Iron, Myelin, and the Brain: Neuroimaging Meets Neurobiology

Möller, Harald E.; Bossoni, L.; Connor, James R.; Crichton, Robert R.; Does, Mark D.; Ward, Roberta J.; Zecca, Luigi; Zucca, Fabio A.; Ronen, Itamar

doi:10.1016/j.tins.2019.03.009

Cited by 159 publications

(187 citation statements)

References 146 publications

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“…The authors have no conflicts of interest to declare. and extracellular space [27], increasing the apparent MWF [28]. Since WM iron is predominantly found in myelin forming oligodendrocytes and contributes to lipid synthesis [29], the sensitivity of the short T2 component to both myelin and iron should be considered.…”

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confidence: 99%

Non-negative least squares computation for in vivo myelin mapping using simulated multi-echo spin-echo T₂decay data

Wiggermann

Vavasour

Kolind

et al. 2020

Preprint

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A revised version of this manuscript was accepted for publication in NMR in Biomedicine.Multi-compartment T 2 -mapping has gained particular relevance for the study of myelin water in brain. As a facilitator of rapid saltatory axonal signal transmission, myelin is a cornerstone indicator of white matter development and function. Regularized non-negative least squares fitting of multi-echo T 2 data has been widely employed for the computation of the myelin water fraction (MWF) and the obtained MWF maps have been histopathologically validated. MWF measurements depend upon the quality of the data acquisition, B1 +homogeneity and a range of fitting parameters. In this special issue article, we discuss the relevance of these factors for the accurate computation of multi-compartment T 2 and MWF maps. We generated multi-echo spin-echo T 2 decay curves following the approach of Carr-Purcell-Meiboom-Gill for various myelin concentrations and myelin T 2 scenarios by simulating the evolution of the magnetization vector between echoes based on the Bloch equations. We demonstrated that noise and imperfect refocusing flip angles yield systematic underestimations in MWF and intra-/extracellular water geometric mean (gm) T 2 . MWF estimates were more stable than myelin water gmT 2 time across different settings of the T 2 analysis. We observed that the lower limit of the T 2 distribution grid should be slightly shorter than TE1. Both TE1 and the acquisition echo spacing also have to be sufficiently short to capture the rapidly decaying myelin water T 2 signal. Among all parameters of interest, the estimated MWF and intra-/extracellular water gmT 2 differed by approximately 0.13-4 percentage points and 3-4 ms, respectively, from the true values, with larger deviations observed in the presence of greater B1 + -inhomogeneities and at lower signal-to-noise ratio. Tailoring acquisition strategies may allow to better characterize the T 2 distribution, including the myelin water, in vivo.

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confidence: 99%

Non-negative least squares computation for in vivo myelin mapping using simulated multi-echo spin-echo T₂decay data

Wiggermann

Vavasour

Kolind

et al. 2020

Preprint

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“…It is not yet clear what the underlying phenomena leading to brain iron accumulation in the context of AD are. However, it is likely that localized accumulation of iron might deprive other brain areas of this metal, thus impairing neuronal function 5 . Altered iron-homeostasis is reflected by the modified heavy-to-light (H/L) ratio of the chains composing the shell of ferritin proteins: AD brains present increased H/L ratio in the frontal cortex, as a possible means of copying with increased iron levels 39 .…”

Section: Discussionmentioning

confidence: 99%

“…These findings are of biological interest because magnetite, an iron-oxide mineral hosting both Fe(III) and Fe(II) in its crystal structure, has been proposed as a source of cellular toxicity, involving many different mechanisms. For example, in addition to the well known hypothesis that iron may produce reactive oxygen species via the catalytic Fenton reaction 4,5 , a more recent hypothesis concerns the effects of the magnetic field associated with the magnetic moment of these nanoparticles: a few studies have related the prolonged effect of such local static magnetic fields to a series of harmful biological phenomena, including protein structural alteration 6 and suppression of the threshold of the neuronal action potential 7 . Recent literature has suggested a relation between the presence of magnetite nanoparticles in the brain and the incidence of Alzheimer's pathology and its hallmark, amyloid beta plaques [8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

Effects of Alzheimer’s disease and formalin fixation on the different mineralised-iron forms in the human brain

