title: Glial and axonal changes in systemic lupus erythematosus measured with diffusion of intracellular metabolites.
abstract: Systemic lupus erythematosus is an inflammatory autoimmune disease with multi-organ involvement. Central nervous system involvement in systemic lupus erythematosus is common and results in several neurological and psychiatric symptoms that are poorly linked to standard magnetic resonance imaging outcome. Magnetic resonance imaging methods sensitive to tissue microstructural changes, such as diffusion tensor imaging and magnetization transfer imaging, show some correlation with neuropsychiatric systemic lupus erythematosus (NPSLE) symptoms. Histological examination of NPSLE brains reveals presence of cerebral oedema, loss of neurons and myelinated axons, microglial proliferation and reactive astrocytosis, microinfacrts and diffuse ischaemic changes, all of which can affect both diffusion tensor imaging and magnetization transfer imaging in a non-specific manner. Here we investigated the underlying cell-type specific microstructural alterations in the brain of patients with systemic lupus erythematosus with and without a history of central nervous system involvement. We did so combining diffusion tensor imaging with diffusion-weighted magnetic resonance spectroscopy, a powerful tool capable of characterizing cell-specific cytomorphological changes based on diffusion of intracellular metabolites. We used a 7 T magnetic resonance imaging scanner to acquire T1-weighted images, diffusion tensor imaging datasets, and single volume diffusion-weighted magnetic resonance spectroscopy data from the anterior body of the corpus callosum of 13 patients with systemic lupus erythematosus with past NPSLE, 16 patients with systemic lupus erythematosus without past NPSLE, and 19 healthy control subjects. Group comparisons were made between patients with systemic lupus erythematosus with/without past NPSLE and healthy controls on diffusion tensor imaging metrics and on diffusion coefficients of three brain metabolites: the exclusively neuronal/axonal N-acetylaspartate, and the predominantly glial creatine + phosphocreatine and choline compounds. In patients with systemic lupus erythematosus with past NPSLE, significantly higher diffusion tensor imaging mean and radial diffusivities were accompanied by a significantly higher intracellular diffusion of total creatine (0.202 ± 0.032 μm(2)/ms, P = 0.018) and total choline (0.142 ± 0.031 μm(2)/ms, P = 0.044) compared to healthy controls (0.171 ± 0.024 μm(2)/ms, 0.124 ± 0.018 μm(2)/ms, respectively). Total N-acetylaspartate, total creatine and total choline diffusion values from all patients with systemic lupus erythematosus correlated positively with systemic lupus erythematosus disease activity index score (P = 0.033, P = 0.040, P = 0.008, respectively). Our results indicate that intracellular alterations, and in particular changes in glia, as evidenced by increase in the average diffusivities of total choline and total creatine, correlate with systemic lupus erythematosus activity. The higher diffusivity of total creatine and total choline in patients with NPSLE, as well as the positive correlation of these diffusivities with the systemic lupus erythematosus disease activity index are in line with cytomorphological changes in reactive glia, suggesting that the diffusivities of choline compounds and of total creatine are potentially unique markers for glial reactivity in response to inflammation.
authors.affiliation: C. J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ece
authors.initials: E
authors.lastname: Ercan
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Cesar
authors.initials: C
authors.lastname: Magro-Checa
authors.affiliation: Institut du Cerveau et de la Moelle épinière - ICM, Centre for NeuroImaging Research - CENIR, Paris, France Sorbonne Universités, UPMC Paris 06, Inserm UMR S 1127, CNRS UMR 7225, F-75013, Paris, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Valabregue
authors.affiliation: Institut du Cerveau et de la Moelle épinière - ICM, Centre for NeuroImaging Research - CENIR, Paris, France Sorbonne Universités, UPMC Paris 06, Inserm UMR S 1127, CNRS UMR 7225, F-75013, Paris, France.
authors.forename: Francesca
authors.initials: F
authors.lastname: Branzoli
authors.affiliation: Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland, USA Translational Neuroradiology Unit and 4 Neuroimmunology Clinic (NINDS), National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Emily T
authors.initials: ET
authors.lastname: Wood
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Gerda M
authors.initials: GM
authors.lastname: Steup-Beekman
authors.affiliation: C. J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Webb
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Mark A
authors.initials: MA
authors.lastname: van Buchem
authors.affiliation: C. J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands i.ronen@lumc.nl.
authors.forename: Itamar
authors.initials: I
authors.lastname: Ronen
mesh_terms: D000328:Adult; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D001369:Axons / Q000378:metabolism*; D016022:Case-Control Studies; D002794:Choline / Q000378:metabolism*; D003337:Corpus Callosum / Q000378:metabolism; D003401:Creatine / Q000378:metabolism*; D056324:Diffusion Tensor Imaging; D005260:Female; D006801:Humans; D020945:Lupus Vasculitis, Central Nervous System / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009457:Neuroglia / Q000378:metabolism*; D010725:Phosphocreatine / Q000378:metabolism*
chemical_list: D010725:Phosphocreatine; D001224:Aspartic Acid; C000179:N-acetylaspartate; D003401:Creatine; D002794:Choline
keywords: astrocytes; biomarkers; gliosis; inflammation; neuropsychiatry