Background: Low-dose lipopolysaccharide (LPS) is a well-established experimental method for inducing systemic inflammation and shown by microscopy to activate microglia in rodents. Currently,... Show moreBackground: Low-dose lipopolysaccharide (LPS) is a well-established experimental method for inducing systemic inflammation and shown by microscopy to activate microglia in rodents. Currently, techniques for in-vivo imaging of glia in humans are limited to TSPO (Translocator protein) PET, which is expensive, methodologically challenging, and has poor cellular specificity. Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) sensitizes MR spectra to diffusion of intracellular metabolites, potentially providing cell-specific information about cellular morphology. In this preliminary study, we applied DW-MRS to measure changes in the apparent diffusion coefficients (ADC) of glial and neuronal metabolites to healthy participants who underwent an LPS administration protocol. We hypothesized that the ADC of glial metabolites will be selectively modulated by LPSinduced glial activation. Methods: Seven healthy male volunteers, (mean 25.3 +/- 5.9 years) were each tested in two separate sessions once after LPS (1 ng/Kg intravenously) and once after placebo (saline). Physiological responses were monitored during each session and serial blood samples and Profile of Mood States (POMS) completed to quantify white blood cell (WBC), cytokine and mood responses. DW-MRS data were acquired 5-51/2 hours after injection from two brain regions: grey matter in the left thalamus, and frontal white matter. Results: Body temperature, heart rate, WBC and inflammatory cytokines were significantly higher in the LPS compared to the placebo condition (p < 0.001). The ADC of the glial metabolite choline (tCho) was also significantly increased after LPS administration compared to placebo (p = 0.008) in the thalamus which scaled with LPS-induced changes in POMS total and negative mood (Adj R-2 = 0.83; p = 0.004). Conclusions: DW-MRS may be a powerful new tool sensitive to glial cytomorphological changes in grey matter induced by systemic inflammation. Show less
Genovese, G.; Marjanska, M.; Auerbach, E.J.; Cherif, L.Y.; Ronen, I.; Lehericy, S.; Branzoli, F. 2020
Diffusion-weighted (DW-) MRS investigates non-invasively microstructural properties of tissue by probing metabolite diffusion in vivo. Despite the growing interest in DW-MRS for clinical... Show moreDiffusion-weighted (DW-) MRS investigates non-invasively microstructural properties of tissue by probing metabolite diffusion in vivo. Despite the growing interest in DW-MRS for clinical applications, little has been published on the reproducibility of this technique. In this study, we explored the optimization of a single-voxel DW-semi-LASER sequence for clinical applications at 3 T, and evaluated the reproducibility of the method under different experimental conditions. DW-MRS measurements were carried out in 10 healthy participants and repeated across three sessions. Metabolite apparent diffusion coefficients (ADCs) were calculated from mono-exponential fits (ADC(exp)) up to b = 3300 s/mm(2), and from the diffusional kurtosis approach (ADC(K)) up to b = 7300 s/mm(2). The inter-subject variabilities of ADCs of N-acetylaspartate + N-acetylaspartylglutamate (tNAA), creatine + phosphocreatine, choline containing compounds, and myo-inositol were calculated in the posterior cingulate cortex (PCC) and in the corona radiata (CR). We explored the effect of physiological motion on the DW-MRS signal and the importance of cardiac gating and peak thresholding to account for signal amplitude fluctuations. Additionally, we investigated the dependence of the intra-subject variability on the acquisition scheme using a bootstrapping resampling method. Coefficients of variation were lower in PCC than CR, likely due to the different sensitivities to motion artifacts of the two regions. Finally, we computed coefficients of repeatability for ADC(exp) and performed power calculations needed for designing clinical studies. The power calculation for ADC(exp) of tNAA showed that in the PCC seven subjects per group are sufficient to detect a difference of 5% between two groups with an acquisition time of 4 min, suggesting that ADC(exp) of tNAA is a suitable marker for disease-related intracellular alteration even in small case-control studies. In the CR, further work is needed to evaluate the voxel size and location that minimize the motion artifacts and variability of the ADC measurements. Show less
Bodini, B.; Branzoli, F.; Poirion, E.; Garcia-Lorenzo, D.; Didier, M.; Maillart, E.; ... ; Stankoff, B. 2018
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... Show moreSystemic 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 μm2/ms, P = 0.018) and total choline (0.142 ± 0.031 μm2/ms, P = 0.044) compared to healthy controls (0.171 ± 0.024 μm2/ms, 0.124 ± 0.018 μm2/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. Show less
