This scientific commentary refers to ‘Time is myelin: early cortical myelin repair prevents atrophy and clinical progression in multiple sclerosis’ by Lazzarotto et al. ...(https://doi.org/10.1093/brain/awae024).
Cortical lesions are an established pathological feature of multiple sclerosis, develop from the earliest disease stages and contribute to disease progression. Here, we discuss current imaging ...approaches for detecting cortical lesions in vivo and their contribution for improving our understanding of cortical lesion pathogenesis as well as their clinical significance.
Although a variable portion of cortical lesions goes undetected at clinical field strength and even at ultra-high field MRI, their evaluation is still clinically relevant. Cortical lesions are important for differential multiple sclerosis (MS) diagnosis, have relevant prognostic value and independently predict disease progression. Some studies also show that cortical lesion assessment could be used as a therapeutic outcome target in clinical trials. Advances in ultra-high field MRI not only allow increased cortical lesion detection in vivo but also the disclosing of some interesting features of cortical lesions related to their pattern of development and evolution as well to the nature of associated pathological changes, which might prove relevant for better understanding the pathogenesis of these lesions.
Despite some limitations, imaging of cortical lesions is of paramount importance in MS for elucidating disease mechanisms as well as for improving patient management in clinic.
Over the past few years, MRI has become an indispensable tool for diagnosing multiple sclerosis (MS). However, the current MRI criteria for MS diagnosis have imperfect sensitivity and specificity. ...The central vein sign (CVS) has recently been proposed as a novel MRI biomarker to improve the accuracy and speed of MS diagnosis. Evidence indicates that the presence of the CVS in individual lesions can accurately differentiate MS from other diseases that mimic this condition. However, the predictive value of the CVS for the development of clinical MS in patients with suspected demyelinating disease is still unknown. Moreover, the lack of standardization for the definition and imaging of the CVS currently limits its clinical implementation and validation. On the basis of a thorough review of the existing literature on the CVS and the consensus opinion of the members of the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative, this article provides statements and recommendations aimed at helping radiologists and neurologists to better understand, refine, standardize and evaluate the CVS in the diagnosis of MS.
Objective
In multiple sclerosis (MS), using simultaneous magnetic resonance–positron emission tomography (MR‐PET) imaging with 11C‐PBR28, we quantified expression of the 18kDa translocator protein ...(TSPO), a marker of activated microglia/macrophages, in cortex, cortical lesions, deep gray matter (GM), white matter (WM) lesions, and normal‐appearing WM (NAWM) to investigate the in vivo pathological and clinical relevance of neuroinflammation.
Methods
Fifteen secondary‐progressive MS (SPMS) patients, 12 relapsing–remitting MS (RRMS) patients, and 14 matched healthy controls underwent 11C‐PBR28 MR‐PET. MS subjects underwent 7T
T2*‐weighted imaging for cortical lesion segmentation, and neurological and cognitive evaluation. 11C‐PBR28 binding was measured using normalized 60‐ to 90‐minute standardized uptake values and volume of distribution ratios.
Results
Relative to controls, MS subjects exhibited abnormally high 11C‐PBR28 binding across the brain, the greatest increases being in cortex and cortical lesions, thalamus, hippocampus, and NAWM. MS WM lesions showed relatively modest TSPO increases. With the exception of cortical lesions, where TSPO expression was similar, 11C‐PBR28 uptake across the brain was greater in SPMS than in RRMS. In MS, increased 11C‐PBR28 binding in cortex, deep GM, and NAWM correlated with neurological disability and impaired cognitive performance; cortical thinning correlated with increased thalamic TSPO levels.
Interpretation
In MS, neuroinflammation is present in the cortex, cortical lesions, deep GM, and NAWM, is closely linked to poor clinical outcome, and is at least partly linked to neurodegeneration. Distinct inflammatory‐mediated factors may underlie accumulation of cortical and WM lesions. Quantification of TSPO levels in MS could prove to be a sensitive tool for evaluating in vivo the inflammatory component of GM pathology, particularly in cortical lesions. Ann Neurol 2016;80:776–790
Ultra-high field 7 T MRI has multiple applications for the in vivo characterization of the heterogeneous aspects underlying multiple sclerosis including the identification of cortical lesions, ...characterization of the different types of white matter plaques, evaluation of structures difficult to assess with conventional MRI (thalamus, cerebellum, spinal cord, meninges).
The sensitivity of cortical lesion detection at 7 T is twice than at lower field MRI, especially for subpial lesions, the most common cortical lesion type in multiple sclerosis. Cortical lesion load accrual is independent of that in the white matter and predicts disability progression.Seven Tesla MRI provides details on tissue microstructure that can be used to improve white matter lesion characterization. These include the presence of a central vein, whose identification can be used to improve multiple sclerosis diagnosis, or the appearance of an iron-rich paramagnetic rim on susceptibility-weighted images, which corresponds to iron-rich microglia at the periphery of slow expanding lesions. Improvements in cerebellar and spinal cord tissue delineation and lesion characterization have also been demonstrated.
Imaging at 7 T allows assessing more comprehensively the complementary pathophysiological aspects of multiple sclerosis, opening up novel perspectives for clinical and therapeutics evaluation.
