Characterization of cortico-meningeal translocator protein expression in multiple sclerosis.

Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. Positron emission tomography targeting the 18 kDa mitochondrial Translocator Protein (TSPO) is a molecular-specific approach to quantify immune cell-mediated density in the cortico-meningeal tissue compartment in vivo. The aim of this study was to characterize cortical and meningeal TSPO expression in a heterogeneous cohort of multiple sclerosis cases using in vivo simultaneous MR-PET with 11C-PBR28, a second-generation TSPO radioligand, and ex vivo immunohistochemistry. Forty-nine multiple sclerosis patients (21 with secondary progressive and 28 with relapsing-remitting multiple sclerosis) with mixed or high affinity binding for 11C-PBR28 underwent 90-min 11C-PBR28 simultaneous MR-PET. Tracer binding was measured using 60-90 min normalized standardized uptake value ratio values sampled at mid-cortical depth and ∼3 mm above the pial surface. Data in multiple sclerosis patients were compared to 21 age-matched healthy controls. To characterize the nature of 11C-PBR28 PET uptake, the meningeal and cortical lesion cellular expression of TSPO was further described in post-mortem brain tissue from 20 cases with secondary progressive multiple sclerosis and five age-matched healthy donors. Relative to healthy controls, patients with multiple sclerosis exhibited abnormally increased TSPO signal in the cortex and meningeal tissue, diffusively in progressive disease and more localized in relapsing-remitting multiple sclerosis. In multiple sclerosis, increased meningeal TSPO levels were associated with increased Expanded Disability Status Scale scores (p = 0.007, by linear regression). Immunohistochemistry, validated using in-situ sequencing analysis, revealed increased TSPO expression in the meninges and adjacent subpial cortical lesions of post-mortem secondary progressive multiple sclerosis cases relative to control tissue. In these cases, increased TSPO expression was related to meningeal inflammation. Translocator Protein immunostaining was detected on meningeal major histocompatibility complex (MHC)-class II + macrophages and cortical activated MHC-class II + transmembrane protein (TMEM)119+ microglia. In vivo arterial blood data and neuropathology showed that endothelial binding did not significantly account for increased TSPO cortico-meningeal expression in multiple sclerosis. Our findings support the use of TSPO-PET in multiple sclerosis for imaging in vivo inflammation in the cortico-meningeal brain tissue compartment and provide in vivo evidence implicating meningeal inflammation in the pathogenesis of the disease.

A Genetic Risk Variant for Multiple Sclerosis Severity is Associated with Brain Atrophy.

The minor allele of the genetic variant rs10191329 in the DYSF-ZNF638 locus is associated with unfavorable long-term clinical outcomes in multiple sclerosis patients. We investigated if rs10191329 is associated with brain atrophy measured by magnetic resonance imaging in a discovery cohort of 748 and a replication cohort of 360 people with relapsing multiple sclerosis. We observed an association with 28% more brain atrophy per rs10191329*A allele. Our results encourage stratification for rs10191329 in clinical trials. Unraveling the underlying mechanisms may enhance our understanding of pathophysiology and identify treatment targets. ANN NEUROL 2023;94:1080-1085.

Clinical and neuroimaging phenotypes of autoimmune glial fibrillary acidic protein astrocytopathy: A systematic review and meta-analysis.

OBJECTIVE: This study was undertaken to provide a comprehensive review of neuroimaging characteristics and corresponding clinical phenotypes of autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A), a rare but severe neuroinflammatory disorder, to facilitate early diagnosis and appropriate treatment. METHODS: A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis)-conforming systematic review and meta-analysis was performed on all available data from January 2016 to June 2023. Clinical and neuroimaging phenotypes were extracted for both adult and paediatric forms. RESULTS: A total of 93 studies with 681 cases (55% males; median age = 46, range = 1-103 years) were included. Of these, 13 studies with a total of 535 cases were eligible for the meta-analysis. Clinically, GFAP-A was often preceded by a viral prodromal state (45% of cases) and manifested as meningitis, encephalitis, and/or myelitis. The most common symptoms were headache, fever, and movement disturbances. Coexisting autoantibodies (45%) and neoplasms (18%) were relatively frequent. Corticosteroid treatment resulted in partial/complete remission in a majority of cases (83%). Neuroimaging often revealed T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities (74%) as well as perivascular (45%) and/or leptomeningeal (30%) enhancement. Spinal cord abnormalities were also frequent (49%), most commonly manifesting as longitudinally extensive myelitis. There were 88 paediatric cases; they had less prominent neuroimaging findings with lower frequencies of both T2/FLAIR hyperintensities (38%) and contrast enhancement (19%). CONCLUSIONS: This systematic review and meta-analysis provide high-level evidence for clinical and imaging phenotypes of GFAP-A, which will benefit the identification and clinical workup of suspected cases. Differential diagnostic cues to distinguish GFAP-A from common clinical and imaging mimics are provided as well as suitable magnetic resonance imaging protocol recommendations.

