Author name cluster

Itamar Ronen

Possible papers associated with this exact author name in Arrow. This page groups case-insensitive exact name matches and is not a full identity disambiguation profile.

13 papers

1 author row

YNICL Journal 2023 Journal Article

Study protocol of IMAGINE-HD: Imaging iron accumulation and neuroinflammation with 7T-MRI + CSF in Huntington’s disease

Nadine Anniek van de Zande
Marjolein Bulk
Chloé Najac
Louise van der Weerd
Jeroen de Bresser
Jan Lewerenz
Itamar Ronen
Susanne Tamara de Bot

INTRODUCTION: Strong 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. METHODS: This 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. DISCUSSION: Results 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.

Details DOI

YNIMG Journal 2021 Journal Article

Compartmental diffusion and microstructural properties of human brain gray and white matter studied with double diffusion encoding magnetic resonance spectroscopy of metabolites and water

Henrik Lundell
Chloé Najac
Marjolein Bulk
Hermien E. Kan
Andrew G. Webb
Itamar Ronen

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 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 (μFA) and diffusivities can be estimated. Metabolites are largely confined to the intracellular space and therefore provide a benchmark for intracellular μFA and diffusivities of specific cell types. By contrast, water DDES measurements allow examination of the separate contributions to water μFA and diffusivity from the intra- and 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/mm2, while water DDES measurements were performed with a range of b values from 918 to 7199 s/mm2. 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 μFA 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 μFA 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 μFA 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.

Details DOI

YNICL Journal 2021 Journal Article

Cortical glutamate and gamma-aminobutyric acid over the course of a provoked migraine attack, a 7 Tesla magnetic resonance spectroscopy study

Gerrit L.J. Onderwater
Jannie P. Wijnen
Chloé Najac
Robin M. van Dongen
Itamar Ronen
Andrew Webb
Ronald Zielman
Erik W. van Zwet

H-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.

Details DOI

YNICL Journal 2021 Journal Article

Quantitative susceptibility mapping in the thalamus and basal ganglia of systemic lupus erythematosus patients with neuropsychiatric complaints

Marjolein Bulk
Thijs van Harten
Boyd Kenkhuis
Francesca Inglese
Ingrid Hegeman
Sjoerd van Duinen
Ece Ercan
César Magro-Checa

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 (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.

Details DOI

YNICL Journal 2020 Journal Article

Pathological characterization of T2*-weighted MRI contrast in the striatum of Huntington’s disease patients

Marjolein Bulk
Ingrid Hegeman-Kleinn
Boyd Kenkhuis
Ernst Suidgeest
Willeke van Roon-Mom
Jan Lewerenz
Sjoerd van Duinen
Itamar Ronen

Previous MRI studies consistently reported iron accumulation within the striatum of patients with Huntington's disease (HD). However, the pattern and origin of iron accumulation is poorly understood. This study aimed to characterize the histopathological correlates of iron-sensitive ex vivo MRI contrast change in HD brains. To this end, T2*-weighted 7T MRI was performed on postmortem tissue of the striatum of three control subjects and 10 HD patients followed by histological examination. In addition, formalin-fixed paraffin-embedded material of three control subjects and 14 HD patients was selected for only histology to identify the cellular localization of iron using stainings for iron, myelin, microglia and astrocytes. As expected HD striata showed prominent atrophy. Compared to controls, the striatum of HD patients was in general more hypointense on T2*-weighted high-field MRI and showed a more intense histopathological staining for iron. In addition, T2*-weighted MRI identified large focal hypointensities within the striatum of HD patients. Upon histological examination, these large focal hypointensities frequently colocalized with enlarged perivascular spaces and iron was found within the vessel wall and reactive astrocytes. In conclusion, we show that the striatum of HD patients has a distinctive phenotype on T2*-weighted MRI compared to control subjects. On ex vivo MRI, these contrast changes are heavily biased by enlarged perivascular spaces from which it is currently unknown whether this is a fixation artefact or a disease specific observation. Clinically, the observation of iron within reactive astrocytes is of importance for the interpretation and understanding of the potential underlying mechanisms of T2*-weighted MRI results in HD patients.

