Multi-component relaxation in clinically isolated syndrome: Lesion myelination may predict multiple sclerosis conversion
Hagen H. KitzlerHannes WahlJudith EiseleMatthias KühnHenning Schmitz‐PeifferSimone KernBrian K. RuttSean DeoniTjalf ZiemssenJennifer Linn
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Abstract:
We performed a longitudinal case-control study on patients with clinically isolated syndrome (CIS) with the aid of quantitative whole-brain myelin imaging. The aim was (1) to parse early myelin decay and to break down its distribution pattern, and (2) to identify an imaging biomarker of the conversion into clinically definite Multiple Sclerosis (MS) based on in vivo measurable changes of myelination. Imaging and clinical data were collected immediately after the onset of first neurological symptoms and follow-up explorations were performed after 3, 6, and, 12 months. The multi-component Driven Equilibrium Single Pulse Observation of T1/T2 (mcDESPOT) was applied to obtain the volume fraction of myelin water (MWF) in different white matter (WM) regions at every time-point. This measure was subjected to further voxel-based analysis with the aid of a comparison of the normal distribution of myelination measures with an age and sex matched healthy control group. Both global and focal relative myelination content measures were retrieved. We found that (1) CIS patients at the first clinical episode suggestive of MS can be discriminated from healthy control WM conditions (p < 0.001) and therewith reproduced our earlier findings in late CIS, (2) that deficient myelination in the CIS group increased in T2 lesion depending on the presence of gadolinium enhancement (p < 0.05), and (3) that independently the CIS T2 lesion relative myelin content provided a risk estimate of the conversion to clinically definite MS (Odds Ratio 2.52). We initially hypothesized that normal appearing WM myelin loss may determine the severity of early disease and the subsequent risk of clinically definite MS development. However, in contrast we found that WM lesion myelin loss was pivotal for MS conversion. Regional myelination measures may thus play an important role in future clinical risk stratification.Keywords:
Clinically isolated syndrome
Brain myelin and iron content are important parameters in neurodegenerative diseases such as multiple sclerosis (MS). Both myelin and iron content influence the brain's R 2 * relaxation rate. However, their quantification based on R 2 * maps requires a realistic tissue model that can be fitted to the measured data. In structures with low myelin content, such as deep gray matter, R 2 * shows a linear increase with increasing iron content. In white matter, R 2 * is not only affected by iron and myelin but also by the orientation of the myelinated axons with respect to the external magnetic field. Here, we propose a numerical model which incorporates iron and myelin, as well as fibre orientation, to simulate R 2 * decay in white matter. Applying our model to fibre orientation‐dependent in vivo R 2 * data, we are able to determine a unique solution of myelin and iron content in global white matter. We determine an averaged myelin volume fraction of 16.02 ± 2.07% in non‐lesional white matter of patients with MS, 17.32 ± 2.20% in matched healthy controls, and 18.19 ± 2.98% in healthy siblings of patients with MS. Averaged iron content was 35.6 ± 8.9 mg/kg tissue in patients, 43.1 ± 8.3 mg/kg in controls, and 47.8 ± 8.2 mg/kg in siblings. All differences in iron content between groups were significant, while the difference in myelin content between MS patients and the siblings of MS patients was significant. In conclusion, we demonstrate that a model that combines myelin‐induced orientation‐dependent and iron‐induced orientation‐independent components is able to fit in vivo R 2 * data.
