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 positiv...

Insights into brain microstructure from in vivo DW-MRS

“…As was previously mentioned, the cytosolic diffusion coefficient of NAA is a good candidate for a putative marker for intracellular damage such as axonopathy in MS, but this role can be extended to other neurodegenerative disorders, such as tauopathy in AD, where intraneuronal pathological changes are caused by hyperphosphorylation of the tau protein, which is responsible for keeping the integrity of microtubules (152)(153)(154). In a combined DTI -DW-MRS study of patients with neuropsychiatric systemic lupus erythematosus (NPSLE), an increase in the diffusion coefficient of tCho was observed in correlation with neuropsychiatric symptoms and with the SLE disease activity index (SLEDAI), which scales with inflammatory state (155). This points to the possibility that tCho's ADC is modulated by inflammation and reflects glial reactivity in response to inflammation.…”

Modeling diffusion of intracellular metabolites in the mouse brain up to very high diffusion‐weighting: Diffusion in long fibers (almost) accounts for non‐monoexponential attenuation

“…Changes in endogenous metabolite apparent diffusivity (ADC) have already been detected in pathologies. Alterations in the diffusion of metabolites are observed after global ischemia (4)(5)(6)(7)(8)(9), in multiple sclerosis (10), in brain tumor (11)(12)(13), and in lupus erythematosus (14). Although alterations of intracellular diffusion during brain pathologies are often thought to be associated with cell structural damage, the influence of various parameters (eg, viscosity, molecular crowding, cell size, geometry) on DW-MRS measurement is still unclear, and the interpretation of experimental data remains complex.…”

Differentiating between axonal damage and demyelination in healthy aging by combining diffusion-tensor imaging and diffusion-weighted spectroscopy in the human corpus callosum at 7 T

“…tNAA diffusion properties in white matter are therefore solely dictated by the structural properties of intra-axonal components and by the properties of the intra-axonal medium, thus providing a specific marker to the axonal contribution to WM degeneration. Soluble Choline compounds are located mainly in glial cells (Choi, et al, 2007,Le Belle, et al, 2002,Urenjak, et al, 1993 and thus their diffusion properties report on structural changes in glia, resulting from, for example, inflammation (Ercan, et al, 2016). Creatine and phosphocreatine are present in both tissue types and are tightly linked to cell energetics through the creatine kinase cycle (CK), and it has been shown that increase in energy demand modulates the diffusion coefficient of total creatine (Branzoli, et al, 2013).…”