Validation of Rapid Magnetic Resonance Myelin Imaging in Multiple Sclerosis.

OBJECTIVE: Magnetic resonance imaging (MRI) is essential for multiple sclerosis diagnostics but is conventionally not specific to demyelination. Myelin imaging is often hampered by long scanning times, complex postprocessing, or lack of clinical approval. This study aimed to assess the specificity, robustness, and clinical value of Rapid Estimation of Myelin for Diagnostic Imaging, a new myelin imaging technique based on time-efficient simultaneous T1 /T2 relaxometry and proton density mapping in multiple sclerosis. METHODS: Rapid myelin imaging was applied using 3T MRI ex vivo in 3 multiple sclerosis brain samples and in vivo in a prospective cohort of 71 multiple sclerosis patients and 21 age/sex-matched healthy controls, with scan-rescan repeatability in a subcohort. Disability in patients was assessed by the Expanded Disability Status Scale and the Symbol Digit Modalities Test at baseline and 2-year follow-up. RESULTS: Rapid myelin imaging correlated with myelin-related stains (proteolipid protein immunostaining and Luxol fast blue) and demonstrated good precision. Multiple sclerosis patients had, relative to controls, lower normalized whole-brain and normal-appearing white matter myelin fractions, which correlated with baseline cognitive and physical disability. Longitudinally, these myelin fractions correlated with follow-up physical disability, even with correction for baseline disability. INTERPRETATION: Rapid Estimation of Myelin for Diagnostic Imaging provides robust myelin quantification that detects diffuse demyelination in normal-appearing tissue in multiple sclerosis, which is associated with both cognitive and clinical disability. Because the technique is fast, with automatic postprocessing and US Food and Drug Administration/CE clinical approval, it can be a clinically feasible biomarker that may be suitable to monitor myelin dynamics and evaluate treatments aiming at remyelination. ANN NEUROL 2020;87:710-724.

Characterization of thalamic lesions and their correlates in multiple sclerosis by ultra-high-field MRI.

BACKGROUND: Thalamic pathology is a marker for neurodegeneration and multiple sclerosis (MS) disease progression. OBJECTIVE: To characterize (1) the morphology of thalamic lesions, (2) their relation to cortical and white matter (WM) lesions, and (3) clinical measures, and to assess (4) the imaging correlates of thalamic atrophy. METHODS: A total of 90 MS patients and 44 healthy controls underwent acquisition of 7 Tesla images for lesion segmentation and 3 Tesla scans for atrophy evaluation. Thalamic lesions were classified according to the shape and the presence of a central venule. Regression analysis identified the predictors of (1) thalamic atrophy, (2) neurological disability, and (3) information processing speed. RESULTS: Thalamic lesions were mostly ovoid than periventricular, and for the great majority (78%) displayed a central venule. Lesion volume in the thalamus, cortex, and WM did not correlate with each other. Thalamic atrophy was only associated with WM lesion volume (p = 0.002); subpial and WM lesion volumes were associated with neurological disability (p = 0.016; p < 0.001); and WM and thalamic lesion volumes were related with cognitive impairment (p < 0.001; p = 0.03). CONCLUSION: Thalamic lesions are unrelated to those in the cortex and WM, suggesting that they may not share common pathogenic mechanisms and do not contribute to thalamic atrophy. Combined WM, subpial, and thalamic lesion volumes at 7 Tesla contribute to the disease severity.