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Ganglioside
Grey matter
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Studies have provided qualitative evidence of de-myelination and re-myelination in aged brain white matter. However, there have been no quantitative evidences of degeneration and regeneration of myelin sheaths in white matter. The present study was designed to investigate the quantitative changes in myelin sheaths using unbiased stereological techniques and qualitative changes using electron microscopy in aged brain white matter. Results obtained showed that in brain white matter, the total volume of myelin sheaths of old-age female rats was not significantly different from that of young female rats, but the total length of myelinated fibers in old female rats was significantly decreased by 46.1% when compared with that of young female rats. Myelin sheath volume per unit length of myelinated fibers of old female rats was significantly increased by 43.4% compared with that of young female rats. The mean thickness of myelin sheaths in the white matter of the old rats was significantly increased by 33.3%, when compared with that of young female rats. In age-related loss of myelinated fibers, most fibers had diameters less than 1.4 μm, and myelin sheath thicknesses less than 0.14 μm, but the length of myelinated fibers with diameters more than 0.6 μm and myelin sheath thicknesses more than 0.22 μm increased with age. Myelinated fibers with ratios of myelin sheath thicknesses to myelinated fiber external diameter less than 0.21 were significantly lower in elderly rats than in young rats. However, the total length of myelinated fibers with ratios of myelin sheath thicknesses to myelinated fiber external diameter more than 0.23 was higher in aged rats than in young rats. About 6.58% of myelin sheaths showed degenerative alterations, while 0.88% myelin sheaths showed regenerative alterations. This study provides stereological evidence not only for degeneration but also regeneration of myelin sheaths in aged white matter.
Stereology
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Clinically isolated syndrome (CIS) refers to a first episode of multiple sclerosis (MS)–like neurologic symptoms that lasts at least 24 hours followed by complete or partial recovery. Individuals who experience CIS may or may not go on to develop MS. The most notable risk factors for MS during follow-up are MRI lesions and CSF oligoclonal bands.1 More recently, CSF neurofilament light (NfL) concentration, a general marker of axonal injury, has been proposed as predictive of future MS in CIS.2
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Neurofilament
McDonald criteria
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多発性硬化症（multiple sclerosis，MS）患者の85％はclinically isolated syndrome（CIS）と呼称される最初は単一の臨床症状を呈する．CIS患者の38～68％は臨床的に確実なMS（clinically definite MS，CDMS）へ進展する．インターフェロンβ（interferon β，IFNβ）はCISからCDMSへの進展を44～50％有意に抑制する．しかし，CISのすべての症例がMSへ進展するわけではないことから，MS以外の疾患を除外した後に，CDMSへ進展するリスクが高いと思われるMRIで空間的多発性および時間的多発性がみとめられ，McDonald診断基準でMSと診断できるCIS患者がIFNβ治療の適応となると考えられる．
Clinically isolated syndrome
McDonald criteria
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Clinically isolated syndrome
Relapsing remitting
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We investigated changes in myelin sheaths in the myelinated fibers of subcortical white matter in young (6-8 months old), middle-aged (18 months old), and elderly (27-28 months old) female Long-Evans rats using transmission electron microscopy and unbiased stereological techniques. We observed three age-related changes in myelin sheaths in the white matter of elderly rats: local splitting of the major dense line, myelin ballooning, and the formation of abundant myelin sheaths. Stereological analysis showed that the total length of myelinated fibers in white matter was 115±12 km (mean±SD) in young rats, 135±21 km in middle-aged rats, and 62±11 km in elderly rats. Myelinated fibers with diameters less than 1.0 μm and myelin sheath thicknesses less than 0.1 μm were significantly shorter in middle-aged and elderly rats compared with young rats. Age-related changes in myelin sheaths were evident in aged white matter. The loss of myelinated fibers with both small diameters and thin myelin sheaths is a potentially important change in aged white matter. Our results suggest that the myelin sheath changes in aged white matter may have important implications for age-related cognitive impairments.
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Multiple sclerosis is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. In most patients, the disease initiates with an episode of neurological disturbance referred to as clinically isolated syndrome, but not all patients with this syndrome develop multiple sclerosis over time, and currently, there is no clinical test that can conclusively establish whether a patient with a clinically isolated syndrome will eventually develop clinically defined multiple sclerosis. Here, we took advantage of the capabilities of targeted mass spectrometry to establish a diagnostic molecular classifier with high sensitivity and specificity able to differentiate between clinically isolated syndrome patients with a high and a low risk of developing multiple sclerosis. Based on the combination of abundances of proteins chitinase 3-like 1 and ala-β-his-dipeptidase in cerebrospinal fluid, we built a statistical model able to assign to each patient a precise probability of conversion to clinically defined multiple sclerosis. Our results are of special relevance for patients affected by multiple sclerosis as early treatment can prevent brain damage and slow down the disease progression.
Clinically isolated syndrome
Clinical Significance
Demyelinating Disorder
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