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REVIEW ARTICLE Quantitative MRI in Multiple Sclerosis: From Theory to Application M. Tranfa, G. Pontillo, M. Petracca, A. Brunetti, E. Tedeschi, G. Palma, and S. Cocozza ABSTRACT SUMMARY: Quantitative MR imaging techniques allow evaluating different aspects of brain microstructure, providing meaningful in- formation about the pathophysiology of damage in CNS disorders. In the study of patients with MS, quantitative MR imaging tech- niques represent an invaluable tool for studying changes in myelin and iron content occurring in the context of inﬂammatory and neurodegenerative processes. In the ﬁrst section of this review, we summarize the physics behind quantitative MR imaging, here deﬁned as relaxometry and quantitative susceptibility mapping, and describe the neurobiological correlates of quantitative MR imaging ﬁndings. In the second section, we focus on quantitative MR imaging application in MS, reporting the main ﬁndings in both the gray and white matter compartments, separately addressing macroscopically damaged and normal-appearing parenchyma. ABBREVIATIONS: bSSFP ¼ balanced steady-state free precession; CL ¼ cortical lesions; GRE ¼ gradient recalled-echo; NAWM ¼ normal-appearing white matter; PD ¼ proton density; qMRI ¼ quantitative MR imaging; QSM ¼ quantitative susceptibility mapping; RF ¼ radiofrequency 9 10 hile conventional MR imaging plays an unquestionable calcifications, and to evaluate cortical bone mineral density or 1,2 Wrole in the diagnosis and management of MS, it myocardial structural alterations. offers very limited information about the pathophysiology of Although the definition of qMRI is open to different interpre- tissue damage because conventional sequences are not able to tations, several advanced MR imaging techniques are usually detect subtle changes affecting WM and GM. Quantitative grouped under this umbrella, including relaxometry, magnetic MR imaging (qMRI) bridges this gap, detecting brain micro- susceptibility, diffusion invariants, magnetization transfer, and, structural alterations with high sensitivity and robustness to 12 to some extent, perfusion parameters. Each of these techniques interscanner and interobserver variability, thus providing offers different, sometimes complementary, insights into the measures that can be compared among sites and longitudinal 13 complex tissue alterations occurring in MS. In this light, it is examinations. Furthermore, this technique has been success- noteworthy to remember that, while demyelination represents fully used to differentiate MS from other demyelinating dis- the end result of a complex phenomenon of inflammation, ulti- eases, such as neuromyelitis optica, which presents a different mately leading to axonal and neuronal degeneration, change in spectrum of relaxometry alterations and a peculiar spatial iron homeostasis is a crucial step in the pathophysiology of dam- deep gray matter involvement, and alsotocharacterize other age in MS, linked to microglial activation and modifications in conditions with different etiologies, from vascular disease to 14,15 oligodendrocyte functionality. Relaxometry plays a unique 5,6 brain tumors. However, the applications of qMRI extend role, given that most of the above-mentioned qMRI techniques beyond the brain, being able to depict changes in liver iron offer valuable and sensitive tools in myelin assessment but they 7 8 concentration as well as the presence of fibrosis, and prostatic lack iron-detection sensitivity. Indeed, relaxometry assesses abnormalities of iron and myelin, elements that are at the cross- Received January 12, 2022; accepted after revision February 22. roads of the inflammatory and neurodegenerative components in From the Departments of Advanced Biomedical Sciences (M.T., G. Pontillo, A.B., E.T., S.C.), MS pathophysiology. and Electrical Engineering and Information Technology (G. Pontillo), University of Naples In this review, wesummarize theroleand theapplication “Federico II,” Naples, Italy; Department of Human Neurosciences (M.P.), Sapienza University of Rome, Rome, Italy; and Institute of Nanotechnology (G. Palma), National of qMRI techniques, here defined as relaxometry (estimating Research Council, Lecce, Italy. R1, R2, R2*, and, by extension, proton density [PD]) and Please