7 T imaging reveals a gradient in spinal cord lesion distribution in multiple sclerosis.

We used 7 T MRI to: (i) characterize the grey and white matter pathology in the cervical spinal cord of patients with early relapsing-remitting and secondary progressive multiple sclerosis; (ii) assess the spinal cord lesion spatial distribution and the hypothesis of an outside-in pathological process possibly driven by CSF-mediated immune cytotoxic factors; and (iii) evaluate the association of spinal cord pathology with brain burden and its contribution to neurological disability. We prospectively recruited 20 relapsing-remitting, 15 secondary progressive multiple sclerosis participants and 11 age-matched healthy control subjects to undergo 7 T imaging of the cervical spinal cord and brain as well as conventional 3 T brain acquisition. Cervical spinal cord imaging at 7 T was used to segment grey and white matter, including lesions therein. Brain imaging at 7 T was used to segment cortical and white matter lesions and 3 T imaging for cortical thickness estimation. Cervical spinal cord lesions were mapped voxel-wise as a function of distance from the inner central canal CSF pool to the outer subpial surface. Similarly, brain white matter lesions were mapped voxel-wise as a function of distance from the ventricular system. Subjects with relapsing-remitting multiple sclerosis showed a greater predominance of spinal cord lesions nearer the outer subpial surface compared to secondary progressive cases. Inversely, secondary progressive participants presented with more centrally located lesions. Within the brain, there was a strong gradient of lesion formation nearest the ventricular system that was most evident in participants with secondary progressive multiple sclerosis. Lesion fractions within the spinal cord grey and white matter were related to the lesion fraction in cerebral white matter. Cortical thinning was the primary determinant of the Expanded Disability Status Scale, white matter lesion fractions in the spinal cord and brain of the 9-Hole Peg Test and cortical thickness and spinal cord grey matter cross-sectional area of the Timed 25-Foot Walk. Spinal cord lesions were localized nearest the subpial surfaces for those with relapsing-remitting and the central canal CSF surface in progressive disease, possibly implying CSF-mediated pathogenic mechanisms in lesion development that may differ between multiple sclerosis subtypes. These findings show that spinal cord lesions involve both grey and white matter from the early multiple sclerosis stages and occur mostly independent from brain pathology. Despite the prevalence of cervical spinal cord lesions and atrophy, brain pathology seems more strongly related to physical disability as measured by the Expanded Disability Status Scale.

Multiple sclerosis lesions in motor tracts from brain to cervical cord: spatial distribution and correlation with disability.

Despite important efforts to solve the clinico-radiological paradox, correlation between lesion load and physical disability in patients with multiple sclerosis remains modest. One hypothesis could be that lesion location in corticospinal tracts plays a key role in explaining motor impairment. In this study, we describe the distribution of lesions along the corticospinal tracts from the cortex to the cervical spinal cord in patients with various disease phenotypes and disability status. We also assess the link between lesion load and location within corticospinal tracts, and disability at baseline and 2-year follow-up. We retrospectively included 290 patients (22 clinically isolated syndrome, 198 relapsing remitting, 39 secondary progressive, 31 primary progressive multiple sclerosis) from eight sites. Lesions were segmented on both brain (T2-FLAIR or T2-weighted) and cervical (axial T2- or T2*-weighted) MRI scans. Data were processed using an automated and publicly available pipeline. Brain, brainstem and spinal cord portions of the corticospinal tracts were identified using probabilistic atlases to measure the lesion volume fraction. Lesion frequency maps were produced for each phenotype and disability scores assessed with Expanded Disability Status Scale score and pyramidal functional system score. Results show that lesions were not homogeneously distributed along the corticospinal tracts, with the highest lesion frequency in the corona radiata and between C2 and C4 vertebral levels. The lesion volume fraction in the corticospinal tracts was higher in secondary and primary progressive patients (mean = 3.6 ± 2.7% and 2.9 ± 2.4%), compared to relapsing-remitting patients (1.6 ± 2.1%, both P < 0.0001). Voxel-wise analyses confirmed that lesion frequency was higher in progressive compared to relapsing-remitting patients, with significant bilateral clusters in the spinal cord corticospinal tracts (P < 0.01). The baseline Expanded Disability Status Scale score was associated with lesion volume fraction within the brain (r = 0.31, P < 0.0001), brainstem (r = 0.45, P < 0.0001) and spinal cord (r = 0.57, P < 0.0001) corticospinal tracts. The spinal cord corticospinal tracts lesion volume fraction remained the strongest factor in the multiple linear regression model, independently from cord atrophy. Baseline spinal cord corticospinal tracts lesion volume fraction was also associated with disability progression at 2-year follow-up (P = 0.003). Our results suggest a cumulative effect of lesions within the corticospinal tracts along the brain, brainstem and spinal cord portions to explain physical disability in multiple sclerosis patients, with a predominant impact of intramedullary lesions.

