Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum

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Key Points

Question

What are the levels of plasma glial fibrillary acidic protein (GFAP) throughout the Alzheimer disease (AD) continuum, and how do they compare with the levels of cerebrospinal fluid (CSF) GFAP?

Findings

In this cross-sectional study, plasma GFAP levels were elevated in the preclinical and symptomatic stages of AD, with levels higher than those of CSF GFAP. Plasma GFAP had a higher accuracy than CSF GFAP to discriminate between amyloid-β (Aβ)–positive and Aβ-negative individuals, also at the preclinical stage.

Meaning

This study suggests that plasma GFAP is a sensitive biomarker that significantly outperforms CSF GFAP in indicating Aβ pathology in the early stages of AD.

Abstract

Importance

Glial fibrillary acidic protein (GFAP) is a marker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood of individuals with Alzheimer disease (AD). However, it is not known whether there are differences in blood GFAP levels across the entire AD continuum and whether its performance is similar to that of CSF GFAP.

Objective

To evaluate plasma GFAP levels throughout the entire AD continuum, from preclinical AD to AD dementia, compared with CSF GFAP.

Design, Setting, and Participants

This observational, cross-sectional study collected data from July 29, 2014, to January 31, 2020, from 3 centers. The Translational Biomarkers in Aging and Dementia (TRIAD) cohort (Montreal, Canada) included individuals in the entire AD continuum. Results were confirmed in the Alzheimer’s and Families (ALFA+) study (Barcelona, Spain), which included individuals with preclinical AD, and the BioCogBank Paris Lariboisière cohort (Paris, France), which included individuals with symptomatic AD.

Main Outcomes and Measures

Plasma and CSF GFAP levels measured with a Simoa assay were the main outcome. Other measurements included levels of CSF amyloid-β 42/40 (Aβ42/40), phosphorylated tau181 (p-tau181), neurofilament light (NfL), Chitinase-3-like protein 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and levels of plasma p-tau181 and NfL. Results of amyloid positron emission tomography (PET) were available in TRIAD and ALFA+, and results of tau PET were available in TRIAD.

Results

A total of 300 TRIAD participants (177 women [59.0%]; mean [SD] age, 64.6 [17.6] years), 384 ALFA+ participants (234 women [60.9%]; mean [SD] age, 61.1 [4.7] years), and 187 BioCogBank Paris Lariboisière participants (116 women [62.0%]; mean [SD] age, 69.9 [9.2] years) were included. Plasma GFAP levels were significantly higher in individuals with preclinical AD in comparison with cognitively unimpaired (CU) Aβ-negative individuals (TRIAD: Aβ-negative mean [SD], 185.1 [93.5] pg/mL, Aβ-positive mean [SD], 285.0 [142.6] pg/mL; ALFA+: Aβ-negative mean [SD], 121.9 [42.4] pg/mL, Aβ-positive mean [SD], 169.9 [78.5] pg/mL). Plasma GFAP levels were also higher among individuals in symptomatic stages of the AD continuum (TRIAD: CU Aβ-positive mean [SD], 285.0 [142.6] pg/mL, mild cognitive impairment [MCI] Aβ-positive mean [SD], 332.5 [153.6] pg/mL; AD mean [SD], 388.1 [152.8] pg/mL vs CU Aβ-negative mean [SD], 185.1 [93.5] pg/mL; Paris: MCI Aβ-positive, mean [SD], 368.6 [158.5] pg/mL; AD dementia, mean [SD], 376.4 [179.6] pg/mL vs CU Aβ-negative mean [SD], 161.2 [67.1] pg/mL). Plasma GFAP magnitude changes were consistently higher than those of CSF GFAP. Plasma GFAP more accurately discriminated Aβ-positive from Aβ-negative individuals than CSF GFAP (area under the curve for plasma GFAP, 0.69-0.86; area under the curve for CSF GFAP, 0.59-0.76). Moreover, plasma GFAP levels were positively associated with tau pathology only among individuals with concomitant Aβ pathology.

