Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy
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Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy. / Weinhofer, Isabelle; Rommer, Paulus; Gleiss, Andreas; Ponleitner, Markus; Zierfuss, Bettina; Waidhofer-Söllner, Petra; Fourcade, Stéphane; Grabmeier-Pfistershammer, Katharina; Reinert, Marie-Christine; Göpfert, Jens; Heine, Anne; Yska, Hemmo A F; Casasnovas, Carlos; Cantarín, Verónica; Bergner, Caroline G; Mallack, Eric; Forss-Petter, Sonja; Aubourg, Patrick; Bley, Annette; Engelen, Marc; Eichler, Florian; Lund, Troy C; Pujol, Aurora; Köhler, Wolfgang; Kühl, Jörn-Sven; Berger, Johannes.
in: EBIOMEDICINE, Jahrgang 96, 10.2023, S. 104781.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy
AU - Weinhofer, Isabelle
AU - Rommer, Paulus
AU - Gleiss, Andreas
AU - Ponleitner, Markus
AU - Zierfuss, Bettina
AU - Waidhofer-Söllner, Petra
AU - Fourcade, Stéphane
AU - Grabmeier-Pfistershammer, Katharina
AU - Reinert, Marie-Christine
AU - Göpfert, Jens
AU - Heine, Anne
AU - Yska, Hemmo A F
AU - Casasnovas, Carlos
AU - Cantarín, Verónica
AU - Bergner, Caroline G
AU - Mallack, Eric
AU - Forss-Petter, Sonja
AU - Aubourg, Patrick
AU - Bley, Annette
AU - Engelen, Marc
AU - Eichler, Florian
AU - Lund, Troy C
AU - Pujol, Aurora
AU - Köhler, Wolfgang
AU - Kühl, Jörn-Sven
AU - Berger, Johannes
N1 - Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.
PY - 2023/10
Y1 - 2023/10
N2 - BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is highly variable, ranging from slowly progressive adrenomyeloneuropathy to severe brain demyelination and inflammation (cerebral ALD, CALD) affecting males with childhood peak onset. Risk models integrating blood-based biomarkers to indicate CALD onset, enabling timely interventions, are lacking. Therefore, we evaluated the prognostic value of blood biomarkers in addition to current neuroimaging predictors for early detection of CALD.METHODS: We measured blood biomarkers in a retrospective, male CALD risk-assessment cohort consisting of 134 X-ALD patients and 66 controls and in a phenotype-blinded validation set (25 X-ALD boys, 4-13 years) using Simoa®and Luminex® technologies.FINDINGS: Among 25 biomarkers indicating axonal damage, astrocye/microglia activation, or immune-cell recruitment, neurofilament light chain (NfL) had the highest prognostic value for early indication of childhood/adolescent CALD. A plasma NfL cut-off level of 8.33 pg/mL, determined in the assessment cohort, correctly discriminated CALD with an accuracy of 96% [95% CI: 80-100] in the validation group. Multivariable logistic regression models revealed that combining NfL with GFAP or cytokines/chemokines (IL-15, IL-12p40, CXCL8, CCL11, CCL22, and IL-4) that were significantly elevated in CALD vs healthy controls had no additional benefit for detecting neuroinflammation. Some cytokines/chemokines were elevated only in childhood/adolescent CALD and already upregulated in asymptomatic X-ALD children (IL-15, IL-12p40, and CCL7). In adults, NfL levels distinguished CALD but were lower than in childhood/adolescent CALD patients with similar (MRI) lesion severity. Blood GFAP did not differentiate CALD from non-inflammatory X-ALD.INTERPRETATION: Biomarker-based risk prediction with a plasma NfL cut-off value of 8.33 pg/mL, determined by ROC analysis, indicates CALD onset with high sensitivity and specificity in childhood X-ALD patients. A specific pro-inflammatory cytokine/chemokine profile in asymptomatic X-ALD boys may indicate a primed, immanent inflammatory state aligning with peak onset of CALD. Age-related differences in biomarker levels in adult vs childhood CALD patients warrants caution in predicting onset and progression of CALD in adults. Further evaluations are needed to assess clinical utility of the NfL cut-off for risk prognosis of CALD onset.FUNDING: Austrian Science Fund, European Leukodystrophy Association.
AB - BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is highly variable, ranging from slowly progressive adrenomyeloneuropathy to severe brain demyelination and inflammation (cerebral ALD, CALD) affecting males with childhood peak onset. Risk models integrating blood-based biomarkers to indicate CALD onset, enabling timely interventions, are lacking. Therefore, we evaluated the prognostic value of blood biomarkers in addition to current neuroimaging predictors for early detection of CALD.METHODS: We measured blood biomarkers in a retrospective, male CALD risk-assessment cohort consisting of 134 X-ALD patients and 66 controls and in a phenotype-blinded validation set (25 X-ALD boys, 4-13 years) using Simoa®and Luminex® technologies.FINDINGS: Among 25 biomarkers indicating axonal damage, astrocye/microglia activation, or immune-cell recruitment, neurofilament light chain (NfL) had the highest prognostic value for early indication of childhood/adolescent CALD. A plasma NfL cut-off level of 8.33 pg/mL, determined in the assessment cohort, correctly discriminated CALD with an accuracy of 96% [95% CI: 80-100] in the validation group. Multivariable logistic regression models revealed that combining NfL with GFAP or cytokines/chemokines (IL-15, IL-12p40, CXCL8, CCL11, CCL22, and IL-4) that were significantly elevated in CALD vs healthy controls had no additional benefit for detecting neuroinflammation. Some cytokines/chemokines were elevated only in childhood/adolescent CALD and already upregulated in asymptomatic X-ALD children (IL-15, IL-12p40, and CCL7). In adults, NfL levels distinguished CALD but were lower than in childhood/adolescent CALD patients with similar (MRI) lesion severity. Blood GFAP did not differentiate CALD from non-inflammatory X-ALD.INTERPRETATION: Biomarker-based risk prediction with a plasma NfL cut-off value of 8.33 pg/mL, determined by ROC analysis, indicates CALD onset with high sensitivity and specificity in childhood X-ALD patients. A specific pro-inflammatory cytokine/chemokine profile in asymptomatic X-ALD boys may indicate a primed, immanent inflammatory state aligning with peak onset of CALD. Age-related differences in biomarker levels in adult vs childhood CALD patients warrants caution in predicting onset and progression of CALD in adults. Further evaluations are needed to assess clinical utility of the NfL cut-off for risk prognosis of CALD onset.FUNDING: Austrian Science Fund, European Leukodystrophy Association.
U2 - 10.1016/j.ebiom.2023.104781
DO - 10.1016/j.ebiom.2023.104781
M3 - SCORING: Journal article
C2 - 37683329
VL - 96
SP - 104781
JO - EBIOMEDICINE
JF - EBIOMEDICINE
SN - 2352-3964
ER -