Add the specialty areas of your choice to tailor excemed.org to your professional interests.
Save & Create free account
No thanks, just apply selection
I already have an account. Login

User login

We offer our registered users tailored information, free online courses and exclusive content.

Can't find your password?
Reset it here.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Advanced magnetic resonance techniques: Future perspectives

PART OF MS Alumni FEATURE
Advanced magnetic resonance techniques: Future perspectives
  • Neurology

Maria A Rocca[1,2] MD.

[1]Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, and [2]Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Due to its exquisite sensitivity to disease related abnormalities, magnetic resonance imaging (MRI) has become an established tool to diagnose multiple sclerosis (MS) and to monitor its evolution. MRI has been formally included in the diagnostic work up of patients at presentation with clinically isolated syndromes suggestive of MS, and ad hoc criteria have been proposed and are updated on a regular basis. In patients with definite MS, the ability of magnetic resonance (MR) measures in explaining patients’ clinical status and progression of disability is still suboptimal. However, in MS research, conventional MRI has been substantially augmented by quantitative MR techniques, which have shown greater sensitivity and specificity for assessing the heterogeneous pathological substrates of the disease not only in focal T2-visible lesions, but also in the normal-appearing white matter (NAWM) and gray matter (GM). More recently, new imaging methods, capable of measuring pathological processes related to the disease that have been neglected in the past (such as iron deposition and perfusion abnormalities) and the advent of high- and ultra-high field magnets have provided further insight into MS pathobiology.

Established MR techniques for imaging MS patients

T2-weighted, fluid attenuated inversion recovery and post-contrast T1-weighted sequences. T2-weighted and fluid attenuated inversion recovery (FLAIR) sequences are the mainstays in the work-up of MS patients. Together with post-contrast T1-weighted scans, they provide objective information about subclinical disease activity, which occurs at a rate 5 to 10 times higher than suggested by clinical observation. T2, FLAIR, and post-Gd MRI is incorporated into current diagnostic criteria.[1] The identification of MS is helped by the characteristic patterns of lesion location and shape. Evaluation of both brain and spinal cord also helps to exclude other possible diagnoses.[2]In patients with established MS, the correlation between the abnormalities seen on T2 sequences and disability is weak to moderate, depending on the measure and population studied.

T1-weighted sequences. A subset of T2 lesions appears dark on T1-weighted SE images. These T1-hypointense lesions, or T1 black holes, range from mildly hypointense, with intensity similar to GM, to severely hypointense, with intensity similar to CSF. The degree of hypointensity is correlated with the degree of pathologic severity.[3]When followed longitudinally, the majority of black holes resolve over the course of about 6 months. These are referred to as “acute black holes”, and they originate in focal regions of Gd-enhancement. The remaining T1-hyperintensities, the “persistent black holes” constitute only about 36% of all T1-hyperintensities and are believed to represent irreversible axonal loss.[4]

In relapsing-remitting (RR) and secondary progressive (SP) MS, T1-hypointense lesion-load (LL) is about 5-20% of the total T2 LL, on average. T1-hypointense LL is low in the early stage of MS and increases over the course of the disease. In some studies, correlations between T1-hypointense LL and disability are greater than those seen for T2 lesions.

Tracking the evolution of T1-hypointensities in longitudinal studies requires sufficient frequency of MRI scanning and a study duration long enough to count the number of new Gd-enhancing lesions that evolve into persistent black holes. The resulting count is of particular interest in treatment trials, because a reduction in the proportion of new lesions that evolve into persistent black holes may be indicative of neuroprotective effects, particularly when considered in combination with brain atrophy data.