address correspondence to Giuseppe Pontillo, MD, Department of quantitative susceptibility mapping (QSM), to the study of Advanced Biomedical Sciences, University “Federico II,” Via Pansini, 5, 80131 Naples, Italy; e-mail: firstname.lastname@example.org; @NeuroN_Lab patients with MS. Indicates open access to non-subscribers at www.ajnr.org In the first section, we briefly describe the physics behind http://dx.doi.org/10.3174/ajnr.A7536 qMRI, together with its neurobiological correlates. In the second 1688 Tranfa Dec 2022 www.ajnr.org FIG 1. An example of quantitative MR imaging maps. Along with ﬁndings of a conventional FLAIR sequence (A) are examples of R1 (B), PD (C), R2* (D), and QSM (E) maps from a 22 -year-old man with MS. section, we summarize brain qMRI findings in MS for both the the Ernst angle for SNR convenience and, therefore, can be esti- normal-appearing parenchyma and lesions in the GM and WM mated on the basis of the same protocol structure adopted for R1 compartments. mapping. Once R1 and R2* (which rule the signal equation of the spoiled GRE sequence) have been obtained, PD is ideally obtained without qMRI Theory further acquisitions. Nevertheless, the spatial sensitivity of the re- Impact of Excitation Pulses and Significance of 3D Sequences. ceiver coil for the brain is substantially inhomogeneous; therefore, The R1 and R2 relaxation rates, defined as the inverses of T1 and an additional low-resolution acquisition of one of the sequences T2 relaxation times, measure the efficiency of the kinetics mecha- with the body coil helps to mitigate the inhomogeneity bias. nisms restoring the thermal equilibrium of the longitudinal and Finally, the phase of the complex images acquired for R2* transverse components of the spin isochromats. An isochromat mapping permits QSM. The raw phase is first unwrapped and represents the magnetic moment associated with a subset of nuclei then filtered to remove the background component that is not (protons, for our purposes) whose cardinality is large enough to associated with the local magnetization induced in the paren- justify a classic description of its dynamics (in terms of the expec- chyma by the main magnetic field. The filtered phase is finally tation value of the quantum magnetic moment operator) and processed to solve the inverse problem leading to the QSM. In whose spatial extent is small enough to assume a strictly uniform this step, special care must be taken to avoid the occurrence of macroscopic magnetic field throughout the subset. The evolution streaking artifacts that could impact the clinical value of the of the isochromats in an MR imaging sequence (radiofrequency image by mimicking spurious anatomic structures (Fig 1). [RF] and gradient pulses) is strongly dependent on the flip angles they experience. This shows why accurate R1 and R2 mapping is Importance of Denoising Schemes. The mathematic problems only possible through 3D sequences, which, unlike 2D sequences, associated with the qMRI protocols are typically ill-conditioned, guarantee a roughly uniform RF excitation throughout each voxel. thus leading to a detrimental noise propagation from the acquired images to the reconstructed maps. Therefore, besides the custom- Estimation of Quantitative Maps. In general, theviableprotocols ary optimization of the acquisition protocol to maximize the SNR for R1 and R2 mapping in neuroimaging routine rely on the ac- of the quantitative maps, a denoising step is warranted upstream quisition of multiple 3D spoiled gradient recalled echo (GRE, for of the qMRI pipeline. In this context, multispectral versions of the R1) and balanced steady-state free precession (bSSFP, for the non-local means algorithms have been devised to account for the additional information required to estimate R2) sequences at vari- power distribution of noise in parallel imaging and to reconstruct able flip angles. However, several aspects need to be considered the true signal from the raw statistical moments of the acquired 25,26 to obtain accurate relaxation maps. First, nonideal slab profiles images. can be accounted for with a dedicated sequence for flip angle mapping or through an iterative approach based on the infor- Pathophysiologic Correlates of qMRI. The pathophysiology of mation content of the estimated relaxation maps. The bias