Direct spectroscopic quantification of small molecules using low cost, low field (< 0.1 T) large bore portable magnets is not possible using conventional techniques due the presence of strong... Show moreDirect spectroscopic quantification of small molecules using low cost, low field (< 0.1 T) large bore portable magnets is not possible using conventional techniques due the presence of strong homonuclear coupling which results in complicated spectral patterns with resonances separated by much less than the achievable spectral linewidth. In contrast, a method using the signals from a Carr-Purcell-Meiboom-Gill (CPMG) train, in which the data are Fourier transformed in this indirect dimension, can produce so-called J-spectra in which several distinct spectral features can be distinguished. In this work, we evaluate this technique to quantify the amount of alcohol (ethanol) in intact bottles of wines or spirits. Show less
Zande, N.A. van de; Bulk, M.; Najac, C.; Weerd, L. van der; Bresser, J. de; Lewerenz, J.; ... ; Bot, S.T. de 2023
IntroductionStrong evidence suggests a significant role for iron accumulation in the brain in addition to the well-documented neurodegenerative aspects of Huntington’s disease (HD). The putative... Show moreIntroductionStrong evidence suggests a significant role for iron accumulation in the brain in addition to the well-documented neurodegenerative aspects of Huntington’s disease (HD). The putative mechanisms by which iron is linked to the HD pathogenesis are multiple, including oxidative stress, ferroptosis and neuroinflammation. However, no previous study in a neurodegenerative disease has linked the observed increase of brain iron accumulation as measured by MRI with well-established cerebrospinal fluid (CSF) and blood biomarkers for iron accumulation, or with associated processes such as neuroinflammation. This study is designed to link quantitative data from iron levels and neuroinflammation metabolites obtained from 7T MRI of HD patients, with specific and well-known clinical biofluid markers for iron accumulation, neurodegeneration and neuroinflammation. Biofluid markers will provide quantitative measures of overall iron accumulation, neurodegeneration and neuroinflammation, while MRI measurements on the other hand will provide quantitative spatial information on brain pathology, neuroinflammation and brain iron accumulation, which will be linked to clinical outcome measures.MethodsThis is an observational cross-sectional study, IMAGINE-HD, in HD gene expansion carriers and healthy controls. We include premanifest HD gene expansion carriers and patients with manifest HD in an early or moderate stage. The study includes a 7T MRI scan of the brain, clinical evaluation, motor, functional, and neuropsychological assessments, and sampling of CSF and blood for the detection of iron, neurodegenerative and inflammatory markers. Quantitative Susceptibility Maps will be reconstructed using T2* weighted images to quantify brain iron levels and Magnetic Resonance Spectroscopy will be used to obtain information about neuroinflammation by measuring cell-specific intracellular metabolites’ level and diffusion. Age and sex matched healthy subjects are included as a control group.DiscussionResults from this study will provide an important basis for the evaluation of brain iron levels and neuroinflammation metabolites as an imaging biomarker for disease stage in HD and their relationship with the salient pathomechanisms of the disease on the one hand, and with clinical outcome on the other. Show less
We have investigated an approach for obtaining H-1 NMR spectra of different alcohols on a large-bore (27 cm diameter), B (0) = 0.05 T (f (0) = 2 MHz) portable MRI scanner. We used a Carr-Purcell... Show moreWe have investigated an approach for obtaining H-1 NMR spectra of different alcohols on a large-bore (27 cm diameter), B (0) = 0.05 T (f (0) = 2 MHz) portable MRI scanner. We used a Carr-Purcell-Meiboom-Gill (CPMG) sequence to acquire multiecho data from solutions of different alcohols, focusing on ethanol, a molecule of relevance to many applications in the food and beverage industry. Our results show that the Fourier transformed J-spectra at different echo spacings fit well with simulations of the evolution of the echo train signal with excellent signal to noise ratio (SNR) for concentrations of similar to 10 % within a few minutes. Spectra were also obtained from intact bottles of whiskey and wine. Finally, we show that different alcohols with similar chemical structures can be differentiated using this approach. Show less
