Neuroimaging in Multiple Sclerosis: Neurotherapeutic Implications
Imaging techniques, in particular magnetic resonance imaging (MRI), play an important role in the diagnosis and management of multiple sclerosis (MS) and related demyelinating diseases. Findings on MRI studies of the brain and spinal cord are critical for MS diagnosis, are used to monitor treatment response and may aid in predicting disease progression in individual patients. In addition, results of imaging studies serve as essential biomarkers in clinical trials of putative MS therapies and have led to important insights into disease pathophysiology. Although they are useful tools and provide in vivo measures of disease-related activity, there are some important limitations of MRI findings in MS, including the non-specific nature of detectable white matter changes, the poor correlation with clinical disability, the limited sensitivity and ability of standard measures of gadolinium enhancing lesions and T2 lesions to predict future clinical course, and the lack of validated biomarkers of long term outcomes. Advancements that hold promise for the future include new techniques that are sensitive to diffuse changes, the increased use of higher field scanners, measures that capture disease related changes in gray matter, and the use of combined structural and functional imaging approaches to assess the complex and evolving disease process that occurs during the course of MS.
Key WordsMultiple sclerosis magnetic resonance imaging neurodegeneration cognitive impairment diffusion tensor imaging functional magnetic resonance imaging.
Multiple sclerosis (MS) is an inflammatory autoimmune disorder of the central nervous system that is frequently associated with the development of significant disability. There are approximately 400,000 cases of MS in the USA, or 0.1% of the general population. The age of onset is in young adulthood (ages 20–40), and women are affected more commonly than men . The female:male ratio of 2:1 is usually cited, but newer studies suggest an increasing female preponderance, ranging from 4:1 to 7:1 [2, 3]. The reason for this greater skewing by sex is not clear, although several intriguing theories have been proposed [4, 5]. Acute attacks of neurological impairment (relapses) followed by variable degrees of improvement (remission) characterizes relapsing remitting MS (RRMS), representing 85% of newly diagnosed cases. The majority of RRMS patients will eventually transition to a disease stage in which relapses are less common or even absent, and a slowly progressive disability ensues, classified as secondary progressive MS (SPMS). Another form is primary progressive MS, which is associated with a slowly progressive myelopathy, an older age at onset, and equal distribution among men and women; this form accounts for 10% of new MS diagnoses. Progressive-relapsing MS in which relapses occur after an initially progressive form accounts for the remaining 5% of cases . In addition to these classical MS subtypes, there are several MS variants, including neuromyelitis optica and acute disseminated encephalomyelitis .
Barkhof Magnetic Resonance Imaging Criteria
3 of 4 of the following are required:
1. Gadolinium-enhanced lesion or the presence of >9 T2 lesions
2. One infratentorial lesion
3. One juxtacortical lesion
4. 3 periventricular lesions
MRI criteria for diagnosis: A moving target
The original McDonald diagnostic criteria for MS incorporated the modified Barkhof criteria to establish dissemination in space and a somewhat complicated algorithm to establish dissemination in time using findings on serial MR images . Modifications in 2005 reflected the important role that spinal cord imaging plays in the diagnosis of MS and simplified the establishment of dissemination in time . Most recently, the MAGNIMS group has proposed new guidelines that would allow a diagnosis of MS in a CIS patient with a single MRI scan that demonstrated typical white matter lesions meeting Barkhof criteria (dissemination in space) and consisting of a mixture of both enhancing and non-enhancing lesions (dissemination in time) .
Individuals with characteristic MRI findings in the absence of clinical symptoms and with an entirely normal neurological examination have been described as having a “radiologically isolated syndrome” or preclinical MS. Recent longitudinal cohort studies suggest that about one-third of such patients will convert to CIS over the course of 2 years [17, 18] and that the presence of spinal cord lesions is associated with a faster clinical conversion .
MRI as a surrogate marker
Acute inflammatory activity.
Initial studies of MS using serial MRI scans revealed the presence of new inflammatory activity occurring at a rate seven- to tenfold greater than the clinical events [20, 21]. The sensitivity of MRI to detect ongoing disease activity in the absence of less frequent and sometimes hard to define clinical worsening has made it an attractive readout for assessing treatment effects in clinical trials . Subsequent studies have convincingly demonstrated that the presence of active inflammation, as detected with Gd + lesions, is associated with a higher likelihood of relapse activity . As a readout of acute inflammation and short-term clinical activity, Gd + enhancing lesion numbers and volumes are among the most robust MRI biomarkers of MS [23, 24] and short-term disability progression .