from brain damage in MS is multifaceted, being characterized by a nonideal RF spoiling can be removed according to the specific sequence of demyelination and partial remyelination events asso- 19 27 phase increment implemented by each vendor. Finally, to factor ciated with neurodegeneration. out the effects of off-resonance phenomena impacting the bSSFP Microglia activation within normal-appearing WM (NAWM) images in the form of banding artifacts, one needs to adopt a is one of the earliest and most prominent features in MS patho- 18 28 modified version of the original bSSFP approach, based on a physiology. Subsequently, a loss of integrity of the blood-brain synthetic contrast from multiple phase-cycled bSSFP. barrier, driven by proinflammatory mediators produced by resi- The estimation of the free induction decay rate (R2*) is compa- dent and endothelial cells, as well as indirect leukocyte-dependent ratively simpler because it depends only on the ratios of the signals damage, leads to focal demyelination. As the disease progresses, at different TEs, with no RF pulses in between. It is usually oligodendrocyte depletion occurs, as well as oligodendroglial iron obtained through a multi-GRE sequence with flip angles close to release, secondary to the high concentration of proinflammatory AJNR Am J Neuroradiol 43:1688–95 Dec 2022 www.ajnr.org 1689 FIG 2. Conventional and quantitative MR imaging ﬁndings of WM lesions at different stages. In the upper row, conventional ﬁndings (postgadoli- nium T1-weighted and precontrast T2-weighted, ﬁrst and second images from left to right respectively) of a typical pattern of nodular enhance- ment in an early active lesion (arrows) showing isointense signal in QSM (third image, white box) and mild hypointensity in R2* map (fourth image). In late active lesions (middle row, arrows), a peripheral pattern of enhancement is present, coupled with an area of increased signal at QSM and a slightly more pronounced hypointensity on R2* maps compared with the previous stage. As lesion staging further increases, the lesion eventually enters its chronic inactive stage (lower row, arrows), characterized by absent gadolinium enhancement, a QSM hyperintensity, and a hypointense R2* signal. Modiﬁed with permission from Zhang et al. cytokines produced by the chronically activated microglia, with WM Lesions these mechanisms ultimately resulting in oxidative stress via Fenton Focal WM lesions represent the most typical expression of tissue chemistry and reduced regenerative capacity. damage in MS. According to their activity phase, WM lesions can Because these different microstructural changes influence be histologically subcategorized as early active, late active, chronic multiple MR imaging contrasts contemporarily, multiparameter active (also described as slowly expanding or smoldering lesions), qMRI represents the most apt approach to explore pathologic chronic inactive, and shadow plaques (remyelinated lesions). alterations occurring in the MS brain. The undeniable advantage In early active lesions, inflammatory activity blooms from ven- of qMRI relies on the possibility of generating spatial maps in ules, following blood-brain barrier disruption and immune cell infil- which each voxel corresponds to a numeric value reflecting the tration, thus leading to progressive demyelination and axonal loss physical properties of the examined tissues, such as free water with a centrifugal spread. From an MR imaging perspective, these proportion (PD, R1, R2), myelination (R1, R2, R2*, QSM), or phenomena are mirrored by the pattern of enhancement after gado- 31,32 iron content (R2* and QSM). linium administration. Indeed, at this stage, lesions usually enhance While PD is an established measure of the brain free water centrifugally, with a more pronounced nodular appearance. As pool, with PD increase documented in the presence of vasogenic inflammation proceeds, cellular infiltrates grow and, combined with edema, R1 and R2 vary as a function of free water and myelin myelin breaking down and edema, result in decreased R1 and R2 concentration, with a higher degree of myelination causing relaxa- values, coupled to increased PD values within lesions and transi- 35,36 tion time shortening. tional values in periplaque WM in comparison with NAWM. With reference to iron, in