Nervous System Involvement in Coronavirus Disease 2019: Results from a Retrospective Consecutive Neuroimaging Cohort.

Background Neurologic complications in coronavirus disease 2019 (COVID-19) have been described, but the understanding of their pathophysiologic causes and neuroanatomical correlates remains limited. Purpose To report on the frequency and type of neuroradiological findings in COVID-19. Materials and Methods In this retrospective study, all consecutive adult hospitalized patients with polymerase chain reaction positivity for severe acute respiratory syndrome coronavirus 2 and who underwent neuroimaging at Karolinska University Hospital between March 2 and May 24, 2020, were included. All examinations were systematically re-evaluated by 12 readers. Summary descriptive statistics were calculated. Results A total of 185 patients with COVID-19 (62 years ± 14 [standard deviation]; 138 men) underwent neuroimaging. In total, 222 brain CT, 47 brain MRI, and seven spinal MRI examinations were performed. Intra-axial susceptibility abnormalities were the most common finding (29 of 39; 74%, 95% CI: 58, 87) in patients who underwent brain MRI, often with an ovoid shape suggestive of microvascular pathology and with a predilection for the corpus callosum (23 of 39; 59%; 95% CI: 42, 74) and juxtacortical areas (14 of 39; 36%; 95% CI: 21, 53). Ischemic and macrohemorrhagic manifestations were also observed, but vascular imaging did not demonstrate overt abnormalities. Dynamic susceptibility contrast perfusion MRI in 19 patients did not reveal consistent asymmetries between hemispheres or regions. Many patients (18 of 41; 44%; 95% CI: 28, 60) had leukoencephalopathy and one patient had a cytotoxic lesion of the corpus callosum. Other findings included olfactory bulb signal abnormalities (seven of 37; 19%), prominent optic nerve subarachnoid spaces (20 of 36; 56%), and enhancement of the parenchyma (three of 20; 15%), leptomeninges (three of 20; 15%), cranial nerves (two of 20; 10%), and spinal nerves (two of four; 50%). At MRI follow-up, regression of leukoencephalopathy and progressive leptomeningeal enhancement was observed in one patient each, respectively, which is suggestive of dynamic processes. Conclusion Patients with coronavirus disease 2019 had a wide spectrum of vascular and inflammatory involvement of both the central and peripheral nervous system. © RSNA, 2020 Online supplemental material is available for this article.

Profiles of cortical inflammation in multiple sclerosis by 11C-PBR28 MR-PET and 7 Tesla imaging.

BACKGROUND: Neuroinflammation with microglia activation is thought to be closely related to cortical multiple sclerosis (MS) lesion pathogenesis. OBJECTIVE: Using 11C-PBR28 and 7 Tesla (7T) imaging, we assessed in 9 relapsing-remitting multiple sclerosis (RRMS) and 10 secondary progressive multiple sclerosis (SPMS) patients the following: (1) microglia activation in lesioned and normal-appearing cortex, (2) cortical lesion inflammatory profiles, and (3) the relationship between neuroinflammation and cortical integrity. METHODS: Mean 11C-PBR28 uptake was measured in focal cortical lesions, cortical areas with 7T quantitative T2* (q-T2*) abnormalities, and normal-appearing cortex. The relative difference in cortical 11C-PBR28 uptake between patients and 14 controls was used to classify cortical lesions as either active or inactive. Disease burden was investigated according to cortical lesion inflammatory profiles. The relation between q-T2* and 11C-PBR28 uptake along the cortex was assessed. RESULTS: 11C-PBR28 uptake was abnormally high in cortical lesions in RRMS and SPMS; in SPMS, tracer uptake was significantly increased also in normal-appearing cortex. 11C-PBR28 uptake and q-T2* correlated positively in many cortical areas, negatively in some regions. Patients with high cortical lesion inflammation had worse clinical outcome and higher intracortical lesion burden than patients with low inflammation. CONCLUSION: 11C-PBR28 and 7T imaging reveal distinct profiles of cortical inflammation in MS, which are related to disease burden.

Evidence of diffuse cerebellar neuroinflammation in multiple sclerosis by 11C-PBR28 MR-PET.