Details DOI

YNIMG Journal 2020 Journal Article

Quantitative MRI and laser ablation-inductively coupled plasma-mass spectrometry imaging of iron in the frontal cortex of healthy controls and Alzheimer’s disease patients

Marjolein Bulk
Walid M. Abdelmoula
Hanneke Geut
Wim Wiarda
Itamar Ronen
Jouke Dijkstra
Louise van der Weerd

Accumulation of iron within the cortex of Alzheimer’s disease (AD) patients has been reported by numerous MRI studies using iron-sensitive methods. Validation of iron-sensitive MRI is important for the interpretation of in vivo findings. In this study, the relation between the spatial iron distribution and T2∗-weighted MRI in the human brain was investigated using a direct comparison of spatial maps of iron as detected by T2∗-weighted MRI, iron histochemistry and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS), in postmortem brain tissue of the medial frontal gyrus of three control subjects and six AD patients. In addition, iron levels measured by LA-ICP-MS and three quantitative MRI methods, namely R2∗ (=1/T2∗), image phase and quantitative susceptibility mapping (QSM), were compared between 19 AD and 11 controls. Histochemistry results we obtained with the modified Meguro staining were highly correlated with iron levels as detected by LA-ICP-MS (r2 = 0. 82, P < 0. 0001). Significant positive correlations were also found between LA-ICP-MS and the three quantitative MRI measurements: R2∗ (r2 = 0. 63), image phase (r2 = 0. 70) and QSM (r2 = 0. 74 (all p < 0. 0001)). R2∗ and QSM showed the strongest correlation with iron content; the correlation of phase with iron clearly showed increased variation, probably due to its high orientation dependence. Despite the obvious differences in iron distribution patterns within the cortex between AD patients and controls, no overall significant differences were found in iron as measured by LA-ICP-MS, nor in R2∗, phase or susceptibility. In conclusion, our results show that histochemistry as well as quantitative MRI methods such as R2∗ mapping and QSM provide reliable measures of iron distribution in the cortex. These results support the use of MRI studies focusing on iron distribution in both the healthy and the diseased brain.

Details DOI

YNIMG Journal 2018 Journal Article

Insights into brain microstructure from in vivo DW-MRS

Marco Palombo
Noam Shemesh
Itamar Ronen
Julien Valette

Many developmental processes, such as plasticity and aging, or pathological processes such as neurological diseases are characterized by modulations of specific cellular types and their microstructures. Diffusion-weighted Magnetic Resonance Imaging (DW-MRI) is a powerful technique for probing microstructure, yet its information arises from the ubiquitous, non-specific water signal. By contrast, diffusion-weighted Magnetic Resonance Spectroscopy (DW-MRS) allows specific characterizations of tissues such as brain and muscle in vivo by quantifying the diffusion properties of MR-observable metabolites. Many brain metabolites are predominantly intracellular, and some of them are preferentially localized in specific brain cell populations, e. g. , neurons and glia. Given the microstructural sensitivity of diffusion-encoding filters, investigation of metabolite diffusion properties using DW-MRS can thus provide exclusive cell and compartment-specific information. Furthermore, since many models and assumptions are used for quantification of water diffusion, metabolite diffusion may serve to generate a-priori information for model selection in DW-MRI. However, DW-MRS measurements are extremely challenging, from the acquisition to the accurate and correct analysis and quantification stages. In this review, we survey the state-of-the-art methods that have been developed for the robust acquisition, quantification and analysis of DW-MRS data and discuss the potential relevance of DW-MRS for elucidating brain microstructure in vivo. The review highlights that when accurate data on the diffusion of multiple metabolites is combined with accurate computational and geometrical modeling, DW-MRS can provide unique cell-specific information on the intracellular structure of brain tissue, in health and disease, which could serve as incentives for further application in vivo in human research and clinical MRI.

Details DOI

YNICL Journal 2017 Journal Article

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

Emily Turner Wood
Ece Ercan
Pascal Sati
Irene C.M. Cortese
Itamar Ronen
Daniel S. Reich

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 6months 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.

Details DOI

YNICL Journal 2015 Journal Article

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

Ece Ercan
Carson Ingo
Oranan Tritanon
Cesar Magro-Checa
Alex Smith
Seth Smith
Tom Huizinga
Mark A. van Buchem

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.

Details DOI

YNIMG Journal 2008 Journal Article

Diffusion tensor spectroscopy and imaging of the arcuate fasciculus

Jaymin Upadhyay
Kevin Hallock
Mathieu Ducros
Dae-Shik Kim
Itamar Ronen

The arcuate fasciculus (AF) is a fiber pathway in the human brain relevant for language processes and has recently been characterized by means of diffusion tensor tractography. The observations made concerning the left and right hemisphere AF include a characterization of the trajectories and quantification of physical properties such as fractional anisotropy, DTI-based fiber density and volume. However, these observations were based on the diffusion of water, which is not particular to either the intra- or extra-axonal compartments, and thus its usefulness for tissue characterization is limited. If the diffusion properties and in turn the geometric properties of only one tissue compartment can be isolated and characterized, a better microstructural characterization of AF is possible. In this study, water-based diffusion tensor probabilistic mapping was first implemented to segment the AF. Subsequently, diffusion tensor spectroscopic measurements of N-acetyl aspartate (NAA) were performed to measure the intra-axonal specific diffusion in left and right AF. Diffusion properties of NAA, which solely reflect the intra-axonal space, indicated possible leftward asymmetry in axonal diameter, where those of water, which are not compartment-specific, showed laterality to a lesser extent.

