Target participants include clinicians (including radiologists, neurologists) and scientists (including physicists, engineers, biologists, chemists) working within the field of MRITo provide an overview of the current clinical applications of quantitative susceptibility mapping (QSM). Participants will be presented with a brief review of the clinical application of QSM to various neurodegenerative diseases and to neuroimaging diagnostic challenges. A more detailed discussion will focus on the direct application of QSM to multiple sclerosis (MS) and the potential for QSM to investigate dynamic biological changes occurring within the MS lesions.

The tissue field generated by a magnetic susceptibility source, such as iron, and experienced by the surrounding water protons is linearly related to the MR signal phase, which can be measured with high precision in MRI. QSM provides an effective means to directly map the distribution of susceptibility sources by solving the field-to-source inversion problem.1 The clinical utility of QSM has been primarily applied to the brain and has shown utility across a vast range of neurodegenerative diseases.¹ More recently, the clinical translation of QSM has included the study of the breast, liver, bone and kidney.¹ This presentation will provide the participants an opportunity to gain insight into the clinical potential of QSM, especially as it relates to the study of MS.

MS is an inflammatory demyelinating disease of the central nervous system (CNS), in which focal lesions characterize the early phase and diffuse neuronal loss prevails in the progressive stages.² Major advances in immunomodulatory therapy effectively reduce the number of clinical relapses and new focal lesions on MRI in patients with relapsing-remitting (RR) MS. However, no therapeutic options impact the progressive stage of MS,³ which represents the most significant unmet treatment need for MS patients. Effective treatment of progressive forms of MS has been largely non-existent due to a poor understanding of the relevant pathophysiologic mechanisms. Our group has utilized QSM to identify potential mechanisms of tissue injury in MS lesions.

I. An overview of neurological diseases for which QSM has been utilized to study will be briefly reviewed and include the following:

1. Excessive iron deposition within various brain regions has been demonstrated within number of Neurodegenerative diseases. Extensive work has reported in Parkinson’s disease wherein QSM has demonstrated potential feasibility as a quantitative biomarker for the disease. Iron deposition within the substantia nigra, as reflected by QSM, can distinguish early Parkinson’s patients from healthy individuals^4,5 and has demonstrated a spread of iron deposition, which correlates with disease duration.⁶ QSM has also allowed precision mapping of substructures of the basal ganglia, which improves the surgical targets for deep brain stimulation.^{7 8,9} QSM has also demonstrated excessive iron deposition within the deep grey matter structures in Alzheimer’s disease10, Huntington’s disease^11,12, neuropsychiatric systemic lupus erythematosus¹³ and multiple sclerosis¹⁴ as well as in the motor cortex in amyotrophic lateral sclerosis and primary lateral sclerosis¹⁵ .

2. QSM has demonstrated a utility in detection of brain calcifications associated with tumors such as meningiomas as well as in infections such as neurocysticercosis.¹⁶

3. QSM has been utilized for staging and quantification of large cerebral hemorrhages¹⁷, cavernous angiomas¹⁸, detection of micro-hemorrhages¹⁶, measuring cerebral oxygen consumption¹⁹ as well as measuring cerebral perfusion through dynamic QSM.²⁰

4. QSM has also provided insight into the normal age related iron changes within the brain, which may provide insight into normal cerebral iron metabolism and how this relates to various neurodegenerative diseases.^21,22

II. The application of QSM to Multiple Sclerosis. As mention above, excessive iron deposition within the deep grey matter has been observed in patients with MS.

Our group has expanded the clinical translation of QSM to investigate the MS lesion and below is the highlight of this work, which will be discussed in detail.

1. MS lesion susceptibility time course.²³ Thirty-two MS patients who had two MRIs (mean 0.43 years (y) interval) were studied. We found 162 lesions in which ages were measurable based on prior MRIs. The susceptibilities relative to normal appearing white matter (NAWM) and temporal rates of change in lesion susceptibility relative to CSF were calculated for new gadolinium (Gd) enhancing lesions (age=0y), non-enhancing lesions at age = 0-4y, and old non-enhancing lesions (age >7y). We found in MS lesions: 1) a sharp susceptibility jump within the first 3 months, 2) a slow and steady susceptibility rise in MS lesions within the first year, 3) a high susceptibility that lasted into 2 to 4 years, 4) and a susceptibility drop back to that of NAWM after 4 years. This cross-sectional study demonstrated that a dramatic increase in susceptibility occurs within the early stages after lesion development, which plateaus and then found to decrease after many years.