In multiple sclerosis (MS), it would be of clinical value to be able to track the progression of axonal pathology, especially before the manifestation of clinical disability. However, non-invasive ...evaluation of short-term longitudinal progression of white matter integrity is challenging. This study aims at assessing longitudinal changes in the restricted (i.e. intracellular) diffusion signal fraction (FR) in early-stage MS by using ultra-high gradient strength multi-shell diffusion magnetic resonance imaging. In 11 early MS subjects (disease duration ≤5 years), FR was obtained at two timepoints (one year apart) through the Composite Hindered and Restricted Model of Diffusion, along with conventional Diffusion Tensor Imaging metrics. At follow-up, no statistically significant change was detected in clinical variables, while all imaging metrics showed statistically significant longitudinal changes (p < 0.01, corrected for multiple comparisons) in widespread regions in normal-appearing white matter (NAWM). The most extensive longitudinal changes were observed in FR, including areas known to include a large fraction of crossing fibers. Furthermore, FR was also the only metric showing significant longitudinal changes in lesions that were present at both time points (p = 0.007), with no significant differences found for conventional diffusion metrics. Finally, FR was the only diffusion metric (as compared to Diffusion Tensor Imaging) that revealed pre-lesional changes already present at baseline. Taken together, our data provide evidence for progressive microstructural damage in the NAWM of early MS cases detectable already at 1-year follow-up. Our study highlights the value of multi-shell diffusion imaging for sensitive tracking of disease evolution in MS before any clinical changes are observed.
This article is part of a Special Issue entitled: SI: MRI and Neuroinflammation.
•We use the CHARMED diffusion model to assess restricted signal fraction (FR) in 11 multiple sclerosis patients at 1 year follow-up.•The most extensive longitudinal changes were observed in FR, including areas known to include a large fraction of crossing fibers.•FR was the only metric showing significant longitudinal changes in lesions that were present at both time points.•FR was the only metric that revealed pre-lesional changes already present at baseline.•We evidence for progressive microstructural damage in the NAWM of early MS cases detectable already at 1-year follow-up.
Axonal degeneration is a central pathological feature of multiple sclerosis and is closely associated with irreversible clinical disability. Current noninvasive methods to detect axonal damage in ...vivo are limited in their specificity and clinical applicability, and by the lack of proper validation. We aimed to validate an MRI framework based on multicompartment modeling of the diffusion signal (AxCaliber) in rats in the presence of axonal pathology, achieved through injection of a neurotoxin damaging the neuronal terminal of axons. We then applied the same MRI protocol to map axonal integrity in the brain of multiple sclerosis relapsing-remitting patients and age-matched healthy controls. AxCaliber is sensitive to acute axonal damage in rats, as demonstrated by a significant increase in the mean axonal caliber along the targeted tract, which correlated with neurofilament staining. Electron microscopy confirmed that increased mean axonal diameter is associated with acute axonal pathology. In humans with multiple sclerosis, we uncovered a diffuse increase in mean axonal caliber in most areas of the normal-appearing white matter, preferentially affecting patients with short disease duration. Our results demonstrate that MRI-based axonal diameter mapping is a sensitive and specific imaging biomarker that links noninvasive imaging contrasts with the underlying biological substrate, uncovering generalized axonal damage in multiple sclerosis as an early event.
Irreversible white matter (WM) damage, including severe demyelination and axonal loss, is a main determinant of long-term disability in multiple sclerosis (MS). Non-invasive detection of changes in ...microstructural WM integrity in the disease is challenging since commonly used imaging metrics lack the necessary sensitivity, especially in the early phase of the disease. This study aims at assessing microstructural WM abnormalities in early-stage MS by using ultra-high gradient strength multi-shell diffusion MRI and the restricted signal fraction (FR) from the Composite Hindered and Restricted Model of Diffusion (CHARMED), a metric sensitive to the volume fraction of axons. In 22 early MS subjects (disease duration ≤5 years) and 15 age-matched healthy controls, restricted fraction estimates were obtained through the CHARMED model along with conventional Diffusion Tensor Imaging (DTI) metrics. All imaging parameters were compared cross-sectionally between the MS subjects and controls both in WM lesions and normal-appearing white matter (NAWM). We found a significant reduction in FR focally in WM lesions and widespread in the NAWM in MS patients relative to controls (corrected p < .05). Signal fraction changes in NAWM were not driven by perilesional tissue, nor were they influenced by proximity to the ventricles, challenging the hypothesis of an outside-in pathological process driven by CSF-mediated immune cytotoxic factors. No significant differences were found in conventional DTI parameters. In a cross-validated classification task, FR showed the largest effect size and outperformed all other diffusion imaging metrics in discerning lesions from contralateral NAWM. Taken together, our data provide evidence for the presence of widespread microstructural changes in the NAWM in early MS stages that are, at least in part, unrelated to focal demyelinating lesions. Interestingly, these pathological changes were not yet detectable by conventional diffusion imaging at this early disease stage, highlighting the sensitivity and value of multi-shell diffusion imaging for better characterizing axonal microstructure in MS.
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