Ece Ercan

Axonal and glial microstructural information obtained with diffusion-weighted magnetic resonance spectroscopy at 7T

Diffusion-weighted magnetic resonance spectroscopy (DWS) offers unique access to compartment-specific microstructural information on tissue, and potentially sensitive detection of compartment-specific changes in disease. The specificity of DWS is, however, offset by its relative low sensitivity, intrinsic to all MRS-based methods, and further exacerbated by the signal loss due to the diffusion weighting and long echo times. In this work we first provide an experimental example for the type of compartment-specific information that can be obtained with DWS from a small volume of interest (VOI) in brain white matter. We then propose and discuss a strategy for the analysis of DWS data, which includes the use of models of diffusion in compartments with simple geometries. We conclude with a broader discussion of the potential role of DWS in the characterization of tissue microstructure and the complementarity of DWS with less-specific but more sensitive microstructural tools such as diffusion tensor imaging.

A multimodal MRI approach to identify and characterize microstructural brain changes in neuropsychiatric systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-organ involvement and results in neurological and psychiatric (NP) symptoms in up to 40% of the patients. To date, the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) poses a challenge due to the lack of neuroradiological gold standards. In this study, we aimed to better localize and characterize normal appearing white matter (NAWM) changes in NPSLE by combining data from two quantitative MRI techniques, diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI). 9 active NPSLE patients (37 ± 13 years, all females), 9 SLE patients without NP symptoms (44 ± 11 years, all females), and 14 healthy controls (HC) (40 ± 9 years, all females) were included in the study. MTI, DTI and fluid attenuated inversion recovery (FLAIR) images were collected from all subjects on a 3 T MRI scanner. Magnetization transfer ratio (MTR), mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) maps and white matter lesion maps based on the FLAIR images were created for each subject. MTR and DTI data were then co-analyzed using tract-based spatial statistics and a cumulative lesion map to exclude lesions. Significantly lower MTR and FA and significantly higher AD, RD and MD were found in NPSLE compared to HC in NAWM regions. The differences in DTI measures and in MTR, however, were only moderately co-localized. Additionally, significant differences in DTI measures, but not in MTR, were found between NPSLE and SLE patients, suggesting that the underlying microstructural changes detected by MD are linked to the onset of NPSLE. The co-analysis of the anatomical distribution of MTI and DTI measures can potentially improve the diagnosis of NPSLE and contribute to the understanding of the underlying microstructural damage.

Glial and axonal changes in systemic lupus erythematosus measured with diffusion of intracellular metabolites

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.

The interaction between apparent diffusion coefficients and transverse relaxation rates of human brain metabolites and water studied by diffusion‐weighted spectroscopy at 7 T

The dependence of apparent diffusion coefficients (ADCs) of molecules in biological tissues on an acquisition‐specific timescale is a powerful mechanism for studying tissue microstructure. Unlike water, metabolites are confined mainly to intracellular compartments, thus providing higher specificity to tissue microstructure. Compartment‐specific structural and chemical properties may also affect molecule transverse relaxation times (T2). Here, we investigated the correlation between diffusion and relaxation for N‐acetylaspartate, creatine and choline compounds in human brain white matter in vivo at 7 T, and compared them with those of water under the same experimental conditions. Data were acquired in a volume of interest in parietal white matter at two different diffusion times, Δ = 44 and 246 ms, using a matrix of three echo times (TE) and five diffusion weighting values (up to 4575 s/mm2). Significant differences in the dependence of the ADCs on TE were found between water and metabolites, as well as among the different metabolites. A significant decrease in water ADC as a function of TE was observed only at the longest diffusion time (p < 0.001), supporting the hypothesis that at least part of the restricted water pool can be associated with longer T2, as suggested by previous studies in vitro. Metabolite data showed an increase of creatine (p < 0.05) and N‐acetylaspartate (p < 0.05) ADCs with TE at Δ = 44 ms, and a decrease of creatine (p < 0.05) and N‐acetylaspartate (p = 0.1) ADCs with TE at Δ = 246 ms. No dependence of choline ADC on TE was observed. The metabolite results suggest that diffusion and relaxation properties are dictated not only by metabolite distribution in different cell types, but also by other mechanisms, such as interactions with membranes, exchange between “free” and “bound” states or interactions with microsusceptibility gradients. Copyright

Changes in white matter microstructure suggest an inflammatory origin of neuropsychiatric systemic lupus erythematosus

To assess white matter (WM) and gray matter (GM) magnetization transfer ratio histogram peak heights (MTR‐HPHs) in different subsets of patients with neuropsychiatric systemic lupus erythematosus (NPSLE) who have unremarkable findings on 3T magnetic resonance imaging of the brain and to evaluate whether these values could be used to highlight different clinically suspected underlying pathogenic processes or identify the clinical NPSLE status or whether they could be associated with a specific NPSLE syndrome.

