We used ultra-high field MRI to visualize cortical lesion types described by neuropathology in 16 patients with multiple sclerosis (MS) compared with 8 age-matched controls; to characterize the ...contrast properties of cortical lesions including T2*, T2, T1, and phase images; and to investigate the relationship between cortical lesion types and clinical data.
We collected, on a 7-T scanner, 2-dimensional fast low-angle shot (FLASH)-T2*-weighted spoiled gradient-echo, T2-weighted turbo spin-echo (TSE) images (0.33 x 033 x 1 mm(3)), and a 3-dimensional magnetization-prepared rapid gradient echo.
Overall, 199 cortical lesions were detected in patients on both FLASH-T2* and T2-TSE scans. Seven-tesla MRI allowed for characterization of cortical plaques into type I (leukocortical), type II (intracortical), and type III/IV (subpial extending partly or completely through the cortical width) lesions as described histopathologically. Types III and IV were the most frequent type of cortical plaques (50.2%), followed by type I (36.2%) and type II (13.6%) lesions. Each lesion type was more frequent in secondary progressive than in relapsing-remitting MS. This difference, however, was significant only for type III/IV lesions. T2*-weighted images showed the highest, while phase images showed the lowest, contrast-to-noise ratio for all cortical lesion types. In patients, the number of type III/IV lesions was associated with greater disability (p < 0.02 by Spearman test) and older age (p < 0.04 by Spearman test).
Seven-tesla MRI detected different histologic cortical lesion types in our small multiple sclerosis (MS) sample, suggesting, if validated in a larger population, that it may prove a valuable tool to assess the contribution of cortical MS pathology to clinical disability.
Brain imaging studies detect abnormalities in normal-appearing white matter in patients with MS.
To investigate the histopathologic basis for these changes in autopsy tissue from a patient with MS ...with 9 months' disease duration and a terminal brain stem lesion.
The brain stem and spinal cord were analyzed ultrastructurally and immunocytochemically for axons, myelin, and activated microglia/macrophages.
Pathologic findings were consistent with a terminal inflammatory demyelinated lesion at the cervicomedullary junction. The ventral spinal cord column, containing descending tracts, exhibited 22% axonal loss at segment C7, but grossly normal immunostaining for myelin. Confocal and electron microscopy revealed myelin sheaths without axonal content and initial stages of myelin degradation by activated microglia/macrophages among intact myelinated axons. Axonal number and appearance was normal in ascending sensory tracts.
These studies confirm axonal degeneration in the absence of myelin loss as one histopathologic correlate to abnormal MR findings in patients with 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
Approximately 85% of multiple sclerosis (MS) cases begin as clinically isolated syndromes (CIS). Results from the Controlled High-Risk Subjects Avonex® Multiple Sclerosis Prevention Study (CHAMPS) ...demonstrated that, in patients with CIS, treatment with intramuscular (IM) interferon beta-1a (IFNβ-1a) 30 μg once weekly delayed conversion to clinically definite MS (CDMS) in the total population and in subgroups based on presenting syndromes and baseline magnetic resonance imaging (MRI) characteristics. Changes to clinical and MRI risk classification of presenting symptoms in recent studies prompted reanalysis of CHAMPS data. Presenting syndromes were assessed using a derived algorithm that stratifies patients into mono- or multifocal categories based on functional system scores. The ability of IM IFNβ-1a to delay progression to CDMS in subgroups based on clinical presentation and MRI characteristics was assessed. Reanalysis of CHAMPS patients showed that 30% could be classified by clinical criteria as having multifocal disease at baseline. IM IFNβ-1a initiated at a first demyelinating attack delayed CDMS in monofocal patients (P = 0.0013), patients with or without gadolinium-enhancing lesions (P = 0.0007, P = 0.0405) and patients with at least nine T2 lesions at baseline (P = 0.0044). These data confirm that IM IFNβ-1a delays conversion to CDMS in patients with CIS.