2. Confirmed early susceptibility changes in new MS lesions.²⁴ We examined MR images of MS patients with at least two successive MRI sessions (mean time interval 0.91 ± 0.61 years) that included T2-weighted (T2w), Gd-enhanced T1-weighted (T1w+Gd) and GRE imaging and a subset of new Gd-enhancing lesions were identified. GRE data were processed using QSM to measure mean susceptibility in the lesions relative to normal-appearing white matter (NAWM). A total of 51 new enhancing lesions were found in 29 unique MS patients on the baseline MRI scans and non-enhancing on the follow-up MRI scans. This longitudinal study confirmed that a significant increase in susceptibility compared to NAWM occurred as lesions transitioned from enhancing on baseline to non-enhancing on follow-up (4.14 ± 6.39 ppb versus 19.25 ± 8.45 ppb, P < .001)

3. Histological validation of QSM signal within MS lesions.²⁵ In order to understand what underlying pathophysiology causes the observed QSM signal within the MS lesion (i.e. demyelination vs iron deposition), we performed a histopathological correlation study with QSM. Lesion iron was measured by performing laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS)26, which was used in conjunction with immunohistochemical staining for myelin basic protein (MBP) to detect the presence of myelin and staining for immune cell activities. A chronic MS lesion was demonstrated to have susceptibility within the core of the lesion to be fully explained by the contribution from iron as measured by LA-ICP-MS. After subtracting the susceptibility contribution of iron, myelin phospholipid fraction (PF) was estimated from the residual susceptibility, which was in good agreement with MBP staining. It was also demonstrated that CD 68 labeling for active microglia was associated with the iron detected on LA-ICP-MS. This demonstrates that lesion iron is taken up by microglia and contributes to their active state. From QSM and ICP iron map, we can estimate a PF map using a myelin susceptibility tensor model and TDI defined orientation for myelin. This PF map correlates well with histology using MBP staining.

4. QSM and R2* measured changes in multiple sclerosis lesions: myelin breaking down, myelin debris, degradation and removal, and iron accumulation (AJNR in press). This work was designed to characterize lesion changes on QSM and R2* at various gadolinium-enhancement stages. 64 MS patients were included to identify new T2 white matter lesions, which were classified as nodular-enhancing (early-active), shell-enhancing (late-active), new non-enhancing (<1 year old, chronic-active) or chronic non-enhancing lesions (1- 3yrs old, chronic-stable). Susceptibility values measured on QSM and R2* values relative to lesions’ contralateral NAWM were compared among the four lesion types representing early active, late active, chronic active and stable stages. The results demonstrated a differential pattern in QSM and R2* among the early-active and late-active stage of MS lesions. At the time of nodular enhancement (early active), QSM is isointense and R2* decreases, reflecting myelin breaking down; in the late active stage (shell enhancement), QSM begins to rise and R2* decreases, reflecting myelin debris removal; late or chronic-active and chronic-stable staged lesions demonstrate both QSM and R2* increase, reflecting iron accumulation.

The clinical translation of QSM within neurological diseases has vast potential by providing insight into iron dynamics in normal aging and in neurodegenerative diseases. QSM has provided extensive insight into the early MS lesion, opening a new venue to investigate inflammatory activity after blood brain barrier closure, which is beyond the capability of current Gd-enhancement MRI protocol. We can now begin to further assess the influence of iron on tissue destruction and factors influencing repair in MS lesions.

Our work demonstrates that lesion MR susceptibility, as measured by QSM, quickly rises during the early stages of lesion development, which is consistent with the release of iron secondary to myelin and oligodendrocyte destruction.^27,28 Increases in iron release marks two important biologic events in the acute MS lesion: 1) myelin/oligodendrocytes destruction and 2) iron driven amplification of oxidative stress and inflammation.^27-31 This iron increase measureable on QSM would shine light on potential mechanisms leading to neurodegeneration in MS, which is regarded as the cause of the devastating secondary progression in MS.

In summary, brain MRI protocols should include the gradient echo sequence, which will allow the generation of QSM to assess the relationship of invariable iron deposition with subsequent neuronal loss among all neurodegenerative diseases. In MS, we think QSM can overcome the limitation of current Gd-enhancement MRI for MS, provide insight into therapeutic strategies to decrease secondary progression in MS, and serve as a novel biomarker for predicting future clinical outcomes in MS patient management.