 Atrophy Measurements. Brain atrophy, which is usually quantified on T1-weighted images, is another marker of MS disease burden.[5]The rate of whole brain atrophy in MS is only 0.5-1% per year and, therefore, the techniques used to measure atrophy must be highly reproducible and sensitive to small changes. Brain atrophy begins at the earliest stage of MS and progresses through the whole disease course, probably at a constant rate.[6]It tends to correlate better with disability and cognitive impairment than other conventional MRI measures, in both cross-sectional and longitudinal studies. In comparison to WM, GM atrophy is more strongly associated with disease progression.[7]Atrophy in deep GM structures begins very early in the disease and cortical thinning is detectable soon thereafter. Focal and diffuse damage measured in the WM predict subsequent GM atrophy in RRMS, but predictors of GM atrophy are lacking in SPMS, when GM atrophy may accelerate.[8]The association between spinal cord atrophy and disability progression is also relatively strong.

MR techniques ready to be moved to routine research acquisition in the near future

Double inversion recovery sequences. Double inversion recovery (DIR) sequences have improved the ability of MRI to detect cortical lesions (CLs).[9]CLs have been seen in all the major MS clinical phenotypes, including CIS patients. [10]An assessment of CLs contributes to the identification of CIS patients at risk of evolution to definite MS. [11] Nevertheless, CLs are more frequently seen in patients with SPMS than in patients with CIS or RRMS.[10] CLs have also been seen in the hippocampus,[12] and continue to form over time in patients with different MS clinical phenotypes. An association between CL burden and progression of disability and the severity of cognitive impairment has also been found.[10]

Magnetization transfer MRI, diffusion tensor MRI, proton MR spectroscopy. Several advanced MR techniques have been developed over the last couple of decades, providing imaging biomarkers that, compared with conventional MRI measures, are better able to capture the complexity of the pathological processes occurring in the CNS of MS patients. Magnetization transfer (MT) MRI, which is based on the interactions between free-water protons and protons bound to macromolecules, has proven in several studies to be superior to conventional MRI for the detection and quantification of subtle brain tissue changes. When assessed in the brain, MT MRI provides an index of tissue integrity (the MT ratio [MTR]), which may be an expression of the extent of tissue damage.[13] The MTR reduction in MS lesions and NAWM has been related to the percentage of residual axons, and the degree of demyelination.[14] MT-derived measures are sensitive to MS-related changes over short periods of time and can provide evidence predicting the accumulation of clinical disability.[13] An annual measure of MTR has been incorporated as an exploratory endpoint to assess treatment efficacy in large-scale, multi-centre trials.[15,16]

Diffusion tensor (DT) MRI has also proved useful in MS.[17] Low fractional anisotropy (FA) and high mean diffusivity (MD) have been reported in lesions and NAWM. DT MRI findings in MS lesions appear to relate to different pathological features of tissue damage,[18] and longitudinal studies have demonstrated that DT MRI is sensitive to the evolution of tissue damage within MS lesions.[17] Associations between DT MRI measures in MS brains and clinical disability have also been investigated, although with conflicting findings.[17] Overall, DT MRI appears to be a promising tool for evaluating the integrity of brain structure in MS, but further investigations are warranted to elucidate the correlates with pathological tissue damage.

Proton MR spectroscopy (1H-MRS) has the unique ability to provide chemical-pathological characterization of MR-visible lesions and normal-appearing brain tissues.[19] By providing evidence of neuro-axonal dysfunction or loss (based on levels of N-acetylaspartate [NAA]) from the earliest stages of the disease, 1H-MRS studies have led to a reconsideration of the role of axonal damage and, by measuring changes in the levels of metabolites such as choline (Cho) and myoinositol (mI), have highlighted the importance of assessing myelin damage and repair. However, longitudinal studies exploiting these unique properties are rather scant, probably because of the technical challenges, which can be largely overcome by following appropriate guidelines.[20]

Functional MRI. Studies with functional MRI (fMRI) of the visual, cognitive and motor systems have consistently demonstrated functional cortical changes in all MS phenotypes, with altered activation of regions normally devoted to the performance of a given task and/or the recruitment of additional areas in comparison to healthy subjects.[21] Similar results have been seen with fMRI in the cervical spinal cord.[22] fMRI abnormalities in MS patients occur relatively early in the course of the disease, even in patients with CIS and pediatric MS,23and tend to vary over the course of the disease, not only after an acute relapse, but also in clinically stable patients.[21]