Rapid multi‐echo measurement of brain metabolite T2 values at 7 T using a single‐shot spectroscopic Carr–Purcell–Meiboom–Gill sequence and prior information

We present a method for the robust and accurate estimation of brain metabolite transverse relaxation times (T2) from multiple spin‐echo data acquired with a single‐shot Carr–Purcell–Meiboom–Gill (CPMG) spectroscopic sequence. Each acquired echo consists of a small number of complex time‐domain data points. The amplitudes of the spectral components in each echo are calculated by solving a set of linear equations in which previously estimated frequencies and linewidths serve as prior information. These priors are obtained from a short MRS experiment in which a large number of time‐domain data points are acquired, and are subsequently estimated using linear prediction with singular value decomposition (LPSVD) processing. We show that this process can be used to accurately and rapidly measure the T2 values for the main singlet resonances in single‐volume MRS measurements in the brain. The proposed method can be generalized to any set of MRS experiments comprising repeated measurements of amplitude changes, e.g. as a function of an experimental parameter, such as TE, inversion time or diffusion weighting. Copyright

Longitudinal MR spectroscopy of neurodegeneration in multiple sclerosis with diffusion of the intra-axonal constituent N-acetylaspartate

Multiple sclerosis (MS) is a pathologically complex CNS disease: inflammation, demyelination, and neuroaxonal degeneration occur concurrently and may depend on one another. Current therapies are aimed at the immune-mediated, inflammatory destruction of myelin, whereas axonal degeneration is ongoing and not specifically targeted. Diffusion-weighted magnetic resonance spectroscopy can measure the diffusivity of metabolites in vivo, such as the axonal/neuronal constituent N-acetylaspartate, allowing compartment-specific assessment of disease-related changes. Previously, we found significantly lower N-acetylaspartate diffusivity in people with MS compared to healthy controls (Wood et al., 2012) suggesting that this technique can measure axonal degeneration and could be useful in developing neuroprotective agents. In this longitudinal study, we found that N-acetylaspartate diffusivity decreased by 8.3% (p < 0.05) over 6 months in participants who were experiencing clinical or MRI evidence of inflammatory activity (n = 13), whereas there was no significant change in N-acetylaspartate diffusivity in the context of clinical and radiological stability (n = 6). As N-acetylaspartate diffusivity measurements are thought to more specifically reflect the intra-axonal space, these data suggest that N-acetylaspartate diffusivity can report on axonal health on the background of multiple pathological processes in MS, both cross-sectionally and longitudinally.

Cerebral magnetic resonance imaging in quiescent Crohn's disease patients with fatigue

AIM To evaluate brain involvement in quiescent Crohn’s disease (CD) patients with fatigue using quantitative magnetic resonance imaging (MRI). METHODS Multiple MRI techniques were used to assess cerebral changes in 20 quiescent CD patients with fatigue (defined with at least 6 points out of an 11-point numeric rating scale compared with 17 healthy age and gender matched controls without fatigue. Furthermore, mental status was assessed by cognitive functioning, based on the neuropsychological inventory including the different domains global cognitive functioning, memory and executive functioning and in addition mood and quality of life scores. Cognitive functioning and mood status were correlated with MRI findings in the both study groups. RESULTS Reduced glutamate + glutamine (Glx = Glu + Gln) concentrations (P = 0.02) and ratios to total creatine (P = 0.02) were found in CD patients compared with controls. Significant increased Cerebral Blood Flow (P = 0.05) was found in CD patients (53.08 ± 6.14 mL/100 g/min) compared with controls (47.60 ± 8.62 mL/100 g/min). CD patients encountered significantly more depressive symptoms (P < 0.001). Cognitive functioning scores related to memory (P = 0.007) and executive functioning (P = 0.02) were lower in CD patients and both scores showed correlation with depression and anxiety. No correlation was found subcortical volumes between CD patients and controls in the T1-weighted analysis. In addition, no correlation was found between mental status and MRI findings. CONCLUSION This work shows evidence for perfusion, neurochemical and mental differences in the brain of CD patients with fatigue compared with healthy controls.

AB0705 Psychopathologic Involvement in Systemic Sclerosis: A Pilot Study

Background Involvement of the brain in systemic sclerosis (SSc) could be suspected given the presence of disturbances on cerebrovascular imaging or mental dysfunction, including disorders of cognition or mood. It is important to confirm this since the intervention of first choice for cognitive disorders is highly depending on the pathophysiology. Objectives To investigate whether mental complaints in patients with SSc are related to organic brain dysfunction. Methods Twenty SSc patients with self-reported mental complaints, including concentration problems, fatigue, memory loss, or depression, were cross-sectionally assessed by neuropsychological testing, psychiatric evaluation and magnetic resonance imaging (MRI) of the brain. All patients completed the Hospital Anxiety and Depression Scale, Dissociation Experience Scale, a screenings tool for fatigue (MFI-20), Short Form-36 and Neuropsychiatric Inventory. Patients were compared with 20 age and sex matched healthy controls. Results Patients and healthy controls did not differ with respect to sociodemographic characteristics. In 5 SSc patients cognitive dysfunction was considered questionable by the neuropsychologist. Patients performed slightly worse on cognition tasks as compared to healthy controls, but all test results were within the normal range. The MRI showed small white matter hyperintensities (WMH) in 18 patients and in 15 healthy controls. The neuropsychological tests were completely normal within those 15 healthy controls. Thirteen SSc patients with WMH on MRI, had normal neuropsychological tests and no mood disorder. Four patients with WMH had a mood disorder. Conclusions Based on this pilot study, SSc patients show slight disturbances of mental functioning as compared to healthy controls, but their performance is within the normal range. No clear association between mental dysfunction and organic brain abnormalities could be detected. In case of mental dysfunctioning in SSc patients, we propose psychological intervention, starting with psychoeducation and in some cases cognitive-behavioural therapy, is the best treatment. Disclosure of Interest J. Meijs Grant/research support from: Jessica Meijs was supported by an unrestricted educational grant of Actelion Pharmaceuticals Nederland BV (Woerden, The Netherlands)., E. Ercan: None declared, E. Baptist: None declared, N. van der Wee: None declared, O. Tritanon: None declared, M. van Buchem: None declared, T. Huizinga: None declared, A. Schouffoer: None declared, H. Middelkoop: None declared, J. de Vries-Bouwstra: None declared