BACKGROUND: Activated microglia, which can be detected in vivo by 11C-PBR28 positron emission tomography (PET), represent a main component of MS pathology in the brain. Their role in the cerebellum is still unexplored, although cerebellar involvement in MS is frequent and accounts for disability progression. OBJECTIVES: We aimed at characterizing cerebellar neuroinflammation in MS patients compared to healthy subjects by combining 11C-PBR28 MRI-Positron Emission Tomography (MR-PET) with 7 Tesla (T) MRI and assessing its relationship with brain neuroinflammation and clinical outcome measures. METHODS: Twenty-eight MS patients and 16 healthy controls underwent 11C-PBR28 MR-PET to measure microglia activation in normal appearing cerebellum and lesions segmented from 7 T scans. Patients were evaluated using the Expanded Disability Status Scale and Symbol Digit Modalities Test. 11C-PBR28 binding was assessed in regions of interest using 60-90 minutes standardized uptake values normalized by a pseudo-reference region in the brain normal appearing white matter. Multilinear regression was used to compare tracer uptake in MS and healthy controls and assess correlations with clinical scores. RESULTS: In all cerebellar regions examined, MS patients showed abnormally increased tracer uptake, which correlated with cognitive and neurological disability. CONCLUSION: Neuroinflammation is widespread in the cerebellum of patients with MS and related to neurological disability and cognitive impairment.

Spatial distribution of multiple sclerosis lesions in the cervical spinal cord.

Spinal cord lesions detected on MRI hold important diagnostic and prognostic value for multiple sclerosis. Previous attempts to correlate lesion burden with clinical status have had limited success, however, suggesting that lesion location may be a contributor. Our aim was to explore the spatial distribution of multiple sclerosis lesions in the cervical spinal cord, with respect to clinical status. We included 642 suspected or confirmed multiple sclerosis patients (31 clinically isolated syndrome, and 416 relapsing-remitting, 84 secondary progressive, and 73 primary progressive multiple sclerosis) from 13 clinical sites. Cervical spine lesions were manually delineated on T2- and T2*-weighted axial and sagittal MRI scans acquired at 3 or 7 T. With an automatic publicly-available analysis pipeline we produced voxelwise lesion frequency maps to identify predilection sites in various patient groups characterized by clinical subtype, Expanded Disability Status Scale score and disease duration. We also measured absolute and normalized lesion volumes in several regions of interest using an atlas-based approach, and evaluated differences within and between groups. The lateral funiculi were more frequently affected by lesions in progressive subtypes than in relapsing in voxelwise analysis (P < 0.001), which was further confirmed by absolute and normalized lesion volumes (P < 0.01). The central cord area was more often affected by lesions in primary progressive than relapse-remitting patients (P < 0.001). Between white and grey matter, the absolute lesion volume in the white matter was greater than in the grey matter in all phenotypes (P < 0.001); however when normalizing by each region, normalized lesion volumes were comparable between white and grey matter in primary progressive patients. Lesions appearing in the lateral funiculi and central cord area were significantly correlated with Expanded Disability Status Scale score (P < 0.001). High lesion frequencies were observed in patients with a more aggressive disease course, rather than long disease duration. Lesions located in the lateral funiculi and central cord area of the cervical spine may influence clinical status in multiple sclerosis. This work shows the added value of cervical spine lesions, and provides an avenue for evaluating the distribution of spinal cord lesions in various patient groups.

Automatic segmentation of the spinal cord and intramedullary multiple sclerosis lesions with convolutional neural networks.

The spinal cord is frequently affected by atrophy and/or lesions in multiple sclerosis (MS) patients. Segmentation of the spinal cord and lesions from MRI data provides measures of damage, which are key criteria for the diagnosis, prognosis, and longitudinal monitoring in MS. Automating this operation eliminates inter-rater variability and increases the efficiency of large-throughput analysis pipelines. Robust and reliable segmentation across multi-site spinal cord data is challenging because of the large variability related to acquisition parameters and image artifacts. In particular, a precise delineation of lesions is hindered by a broad heterogeneity of lesion contrast, size, location, and shape. The goal of this study was to develop a fully-automatic framework - robust to variability in both image parameters and clinical condition - for segmentation of the spinal cord and intramedullary MS lesions from conventional MRI data of MS and non-MS cases. Scans of 1042 subjects (459 healthy controls, 471 MS patients, and 112 with other spinal pathologies) were included in this multi-site study (n = 30). Data spanned three contrasts (T1-, T2-, and T2∗-weighted) for a total of 1943 vol and featured large heterogeneity in terms of resolution, orientation, coverage, and clinical conditions. The proposed cord and lesion automatic segmentation approach is based on a sequence of two Convolutional Neural Networks (CNNs). To deal with the very small proportion of spinal cord and/or lesion voxels compared to the rest of the volume, a first CNN with 2D dilated convolutions detects the spinal cord centerline, followed by a second CNN with 3D convolutions that segments the spinal cord and/or lesions. CNNs were trained independently with the Dice loss. When compared against manual segmentation, our CNN-based approach showed a median Dice of 95% vs. 88% for PropSeg (p ≤ 0.05), a state-of-the-art spinal cord segmentation method. Regarding lesion segmentation on MS data, our framework provided a Dice of 60%, a relative volume difference of -15%, and a lesion-wise detection sensitivity and precision of 83% and 77%, respectively. In this study, we introduce a robust method to segment the spinal cord and intramedullary MS lesions on a variety of MRI contrasts. The proposed framework is open-source and readily available in the Spinal Cord Toolbox.