Conclusions and Relevance

This study suggests that plasma GFAP is a sensitive biomarker for detecting and tracking reactive astrogliosis and Aβ pathology even among individuals in the early stages of AD.

Abstract

This cross-sectional cohort study evaluates plasma glial fibrillary acidic protein levels throughout the entire Alzheimer disease continuum, from preclinical Alzheimer disease to Alzheimer disease dementia, compared with cerebrospinal fluid glial fibrillary acidic protein.

Related collections

Most cited references 58

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NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

Clifford R. Jack, David Bennett, Kaj Blennow … (2018)

In 2011, the National Institute on Aging and Alzheimer’s Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer’s disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer’s Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer’s Association Research Framework, Alzheimer’s disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

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A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.

Jeffrey J. Iliff, Minghuan Wang, Yonghong Liao … (2012)

Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.

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Structural and functional features of central nervous system lymphatics

Antoine Louveau, Igor Smirnov, Timothy Keyes … (2015)

One of the characteristics of the CNS is the lack of a classical lymphatic drainage system. Although it is now accepted that the CNS undergoes constant immune surveillance that takes place within the meningeal compartment 1–3 , the mechanisms governing the entrance and exit of immune cells from the CNS remain poorly understood 4–6 . In searching for T cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the CSF, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the CNS. The discovery of the CNS lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and shed new light on the etiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.

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Author and article information

Journal

Journal ID (nlm-ta): JAMA Neurol

Journal ID (iso-abbrev): JAMA Neurol

Title: JAMA Neurology

Publisher: American Medical Association

ISSN (Print): 2168-6149

ISSN (Electronic): 2168-6157

Publication date (Electronic): 18 October 2021

Publication date (Print): December 2021

Publication date PMC-release: 18 October 2021

Volume: 78

Issue: 12

Pages: 1-13

Affiliations

[1 ]Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

[2 ]Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, McGill University, Montreal, Quebec, Canada

[3 ]Barcelonaßeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain

[4 ]IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain

[5 ]Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain

[6 ]Universitat Pompeu Fabra, Barcelona, Spain

[7 ]Université de Paris, Institut national de la santé et de la recherche médicale U1144 Optimisation Thérapeutique en Neuropsychopharmacologie, Paris, France

[8 ]Centre de Neurologie Cognitive, Groupe Hospitalo Universitaire Assistance Publique Hôpitaux de Paris Nord Hôpital Lariboisière Fernand-Widal, Paris, France

[9 ]Wallenberg Centre for Molecular and Translational Medicine, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

[10 ]Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom

[11 ]National Institute for Health Research Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley National Health Service Foundation, London, United Kingdom

[12 ]Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina, Madrid, Spain

[13 ]Roche Diagnostics GmbH, Penzberg, Germany

[14 ]Roche Diagnostics International Ltd, Rotkreuz, Switzerland

[15 ]Department of Pharmacology, Graduate Program in Biological Sciences: Biochemistry (PPGBioq) and Phamacology and Therapeutics (PPGFT), Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

[16 ]Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

[17 ]Department of Neurodegenerative Disease, University College London Institute of Neurology, London, United Kingdom

[18 ]UK Dementia Research Institute at University College London, London, United Kingdom

[19 ]Montreal Neurological Institute, Montreal, Quebec, Canada

[20 ]Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada

[21 ]Servei de Neurologia, Hospital del Mar, Barcelona, Spain

Author notes

Article Information

Group Information: The members of the Translational Biomarkers in Aging and Dementia (TRIAD) study, Alzheimer’s and Families (ALFA) study, and BioCogBank Paris Lariboisière cohort are listed in Supplement 2.

Accepted for Publication: August 16, 2021.

Published Online: October 18, 2021. doi:10.1001/jamaneurol.2021.3671

Corresponding Authors: Kaj Blennow, MD, PhD, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, SE 43180 Gothenburg, Sweden ( kaj.blennow@ 123456neuro.gu.se ); Marc Suárez-Calvet, MD, PhD, Alzheimer Prevention Program–Barcelonaßeta Brain Research Center, Wellington 30, 08005 Barcelona, Spain ( msuarez@ 123456barcelonabeta.org ).