Functional and structural MRI abnormalities in MS patients are strictly correlated,[21] suggesting that increased recruitment of “critical” cortical networks helps to limit the functional impact of MS-related damage. However, increased cortical recruitment cannot continue indefinitely, and a lack of, or exhaustion of, the “classical” adaptive mechanisms has been considered as a possible factor responsible for unfavorable clinical evolution or for accelerated cognitive decline.[21]

Emerging techniques and technologies

Alternative contrast agents. New iron-based MRI contrast agents (ultrasmall particles of iron oxide [USPIOs] or super-paramagnetic iron particles of oxide [SPIOs]) are useful for tracking peripheral macrophages. In vivo MS studies using both USPIOs and Gd, demonstrated heterogeneity in contrast enhancement, suggesting that they provide complementary information.[24]

Perfusion imaging. Cerebral perfusion is defined as the volume of blood flowing through a unit volume of tissue per unit of time, and can be measured by MRI techniques that use either exogenous tracers, such as Gd chelates (bolus tracking), or arterial water as an endogenous tracer (arterial spin labeling).[25] In vivo perfusion studies of MS patients have demonstrated that, while acute inflammatory lesions show increased perfusion, likely reflecting inflammatory-related brain vasodilatation, most non-enhancing MS lesions are characterized by decreased cerebral blood flow and volume.[26] In addition, brain perfusion changes have been reported in NAWM, and both cortical and sub-cortical GM.[27] While perfusion changes in the NAWM of early RRMS patients are likely to reflect inflammatory related microvascular abnormalities and changes in BBB permeability, decreased GM perfusion, especially in progressive MS patients,[28] is more likely to indicate reduced blood supply demand secondary to tissue loss.

Iron quantification. In MS patients, GM areas, including the thalamus, dentate nucleus, other basal ganglia nuclei and rolandic cortex, commonly show hypointensity on T2-weighted images, suggesting iron deposition.[29] Although it remains unclear whether iron deposition contributes to neurotoxicity in GM or is purely an epiphenomenon, MRI-based studies suggest a link between iron deposition, GM damage, and clinical status.

Susceptibility-weighted imaging. Susceptibility-weighted imaging (SWI) uses a velocity-compensated high-resolution 3D gradient-echo sequence that creates magnitude and filtered phase information, both separately and in combination, enhance the effects of local magnetic susceptibility variation and create new sources of contrast. Recently, SWI filtered-phase images of MS patients were shown to be useful for detecting increased iron content not only in basal ganglia but also in lesions. In addition, ring-like hypointensity around some MS lesions visible on SWI, but not on conventional images, has been attributed to iron deposition. Finally, SWI enables precise in vivo visualization of the venous architecture of the brain and can help improve our understanding of the pathophysiology of MS lesions.

Ultra-high field MRI. Imaging at ultra-high field (>3.0 T) affords advantages in signal-to-noise ratio, image contrast and resolution. However, these benefits can only be realized when using the appropriate radio-frequency coils and intensity uniformity correction. Specialized phased array coils, giving improved GM and WM differentiation, were used in an effort to improve visualization of MS lesions in vivo at 7.0 T, providing important clues for identifying GM lesions.[30] Imaging at 7.0 T was demonstrated to be safe, well tolerated, and provided high-resolution anatomical images allowing visualization of structural abnormalities located within or near the cortical layers. Clear involvement of the GM was observed with improved morphological detail in comparison to imaging at lower-field strength. SWI is particularly effective at high field strength, with greater sensitivity to localized iron deposition,[31] revealing that iron content was strongly correlated with disease duration. The images also showed distinct peripheral rings, which may be consistent with histological data demonstrating iron-rich macrophages at the periphery of lesions. In vivo MRS also benefits from increased signal-to-noise at ultra-high field. Additional metabolites relevant to MS are under active investigation, such as glutathione, glutamate, GABA, ascorbic acid (vitamin C), as well as the macromolecular (background) signal. The quantification of such a broad neurochemical profile by use of a single method should provide insights into the roles of neurodegeneration, tissue repair, antioxidant therapy, and oxidative stress in MS. Preliminary findings suggest that glutathione concentrations in MS GM could be abnormally reduced relative to healthy controls.[32]