Cumulative disease burden.
While Gd + lesions reflect transient inflammatory events, changes in T2/FLAIR lesion numbers and volumes are measures of cumulative lesion formation and can be used in lieu of Gd + lesion counts . The relationship to future disability is only modest , and other measures that reflect global and gray matter changes have been shown to be better predictors of long-term outcomes [28, 29]. Despite this evidence, MRI outcomes for exploratory Phase II studies of MS therapies continue to use Gd + lesions and T2 volumes. While clinical metrics (decrease in relapse rate or slowing of disability progression) are the primary outcome measures in definitive Phase III clinical trials, changes in lesion burden detected by MRI remain important secondary outcome measures.
All currently available disease-modifying therapies for MS have been shown to have significant effects on MRI measures of white matter inflammation. The original studies with interferon-β showed a dramatic reduction in Gd + activity  and subsequently a more modest decrease in relapse rate . Treatment with the first-generation injectable therapies, such as interferon beta-1b (Betaseron; Bayer Healthcare Pharmaceuticals, Wayne, JF), and interferon beta-1a [Avonex (Biogen Idec, Weston, MA); Rebif (Merck Serono, Geneva, Switzerland)] and glatiramer acetatate (Copaxone; Teva Pharmaceuticals, Petah Tikva, Israel), leads to variable decreases in Gd + activity and the number and volume of T2 lesions [31, 32, 33, 34, 35, 36, 37] and, on average, a 30% reduction in relapses [7, 31, 36, 38, 39]. However, a dose/response relationship is evident with high doses of interferon-β associated with more pronounced reductions in MR disease activity and relapses [36, 40, 41, 42].
Newer therapies have also shown pronounced effects on inflammatory activity and significant decreases in relapse rates. Natalizumab (Tysabri; Biogen Idec and Élan, Roscommon, Ireland) was tested first in combination with interferon beta-1a , which may have increased the risk for developing progressive multifocal leukoencephalopathy. Subsequent Phase III trials showed what appeared to be more prominent treatment benefits of natalizumab versus the first-generation injectable therapies. In both the SENTINAL  and AFFIRM  studies, MRI activity and relapse rates were suppressed significantly. However, the patient cohorts tested were diagnosed using McDonald criteria, were younger, and had overall lower disease activity which may have led to an overestimation of the treatment response , especially if the relative risk reduction is reported instead of absolute risk reduction .
The limitations of relying solely on markers of inflammation came into focus when these therapies were used to treat patients with progressive forms of MS. The European trial of interferon beta-1b in SPMS found benefits in markers of inflammation and disease progression [48, 49]. However, a North American trial failed to find a similar effect . Subsequent analysis of the two patient cohorts revealed that the benefits of interferon therapy on disease progression was limited to the group with higher levels of Gd + activity and continued relapses . The results from a series of studies with alemtuzamb (Campath; Genzyme, Cambridge, MA) provided more evidence for the complex role that inflammation plays in causing future disability. When used in progressive patients, Campath eliminates all traces of inflammatory lesion activity, but it has no impact on disability progression. However, treatment in early RRMS appears to stabilize the disease, suggesting that early inflammatory events lead to future neurodegenerative changes and worsening neurological function [52, 53]. Results from these therapeutic trials provide further evidence for the early treatment of MS with potent therapies.
TI black holes.
MRI-derived measures of atrophy have emerged as the most frequently used metric to capture the neurodegenerative process in MS, while Gd + activity and T2 lesion volume accumulation are measures of the “inflammatory” component of the disease. In practice, the distinction is not so neat, as inflammatory activity and brain volume measures are intertwined, making assessing treatment effects nuanced. Initial studies using global brain volume measures convincingly demonstrated that atrophy could be detected in RRMS  and could be measured accurately and reproducibly using automated techniques, such as the brain parenchymal fraction. In turn, these automated measures were used to monitor treatment effects on brain atrophy rates . However, it has became clear that global brain volume measures are sensitive to changes in brain water content, which in turn fluctuate with disease activity and fluid status. For example, therapies with potent anti-inflammatory effects produce a more rapid, but transient rate of brain volume loss—the so-called pseudoatrophy effect—but may have differing effects in slowing brain volume loss with longer term treatment .