Weerd

Lefering

Webb

et al. 2020

Preprint

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Iron accumulation in the brain is a phenomenon common to many neurodegenerative diseases, perhaps most notably Alzheimer's disease (AD). We present here magnetic analyses of post-mortem brain tissue of patients who had severe Alzheimer's disease, and compare the results with those from healthy controls. Isothermal remanent magnetization experiments were performed to assess the extent to which different magnetic carriers are affected by AD pathology and formalin fixation. While Alzheimer's brain material did not show higher levels of magnetite/maghemite nanoparticles than corresponding controls, the ferrihydrite mineral, known to be found within the core of ferritin proteins and hemosiderin aggregates, almost doubled in concentration in patients with Alzheimer's pathology, strengthening the conclusions of our previous studies. As part of this study, we also investigated the effects of sample preparation, by performing experiments on frozen tissue as well as tissue which had been fixed in formalin for a period of five months. Our results showed that the two different preparations did not critically affect the concentration of magnetic carriers in brain tissue, as observable by SQUID magnetometry. 2/11

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“…cubic mm-sized voxels. This is possible because many aspects of MR physics are influenced by myelination (Does, 2018;Edwards et al, 2018;Möller et al, 2019;Novikov et al, 2019). Macromolecules in the myelin sheath influence relaxation rates (as measured by the longitudinal relaxation rate R1, the transverse relaxation rate R2, the effective transverse relaxation rate R2*, and myelin water fraction MWF) as well as magnetization transfer (MT; as quantified by the magnetization transfer ratio MTR, and the macromolecular pool size MP).…”

Section: Introductionmentioning

confidence: 99%

Can MRI measure myelin? Systematic review, qualitative assessment, and meta-analysis of studies validating microstructural imaging with myelin histology

Lazari

Lipp

2020

Preprint

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Recent years have seen an increased understanding of the importance of myelination in healthy brain function and neuropsychiatric diseases. Non-invasive microstructural magnetic resonance imaging (MRI) holds the potential to expand and translate these insights to basic and clinical human research, but the sensitivity and specificity of different MR markers to myelination is a subject of debate.To consolidate current knowledge on the topic, we perform a systematic review and meta-analysis of studies that validate microstructural imaging by combining it with myelin histology.We find meta-analytic evidence for correlations between myelin histology and markers from different MRI modalities, including diffusion-weighted imaging, relaxometry, quantitative susceptibility mapping and magnetization transfer imaging. Meta-analytic correlation effect sizes range widely, between R2 = 0.26 and R2 = 0.82. However, formal comparisons between MRI-based myelin markers are limited by methodological variability, inconsistent reporting and potential for publication bias, thus preventing the establishment of a single most sensitive strategy to measure myelin with MRI.To facilitate further progress, we provide a detailed characterisation of the studies in our analysis as an online resource. We also share a set of recommendations for future studies validating putative MR-based myelin markers and deploying them in vivo in humans.HighlightsSystematic review and meta-analysis of studies validating microstructural imaging with myelin histologyWe find many MR markers are sensitive to myelin, including FA, RD, MP, MTR, Susceptibility, R1, but not MDFormal comparisons between MRI-based myelin markers are limited by methodological variability, inconsistent reporting and potential for publication biasResults emphasize the advantage of using multimodal imaging when testing hypotheses related to myelin in vivo in humans.

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Iron, Myelin, and the Brain: Neuroimaging Meets Neurobiology

Cited by 159 publications

References 146 publications

Non-negative least squares computation for in vivo myelin mapping using simulated multi-echo spin-echo T₂decay data

Non-negative least squares computation for in vivo myelin mapping using simulated multi-echo spin-echo T₂decay data

Effects of Alzheimer’s disease and formalin fixation on the different mineralised-iron forms in the human brain

Can MRI measure myelin? Systematic review, qualitative assessment, and meta-analysis of studies validating microstructural imaging with myelin histology

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Iron, Myelin, and the Brain: Neuroimaging Meets Neurobiology

Cited by 159 publications

References 146 publications

Non-negative least squares computation for in vivo myelin mapping using simulated multi-echo spin-echo T2decay data

Non-negative least squares computation for in vivo myelin mapping using simulated multi-echo spin-echo T2decay data

Effects of Alzheimer’s disease and formalin fixation on the different mineralised-iron forms in the human brain

Can MRI measure myelin? Systematic review, qualitative assessment, and meta-analysis of studies validating microstructural imaging with myelin histology

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Non-negative least squares computation for in vivo myelin mapping using simulated multi-echo spin-echo T₂decay data

Non-negative least squares computation for in vivo myelin mapping using simulated multi-echo spin-echo T₂decay data