normal brain tissue, it is mostly These findings are associated with a similar edema-driven R2* boundto ferritininoligodendrocytes, and its presence is required decrease, with no QSM changes because the loss of diamagnetic for the activity of enzymes involved in myelin production and pres- myelin is not detectable at this stage (Fig 2). ervation. Along with myelin, iron accounts for the larger part of In late active lesions, showing a peripheral or ringlike pattern of 38 42 the MR imaging contrast obtained through R2* and QSM. enhancement, myelin degradation and removal become progres- However, whereas both iron and myelin determine an R2* increase, sively more substantial, therefore influencing lesion magnetic sus- 45,46 they play opposite roles in QSM. Given the paramagnetic properties ceptibility as assessed by QSM. At this stage, R1, R2, and PD of iron, an increase in its concentration is unequivocally coupled to values show the same pattern of changes as the early active lesions an increase in susceptibility, while myelin, being a diamagnetic in comparison with NAWM, while in R2*, a further signal decrease compound, influences susceptibility in the opposite direction. is present, coupled to a QSM increase, especially in the lesion 1690 Tranfa Dec 2022 www.ajnr.org Table 1: Major qMRI findings in MS—WM compartment in iron homeostasis, can be assessed Site Pathologic Processes and qMRI Correlates through relaxation and magnetic suscep- 24,38 WM lesions tibility variations. Early active Decreased R1, R2, and R2* values, along with increased PD, The NAWM usually shows lower R1 43,45 reﬂecting initial myelin degradation and edema and R2and higher PD values,compared 50,51 Late active Decreased R1 and R2 values, coupled with increased PD, with with the WM of healthy controls. myelin debris removal that determines further R2* decrease and These changes seem to be mostly related 43,45,51 QSM increase to inflammatory infiltration, with edema Chronic active Further R1 and R2 decrease, with PD increase, due to demyelination and myelin loss. A decrease in iron progression; increased R2* and QSM at the periphery of the concentration has been observed in 45,46 lesions due to iron-laden microglia and macrophages patients with MS in comparison with Chronic inactive Compared with chronic active, R2* decreases with high QSM healthy controls using R2* maps. This values; across time, susceptibility values gradually become similar reduced relaxation rate might be driven to those in NAWM by iron release from oligodendrocytes 14,29 NAWM Decreased R1 and R2 values, with increased PD, compared with the during chronic inflammation. Most 50,51 WM of healthy controls, reﬂecting edema and myelin loss interesting, the iron level in NAWM, secondary to inﬂammatory inﬁltration. estimated by QSM, is not stationary but During active phases of the disease, iron is released from fluctuates according to the presence of oligodendrocytes and begins to accumulate in newly forming 52 inflammatory activity. Indeed, during lesions, causing an R2* decrease and no relevant modiﬁcation 52 theactivephases of the disease, when of QSM signal iron begins to accumulate in newly forming lesions, NAWM magnetic sus- ceptibility values appear to be similar to 45 52 center, due to additional myelin debris removal by anti-inflam- those observed in the WM of healthy controls, as also confirmed 14 29 matory M2 macrophages. Although iron begins concentrating in by ex vivo data. On the contrary, mean QSM values of the M1 macrophages and activated microglia at a later stage, its levels NAWM seem to increase in the absence of gadolinium-enhancing may acutely increase following rapid oligodendrocyte destruction, lesions, suggesting that iron might play a role in tissue regeneration counterbalancing myelin loss in R2* and reinforcing QSM hyper- during periods of disease inactivity. intensity in some lesions (Fig 2). Main qMRI findings in the WM compartment are reported in When blood-brain barrier damage is resolved, MS lesions no Table 1. longer show postgadolinium enhancement and are, therefore, cate- Deep Gray Matter gorized as chronic, further subdivided into active or inactive, The major structures of the deep gray matter nuclei can be ana- depending on whether some degree of inflammatory activity per- tomically and functionally