A recent study found that the rate of global brain atrophy varies across patients with MS; however, when baseline atrophy is accounted for, the rate is similar across the disease spectrum . Long-term studies have validated the relationship between global brain atrophy and disability, as measured by the Expanded Disability Status Scale (EDSS) and the MS functional composite score (MSFC) , and also indicated that brain atrophy rate during the RR phase was a significant predictor of subsequent disability , suggesting that atrophy is clinically relevant.
Interferon preparations have been shown to slow the rate of brain atrophy in the second year of treatment in RRMS [73, 74, 75] but not in SPMS . An initial analysis of a study using a less sensitive central brain slice methodology failed to find an effect of copolymer-1 in slowing the rate of brain atrophy , but a subsequent re-analysis using the automated SEINA approach did demonstrate a benefit of treatment .
Measures of specific tissue types reveal that there are distinct atrophy rates in gray matter versus white matter regions in the brain, and that while white matter regions show a steady decrease, gray matter atrophy accelerates over time and is a more sensitive predictor of future disability [28, 29]. There is emerging evidence that the appearance of white matter lesions is linked to subsequent cortical gray matter changes, although the specific location of the lesions may influence the degree of gray matter change detected . This fits with the treatment effects on whole brain atrophy reported above, which found a slowing of brain atrophy after several months of treatment, thus reflecting the delayed impact of suppressing white matter inflammatory changes.
Only a few studies have specifically assessed treatment effects on gray matter atrophy, although measuring neuroprotective and remyelination effects is of great importance for future MS therapeutics . One study suggests a benefit of interferon beta-1a (Avonex) in slowing the rate of gray matter atrophy, detectable at 2 and 3 years after initiating treatment . Another recent study found that gray matter loss was detected in patients treated with interferon-β but not in untreated or Copaxone-treated patients assessed over a 2-year period using a voxel-based morphometry approach . However, interpretation of the latter study is limited by the small sample size and the lack of randomization.
Regional gray matter changes.
There is increasing evidence that gray matter regions are also impacted in MS and that some gray matter regions are especially susceptible. For example, newer techniques at higher fields as well as detailed pathological analyses have revealed widespread demyelination in the cerebral cortex [82, 83, 84, 85]. The impact of disease modifying agents (DMAs) on cortical plaques has not been studied in detail to date. and such studies will be complicated by the lack of sensitivity of current imaging techniques in detecting the majority of cortical plaques . In addition to the cortical rim, deep gray matter structures are also impacted in MS, with the thalamus showing early and significant atrophy associated with axonal and neuronal loss [87, 88]. Thalamic atrophy has been linked with fatigue and cognitive impairment [89, 90], but the effect of DMAs on thalamic volume or function has not been assessed. The hippocampus is an archicortical gray matter structure that is impacted by MS and related to cognitive impairment . Pathological studies show demyelination and neuronal loss throughout the hippocampal formation [92, 93]. Recent evidence suggests that there may be subregional susceptibility to distinct MS disease processes linked to depression and cognitive impairment in the hippocampus [94, 95]. Although changes in these distinct gray matter areas are well documented, few current studies are targeting MR outcome measures to assess specific treatment effects on these key brain areas.
MEASURING THERAPEUTIC EFFICACY
Although it is an important outcome measure for the assessment of new therapies, the use of MRI to monitor treatment response lacks consensus among practitioners [59, 96]. It is difficult to define “breakthrough” disease, although most experienced clinicians seem to “know it when they see it”. However, there is some evidence that in the setting of clinical events, the presence of new inflammatory activity detected on MR images should prompt a consideration to change therapy . The search for relevant biomarkers continues, with a recent finding that baseline cytokine levels can predict the response to interferon treatment a promising advance , although other approaches, such as monitoring biological response markers, seem to be unhelpful in identifying non-responders .
Findings on conventional MRI scans have contributed significantly to the clinical care of persons with MS by allowing for early diagnosis and treatment. In addition, key pathophysiological insights have been gleaned from MRI data obtained in practice and in clinical trials. New challenges are to develop sensitive and more specific markers of disease effects beyond detectable white matter lesion areas. Newer therapies developed to slow neurodegeneration or promote remyelination will require the use of advanced multimodal MRI techniques that capture structural and functional changes. The adoption of these cutting edge techniques into multicenter trials will be technically challenging, but feasible in the near future.
Funding is from the National MS Society (RG3914, RG4176, RG3915-A-15) and the NIH/NINDS (RO1 NS 051591).
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