Author Contributions: Drs Blennow and Suárez-Calvet had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr Benedet, Ms Milà-Alomà, and Dr Vrillon contributed equally to this work. Drs Paquet, Rosa-Neto, Blennow, and Suárez-Calvet are equal co–senior authors on this work.

Concept and design: Benedet, Milà-Alomà, Vrillon, Ashton, Karikari, Minguillon, Zetterberg, Molinuevo, Rosa-Neto, Suárez-Calvet.

Acquisition, analysis, or interpretation of data: Benedet, Milà-Alomà, Vrillon, Ashton, Pascoal, Lussier, Karikari, Hourregue, Cognat, Dumurgier, Stevenson, Rahmouni, Pallen, Poltronetti, Salvadó, Shekari, Operto, Gispert, Fauria, Kollmorgen, Suridjan, Zimmer, Zetterberg, Paquet, Rosa-Neto, Blennow, Suárez-Calvet.

Drafting of the manuscript: Benedet, Milà-Alomà, Vrillon, Ashton, Pallen, Paquet, Rosa-Neto, Suárez-Calvet.

Critical revision of the manuscript for important intellectual content: Benedet, Milà-Alomà, Vrillon, Ashton, Pascoal, Lussier, Karikari, Hourregue, Cognat, Dumurgier, Stevenson, Rahmouni, Poltronetti, Salvadó, Shekari, Operto, Gispert, Minguillon, Fauria, Kollmorgen, Suridjan, Zimmer, Zetterberg, Molinuevo, Rosa-Neto, Blennow, Suárez-Calvet.

Statistical analysis: Benedet, Milà-Alomà, Ashton, Salvadó, Gispert, Rosa-Neto, Suárez-Calvet.

Obtained funding: Gispert, Suridjan, Molinuevo, Rosa-Neto, Blennow, Suárez-Calvet.

Administrative, technical, or material support: Benedet, Pascoal, Lussier, Karikari, Stevenson, Rahmouni, Operto, Fauria, Kollmorgen, Suridjan, Zetterberg, Paquet, Rosa-Neto, Suárez-Calvet.

Supervision: Ashton, Minguillon, Molinuevo, Rosa-Neto, Blennow, Suárez-Calvet.

Conflict of Interest Disclosures: Dr Vrillon reported receiving grants from Fondation Ophtalmologique Adolphe de Rothschild, Fondation Philipe Chatrier, Amicale des Anciens Internes des Hôpitaux de Paris, and Fondation Vaincre Alzheimer during the conduct of the study. Dr Gispert reported receiving grants from GE Healthcare, Roche Diagnostics, and F. Hoffman-La Roche; and speaker’s fees from Philips and Biogen during the conduct of the study. Dr Suridjan reported being an employee of and owning stocks in Roche Diagnostics. Dr Zetterberg reported receiving personal fees from Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, CogRx, Red Abbey Labs, Cellectricon, Alzecure, Fujirebio, and Biogen and also reported being cofounder of and holding stock in Brain Biomarker Solutions in Gothenburg AB outside the submitted work. Dr Molinuevo reported receiving in-kind reagents from Roche Diagnostics and GE Healthcare and grants from “La Caixa” Foundation NA and Alzheimer’s Association NA during the conduct of the study as well as being an employee of Lundbeck A/S and serving on the advisory board for Genentech, Roche Diagnostics, Novartis, Genentech, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, BioCross, and ProMis Neurosciences outside the submitted work. Dr Paquet reported receiving personal fees from Roche, Biogen, and Lilly during the conduct of the study. Dr Blennow reported personal fees from Abcam, Axon, Biogen, JOMDD/Shimadzu, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens outside the submitted work and being cofounder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program. Dr Suárez-Calvet reported receiving personal fees from Roche Diagnostics International and Roche Farma, SA outside the submitted work. No other disclosures were reported.