subdivided in the thalamus and basal sists. In chronic lesions, the combination of demyelination, hypo- ganglia, whose most relevant nuclei are the globus pallidus, puta- cellularity, and free water fraction increase leads to R1 and R2 men, and caudate nucleus. Given their relatively different histol- decrease, while PD increases, compared with early and late active ogy, the thalamus and basal ganglia will be discussed separately. lesions. Transition to chronicity is associated with a complex pat- tern of changes in iron content. Indeed, while iron concentration Thalamus. Thalamic involvement in MS has been documented by may decrease due to myelin sheaths and oligodendrocyte deple- 53-55 53 29,37 both ex- and in vivo studies. This region is not only a site of pri- tion, some degree of iron accumulation occurs, in parallel, mary axonal damage, but given its high interconnectivity with other within iron-laden macrophages and microglia at lesions bor- 14,32 brain regions, it suffers from secondary degeneration caused by WM ders. In chronic active lesions, this inflammation-related iron 53,54 lesions involving thalamic projection fibers. Recently, a decrease accumulation at the rim of the lesions is emphasized, leading to 56-61 45,46 in both thalamic iron content and concentration has been docu- increasedR2* andQSM values. With time, lesions eventually mented in patients with MS in comparison with healthy controls, become chronic inactive or shadow plaques, with low R2* values 59,61 with the most evident changes detected within the pulvinar. but still high QSM signal, which only ultimately decreases in very 62-66 Previous studies, however, reported conflicting results, late stages to resemble NAWM signal, due to iron depletion and only partially ascribable to the physiologic nonlinear trajectory fol- partial remyelination (Fig 2). lowed by thalamic iron concentration during the life span. Such NAWM conflicting data should be interpreted considering the impact of at- 57,68 Despite appearing spared by lesions on conventional MR imaging rophyonironconcentration. In particular, the concept of R2* sequences, NAWM is characterized by complex microstructural mass (the sum of all the R2* values in a specific region) was changes reflecting inflammation, demyelination, gliosis, and axonal recently introduced as an index of iron content independent of at- loss. The mechanisms underlying NAWM damage are mainly rophy. With this approach, the decrease in thalamic iron content Wallerian degeneration of fibers transected by focal lesions and dif- has been confirmed, highlighting the importance of distinguish- 28,48 49 fuse microglial activation. Axonal swelling and edema have ingbetween (and reportingboth) iron concentration and content 56,57,59,60 also been observed globally in NAWM and, together with alteration (Fig 3). AJNR Am J Neuroradiol 43:1688–95 Dec 2022 www.ajnr.org 1691 Similar to what we described for the thalamus, the progressive damage of the basal ganglia leads to atrophy. Here, studies have 58,64-66,70,71 more consistently reported an increase in R2* or sus- 61,64,66,70,72 ceptibility in patients with MS compared with controls, suggesting a progressive iron accumulation, beyond the analogous physiologic process detectable in healthy individuals. Nonetheless, these findings should also be interpreted in view of the effect of atrophy on tissue iron concentration. Indeed, even with stable regional iron content, volume reduction leads to increased mean iron concentration. In particular, a prominent decline in iron content with time in all basal ganglia has been demonstrated, coupled with an increased or stable iron concen- tration compared with controls at the level of putamen, caudate 60,72 nucleus, and globus pallidus. In line with these results, some recent studies failed to identify any difference between patients with MS and controls in terms of iron content, while others reported a decrease of this parameter in the putamen and caudate 56,57 nucleus of patients with MS (Fig 3). Cortical Lesions From a relaxometry perspective, no studies have investigated R1 changes in cortical lesions (CL). However, beyond demyelination, CL are characterized by a decreased iron load, a feature that allows differentiating them from a normal-appearing cortex through the 74,75 evaluation of