Currently, little is known about the spatial distribution of white matter hyperintensities (WMH) in the brain of patients with Systemic Lupus erythematosus (SLE). Previous lesion markers, such as... Show moreCurrently, little is known about the spatial distribution of white matter hyperintensities (WMH) in the brain of patients with Systemic Lupus erythematosus (SLE). Previous lesion markers, such as number and volume, ignore the strategic location of WMH. The goal of this work was to develop a fully-automated method to identify predominant patterns of WMH across WM tracts based on cluster analysis. A total of 221 SLE patients with and without neuropsychiatric symptoms from two different sites were included in this study. WMH segmentations and lesion locations were acquired automatically. Cluster analysis was performed on the WMH distribution in 20 WM tracts. Our pipeline identified five distinct clusters with predominant involvement of the forceps major, forceps minor, as well as right and left anterior thalamic radiations and the right inferior fronto-occipital fasciculus. The patterns of the affected WM tracts were consistent over the SLE subtypes and sites. Our approach revealed distinct and robust tract-based WMH patterns within SLE patients. This method could provide a basis, to link the location of WMH with clinical symptoms. Furthermore, it could be used for other diseases characterized by presence of WMH to investigate both the clinical relevance of WMH and underlying pathomechanism in the brain. Show less
In a standard spin echo, the time evolution due to homonuclear couplings is not reversed, leading to echo time (TE)-dependent modulation of the signal amplitude and signal loss in the case of... Show moreIn a standard spin echo, the time evolution due to homonuclear couplings is not reversed, leading to echo time (TE)-dependent modulation of the signal amplitude and signal loss in the case of overlapping multiplet resonances. This has an adverse effect on quantification of several important metabolites such as glutamate and glutamine. Here, we propose a J-refocused variant of the sLASER sequence (J-sLASER) to improve quantification of J-coupled metabolites at ultrahigh field (UHF). The use of the sLASER sequence is particularly advantageous at UHF as it minimizes chemical shift displacement error and results in relatively homogenous refocusing. We simulated the MRS signal from brain metabolites over a broad range of TE values with sLASER and J-sLASER, and showed that the signal of J-coupled metabolites was increased with J-sLASER with TE values up to similar to 80 ms. We further simulated "brain-like" spectra with both sequences at the shortest TE available on our scanner. We showed that, despite the slightly longer TE, the J-sLASER sequence results in significantly lower Cramer-Rao lower bounds (CRLBs) for J-coupled metabolites compared with those obtained with sLASER. Following phantom validation, we acquired spectra from two brain regions in 10 healthy volunteers (age 38 +/- 15 years) using both sequences. We showed that using J-sLASER results in a decrease of CRLBs for J-coupled metabolites. In particular, we measured a robust similar to 38% decrease in the mean CRLB (glutamine) in parietal white matter and posterior cingulate cortex (PCC). We further showed, in 10 additional healthy volunteers (age 34 +/- 15 years), that metabolite quantification following two separate acquisitions with J-sLASER in the PCC was repeatable. The improvement in quantification of glutamine may in turn improve the independent quantification of glutamate, the main excitatory neurotransmitter in the brain, and will simultaneously help to track possible modulations of glutamine, which is a key player in the glutamatergic cycle in astrocytes. Show less
Inglese, F.; Kim, M.; Steup-Beekman, G.M.; Huizinga, T.W.J.; Buchem, M.A. van; Bresser, J. de; ... ; Ronen, I. 2022
Introduction/PurposeSystemic lupus erythematosus (SLE) is a chronic auto-immune disease with a broad spectrum of clinical presentations, including heterogeneous neuropsychiatric (NP) syndromes.... Show moreIntroduction/PurposeSystemic lupus erythematosus (SLE) is a chronic auto-immune disease with a broad spectrum of clinical presentations, including heterogeneous neuropsychiatric (NP) syndromes. Structural brain abnormalities are commonly found in SLE and NPSLE, but their role in diagnosis is limited, and their usefulness in distinguishing between NPSLE patients and patients in which the NP symptoms are not primarily attributed to SLE (non-NPSLE) is non-existent. Self-supervised contrastive learning algorithms proved to be useful in classification tasks in rare diseases with limited number of datasets. Our aim was to apply self-supervised contrastive learning on T-1-weighted images acquired from a well-defined cohort of SLE patients, aiming to