Longitudinal Characterization of Cortical Lesion Development and Evolution in Multiple Sclerosis with 7.0-T MRI.

Background Cortical lesions develop early in multiple sclerosis (MS) and play a major role in disease progression. MRI at 7.0 T shows high sensitivity for detection of cortical lesions as well as better spatial resolution and signal-to-noise ratio compared with lower field strengths. Purpose To longitudinally characterize (a) the development and evolution of cortical lesions in multiple sclerosis across the cortical width, sulci, and gyri; (b) their relation with white matter lesion accrual; and (c) the contribution of 7.0-T cortical and white matter lesion load and cortical thickness to neurologic disability. Materials and Methods Twenty participants with relapsing-remitting MS and 13 with secondary progressive MS, along with 10 age-matched healthy controls, were prospectively recruited from 2010 to 2016 to acquire, in two imaging sessions (mean interval, 1.5 years), 7.0-T MRI T2*-weighted gradient-echo images (0.33 × 0.33 × 1.0 mm3) for cortical and white matter lesion segmentation and 3.0-T T1-weighted images for cortical surface reconstruction and cortical thickness estimation. Cortical lesions were sampled through the cortex to quantify cortical lesion distribution. The Expanded Disability Status Scale (EDSS) was used to assess neurologic disability. Nonparametric statistics assessed differences between and within groups in MRI metrics of cortical and white matter lesion burden; regression analysis explored associations of disability with MRI metrics. Results Twenty-five of 31 (81%) participants developed new cortical lesions per year (intracortical, 1.3 ± 1.7 vs leukocortical, 0.7 ± 1.9; P = .04), surpassing white matter lesion accrual (cortical, 2.0 ± 2.8 vs white matter, 0.7 ± 0.6; P = .01). In contrast to white matter lesions, cortical lesion accrual was greater in participants with secondary progressive MS than with relapsing-remitting MS (3.6 lesions/year ± 4.2 vs 1.1 lesions/year ± 0.9, respectively; P = .03) and preferentially localized in sulci. Total cortical lesion volume independently predicted baseline EDSS (ß = 1.5, P < .001) and EDSS changes at follow-up (ß = 0.5, P = .003). Conclusion Cortical lesions predominantly develop intracortically and within sulci, suggesting an inflammatory cerebrospinal fluid-mediated lesion pathogenesis. Cortical lesion accumulation was prominent at 7.0 T and independently predicted neurologic disability progression. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Filippi and Rocca in this issue.

Changes in structural network are associated with cortical demyelination in early multiple sclerosis.

The aim of this study was to investigate the interplay between structural connectivity and cortical demyelination in early multiple sclerosis. About 27 multiple sclerosis patients and 18 age-matched controls underwent two MRI scanning sessions. The first was done at 7T and involved acquiring quantitative T1 and T2 * high-resolution maps to estimate cortical myelination. The second was done on a Connectom scanner and consisted of acquiring high angular resolution diffusion-weighted images to compute white matter structural connectivity metrics: strength, clustering and local efficiency. To further investigate the interplay between structural connectivity and cortical demyelination, patients were divided into four groups according to disease-duration: 0-1 year, 1-2 years, 2-3 years, and >3 years. ANOVA and Spearman's correlations were used to highlight relations between metrics. ANOVA detected a significant effect between disease duration and both cortical myelin (p = 2 × 10-8 ) and connectivity metrics (p < 10-4 ). We observed significant cortical myelin loss in the shorter disease-duration cohorts (0-1 year, p = .0015), and an increase in connectivity in the longer disease-duration cohort (2-3 years, strength: p = .01, local efficiency: p = .002, clustering: p = .001). Moreover, significant covariations between myelin estimation and white matter connectivity metrics were observed: Spearman's Rho correlation coefficients of 0.52 (p = .0003), 0.55 (p = .0001), and 0.53 (p = .0001) for strength, local efficiency, and clustering, respectively. An association between cortical myelin loss and changes in white matter connectivity in early multiple sclerosis was detected. These changes in network organization might be the result of compensatory mechanisms in response to the ongoing cortical diffuse damage in the early stages of multiple sclerosis.