Funding/Support: The Translational Biomarkers in Aging and Dementia (TRIAD) is supported by the Canadian Institutes of Health Research (MOP-11-51-31; RFN 152985, 159815, 162303); Canadian Consortium of Neurodegeneration and Aging (MOP-11-51-31 -team 1); Weston Brain Institute, Brain Canada Foundation (Canadian Foundation for Innovation Project 34874; 33397), and the Fonds de Recherche du Québec–Santé (Chercheur Boursier, 2020-VICO-279314). The Alzheimer’s and Families (ALFA) study receives funding from “La Caixa” Foundation (LCF/PR/GN17/10300004) and the Alzheimer’s Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa-17-519007). Dr Benedet is supported by the Swedish Alzheimer Foundation, Stiftelsen för Gamla Tjänarinnor, and Stohne Stiftelsen. Dr Vrillon is supported by Fondation Adolphe de Rotschild, Fondation Philippe Chatrier, Association des Anciens Internes des Hôpitaux de Paris, Fondation Vaincre Alzheimer, Stiftelsen för Gamla Tjänarinnor, Demensfundet, and Stohne Stiftelsen. Dr Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (grant 2018-02532), the European Research Council (grant 681712), Swedish State Support for Clinical Research (grant ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF) (grant 201809-2016862), the Alzheimer Disease (AD) Strategic Fund and the Alzheimer’s Association (grants ADSF-21-831376-C, ADSF-21-831381-C, and ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (grant FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at University College London. Dr Blennow is supported by the Swedish Research Council (grant 2017-00915), the ADDF (grant RDAPB-201809-2016615), the Swedish Alzheimer Foundation (grant AF-742881), Hjärnfonden, Sweden (grant FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the Avtal om Läkarutbildning och Forskining agreement (grant ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (grant JPND2019-466-236), and the National Institutes of Health (grant 1R01AG068398-01). Dr Suárez-Calvet receives funding from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant 948677), the Instituto de Salud Carlos III (grant PI19/00155), and the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva Programme grant IJC2018-037478-I).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The members of the TRIAD study, ALFA study, and BioCogBank Paris Lariboisière cohort are listed in Supplement 2.

Additional Contributions: The authors would like to express their most sincere gratitude to the TRIAD, ALFA, and BioCogBank Paris project participants and relatives without whom this research would have not been possible. The authors thank all of the staff at the University of Gothenburg, Sahlgrenska University Hospital, McGill University Research Centre for Studies, and Montreal Neurological Institute who supported this project. The authors thank Roche Diagnostics International Ltd for providing the kits to measure cerebrospinal fluid biomarkers, Cerveau Technologies for MK-6240, and GE Healthcare for the [ ¹⁸F]flutemetamol doses for ALFA+ study participants.

Additional Information: This publication is part of the TRIAD, the ALFA, and the BioCogBank Paris Lariboisière studies. ELECSYS, COBAS, and COBAS E are trademarks of Roche. The Roche NeuroToolKit is a panel of exploratory prototype assays designed to robustly evaluate biomarkers associated with key pathologic events characteristic of Alzheimer disease and other neurologic disorders, used for research purposes only and not approved for clinical use. All requests for raw and analyzed data and materials will be promptly reviewed by the senior authors to verify whether the request is subject to any intellectual property or confidentiality obligations. Bulk anonymized data can be shared by request from any qualified investigator for the sole purpose of replicating procedures and results presented in the article, providing data transfer is in agreement with European Union legislation and decisions by the institutional review board of each participating center.

Article

Publisher ID: noi210065

DOI: 10.1001/jamaneurol.2021.3671

PMC ID: 8524356

PubMed ID: 34661615

SO-VID: 46e5e484-d2fe-4f5a-b446-f4e2e7e55a63

License:

This is an open access article distributed under the terms of the CC-BY License.

History

Date received : 10 June 2021

Date accepted : 16 August 2021

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Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum

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Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Main Outcomes and Measures

Results

Conclusions and Relevance

Abstract

Related collections

Functional role of amyloid

Most cited references 58

NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.

Structural and functional features of central nervous system lymphatics

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Cited by 122

Most referenced authors 1,165