R2* maps, as shown in postmortem samples. In particular, the progressive destruction of iron-rich myelin sheaths and oligodendrocytes and the subsequent uptake of iron and myelin debris by activated macrophages and microglia lead to decreased R2* values in CL. On the other hand, QSM has been used to analyze the heterogeneity of CL in different disease stages, showing a mixed pattern of appearance. While QSM- hyperintense CL have been more frequently observed in patients with relapsing-remitting MS, QSM-hypointense CL are mostly identified in subjects with a secondary-progressive phenotype. While the increased susceptibility might be due to iron release from oligodendrocytes, typical of the inflammatory phase of the disease, the reduced susceptibility might be linked to iron deple- tion in chronic lesions. Normal-Appearing Cortex Similar to the NAWM, the cortex, which does not show signal changes on conventional MR imaging, is subject, from a patho- logic standpoint, to neuronal and axonal loss occurring regardless 76,79 of demyelination. The assessment of relaxometry and QSM changes in normal-appearing cortex is confounded by the physio- logic layer-specific iron content, which represents the main FIG 3. Pattern of iron concentration, iron content, and myelin con- 81 36 tent changes in deep gray matter nuclei in MS. Results of voxelwise source of cortical R2* and susceptibility contrast. Nevertheless, analyses comparing patients with MS with healthy controls, showing a decrease in both R1 and R2* values has been reported in MS in the presence of an increased iron concentration at the level of the normal-appearing cortex, accounting for demyelination and iron basal ganglia (red-yellow), coupled with a decrease in iron and myelin depletion, respectively. Consistent with the hypothesis of cortical content mainly affecting the thalami and, in particular, the pulvinar nuclei (blue-light blue). Modiﬁed with permission from Pontillo et demyelination triggered by chemokines produced by lymphocytic al. HC indicates healthy control; 1-r, 1 minus P value. infiltrates in the meningeal compartment, a recent study has reported coherent cortical gradients of R1 and R2*, oriented from the subpial layer to the WM interface. In thesamestudy, QSM Basal Ganglia. The basal ganglia are also the site of both demye- showed a lack of sensitivity in distinguishing the different layers, lination and neurodegeneration, with reduced neuronal density, probably due to the counteracting effects of diamagnetic myelin 44,55 axonal damage, and oligodendrocytes loss. and paramagnetic iron modifications. 1692 Tranfa Dec 2022 www.ajnr.org Table 2: Major qMRI findings in MS—GM compartment of liver iron concentration. JMagn Reson Imaging 2018;48:1069–79 CrossRef Site Pathologic Processes and qMRI Correlates Medline Deep gray matter 58,64-66,70,71 61,64,66,70,72 8. Banerjee R, Pavlides M, Tunnicliffe EM, Basal ganglia Increased R2* and QSM values indicating et al. Multiparametric magnetic reso- increased iron concentrations, with atrophy that might play a 57,68 nance for the non-invasive diagnosis role in causing these changes of liver disease. 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Significant inﬂammatory activity correlations between human cortical bone mineral density and quantitative Normal-appearing Demyelination and iron depletion lead to reduced R1 and R2* 50 83 susceptibility mapping (QSM) obtained cortex values, with a gradient indicating the WM interface with 3D cones ultrashort echo time magnetic resonance imaging (UTE- MRI). Magn Reson Imaging 2019;62:104– 10 CrossRef Medline The main qMRI findings of the GM compartment are 11. Karur GR, Hanneman K. Cardiac MRI T1, T2, and T2* mapping in clinical practice. Advances in Clinica Radiology 2019;1:27–41 CrossRef reported in Table 2. 12. Granziera C, Wuerfel J, Barkhof F, et al; MAGNIMS Study Group. Quantitative magnetic resonance imaging towards clinical applica- CONCLUSIONS tion in multiple sclerosis. Brain 2021;144:1296–1311 CrossRef Medline In this review, we offered a comprehensive overview of qMRI 13. Pontillo G, Cocozza S, Lanzillo R, et al. 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American Journal of Neuroradiology – American Journal of Neuroradiology
Published: Dec 1, 2022
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