Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophyResearch in context
Isabelle Weinhofer,
Paulus Rommer,
Andreas Gleiss,
Markus Ponleitner,
Bettina Zierfuss,
Petra Waidhofer-Söllner,
Stéphane Fourcade,
Katharina Grabmeier-Pfistershammer,
Marie-Christine Reinert,
Jens Göpfert,
Anne Heine,
Hemmo A.F. Yska,
Carlos Casasnovas,
Verónica Cantarín,
Caroline G. Bergner,
Eric Mallack,
Sonja Forss-Petter,
Patrick Aubourg,
Annette Bley,
Marc Engelen,
Florian Eichler,
Troy C. Lund,
Aurora Pujol,
Wolfgang Köhler,
Jörn-Sven Kühl,
Johannes Berger
Affiliations
Isabelle Weinhofer
Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria; Corresponding author.
Paulus Rommer
Department of Neurology, Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria
Andreas Gleiss
Institute of Clinical Biometrics, Center for Medical Data Science, Medical University of Vienna, Vienna, Austria
Markus Ponleitner
Department of Neurology, Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria
Bettina Zierfuss
Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria; Department of Neuroscience, Centre de Recherche du CHUM, Université de Montréal, Montréal, Canada
Petra Waidhofer-Söllner
Division of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria
Stéphane Fourcade
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain; Biomedical Research Networking Center on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
Katharina Grabmeier-Pfistershammer
Division of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria
Marie-Christine Reinert
Division of Pediatric Neurology, Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, Göttingen, Germany
Jens Göpfert
Applied Biomarkers and Immunoassays Working Group, NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
Anne Heine
Applied Biomarkers and Immunoassays Working Group, NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
Hemmo A.F. Yska
Department of Pediatric Neurology, Amsterdam Public Health, Amsterdam University Medical Center, Amsterdam, the Netherlands
Carlos Casasnovas
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain; Biomedical Research Networking Center on Rare Diseases (CIBERER), ISCIII, Madrid, Spain; Neuromuscular Unit, Neurology Department, Hospital Universitario Bellvitge, Bellvitge Biomedical Research Unit, Barcelona, Spain
Verónica Cantarín
Infant Jesus Children´s Hospital and Biomedical Research Networking Center on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
Caroline G. Bergner
Department of Neurology, Leukodystrophy Clinic, University of Leipzig Medical Center, Leipzig, Germany
Eric Mallack
Leukodystrophy Center, Division of Child Neurology, Department of Pediatrics, Weill Cornell Medical College, NewYork-Presbyterian Hospital, New York, NY, USA
Sonja Forss-Petter
Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria
Patrick Aubourg
Kremlin-Bicêtre-Hospital, University Paris-Saclay, Paris, France
Annette Bley
Department of Pediatrics, University Medical Center Hamburg Eppendorf, Hamburg, Germany
Marc Engelen
Department of Pediatric Neurology, Amsterdam Public Health, Amsterdam University Medical Center, Amsterdam, the Netherlands
Florian Eichler
Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA
Troy C. Lund
Pediatric Blood and Marrow Transplant Program, Global Pediatrics, Division of Pediatric Blood and Marrow Transplantation, MCRB, University of Minnesota, Minneapolis, MN, USA
Aurora Pujol
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain; Biomedical Research Networking Center on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
Wolfgang Köhler
Department of Neurology, Leukodystrophy Clinic, University of Leipzig Medical Center, Leipzig, Germany
Jörn-Sven Kühl
Department of Pediatric Oncology, Hematology and Hemostaseology, University Hospital Leipzig, Leipzig, Germany
Johannes Berger
Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria; Corresponding author.
Summary: 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.