distinguish between NPSLE and non-NPSLE patients. Subjects and MethodsWe used 3T MRI T-1-weighted images of 163 patients. The training set comprised 68 non-NPSLE and 34 NPSLE patients. We applied random geometric transformations between iterations to augment our data sets. The ML pipeline consisted of convolutional base encoder and linear projector. To test the classification task, the projector was removed and one linear layer was measured. Validation of the method consisted of 6 repeated random sub-samplings, each using a random selection of a small group of patients of both subtypes. ResultsIn the 6 trials, between 79% and 83% of the patients were correctly classified as NPSLE or non-NPSLE. For a qualitative evaluation of spatial distribution of the common features found in both groups, Gradient-weighted Class Activation Maps (Grad-CAM) were examined. Thresholded Grad-CAM maps show areas of common features identified for the NPSLE cohort, while no such communality was found for the non-NPSLE group. Discussion/ConclusionThe self-supervised contrastive learning model was effective in capturing common brain MRI features from a limited but well-defined cohort of SLE patients with NP symptoms. The interpretation of the Grad-CAM results is not straightforward, but indicates involvement of the lateral and third ventricles, periventricular white matter and basal cisterns. We believe that the common features found in the NPSLE population in this study indicate a combination of tissue loss, local atrophy and to some extent that of periventricular white matter lesions, which are commonly found in NPSLE patients and appear hypointense on T-1-weighted images. Show less
Marco, R. de; Ronen, I.; Branzoli, F.; Amato, M.L.; Asllani, I.; Colasanti, A.; ... ; Cercignani, M. 2022
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
Inglese, F.; Jaarsma-Coes, M.G.; Steup-Beekman, G.M.; Monahan, R.; Huizinga, T.; Buchem, M.A. van; ... ; Bresser, J. de 2021
Objectives Advanced white matter hyperintensity (WMH) markers on brain MRI may help reveal underlying mechanisms and aid in the diagnosis of different phenotypes of SLE patients experiencing... Show moreObjectives Advanced white matter hyperintensity (WMH) markers on brain MRI may help reveal underlying mechanisms and aid in the diagnosis of different phenotypes of SLE patients experiencing neuropsychiatric (NP) manifestations. Methods In this prospective cohort study, we included a clinically well-defined cohort of 155 patients consisting of 38 patients with NPSLE (26 inflammatory and 12 ischaemic phenotype) and 117 non-NPSLE patients. Differences in 3 T MRI WMH markers (volume, type and shape) were compared between patients with NPSLE and non-NPSLE and between patients with inflammatory and ischaemic NPSLE by linear and logistic regression analyses corrected for age, sex and intracranial volume. Results Compared with non-NPSLE [92% female; mean age 42 (13) years], patients with NPSLE [87% female; mean age 40 (14) years] showed a higher total WMH volume [B (95%-CI)]: 0.46 (0.0 7 <-> 0.86); P = 0.021], a higher periventricular/confluent WMH volume [0.46 (0.0 6 <-> 0.86); P = 0.024], a higher occurrence of periventricular with deep WMH type [0.32 (0.1 3 <-> 0.77); P = 0.011], a higher number of deep WMH lesions [3.06 (1.2 1 <-> 4.90); P = 0.001] and a more complex WMH shape [convexity: -0.07 (-0.12 <-> -0.02); P = 0.011, concavity index: 0.05 (0.0 1 <-> 0.08); P = 0.007]. WMH shape was more complex in inflammatory NPSLE patients [89% female; mean age 39 (15) years] compared with patients with the ischaemic phenotype [83% female; mean age 41 (11) years] [concavity index: 0.08 (0.0 1 <-> 0.15); P = 0.034]. Conclusion We demonstrated that patients with NPSLE showed a higher periventricular/confluent WMH volume and more complex shape of WMH compared with non-NPSLE patients. This finding was particularly significant in inflammatory NPLSE patients, suggesting different or more severe underlying pathophysiological abnormalities. Show less
Lundell, H.; Najac, C.; Bulk, M.; Kan, H.E.; Webb, A.G.; Ronen, I. 2021
