Plasma Glial Fibrillary Acidic Protein Levels Differ Along the Spectra of Amyloid Burden and Clinical Disease Stage

Asken, Breton M; Elahi, Fanny M.; Joie, Renaud La; Strom, Amelia; Staffaroni, Adam M.; Lindbergh, Cutter A.; Apple, Alexandra C.; You, Michelle; Weiner‐Light, Sophia; Brathaban, Nivetha; Fernandes, Natália C.; Karydas, Anna; Wang, Paul; Rojas, Julio C.; Boxer, Adam L.; Miller, Bruce L.; Rabinovici, Gil D.; Kramer, Joel H.; Casaletto, Kaitlin B.

doi:10.3233/jad-219001

Cited by 24 publications

(42 citation statements)

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“…High GFAP concentrations have been detected in the CSF of patients with dementia of various aetiologies [17][18][19] , and increased blood GFAP levels were also found in patients with AD in comparison to healthy controls 20,21 . Furthermore, an association between plasma GFAP levels and amyloid load in AD patients has been recently observed [20][21][22][23] , corroborating neuropathological ndings.…”

supporting

confidence: 72%

“…To our knowledge, only few studies have evaluated the combination of GFAP with other biomarkers so far, and presented the utility of plasma GFAP not just in discriminating healthy controls from patients with AD but also in distinguishing Ab + from Ab-individuals [21][22][23] . Furthermore, higher GFAP levels have been associated with an increased risk for future progression to dementia and a steeper cognitive decline 43,49 .…”

Section: Admentioning

confidence: 99%

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Promising Diagnostic Accuracy of Plasma GFAP and NfL Within The AD Continuum

Parvizi¹,

König²,

Wurm³

et al. 2021

Preprint

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Background: Blood-based biomarkers may add a great benefit in detecting the earliest neuropathological changes in patients with Alzheimer’s disease (AD). We examined the utility of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in plasma and cerebrospinal fluid (CSF) regarding clinical diagnosis and amyloid positivity in an outpatient memory clinic - based cohort. Methods: In this retrospective analysis, we included a total of 185 patients, 141 patients along clinical the AD continuum, i.e. subjective cognitive decline (SCD, n=18), mild cognitive impairment (MCI, n=63), AD (n=60) and 44 age-matched healthy controls (HC). CSF and plasma concentrations of NfL and GFAP were measured with single molecule array (SIMOAâ) technology using the Neurology 2-Plex B kit from Quanterix. Amyloid-PET was performed in 75 patients and graded as amyloid positive and negative by visual rating. To assess the discriminatory potential of different biomarkers, age- and sex-adjusted receiver operating characteristic (ROC) curves were calculated and the area under the curve (AUC) of each model was compared using DeLong’s test for correlated AUC curves.Results: We constructed a panel combining plasma NfL and GFAP with known AD risk factors (age+sex+APOE4+GFAP+NfL panel). Using this panel, AUC was 91.6% for HC vs. AD, 81.7% for HC vs. MCI, 85% for SCD vs. AD, 81.3% for SCD vs. MCI, 77.7% for HC vs. SCD and 72.3% for MCI vs. AD. In terms of predicting amyloid PET status, we computed an AUC of 88.4%. Conclusion: The combination of plasma GFAP and NfL with well-established risk factors could contribute crucially to the identification of patients at risk, and thereby facilitate inclusion of patients in clinical trials for disease modifying therapies.

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supporting

confidence: 72%

Section: Admentioning

confidence: 99%

Promising Diagnostic Accuracy of Plasma GFAP and NfL Within The AD Continuum

Parvizi¹,

König²,

Wurm³

et al. 2021

Preprint

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“…In particular, the recent assays that allow measuring the concentrations of GFAP in the blood have already demonstrated the potential of plasma GFAP in distinguishing different stages of AD and detecting Aβ positivity on positron emission tomography (PET). [10][11][12][13][14][15][16][17][18] However, no study has yet assessed whether plasma GFAP is also associated with tau-PET burden. Moreover, to this date, it is not known whether astrocytosis is independently related to Aβ or tau pathology, respectively, in vivo.…”

Section: Introductionmentioning

confidence: 99%

Plasma glial fibrillary acidic protein is an early marker of Aβ pathology in Alzheimer’s disease

