Petr Dusek1,2, Ralf Mekle3,4, Marta Skowronska5, Julio Acosta-Cabronero6, Till Huelnhagen7, Simon Daniel Robinson8, Florian Schubert3, Marcus Deschauer9, Antje Els7, Bernd Ittermann3, Gudrun Schottmann10, Vince I Madai4,11, Friedemann Paul10, Thomas Klopstock12,13,14, Tomasz Kmiec15, Thoralf Niendorf7, Jens Wuerfel10,16, Susanne A Schneider17. 1. Department of Neurology and Centre of Clinical Neuroscience, Charles University, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czechia. 2. Department of Radiology, Charles University, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czechia. 3. Physikalisch-Technische Bundesanstalt (PTB), Braunschweig and Berlin, Germany. 4. Center for Stroke Research Berlin (CSB), Charité Universitätsmedizin Berlin, Berlin, Germany. 5. 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland. 6. Wellcome Centre for Human Neuroimaging, UCL Institute of Neurology, University College London, London, United Kingdom. 7. Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. 8. High Field MR Centre, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria. 9. Department of Neurology, Technical University Munich, Munich, Germany. 10. NeuroCure Clinical Research Center and Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitaetsmedizin Berlin, Berlin, Germany. 11. Department of Neurosurgery, Charité Universitätsmedizin Berlin, Berlin, Germany. 12. Department of Neurology with Friedrich-Baur-Institute, Ludwig-Maximilians-University of Munich, Munich, Germany. 13. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. 14. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 15. Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland. 16. Medical Image Analysis Center and Department Biomedical Engineering, University Basel, Basel, Switzerland. 17. Neurology Department, Ludwig Maximilians-University of Munich, Germany.
Abstract
BACKGROUND: Mitochondrial membrane protein-associated neurodegeneration is an autosomal-recessive disorder caused by C19orf12 mutations and characterized by iron deposits in the basal ganglia. OBJECTIVES: The aim of this study was to quantify iron concentrations in deep gray matter structures using quantitative susceptibility mapping MRI and to characterize metabolic abnormalities in the pyramidal pathway using 1 H MR spectroscopy in clinically manifesting membrane protein-associated neurodegeneration patients and asymptomatic C19orf12 gene mutation heterozygous carriers. METHODS: We present data of 4 clinically affected membrane protein-associated neurodegeneration patients (mean age: 21.0 ± 2.9 years) and 9 heterozygous gene mutation carriers (mean age: 50.4 ± 9.8 years), compared to age-matched healthy controls. MRI assessments were performed on a 7.0 Tesla whole-body system, consisting of whole-brain gradient-echo scans and short echo time, single-volume MR spectroscopy in the white matter of the precentral/postcentral gyrus. Quantitative susceptibility mapping, a surrogate marker for iron concentration, was performed using a state-of-the-art multiscale dipole inversion approach with focus on the globus pallidus, thalamus, putamen, caudate nucleus, and SN. RESULTS AND CONCLUSION: In membrane protein-associated neurodegeneration patients, magnetic susceptibilities were 2 to 3 times higher in the globus pallidus (P = 0.02) and SN (P = 0.02) compared to controls. In addition, significantly higher magnetic susceptibility was observed in the caudate nucleus (P = 0.02). Non-manifesting heterozygous mutation carriers exhibited significantly increased magnetic susceptibility (relative to controls) in the putamen (P = 0.003) and caudate nucleus (P = 0.001), which may be an endophenotypic marker of genetic heterozygosity. MR spectroscopy revealed significantly increased levels of glutamate, taurine, and the combined concentration of glutamate and glutamine in membrane protein-associated neurodegeneration, which may be a correlate of corticospinal pathway dysfunction frequently observed in membrane protein-associated neurodegeneration patients.
BACKGROUND: Mitochondrial membrane protein-associated neurodegeneration is an autosomal-recessive disorder caused by C19orf12 mutations and characterized by iron deposits in the basal ganglia. OBJECTIVES: The aim of this study was to quantify iron concentrations in deep gray matter structures using quantitative susceptibility mapping MRI and to characterize metabolic abnormalities in the pyramidal pathway using 1 H MR spectroscopy in clinically manifesting membrane protein-associated neurodegenerationpatients and asymptomatic C19orf12 gene mutation heterozygous carriers. METHODS: We present data of 4 clinically affected membrane protein-associated neurodegenerationpatients (mean age: 21.0 ± 2.9 years) and 9 heterozygous gene mutation carriers (mean age: 50.4 ± 9.8 years), compared to age-matched healthy controls. MRI assessments were performed on a 7.0 Tesla whole-body system, consisting of whole-brain gradient-echo scans and short echo time, single-volume MR spectroscopy in the white matter of the precentral/postcentral gyrus. Quantitative susceptibility mapping, a surrogate marker for iron concentration, was performed using a state-of-the-art multiscale dipole inversion approach with focus on the globus pallidus, thalamus, putamen, caudate nucleus, and SN. RESULTS AND CONCLUSION: In membrane protein-associated neurodegenerationpatients, magnetic susceptibilities were 2 to 3 times higher in the globus pallidus (P = 0.02) and SN (P = 0.02) compared to controls. In addition, significantly higher magnetic susceptibility was observed in the caudate nucleus (P = 0.02). Non-manifesting heterozygous mutation carriers exhibited significantly increased magnetic susceptibility (relative to controls) in the putamen (P = 0.003) and caudate nucleus (P = 0.001), which may be an endophenotypic marker of genetic heterozygosity. MR spectroscopy revealed significantly increased levels of glutamate, taurine, and the combined concentration of glutamate and glutamine in membrane protein-associated neurodegeneration, which may be a correlate of corticospinal pathway dysfunction frequently observed in membrane protein-associated neurodegenerationpatients.
Keywords:
7 Tesla MRI; glutamate; magnetic resonance spectroscopy; mitochondrial membrane protein-associated neurodegeneration (MPAN); neurodegeneration with brain iron accumulation (NBIA); quantitative susceptibility mapping, iron