Double diffusion encoding (DDE) of the water signal offers a unique ability to separate the effect of microscopic anisotropic diffusion in structural units of tissue from the overall macroscopic... Show moreDouble diffusion encoding (DDE) of the water signal offers a unique ability to separate the effect of microscopic anisotropic diffusion in structural units of tissue from the overall macroscopic orientational distribution of cells. However, the specificity in detected microscopic anisotropy is limited as the signal is averaged over different cell types and across tissue compartments. Performing side-by-side water and metabolite DDE spectroscopic (DDES) experiments provides complementary measures from which intracellular and extracellular microscopic fractional anisotropies (mu FA) and diffusivities can be estimated. Metabolites are largely confined to the intracellular space and therefore provide a benchmark for intracellular mu FA and diffusivities of specific cell types. By contrast, water DDES measurements allow examination of the separate contributions to water mu FA and diffusivity from the intraand extracellular spaces, by using a wide range of b values to gradually eliminate the extracellular contribution. Here, we aimed to estimate tissue and compartment specific human brain microstructure by combining water and metabolites DDES experiments. We performed our DDES measurements in two brain regions that contain widely different amounts of white matter (WM) and gray matter (GM): parietal white matter (PWM) and occipital gray matter (OGM) in a total of 20 healthy volunteers at 7 Tesla. Metabolite DDES measurements were performed at b = 7199 s/mm(2), while water DDES measurements were performed with a range of b values from 918 to 7199 s/mm(2). The experimental framework we employed here resulted in a set of insights pertaining to the morphology of the intracellular and extracellular spaces in both gray and white matter. Results of the metabolite DDES experiments in both PWM and OGM suggest a highly anisotropic intracellular space within neurons and glia, with the possible exception of gray matter glia. The water mu FA obtained from the DDES results at high b values in both regions converged with that of the metabolite DDES, suggesting that the signal from the extracellular space is indeed effectively suppressed at the highest b value. The mu FA measured in the OGM significantly decreased at lower b values, suggesting a considerably lower anisotropy of the extracellular space in GM compared to WM. In PWM, the water mu FA remained high even at the lowest b value, indicating a high degree of organization in the interstitial space in WM. Tortuosity values in the cytoplasm for water and tNAA, obtained with correlation analysis of microscopic parallel diffusivity with respect to GM/WM tissue fraction in the volume of interest, are remarkably similar for both molecules, while exhibiting a clear difference between gray and white matter, suggesting a more crowded cytoplasm and more complex cytomorphology of neuronal cell bodies and dendrites in GM than those found in long-range axons in WM. Show less
Silvagni, E.; Inglese, F.; Bortoluzzi, A.; Borrelli, M.; Goeman, J.J.; Revenaz, A.; ... ; Ercan, E. 2021
Objectives. To evaluate longitudinal variations in diffusion tensor imaging (DTI) metrics of different white matter (WM) tracts of newly diagnosed SLE patients, and to assess whether DTI changes... Show moreObjectives. To evaluate longitudinal variations in diffusion tensor imaging (DTI) metrics of different white matter (WM) tracts of newly diagnosed SLE patients, and to assess whether DTI changes relate to changes in clinical characteristics over time.Methods. A total of 17 newly diagnosed SLE patients (19-55 years) were assessed within 24 months from diagnosis with brain MRI (1.5 T Philips Achieva) at baseline, and after at least 12 months. Fractional anisotropy, mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity values were calculated in several normal-appearing WM tracts. Longitudinal variations in DTI metrics were analysed by repeated measures analysis of variance. DTI changes were separately assessed for 21 WM tracts. Associations between longitudinal alterations of DTI metrics and clinical variables (SLEDAI-2K, complement levels, glucocorticoid dosage) were evaluated using adjusted Spearman correlation analysis.Results. Mean MD and RD values from the normal-appearing WM significantly increased over time (P = 0.019 and P = 0.021, respectively). A significant increase in RD (P = 0.005) and MD (P = 0.012) was found in the left posterior limb of the internal capsule; RD significantly increased in the left retro-lenticular part of the internal capsule (P = 0.013), and fractional anisotropy significantly decreased in the left corticospinal tract (P = 0.029). No significant correlation was found between the longitudinal change in DTI metrics and the change in clinical measures.Conclusion. Increase in diffusivity, reflecting a compromised WM tissue microstructure, starts in initial phases of the SLE disease course, even in the absence of overt neuropsychiatric (NP) symptoms. These results indicate the importance of monitoring NP involvement in SLE, even shortly after diagnosis. Show less
