Abstract
Original language | English |
---|---|
Article number | 104781 |
Journal | eBioMedicine |
Volume | 96 |
DOIs | |
Publication status | Published - 1 Oct 2023 |
Keywords
- Biomarker
- Cytokines
- GFAP
- Neurodegeneration
- Neurofilament light chain
- X-ALD
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In: eBioMedicine, Vol. 96, 104781, 01.10.2023.
Research output: Contribution to journal › Article › Academic › peer-review
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, J. rn-Sven
AU - Berger, Johannes
N1 - Funding Information: Austrian Science Fund, European Leukodystrophy Association.MP received support from Amicus, Merck, Novartis and Sanofi-Genzyme; BZ received support from ACTRIMS 2022 and 2023 endMS SPRINT; JG received support from Quanterix; HAY was supported by an emerging investigator grant from ALD connect; CGB received grants from the German Research Foundation and the Ministry for Science and Culture of Lower Saxony; ME received support from Minoryx and is member of the advisory board of Minoryx, Poxel and SwanBio Therapeutics; FE is holding a license for “Intrathecal delivery of nucleic acid sequences encoding ABCD1 for treatment of Adrenomyeloneuropathy” (NO. 29539-021PCT), received consulting fees from SwanBio Therapeutics and UpToDate, is founder of SwanBio Therapeutics, ALD Connect and organizer of trial sites for ASPA, Bluebird Bio Therapeutics, Ionis Pharmaceuticals and Sanofi; AP received consulting fees from Swanbio Therapeutics and Sanofi and is member of the Advisory Board of Bluebird Bio Therapeutics and MedDay Therapeutics. JSK is member of the advisory board for Krabbe Disease of PassageBio. MCR received a grant from Novartis. EM has received funding from the National Institutes of Health (K23NS118044). All remaining authors declare no competing interests.We thank all patients and healthy volunteers who participated in this study. In addition, we are grateful for excellent technical assistance by Martina Rothe and Cristina Guilera. We would also like to thank Prof. Dr. Jutta Gärtner and the Division of Pediatric Neurology, University Medical Center Göttingen, Germany, for providing serum NfL levels of healthy control children. This work was mainly supported by the Austrian Science Fund KLI 837-B to IW and by the European Leukodystrophy Association (ELA) Germany and ELA international 2020-003CIA to JB and IW. BZ was supported by a postdoctoral fellowship from Biogen. The Neurometabolic Diseases Lab was supported by the Institute of Health Carlos III through projects [PI19/01008] to SF and [PI20/00759] (co-funded by the European Regional Development Fund), CIPERER ACCI 2018, the Autonomous Government of Catalonia [2017SGR1206], Swanbio Therapeutics, the Hesperia Foundation, CERTIS Obres I Serveis, and the Crowd Funding Campaign Arnau'97 to AP. We thank the CERCA Program/Generalitat de Catalunya for institutional support. FE was supported by ELA International 2019-012I2, the Arrivederci Foundation, the Cure ALD Foundation, the Leblang Charitable Foundation and the Hammer Family Fund for ALD Research and Therapies for Women and GLIA-CTN under grant number U54NS115052 as a collaboration between NCATS and the National Institute of Neurological Disorders and Stroke (NINDS). The funders of the study had no role in design, data collection, data analyses, data interpretation or writing of the article. The corresponding authors had full access to all the data and had final responsibility for the decision to submit the study for publication. Funding Information: We thank all patients and healthy volunteers who participated in this study. In addition, we are grateful for excellent technical assistance by Martina Rothe and Cristina Guilera. We would also like to thank Prof. Dr. Jutta Gärtner and the Division of Pediatric Neurology, University Medical Center Göttingen, Germany, for providing serum NfL levels of healthy control children. This work was mainly supported by the Austrian Science Fund KLI 837-B to IW and by the European Leukodystrophy Association (ELA) Germany and ELA international 2020-003CIA to JB and IW. BZ was supported by a postdoctoral fellowship from Biogen . The Neurometabolic Diseases Lab was supported by the Institute of Health Carlos III through projects [PI19/01008] to SF and [PI20/00759] (co-funded by the European Regional Development Fund ), CIPERER ACCI 2018, the Autonomous Government of Catalonia [2017SGR1206], Swanbio Therapeutics , the Hesperia Foundation , CERTIS Obres I Serveis, and the Crowd Funding Campaign Arnau'97 to AP. We thank the CERCA Program/Generalitat de Catalunya for institutional support. FE was supported by ELA International 2019-012I2 , the Arrivederci Foundation , the Cure ALD Foundation , the Leblang Charitable Foundation and the Hammer Family Fund for ALD Research and Therapies for Women and GLIA-CTN under grant number U54NS115052 as a collaboration between NCATS and the National Institute of Neurological Disorders and Stroke (NINDS). The funders of the study had no role in design, data collection, data analyses, data interpretation or writing of the article. The corresponding authors had full access to all the data and had final responsibility for the decision to submit the study for publication. Publisher Copyright: © 2023 The Authors
PY - 2023/10/1
Y1 - 2023/10/1
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.
KW - Biomarker
KW - Cytokines
KW - GFAP
KW - Neurodegeneration
KW - Neurofilament light chain
KW - X-ALD
UR - http://www.scopus.com/inward/record.url?scp=85169889264&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ebiom.2023.104781
DO - https://doi.org/10.1016/j.ebiom.2023.104781
M3 - Article
C2 - 37683329
SN - 2352-3964
VL - 96
JO - eBioMedicine
JF - eBioMedicine
M1 - 104781
ER -