Glial Fibrillary Acid Protein (GFAP), Serum

This test may exhibit interference when sample is collected from a person who is consuming a supplement with a high dose of biotin (also termed as vitamin B7 or B8, vitamin H, or coenzyme R). It is recommended to ask all patients who may be indicated for this test about biotin supplementation. Patients should be cautioned to stop biotin consumption at least 72 hours prior to the collection of a sample.

GFAP is a 50 k-Da intermediate filament protein that forms the structural backbone of astrocytes.^2,5-7 Astrocytes represent approximately 35 percent of the cells in the central nervous system^8,9 and serve as an integral part of the blood-brain barrier. These cells facilitate numerous interactions with other cells in the nervous system, including neurons. Astrocytes are central to the normal function of synapses and contribute to axonal metabolic maintenance through the regulation of ion homeostasis.¹⁰ Growing research supports the fundamental role of reactive astrocytosis in neurodegenerative disease with elevated GFAP expression as a primary marker.¹¹ Following plasma membrane damage secondary to neurotrauma, GFAP is released into the interstitial fluid and enters the blood stream by crossing the blood-brain barrier, which is compromised following trauma^12-14 or via the lymphatic system.^13,15 There is a large body of published data on the utility of measuring CSF levels of GFAP.^16-19 With the development of more sensitive assays, accurate measurement of serum levels of GFAP is now available. Increased levels of serum GFAP have been associated with cognitive decline and dementia status due to a number of pathologies.^2,20-24

The formation of pathological GFAP aggregates in vivo can accompany lethal neurological disorders such as Alexander disease.⁵ Alexander disease is caused by various dominant heterozygous mutations in the gene encoding GFAP.²⁵ The pathological hallmark of the disease is the formation of cytoplasmic aggregations in astrocytes.⁵ Owing to the rarity of the disease, studies investigating GFAP levels in the blood of individuals with Alexander disease are limited. One study found a modest elevation of GFAP levels in the serum of participants with infantile and juvenile Alexander disease, but not in adult participants with the disease compared with levels in healthy controls.²⁶

A number of studies have reported that blood GFAP levels are elevated in individuals with brain tumors.^27-34 Some studies have found blood GFAP levels to be higher in participants with glioblastoma multiforme (GBM) than in healthy control participants, patients with other non-glial primary tumors and patients with brain metastasis.^27-30 In patients with GBM, blood GFAP concentration correlated with preoperative tumor volume,^{27,28,30,33,34} volume of necrosis^27,34 and GFAP expression levels in tumor tissue.^27-34 In one study, individuals with systemic metastasis of myxopapillary ependymoma, a brain tumor with high GFAP expression, had very high blood GFAP concentrations compared with those in healthy controls.³²

Glial fibrillary acidic protein (GFAP) concentration is increased following a traumatic brain injury (TBI) in studies of patients with predominantly mild to moderate injuries.^2,5,35-49 There is some evidence that GFAP is associated with and may be able to predict unfavorable outcome following TBI.^50-52 GFAP has been shown to be detectable within one hour of injury,^37,53,54 continues to rise and appears to peak within 20-24 hours^37,54 and then declines over 72 hours³⁷ with a biological half-life of 24-48 hours.⁵⁵ Many studies have examined the utility of GFAP for identifying patients with intracranial abnormalities following TBI.⁵⁶ GFAP is considered useful for this purpose given that it is specific to brain injury^57-59 and has a relatively long half-life compared to other biomarkers.⁵⁵

The results of several studies suggest that serum GFAP could be employed as a biomarker of glial injury indicative of intracerebral hemorrhage in patients presenting with acute stroke symptoms.^60-64 Studies have found serum levels of GFAP to be substantially higher in patients with intracerebral hemorrhage than in patients with ischemic stroke.^60,64 A number of studies investigated the role of GFAP as a predictor of functional outcomes after acute ischemic stroke.^65,66 Like ischemic stroke, blood GFAP concentration at admission could significantly predict poor outcomes after subarachnoid hemorrhage at six months after the event.^67,68

GFAP levels have been shown to be higher in patients with multiple sclerosis (MS) than in healthy controls and individuals with non-inflammatory neurological diseases.^69-72 Higher serum GFAP levels have been reported in patients with progressive MS, whereas the results for the relapsing-remitting MS phenotype differed between studies.^17,69,70 Multiple studies have found a correlation between blood GFAP concentration and severity of disability inpatients with MS.^17,69-73 Increased levels of GFAP have also been reported in patients with neuromyelitis optica spectrum disorder.^73-75

Reactive astrogliosis is a hallmark of frontotemporal dementia (FTD).^76-80 The most common genes linked to familial FTD are MAPT, progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72).⁸⁰ Serum GFAP is raised in symptomatic progranulin-associated frontotemporal dementia but not in those with C9orf72 expansions or MAPT mutations.²⁴

Elevation of GFAP levels has been shown to occur in Alzheimer's disease (AD) and predict future conversion to Alzheimer's dementia in patients with mild cognitive impairment.^18,59,81-84 Histological data have shown a close spatial relationship between reactive astrocytes and amyloid plaques in brain tissue of patients with AD.⁸⁵ While the combination of elevated cerebral amyloid beta and tau is considered specific for AD, glial dysfunction and neuroinflammation manifest across dementia subtypes.⁸⁶ GFAP expression is increased in the brains of individuals with AD, often co-localizing with plaques and tangles.^87,88 Increased GFAP concentrations have been detected in CSF and blood of AD patients, with rising levels observed at the preclinical phase of the disease, as well as an association between GFAP levels and cerebral amyloid pathology, brain atrophy, cognitive decline and future conversion to dementia.^82,89-94 CSF levels have been shown to differentiate individuals with dementia from cognitively unimpaired adults.^95,96 Some recent studies have reported that increased blood levels of GFAP are associated with poorer cognition and AD status.^82,89,97-99 Several studies have observed that serum GFAP performed better than the CSF GFAP in detecting AD pathology,^82,92,100 even in the preclinical or mild cognitive impairment AD stages.^{20,21,92,94,100,101}

Relevant to secondary prevention efforts, serum GFAP levels have also been found to predict amyloid positivity among cognitively unimpaired adults.^85,93,94,100 Several studies have reported negative associations between blood derived GFAP levels and cognition.^20,97,98,100 Studies have found that serum GFAP has utility in discriminating healthy controls from patients with AD but also in distinguishing Ab+ from Ab- individuals.^85,90 In the AIBL cohort, elevated GFAP was observed in A(beta)-PET (positron emission tomography) positive participants across the Alzheimer's disease continuum.⁹³ In addition, higher GFAP levels were associated with prospective cognitive decline, lower serum A(beta)1-42/A(beta)1-40 ratio and increased A(beta)-PET load prospectively.⁹³ Serum GFAP concentrations were higher in A(beta)-CU.¹⁰² Furthermore, higher GFAP levels have been associated with an increased risk for future progression to dementia and a steeper cognitive decline.^91,94