In vivo characterization of cortical and white matter neuroaxonal pathology in early multiple sclerosis.

Neuroaxonal pathology is a main determinant of disease progression in multiple sclerosis; however, its underlying pathophysiological mechanisms, including its link to inflammatory demyelination and temporal occurrence in the disease course are still unknown. We used ultra-high field (7 T), ultra-high gradient strength diffusion and T1/T2-weighted myelin-sensitive magnetic resonance imaging to characterize microstructural changes in myelin and neuroaxonal integrity in the cortex and white matter in early stage multiple sclerosis, their distribution in lesional and normal-appearing tissue, and their correlations with neurological disability. Twenty-six early stage multiple sclerosis subjects (disease duration ≤5 years) and 24 age-matched healthy controls underwent 7 T T2*-weighted imaging for cortical lesion segmentation and 3 T T1/T2-weighted myelin-sensitive imaging and neurite orientation dispersion and density imaging for assessing microstructural myelin, axonal and dendrite integrity in lesional and normal-appearing tissue of the cortex and the white matter. Conventional mean diffusivity and fractional anisotropy metrics were also assessed for comparison. Cortical lesions were identified in 92% of early multiple sclerosis subjects and they were characterized by lower intracellular volume fraction (P = 0.015 by paired t-test), lower myelin-sensitive contrast (P = 0.030 by related-samples Wilcoxon signed-rank test) and higher mean diffusivity (P = 0.022 by related-samples Wilcoxon signed-rank test) relative to the contralateral normal-appearing cortex. Similar findings were observed in white matter lesions relative to normal-appearing white matter (all P < 0.001), accompanied by an increased orientation dispersion (P < 0.001 by paired t-test) and lower fractional anisotropy (P < 0.001 by related-samples Wilcoxon signed-rank test) suggestive of less coherent underlying fibre orientation. Additionally, the normal-appearing white matter in multiple sclerosis subjects had diffusely lower intracellular volume fractions than the white matter in controls (P = 0.029 by unpaired t-test). Cortical thickness did not differ significantly between multiple sclerosis subjects and controls. Higher orientation dispersion in the left primary motor-somatosensory cortex was associated with increased Expanded Disability Status Scale scores in surface-based general linear modelling (P < 0.05). Microstructural pathology was frequent in early multiple sclerosis, and present mainly focally in cortical lesions, whereas more diffusely in white matter. These results suggest early demyelination with loss of cells and/or cell volumes in cortical and white matter lesions, with additional axonal dispersion in white matter lesions. In the cortex, focal lesion changes might precede diffuse atrophy with cortical thinning. Findings in the normal-appearing white matter reveal early axonal pathology outside inflammatory demyelinating lesions.

Neuroinflammatory component of gray matter pathology in multiple sclerosis.

OBJECTIVE: In multiple sclerosis (MS), using simultaneous magnetic resonance-positron emission tomography (MR-PET) imaging with 11 C-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 11 C-PBR28 MR-PET. MS subjects underwent 7T T2*-weighted imaging for cortical lesion segmentation, and neurological and cognitive evaluation. 11 C-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 11 C-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, 11 C-PBR28 uptake across the brain was greater in SPMS than in RRMS. In MS, increased 11 C-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.

In vivo characterization of microglia and myelin relation in multiple sclerosis by combined 11C-PBR28 PET and synthetic MRI.