Details DOI

YNIMG Journal 2008 Journal Article

High-resolution diffusion tensor imaging and tractography of the human optic chiasm at 9.4 T

Alard Roebroeck
Ralf Galuske
Elia Formisano
Oriana Chiry
Hansjürgen Bratzke
Itamar Ronen
Dae-Shik Kim
Rainer Goebel

The optic chiasm with its complex fiber micro-structure is a challenge for diffusion tensor models and tractography methods. Likewise, it is an ideal candidate for evaluation of diffusion tensor imaging tractography approaches in resolving inter-regional connectivity because the macroscopic connectivity of the optic chiasm is well known. Here, high-resolution (156 μm in-plane) diffusion tensor imaging of the human optic chiasm was performed ex vivo at ultra-high field (9. 4 T). Estimated diffusion tensors at this high resolution were able to capture complex fiber configurations such as sharp curves, and convergence and divergence of tracts, but were unable to resolve directions at sites of crossing fibers. Despite the complex microstructure of the fiber paths through the optic chiasm, all known connections could be tracked by a line propagation algorithm. However, fibers crossing from the optic nerve to the contralateral tract were heavily underrepresented, whereas ipsilateral nerve-to-tract connections, as well as tract-to-tract connections, were overrepresented, and erroneous nerve-to-nerve connections were tracked. The effects of spatial resolution and the varying degrees of partial volume averaging of complex fiber architecture on the performance of these methods could be investigated. Errors made by the tractography algorithm at high resolution were shown to increase at lower resolutions closer to those used in vivo. This study shows that increases in resolution, made possible by higher field strengths, improve the accuracy of DTI-based tractography. More generally, post-mortem investigation of fixed tissue samples with diffusion imaging at high field strengths is important in the evaluation of MR-based diffusion models and tractography algorithms.

Details DOI

YNIMG Journal 2006 Journal Article

Spatial resolution dependence of DTI tractography in human occipito-callosal region

Mina Kim
Itamar Ronen
Kamil Ugurbil
Dae-Shik Kim

Diffusion tensor imaging (DTI) and fiber tracking have been used to measure the fiber structural connectivity in humans in a non-invasive manner. However, low sensitivity is a principal limitation of these methods, causing a large number of possibly missing fiber tracts (FTs). Here we studied how the spatial resolution affects the sensitivity of the fiber tracing by rescaling data to different resolutions. Our data suggest that the spatial resolution can change the degree of the asymmetric cross-callosal connections in the lower visual field (loVF) compared to the upper visual field (upVF). Among connections from loVF, a larger voxel size resulted in a smaller number of FTs that was not commensurate to the number of seed points, while the number of connections from upVF was not significantly affected by variation in seeding point numbers. We conclude from our study that the spatial resolution of the acquired data will have to be taken into consideration in interpreting DTI fiber tracking data. Our results further suggest that the acquisition resolution of around 2 mm iso-voxel in the conventional DTI scheme can reconstruct the asymmetric upper and lower white matter structure in occipito-callosal region.

Details DOI

YNIMG Journal 2004 Journal Article

Spatial relationship between neuronal activity and BOLD functional MRI

Dae-Shik Kim
Itamar Ronen
Cheryl Olman
Seong-Gi Kim
Kamil Ugurbil
Louis J Toth

Despite the ubiquitous use of functional magnetic resonance imaging (fMRI), the extent to which the magnitude and spatial scale of the fMRI signal correlates with neuronal activity is poorly understood. In this study, we directly compared single and multiunit neuronal activity with blood oxygenation level-dependent (BOLD) fMRI responses across a large area of the cat area 18. Our data suggest that at the scale of several millimeters, the BOLD contrast correlates linearly with the underlying neuronal activity. At the level of individual electrode recording sites, however, the correlation between the two signals varied substantially. We conclude from our study that T2*-based positive BOLD signals are a robust predictor for neuronal activity only at supra-millimeter spatial scales.

Details DOI