We studied multiple sclerosis fatigue (MSF) and its relationship to depression and disability. Seventy-one patients 50 relapsing-remitting, 21 secondary progressive were grouped by Fatigue Severity ...Scale (FSS) into MS-fatigue (MSF) (FSS>/=5; n=46) or MS-nonfatigue (MSNF) (FSS</=4; n=20). Forty-one patients were grouped into MS-depression (MSD) (n=15) or MS-nondepression (MSND) (n=26) by interview. Higher expanded disability status scale (EDSS) scores were noted in MSF than MSNF patients (P=0.0003); EDSS scores correlated with FSS scores (rho=0.43, P=0.003). However, fatigue was present in 58% (n=29) of relapsing-remitting patients and in 52% (n=26) of patients with mild physical disability (EDSS<3.5). Hamilton/Beck depression severity scores were higher in MSF than MSNF patients and correlated with FSS scores (P<0.05). MSD had higher FSS scores than MSND patients (P=0.008). After controlling for EDSS, depression severity continued to correlate with FSS scores (rho=0.37, P=0.02). After controlling for depression, FSS scores no longer correlated with EDSS scores (rho=0.27, P=0.09). Thus, MSF is independent of physical disability, but is associated with depression, suggesting that common mechanisms play a role in MSF and MSD including psychological factors or brain lesions in specific neuroanatomic pathways. Further study is warranted to determine if antidepressant medications improve fatigue in MS.
It is unclear whether brain MRI lesions are associated with depression in multiple sclerosis (MS). Neurological dysfunction in depressed (n= 19) and non-depressed (n = 29) MS patients was rated by ...expanded disability status scale (EDSS). EDSS was weakly predictive of the presence of (p = 0.03) and severity of (p = 0.01) depression. After correcting for EDSS, the presence of depression was predicted by superior frontal and superior parietal hypointense TI lesions (p<0.01); the severity of depression was predicted by superior frontal, superior parietal and temporal TI lesions, lateral and third ventricular enlargement, and frontal atrophy (p<0.01). Depression was not related to bright T2 lesions or enhancement. We conclude that atrophy and cortical-subcortical disconnection due to frontal and parietal white matter destructive lesions may contribute to depression in MS.
Background:
Patients with clinically isolated syndrome (CIS) and characteristic magnetic resonance imaging (MRI) lesions are at high risk for multiple sclerosis (MS). However, patients with a minimal ...MRI lesion burden (a low T2-hyperintense low T2 lesion count) may have borderline formal diagnostic criteria, presenting a clinical management challenge.
Objective:
Compare the 10-year disease progression of patients with low and higher T2 lesion counts treated over most intervals.
Methods:
CIS patients from the original CHAMPS MS trial were retrospectively assigned to low-T2 (first quartile; 2–8 lesions) or higher-T2 (second through fourth quartiles; ≥ 9 lesions) groups using baseline T2 lesion counts. The 5- and 10-year open-label extension of CHAMPS (CHAMPIONS) evaluated conversion to clinically definite MS (CDMS), MRI activity, relapses, and disability.
Results:
The vast majority of patients showed new disease activity by MRI and/or clinical criteria at 10 years (low-T2 86%; higher-T2 98%). Fewer low-T2 than higher-T2 patients developed CDMS (40% vs. 63%; p = 0.013); low-T2 patients also had fewer new brain lesions, less brain volume loss, and less disability progression.
Conclusion:
CIS patients with low T2 lesion counts show continued disease activity. However, all assessments of disease progression over 10 years indicated a significantly less severe disease course for low-T2 patients.
Cortical subpial demyelination is frequent in multiple sclerosis (MS) and is closely associated with disease progression and poor neurological outcome. Although cortical lesions have been difficult ...to detect using conventional MRI, preliminary data using T2*-weighted imaging at ultra-high field 7T MRI showed improved sensitivity for detecting and categorizing different histological types of cortical MS lesions. In this study we combined high-resolution 7T MRI with a surface-based analysis technique to quantify and map subpial T2*-weighted signal changes in seventeen patients with MS. We applied a robust method to register 7T data with the reconstructed cortical surface of each individual and used a general linear model to assess in vivo an increase in subpial T2*-weighted signal in patients versus age-matched controls, and to investigate the spatial distribution of cortical subpial changes across the cortical ribbon. We also assessed the relationship between subpial T2* signal changes at 7T, Expanded Disability Status Scale (EDSS) score and white matter lesion load (WMLL). Patients with MS showed significant T2*-weighted signal increase in the frontal lobes (parsopercularis, precentral gyrus, middle and superior frontal gyrus, orbitofrontal cortex), anterior cingulate, temporal (superior, middle and inferior temporal gyri), and parietal cortices (superior and inferior parietal cortex, precuneus), but also in occipital regions of the left hemisphere. We found significant correlations between subpial T2*-weighted signal and EDSS score in the precentral gyrus (ρ=0.56, P=0.02) and between T2*-weighted signal and WMLL in the lateral orbitofrontal, superior parietal, cuneus, precentral and superior frontal regions. Our data support the presence of disseminated subpial increases in T2* signal in subjects with MS, which may reflect the diffuse subpial pathology described in neuropathology.
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