Bateman

Smith

et al. 2021

Preprint

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Although recent clinical trials targeting amyloid in Alzheimers disease (AD) have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with amyloid metabolism and amyloid pathology might be important to halt the clinical deterioration. In particular, there is evidence supporting a critical role of astroglial activation and astrocytosis in AD. However, to this date, no studies have assessed whether astrocytosis is independently related to amyloid or tau pathology, respectively, in vivo. To address this question, we determined the levels of the astrocytic marker glial fibrillary acidic protein (GFAP) in plasma and cerebrospinal fluid (CSF) of 217 amyloid-negative cognitively unimpaired individuals, 71 amyloid-positive cognitively unimpaired individuals, 78 amyloid-positive cognitively impaired individuals, 63 amyloid-negative cognitively impaired individuals and 75 patients with a non-AD neurodegenerative disorder from the Swedish BioFINDER-2 study. Subjects underwent longitudinal amyloid (18F-flutemetamol) and tau (18F-RO948) positron emission tomography (PET) as well as cognitive testing. We found that plasma GFAP concentration was significantly increased in all amyloid-positive groups compared with subjects without amyloid pathology (p<0.01). In addition, there were significant associations between plasma GFAP with higher amyloid-PET signal in all amyloid-positive groups, but also in cognitively normal individuals with normal amyloid values (p<0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict amyloid-PET positivity with an area under the curve of 0.76, which was greater than the performance achieved by CSF GFAP (0.69) and other glial markers (CSF YKL-40: 0.64, sTREM2: 0.71). Although correlations were also observed between tau-PET and plasma GFAP, these were no longer significant after controlling for amyloid-PET. In contrast to plasma GFAP, CSF GFAP concentration was significantly increased in non-AD patients compared to other groups (p<0.05) and correlated with amyloid-PET only in amyloid-positive cognitively impaired individuals (p=0.005). Finally, plasma GFAP was associated with both longitudinal amyloid-PET and cognitive decline, and mediated the effect of amyloid-PET on tau-PET burden, suggesting that astrocytosis secondary to amyloid aggregation might promote tau accumulation. Altogether, these findings indicate that plasma GFAP is an early marker associated with brain amyloid pathology but not tau aggregation, even in cognitively normal individuals with a normal amyloid status. This suggests that plasma GFAP should be incorporated in current hypothetical models of AD pathogenesis and be used as a non-invasive and accessible tool to detect early astrocytosis secondary to amyloid pathology.

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“…Por outro lado, foi demonstrado por Oeckl et al 37 com imunoensaio na plataforma Single molecule array (Simoa) que o GFAP sérico é capaz de distinguir DA não só de controles (AUC = 0,91) -sendo superior ao valor encontrado para Aβ42 (0,87) -mas também de indivíduos com a variante comportamental de DFT (AUC = 0,85), e apresentando concentração duas vezes maior que na doença de Parkinson, além de apresentar uma correlação com comprometimento cognitivo 37 . O estudo de Asken et al 48 identificou um crescimento linear em adultos mais velhos com leves alterações de cognição ou com cognição intacta. Contudo, ainda no mesmo estudo, em outra coorte que incluía indivíduos com demência e maior acúmulo amiloide, foi observada uma relação curvilinear entre a concentração plasmática de GFAP e a deposição amiloide, mensurada por PET scan em Centiloids (CLs), foi visto um aumento de GFAP até em torno dos 75 CLs antes de entrar em platô e então diminuir a partir dos 100CLs, havendo forte associação negativa entre GFAP e Aβ-PET em indivíduos com demência 48 .…”

Section: Gfapunclassified

“…O estudo de Asken et al 48 identificou um crescimento linear em adultos mais velhos com leves alterações de cognição ou com cognição intacta. Contudo, ainda no mesmo estudo, em outra coorte que incluía indivíduos com demência e maior acúmulo amiloide, foi observada uma relação curvilinear entre a concentração plasmática de GFAP e a deposição amiloide, mensurada por PET scan em Centiloids (CLs), foi visto um aumento de GFAP até em torno dos 75 CLs antes de entrar em platô e então diminuir a partir dos 100CLs, havendo forte associação negativa entre GFAP e Aβ-PET em indivíduos com demência 48 . Esse padrão pode representar a utilidade de GFAP como um marcador precoce de neurodegeneração, além de que diferentes níveis de GFAP poderiam sinalizar diferentes estágios do desenvolvimento da DA.…”

Section: Gfapunclassified

Biomarcadores gliais da doença de Alzheimer

Bittencourt

Müller

2021

CBR

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Introdução: A neuroinflamação associada às células gliais é um elemento importante do processo patológico da doença de Alzheimer (DA). Este estudo apresenta uma revisão dos marcadores gliais quitinase 3-like 1 (YKL-40), do receptor desencadeado expresso nas células mieloides 2 (Triggering receptor expressed on myeloid cells 2 -TREM2), da proteína acídica fibrilar glial (GFAP) e da proteína B S100 ligante de cálcio (S100B). Métodos: Nesta revisão são analisados os marcadores gliais YKL-40, TREM2, GFAP e S100B presentes em sangue e/ou líquido cefalorraquidiano (LCR), a partir de estudos publicados até 2020 nos bancos de dados do PubMed, Medline e Periódicos Capes. Resultados: Foram recuperados 233 documentos, dentre os quais foram incluídos 60. Todos os marcadores se encontram aumentados na DA em LCR -YKL-40 e TREM2 solúvel (sTREM2), já na fase pré-clínica -, e em sangue, e estão correlacionados ao declínio cognitivo. No entanto, nenhum dos marcadores analisados apresentou grande potencial para o diagnóstico diferencial. Além da proteína TREM2 solúvel no LCR, no sangue também se pode identificar alteração nos níveis do RNAm de TREM2. GFAP sanguíneo mostra ser o melhor em distinguir controles de pacientes com Alzheimer. Há evidências de um efeito protetivo da ativação glial em reação ao acúmulo amiloide. Conclusão: Os marcadores gliais no geral têm pouca utilidade para o diagnóstico diferencial, mas podem auxiliar no prognóstico e como biomarcadores inespecíficos para doenças neurodegenerativas.

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Plasma Glial Fibrillary Acidic Protein Levels Differ Along the Spectra of Amyloid Burden and Clinical Disease Stage

Cited by 24 publications

References 0 publications

Promising Diagnostic Accuracy of Plasma GFAP and NfL Within The AD Continuum

Promising Diagnostic Accuracy of Plasma GFAP and NfL Within The AD Continuum

Plasma glial fibrillary acidic protein is an early marker of Aβ pathology in Alzheimer’s disease

Biomarcadores gliais da doença de Alzheimer

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