Conclusions

Conventional MRI is well-established and widely applied for the diagnosis and evaluation of patients with MS. Standardized acquisition protocols and methods of analysis are currently available and are being applied, relatively homogeneously, by the clinical and research communities. However, these techniques have some intrinsic limitations and lack specificity to the heterogeneous pathological substrates of the disease. Newer MR methods that have been developed during the past decade, such as DIR, are likely to have an important role in the diagnosis of the disease. As a consequence, effort should be devoted to standardizing acquisition between different scanner manufacturers and centres in order to make them available for the clinical community. For other techniques, such as MT MRI, DT MRI, 1H-MRS and fMRI, guidelines for acquisition and analysis have been proposed by experts in the field. This should encourage the research community to apply them not only in the research setting, but also for treatment monitoring. Nevertheless, many challenges remain. With the increased availability of high field and ultra-high field scanners, these issues are now becoming extremely critical.

 

References

1. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Ann Neurol. Feb 2011;69(2):292-302.

2. Charil A, Yousry TA, Rovaris M, et al. MRI and the diagnosis of multiple sclerosis: expanding the concept of "no better explanation". Lancet Neurol. Oct 2006;5(10):841-852.

3. van Walderveen MA, Kamphorst W, Scheltens P, et al. Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology. May 1998;50(5):1282-1288.

4. van Waesberghe JH, van Walderveen MA, Castelijns JA, et al. Patterns of lesion development in multiple sclerosis: longitudinal observations with T1-weighted spin-echo and magnetization transfer MR. AJNR Am J Neuroradiol. Apr 1998;19(4):675-683.

5. Simon JH. Brain atrophy in multiple sclerosis: what we know and would like to know. Mult Scler. Dec 2006;12(6):679-687.

6. De Stefano N, Giorgio A, Battaglini M, et al. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology. Jun 8 2010;74(23):1868-1876.

7. Fisniku LK, Chard DT, Jackson JS, et al. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol. Sep 2008;64(3):247-254.

8. Fisher E, Lee JC, Nakamura K, Rudick RA. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol. Sep 2008;64(3):255-265.

9. Geurts JJ, Pouwels PJ, Uitdehaag BM, Polman CH, Barkhof F, Castelijns JA. Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging. Radiology. Jul 2005;236(1):254-260.

10. Calabrese M, Filippi M, Gallo P. Cortical lesions in multiple sclerosis. Nat Rev Neurol. Aug 2010;6(8):438-444.

11. Filippi M, Rocca MA, Calabrese M, et al. Intracortical lesions: relevance for new diagnostic criteria for multiple sclerosis. Neurology. 2010;In press.

12. Roosendaal SD, Moraal B, Vrenken H, et al. In vivo MR imaging of hippocampal lesions in multiple sclerosis. J Magn Reson Imaging. Apr 2008;27(4):726-731.

13. Filippi M, Rocca MA. Magnetization transfer magnetic resonance imaging of the brain, spinal cord, and optic nerve. Neurotherapeutics. Jul 2007;4(3):401-413.

14. Schmierer K, Scaravilli F, Altmann DR, Barker GJ, Miller DH. Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain. Ann Neurol. Sep 2004;56(3):407-415.

15. Inglese M, van Waesberghe JH, Rovaris M, et al. The effect of interferon beta-1b on quantities derived from MT MRI in secondary progressive MS. Neurology. Mar 11 2003;60(5):853-860.

16. Filippi M, Rocca MA, Pagani E, et al. European study on intravenous immunoglobulin in multiple sclerosis: results of magnetization transfer magnetic resonance imaging analysis. Arch Neurol. Sep 2004;61(9):1409-1412.