Objectives The underlying structural brain correlates of neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) remain unclear, thus hindering correct diagnosis. We compared brain... Show moreObjectives The underlying structural brain correlates of neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) remain unclear, thus hindering correct diagnosis. We compared brain tissue volumes between a clinically well-defined cohort of patients with NPSLE and SLE patients with neuropsychiatric syndromes not attributed to SLE (non-NPSLE). Within the NPSLE patients, we also examined differences between patients with two distinct disease phenotypes: ischemic and inflammatory. Methods In this prospective (May 2007 to April 2015) cohort study, we included 38 NPSLE patients (26 inflammatory and 12 ischemic) and 117 non-NPSLE patients. All patients underwent a 3-T brain MRI scan that was used to automatically determine white matter, grey matter, white matter hyperintensities (WMH) and total brain volumes. Group differences in brain tissue volumes were studied with linear regression analyses corrected for age, gender, and total intracranial volume and expressed as B values and 95% confidence intervals. Results NPSLE patients showed higher WMH volume compared to non-NPSLE patients (p = 0.004). NPSLE inflammatory patients showed lower total brain (p = 0.014) and white matter volumes (p = 0.020), and higher WMH volume (p = 0.002) compared to non-NPSLE patients. Additionally, NPSLE inflammatory patients showed lower white matter (p = 0.020) and total brain volumes (p = 0.038) compared to NPSLE ischemic patients. Conclusion We showed that different phenotypes of NPSLE were related to distinct patterns of underlying structural brain MRI changes. Especially the inflammatory phenotype of NPSLE was associated with the most pronounced brain volume changes, which might facilitate the diagnostic process in SLE patients with neuropsychiatric symptoms. Show less
Monahan, R.C.; Inglese, F.; Middelkoop, H.; Buchem, M. van; Huizinga, T.W.J.; Kloppenburg, M.; ... ; Bresser, J. de 2021
Objective To compare cognitive function between patients with different phenotypes of neuropsychiatric systemic lupus erythematosus (NPSLE) and assess its association with brain and white matter... Show moreObjective To compare cognitive function between patients with different phenotypes of neuropsychiatric systemic lupus erythematosus (NPSLE) and assess its association with brain and white matter hyperintensity (WMH) volumes. Methods Patients attending the Leiden University Medical Centre NPSLE clinic between 2007 and 2015 without large brain infarcts were included (n=151; 42 +/- 13 years, 91% women). In a multidisciplinary consensus meeting, neuropsychiatric symptoms were attributed to systemic lupus erythematosus (SLE) (NPSLE, inflammatory (n=24) or ischaemic (n=12)) or to minor/non-NPSLE (n=115). Multiple regression analyses were performed to compare cognitive function between NPSLE phenotypes and to assess associations between brain and WMH volumes and cognitive function cross-sectionally. Results Global cognitive function was impaired in 5%, learning and memory (LM) in 46%, executive function and complex attention (EFCA) in 39% and psychomotor speed (PS) in 46% of all patients. Patients with inflammatory NPSLE showed the most cognitive impairment in all domains (p <= 0.05). Higher WMH volume associated with lower PS in the total group (B: -0.14 (95% CI -0.32 to -0.02)); especially in inflammatory NPSLE (B: -0.36 (95% CI -0.60 to -0.12). In the total group, lower total brain volume and grey matter volume associated with lower cognitive functioning in all domains (all: 0.00/0.01 (0.00;0.01)) and lower white matter volume associated with lower LM, EFCA and PS (all: 0.00/0.01 (0.00;0.01)). Conclusion We demonstrated that an association between brain and WMH volumes and cognitive function is present in patients with SLE, but differs between (NP)SLE phenotypes. WMHs associated with PS especially in inflammatory NPSLE, which suggests a different, potentially more severe underlying pathophysiological mechanism of cognitive impairment in this phenotype. Show less