BACKGROUND: The in vivo relation between microglia activation and demyelination in multiple sclerosis is still unclear. OBJECTIVE: We combined 11C-PBR28 positron emission tomography and rapid estimation of myelin for diagnostic imaging (REMyDI) to characterize the relation between these pathological processes in a heterogeneous MS cohort. METHODS: 11C-PBR28 standardized uptake values normalized by a pseudo-reference region (SUVR) were used to measure activated microglia. A voxelwise analysis compared 11C-PBR28 SUVR in the white matter of 38 MS patients and 16 matched healthy controls. The relative difference in SUVR served as a threshold to classify patients' lesioned, perilesional and normal-appearing white matter as active or inactive. REMyDI was acquired in 27 MS patients for assessing myelin content in active and inactive white matter and its relationship with SUVR. Finally, we investigated the contribution of radiological metrics to clinical outcomes. RESULTS: 11C-PBR28 SUVR were abnormally higher in several white matter areas in MS. Myelin content was lower in active compared to inactive corresponding white matter regions. An inverse correlation between SUVR and myelin content was found. Radiological metrics correlated with both neurological and cognitive impairment. CONCLUSION: our data suggest an inverse relation of microglia activation and myelination, particularly in perilesional white matter tissue.

MRI detection of brain gadolinium retention in multiple sclerosis: Magnetization transfer vs. T1-weighted imaging.

BACKGROUND AND PURPOSE: Evidence of brain gadolinium retention has affected gadolinium-based contrast agent usage. It is, however, unclear to what extent macrocyclic agents are retained and whether their in vivo detection may necessitate nonconventional MRI. Magnetization transfer (MT) could prove suitable to detect gadolinium-related signal changes since dechelated gadolinium ions bind to macromolecules. Therefore, this study aimed to investigate associations of prior gadolinium administrations with MT and T1 signal abnormalities. METHODS: A cohort of 23 persons with multiple sclerosis (MS) (18 females, 5 males, 57 ± 8.0 years) with multiple past gadolinium administrations (median 6, range 3-12) and 23 age- and sex-matched healthy controls underwent 1.5 Tesla MRI with MT, T1-weighted 2-dimensional spin echo, and T1-weighted 3-dimensional gradient echo. The signal intensity index was assessed by MRI in gadolinium retention predilection sites. RESULTS: There were dose-dependent associations of the globus pallidus signal on gradient echo (r = .55, p < .001) and spin echo (r = .38, p = .013) T1-weighted imaging, but not on MT. Relative to controls, MS patients had higher signal intensity index in the dentate nucleus on T1-weighted gradient echo (1.037 ± 0.040 vs. 1.016 ± 0.023, p = .04) with a similar trend in the globus pallidus on T1-weighted spin echo (1.091 ± 0.034 vs. 1.076 ± 0.014, p = .06). MT detected no group differences. CONCLUSIONS: Conventional T1-weighted imaging provided dose-dependent associations with gadolinium administrations in MS, while these could not be detected with 2-dimensional MT. Future studies could explore newer MT techniques like 3D and inhomogenous MT. Notably, these associations were identified with conventional MRI even though most patients had not received gadolinium administrations in the preceding 9 years, suggestive of long-term retention.

Demographic and disease-related factors impact on cerebrospinal fluid neurofilament light chain levels in multiple sclerosis.

BACKGROUND: Neurofilament light (NfL) levels reflect inflammatory disease activity in multiple sclerosis (MS), but it is less clear if NfL also can serve as a biomarker for MS progression in treated patients without relapses and focal lesion accrual. In addition, it has not been well established if clinically effective treatment re-establishes an age and sex pattern for cerebrospinal fluid NfL (cNfL) as seen in controls, and to what degree levels are affected by disability level and magnetic resonance imaging (MRI) atrophy metrics. METHODS: We included subjects for whom cNfL levels had been determined as per clinical routine or in clinical research, classified as healthy controls (HCs, n = 89), MS-free disease controls (DCs, n = 251), untreated MS patients (uMS; n = 296), relapse-free treated MS patients (tMS; n = 78), and ProTEct-MS clinical trial participants (pMS; n = 41). RESULTS: Using linear regression, we found a positive association between cNfL and age, as well as lower concentrations among women, in all groups, except for uMS patients. In contrast, disability level in the entire MS cohort, or T1 and T2 lesion volumes, brain parenchymal fraction, thalamic fraction, and cortical thickness in the pMS trial cohort, did not correlate with cNfL concentrations. Furthermore, the cNfL levels in tMS and pMS groups did not differ. CONCLUSIONS: In participants with MS lacking signs of inflammatory disease activity, disease modulatory therapy reinstates an age and sex cNfL pattern similar to that of control subjects. No significant association was found between cNfL levels and clinical worsening, disability level, or MRI metrics.