17. Rovaris M, Agosta F, Pagani E, Filippi M. Diffusion tensor MR imaging. Neuroimaging Clin N Am. Feb 2009;19(1):37-43.

18. Schmierer K, Wheeler-Kingshott CA, Boulby PA, et al. Diffusion tensor imaging of post mortem multiple sclerosis brain. Neuroimage. Apr 1 2007;35(2):467-477.

19. De Stefano N, Filippi M. MR spectroscopy in multiple sclerosis. J Neuroimaging. Apr 2007;17 Suppl 1:31S-35S.

20. De Stefano N, Filippi M, Miller D, et al. Guidelines for using proton MR spectroscopy in multicenter clinical MS studies. Neurology. Nov 13 2007;69(20):1942-1952.

21. Filippi M, Rocca MA. Functional MR imaging in multiple sclerosis. Neuroimaging Clin N Am. Feb 2009;19(1):59-70.

22. Valsasina P, Agosta F, Absinta M, Sala S, Caputo D, Filippi M. Cervical Cord Functional MRI Changes in Relapse-Onset MS Patients. J Neurol Neurosurg Psychiatry. Dec 3 2010;81(4):405-408.

23. Rocca MA, Absinta M, Moiola L, et al. Functional and structural connectivity of the motor network in pediatric and adult-onset relapsing-remitting multiple sclerosis. Radiology. Feb 2010;254(2):541-550.

24. Dousset V, Brochet B, Deloire MS, et al. MR imaging of relapsing multiple sclerosis patients using ultra-small-particle iron oxide and compared with gadolinium. AJNR Am J Neuroradiol. May 2006;27(5):1000-1005.

25. Bakshi R, Thompson AJ, Rocca MA, et al. MRI in multiple sclerosis: current status and future prospects. Lancet Neurol. Jul 2008;7(7):615-625.

26. Ge Y, Law M, Johnson G, et al. Dynamic susceptibility contrast perfusion MR imaging of multiple sclerosis lesions: characterizing hemodynamic impairment and inflammatory activity. AJNR Am J Neuroradiol. Jun-Jul 2005;26(6):1539-1547.

27. Adhya S, Johnson G, Herbert J, et al. Pattern of hemodynamic impairment in multiple sclerosis: dynamic susceptibility contrast perfusion MR imaging at 3.0 T. Neuroimage. Dec 2006;33(4):1029-1035.

28. Rashid W, Parkes LM, Ingle GT, et al. Abnormalities of cerebral perfusion in multiple sclerosis. J Neurol Neurosurg Psychiatry. Sep 2004;75(9):1288-1293.

29. Stankiewicz J, Panter SS, Neema M, Arora A, Batt CE, Bakshi R. Iron in chronic brain disorders: imaging and neurotherapeutic implications. Neurotherapeutics. Jul 2007;4(3):371-386.

30. Mainero C, Benner T, Radding A, et al. In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI. Neurology. Jul 29 2009;73(12):941-948.

31. Hammond KE, Metcalf M, Carvajal L, et al. Quantitative in vivo magnetic resonance imaging of multiple sclerosis at 7 Tesla with sensitivity to iron. Ann Neurol. Dec 2008;64(6):707-713.

32. Srinivasan R, Ratiney H, Hammond-Rosenbluth KE, Pelletier D, Nelson SJ. MR spectroscopic imaging of glutathione in the white and gray matter at 7 T with an application to multiple sclerosis. Magn Reson Imaging. Aug 18 2010;28(2):163-170.

Terms of use

This is a copyrighted resource for the sole purpose of education. Resource may be used for classroom training only and must remain as is, including the branding and EXCEMED logo. It is backed by a publishing license, signed by the author.

Preceptorship
Milan, Italy
Oct 30 - 31, 2014
Target audience
Clinicians and scientists currently involved in MS and/or NMO management., Radiologists
EACCME®
by Excemed
Neurology

MS Alumni

The MS Alumni programme is an educational initiative of EXCEMED that is intended to provide ongoing support for young physicians and specialists in neurology.