Enhanced activity of the glutamatergic system has been linked to migraine pathophysiology. The present study aimed to assess the involvement of the glutamatergic system in the onset of attacks. We... Show moreEnhanced activity of the glutamatergic system has been linked to migraine pathophysiology. The present study aimed to assess the involvement of the glutamatergic system in the onset of attacks. We provoked attacks by infusion of glyceryl trinitrate (GTN; 0.5 mu g/kg/min over 20 min) in 24 female episodic migraineurs without aura and 13 female age-matched healthy controls. Over the course of a single day participants were scanned three times at fixed time slots (baseline before GTN infusion, 90 min and 270 min after start of GTN infusion). Single volume proton magnetic resonance spectra (H-1-MRS) were acquired at 7 Tesla from a volume of interest (VOI, 2x2x3 cm) in the visual cortex. We assessed the concentrations of glutamate, its major precursor glutamine, and its product gamma-aminobutyric acid (GABA) over the course of a provoked attack. The preictal state was defined as the period after GTN infusion until the migraine-like headache started, independent of possible experienced premonitory symptoms, and the ictal state was defined as the period with provoked migraine-like headache. Data were analyzed using a linear mixed-effect model for repeated measures. Glutamate and glutamine levels did not change from interictal to the preictal and ictal state. GABA levels increased from interictal towards the preictal state for migraine patients compared with healthy controls. We conclude that high resolution 7T MRS is able to show changes in the glutamatergic system towards a triggered migraine attack, by revealing an increased GABA concentration associated with the onset of a migraine attack. Show less
Bulk, M.; Harten, T. van; Kenkhuis, B.; Inglese, F.; Hegeman, I.; Duinen, S. van; ... ; Ronen, I. 2021
Systemic lupus erythematosus (SLE) is an auto-immune disease characterized by multi-organ involvement. Although uncommon, central nervous system involvement in SLE, termed neuropsychiatric SLE ... Show moreSystemic lupus erythematosus (SLE) is an auto-immune disease characterized by multi-organ involvement. Although uncommon, central nervous system involvement in SLE, termed neuropsychiatric SLE (NPSLE), is not an exception. Current knowledge on underlying pathogenic mechanisms is incomplete, however, neuroinflammation is thought to play a critical role. Evidence from neurodegenerative diseases and multiple sclerosis suggests that neuroinflammation is correlated with brain iron accumulation, making quantitative susceptibility mapping (QSM) a potential hallmark for neuroinflammation in vivo. This study assessed susceptibility values of the thalamus and basal ganglia in (NP)SLE patients and further investigated the in vivo findings with histological analyses of postmortem brain tissue derived from SLE patients. We used a 3T MRI scanner to acquire single-echo T2*-weighted images of 44 SLE patients and 20 age-matched healthy controls. Of the 44 patients with SLE, all had neuropsychiatric complaints, of which 29 were classified as non-NPSLE and 15 as NPSLE (seven as inflammatory NPSLE and eight as ischemic NPSLE). Mean susceptibility values of the thalamus, caudate nucleus, putamen, and globus pallidus were calculated. Formalin-fixed paraffin-embedded post-mortem brain tissue including the putamen and globus pallidus of three additional SLE patients was obtained and stained for iron, microglia and astrocytes. Susceptibility values of SLE patients and age-matched controls showed that iron levels in the thalamus and basal ganglia were not changed due to the disease. No subgroup of SLE showed higher susceptibility values. No correlation was found with disease activity or damage due to SLE. Histological examination of the post-mortem brain showed no increased iron accumulation. Our results suggest that neuroinflammation in NPSLE does not necessarily go hand in hand with iron accumulation, and that the inflammatory pathomechanism in SLE may differ from the one observed in neurodegenerative diseases and in multiple sclerosis. Show less
Ronen, I.; O'Reilly, T.; Froeling, M.; Webb, A.G. 2020
We examined approaches for obtaining H-1 NMR spectra of brain metabolites on a low-field (B-0 = 0.05 T) portable MRI scanner, which was developed in our laboratory with the aim of bringing cost... Show moreWe examined approaches for obtaining H-1 NMR spectra of brain metabolites on a low-field (B-0 = 0.05 T) portable MRI scanner, which was developed in our laboratory with the aim of bringing cost-effective radiological services to populations in underserved, remote regions. The low static magnetic field B-0 dictates low signal to noise ratio for metabolites in the mM concentration range, and results in an overall spectral region for the H-1 resonances of these metabolites narrower than the linewidth obtainable in our scanner. The narrow spectral range also precludes the possibility of suppressing the large contribution of the water resonance at the acquisition stage.We used a spectroscopic Carr-Purcell-Meiboom-Gill (CPMG) sequence to acquire multiecho data from solutions of J-coupled brain metabolites, focusing on lactic acid, a metabolite whose concentration is negligible in the healthy brain and increases significantly in several disease conditions. The J