89 years, who annually completed cognitive assessments, the Clinical Dementia Rating scale (CDR), and dementia consensus reviews. Serum from the baseline examination was assayed to quantify levels of total tau (t‐tau), neurofilament light (NFL), ubiquitin carboxyl‐terminal hydrolase LI (UCHLI), and glial fibrillary acidic protein (GFAP) using the Simoa Neurology 4‐Plex Kit (Quanterix), as well as soluble CD14 (sCD14) and chitinase‐3‐like protein 1 (YKL‐40) using commercial ELISAs (R&amp;D Systems). Generalized estimating equations were used to evaluate the associations between serum biomarkers and longitudinal cognitive outcomes, as well as disease progression (CDR Sum of Boxes), adjusting for covariates of age, sex, ethnicity, education, body mass index, systolic blood pressure, diabetes, APOE ε4 status, and clinical diagnosis. Cox proportional hazard models were used to evaluate the associations between serum biomarkers and incident mild cognitive impairment (MCI) and dementia with adjustment for the covariates listed above.ResultAcross the average four‐year follow‐up period, 162 individuals developed MCI and 96 developed dementia (Table 1). As displayed in Table 2, serum GFAP levels predicted cognitive decline across most cognitive domains. Serum t‐tau levels were associated with declines in global cognition, learning, and memory. Serum GFAP (b=0.154, SE=0.028, p&lt;0.001), NFL (b=0.069, SE=0.026, p=0.007), and t‐tau (b=0.065, SE=0.023, p=0.004) predicted clinical progression. Higher GFAP levels at baseline were associated with increased risk of incident dementia (HR=1.485, p=0.009). None of the biomarkers predicted incident MCI.ConclusionSerum GFAP levels were associated with multi‐domain cognitive decline, clinical progression, and incident dementia risk. The results suggest that reactive astrogliosis may be an important mechanism underlying a progressive neurodegenerative disease course in our predominately Hispanic sample. With further validation, serum GFAP may hold utility for predicting disease progression and monitoring the efficacy of newly emerging treatments.

The association between plasma biomarkers, p‐tau181, glial fibrillary acidic protein, and neurofilament light and clinical AD risk: Results from prospective cohort study followed over 17 years

AbstractBackgroundPlasma biomarkers for Alzheimer’s disease (AD) have emerged as the future of AD prescreening measures and/or clinical risk assessment. In order to confirm clinical utility of plasma biomarkers, further validation in longitudinal cohort studies is necessary. Therefore, the aim of this study was to investigate the relationship between plasma biomarkers, phosphorylated tau (p‐tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) and incident clinical Alzheimer’s disease diagnosis in a community‐based cohort study prospectively followed over 17 years. Secondarily, disease specificity of these biomarkers was assessed with comparison to vascular (VD) and mixed dementia (MD), and the impact of fatal CVD risk on plasma biomarker prediction was explored.MethodP‐tau181, GFAP, and NfL concentration in plasma taken at baseline was measured using the SimoaTM HD‐X Analyzer and the 10‐year risk of fatal CVD using the Systematic Coronary Risk Evaluation (SCORE) was determined in 145 participants diagnosed with AD, 66 participants with VD, and 50 participants with MD during 17 years of follow‐up and 507 participants without dementia diagnosis. Cox regression models adjusted for age, sex, and education were used to assess the association between the plasma biomarker levels and risk of incident dementia subtypes.ResultHigher plasma levels of p‐tau181 and NfL were significantly associated to higher risk of AD development within the first nine years of follow‐up (p‐tau181, p=.02; NfL, p=.01) and were most elevated in AD cases in the first five years of follow‐up, however lacked associations between 9‐17 years. Contrastingly, GFAP levels were consistently elevated in AD cases and significant associations to higher AD risk were evident throughout the 17‐year follow‐up. NfL and GFAP levels additionally exhibited associations to a higher risk of VD and MD; while p‐tau181 did not. Significant interactions between fatal CVD risk and biomarker levels were evident for AD (p‐tau181, p=.03; NfL, p=.01).ConclusionHigher plasma p‐tau181 and NfL levels were associated with higher AD risk within nine years, while higher GFAP levels with higher AD risk consistently throughout 17 years. Plasma levels of p‐tau181 and NfL may be more suited to short‐term AD risk stratification; while GFAP may add important long‐term disease risk information.

Abstract 13579: Serum Neural Biomarkers and Neuroimaging Markers in Neonates With Congenital Heart Disease Undergoing Cardiac Surgery

Introduction: Congenital heart disease (CHD) patients requiring neonatal cardiopulmonary bypass (CPB) surgery often experience abnormal neurodevelopment. Open heart surgery and anesthesia induce changes in the developing brain concomitant with an increase in the level of neuromarkers. The aim of this study is to assess the relationship between neuromarkers, brain dysplasia and neurodevelopmental outcomes for CHD patients undergoing neonatal CPB. Hypothesis: Neuromarkers and neuroimaging brain dysplasia can predict the neurodevelopmental outcomes for CHD patients undergoing neonatal CPB. Methods: 42 neonates with CHD requiring CPB were included in this prospective, observational study. Using the Neurology 4-Plex A Assay, serum levels of glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), neurofilament light (NF-L), and Tau protein were measured pre-operatively and at 0 hours, 24 hours, and 48 hours post-operatively. Brain MRIs were obtained in 24 neonates. Neurodevelopment testing was completed at 6 months to 36 months of age using the Bayley-III Scales of infant. Findings of brain MRI were scored using an internally developed scoring system which evaluates the brains structures individually on degrees of dysplasia, hypoplasia, and abnormalities, as well as providing a comprehensive assessment of overall brain development combining the individual structural abnormalities into a composite total brain dysplasia score (TBDS). Results: Bayley-III scales were negatively correlated with NF-L and Tau. For UCH-L1, a positive correlation was seen at immediate postop. Hemorrhage is associated with low language score (P=0.009) and elevated UCH-L1 levels at 24 hours and 48 hours. Infraction (P=0.0375) and lower maturation (P=0.03) are associated with low fine motor scores. Lower maturation is related to more domains below average (P=0.01). Infarction is associated with high postoperative Tau level (P=0.04).TBDS is associated with high levels of GFAP, NFL-1, and decreased language development. Conclusion: A negative correlation of Tau and NF-L to Bayley-III scales was consistent with their known roles as markers of neural injury. High NF-L and GFAP are associated with brain dysplasia.