spectra we obtained for lactate from the Fourier transformation of the multiecho data are spectrally well-resolved for a range of echo spacing values. We show that the J spectra at different echo spacings fit well with simulations of the evolution of echo train signal of the lactate under the same conditions. Applying a Jrefocused variant of the CPMG sequence, the J modulation of the echo decay is removed, providing a way for subtracting the large contribution of the non-modulated component in the J spectrum in conditions where notching it using post-processing methods is impossible. We also demonstrate by means of experimental data and simulations that in our experimental conditions, J-spectra of other prominent brain metabolites, such as the neurotransmitter glutamate, do not yield discernible peaks and only contribute to a broad peak at zero frequency. (C) 2020 The Author(s). Published by Elsevier Inc. Show less
Bulk, M.; Abdelmoula, W.M.; Geut, H.; Wiarda, W.; Ronen, I.; Dijkstra, J.; Weerd, L. van der 2020
Imaging studies showed that the structure of the corpus callosum (CC) is affected in amyotrophic lateral sclerosis (ALS). Some clinical studies also suggest that interhemispheric connectivity is... Show moreImaging studies showed that the structure of the corpus callosum (CC) is affected in amyotrophic lateral sclerosis (ALS). Some clinical studies also suggest that interhemispheric connectivity is altered, since mirror movements seem to occur in ALS. Finally, reduced interhemispheric inhibition (IHI), studied by transcranial magnetic stimulation (TMS), has been reported. It is not known whether there is any association between these findings. Here, we studied the integrity of the CC in ALS on the morphological, the functional, the electrophysiological, and the clinical level. Twenty-seven right-handed ALS patients and 21 healthy right-handed controls were included. Mirror activity (MA) was quantified using surface EMG. Diffusion tensor imaging tractography was used to segment the CC and quantify fractional anisotropy (FA). We studied the diffusivity of the intra-axonal markers N-acetylaspartate+N-acetyl aspartyl glutamate D(tNAA) within the CC. IHI was studied as a marker of CC function using a double-pulse TMS protocol. ALS patients showed significantly decreased FA in the motor segment of the CC (p < 0.01), and IHI was significantly reduced compared to controls (p = 0.01). However, no differences were observed regarding D(tNAA) and MA. The morphological as well as the functional integrity of the CC are altered in ALS. IHI was reduced in ALS, associated with decreased FA in the motor CC. Patients did not exhibit increased MA. Also, no differences within the CC were observed using diffusion-weighted spectroscopy. IHI might serve as a marker of transcallosal pathway disruption in ALS, even before clinical deficits become apparent. Show less
Lundell, H.; Ingo, C.; Dyrby, T.B.; Ronen, I. 2020
Metabolite diffusion measurable in humans in vivo with diffusion-weighted spectroscopy (DW-MRS) provides a window into the intracellular morphology and state of specific cell types. Anisotropic... Show moreMetabolite diffusion measurable in humans in vivo with diffusion-weighted spectroscopy (DW-MRS) provides a window into the intracellular morphology and state of specific cell types. Anisotropic diffusion in white matter is governed by the microscopic properties of the individual cell types and their structural units (axons, soma, dendrites). However, anisotropy is also markedly affected by the macroscopic orientational distribution over the imaging voxel, particularly in DW-MRS, where the dimensions of the volume of interest (VOI) are much larger than those typically used in diffusion-weighted imaging. One way to address the confound of macroscopic structural features is to average the measurements acquired with uniformly distributed gradient directions to mimic a situation where fibers present in the VOI are orientationally uniformly distributed. This situation allows the extraction of relevant microstructural features such as transverse and longitudinal diffusivities within axons and the related microscopic fractional anisotropy. We present human DW-MRS data acquired at 7 T in two different white matter regions, processed and analyzed as described above, and find that intra-axonal diffusion of the neuronal metabolite N-acetyl aspartate is in good correspondence to simple model interpretations, such as multi-Gaussian diffusion from disperse fibers where the transverse diffusivity can be neglected. We also discuss the implications of our approach for current and future applications of DW-MRS for cell-specific measurements. 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
