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.

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.

Dilated Virchow-Robin spaces are a marker for arterial disease in multiple sclerosis.

BACKGROUND: Virchow-Robin spaces (VRS) have been associated with neurodegeneration and neuroinflammation. However, it remains uncertain to what degree non-dilated or dilated VRS reflect specific features of neuroinflammatory pathology. Thus, we aimed at investigating the clinical relevance of VRS as imaging biomarker in multiple sclerosis (MS) and to correlate VRS to their histopathologic signature. METHODS: In a cohort study comprising 142 MS patients and 30 control subjects, we assessed the association of non-dilated and dilated VRS to clinical and magnetic resonance imaging (MRI) outcomes. Findings were corroborated in a validation cohort comprising 63 MS patients. Brain blocks from 6 MS patients and 3 non-MS controls were histopathologically processed to correlate VRS to their tissue substrate. FINDINGS: In our actively treated clinical cohort, the count of dilated centrum semiovale VRS was associated with increased T1 and T2 lesion volumes. There was no systematic spatial colocalization of dilated VRS with MS lesions. At tissue level, VRS mostly corresponded to arteries and were not associated with MS pathological hallmarks. Interestingly, in our ex vivo cohort comprising mostly progressive MS patients, dilated VRS in MS were associated with signs of small vessel disease. INTERPRETATION: Contrary to prior beliefs, these observations suggest that VRS in MS do not associate with an accumulation of immune cells. But instead, these findings indicate vascular pathology as a driver and/or consequence of neuroinflammatory pathology for this imaging feature. FUNDING: NIH, Swedish Society for Medical Research, Swiss National Science Foundation and University of Zurich.

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.

Dilated Virchow-Robin Spaces are a Marker for Arterial Disease in Multiple Sclerosis.

Virchow-Robin spaces (VRS) have been associated with neurodegeneration and neuroinflammation. However, it remains uncertain to what degree non-dilated or dilated VRS reflect specific features of neuroinflammatory pathology. Thus, we aimed at investigating the clinical relevance of VRS as imaging biomarker in multiple sclerosis (MS) and to correlate VRS to their histopathologic signature. In a cohort study comprising 205 MS patients (including a validation cohort) and 30 control subjects, we assessed the association of non-dilated and dilated VRS to clinical and magnetic resonance imaging (MRI) out-comes. Brain blocks from 6 MS patients and 3 non-MS controls were histopathologically processed to correlate VRS to their tissue substrate. The count of dilated centrum semiovale VRS was associated with increased T1 and T2 lesion volumes. There was no systematic spatial colocalization of dilated VRS with MS lesions. At tissue level, VRS mostly corresponded to arteries and were not associated with MS pathological hallmarks. Interestingly, dilated VRS in MS were associated with signs of small vessel disease. Contrary to prior beliefs, these observations suggest that VRS in MS do not associate with accumulation of immune cells. But instead, these findings indicate vascular pathology as a driver and/or consequence of neuroinflammatory pathology for this imaging feature.

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.

Association between brain volume and disability over time in multiple sclerosis.

Background: Most previous multiple sclerosis (MS) brain atrophy studies using MS impact scale 29 (MSIS-29) or symbol digit modalities test (SDMT) have been cross-sectional with limited sets of clinical outcomes. Objectives: To investigate which brain and lesion volume metrics show the strongest long-term associations with the expanded disability status scale (EDSS), SDMT, and MSIS-29, and whether MRI-clinical associations vary with age. Methods: We acquired MRI and clinical data from a real-world Swedish MS cohort. FreeSurfer and SPM Lesion Segmentation Tool were used to obtain brain parenchymal, cortical and subcortical grey matter, thalamic and white matter fractions as well as T1- and T2-lesion volumes. Mixed-effects and rolling regression models were used in the statistical analyses. Results: We included 989 persons with MS followed for a median of 9.3 (EDSS), 10.1 (SDMT), and 9.3 (MSIS-29) years, respectively. In a cross-sectional analysis, the strength of the associations of the MRI metrics with the EDSS and MSIS-29 was found to drastically increase after 40-50 years of age. Low baseline regional grey matter fractions were associated with longitudinal increase of EDSS and physical MSIS-29 scores and decrease in SDMT scores and these atrophy measures were stronger predictors than the lesion volumes. Conclusions: The strength of MRI-clinical associations increase with age. Grey matter volume fractions are stronger predictors of long-term disability measures than lesion volumes.

Cortical and white matter lesion topology influences focal corpus callosum atrophy in multiple sclerosis.

BACKGROUND AND PURPOSE: Corpus callosum (CC) atrophy is a strong predictor of multiple sclerosis (MS) disability but the contributing pathological mechanisms remain uncertain. We aimed to apply advanced MRI to explore what drives the often nonuniform callosal atrophy. METHODS: Prospective brain 7 Tesla and 3 Tesla Human Connectom Scanner MRI were performed in 92 MS patients. White matter, leukocortical, and intracortical lesions were manually segmented. FreeSurfer was used to segment the CC and topographically classify lesions per lobe or as deep white matter lesions. Regression models were calculated to predict focal CC atrophy. RESULTS: The frontal and parietal lobes contained the majority (≥80%) of all lesion classifications in both relapsing-remitting and secondary progressive MS subtypes. The anterior subsection of the CC had the smallest proportional volume difference between subtypes (11%). Deep, temporal, and occipital white matter lesions, and occipital intracortical lesions were the strongest predictors of middle-posterior callosal atrophy (adjusted R2  = .54-.39, P < .01). CONCLUSIONS: Both white matter and cortical lesions contribute to regional corpus callosal atrophy. The lobe-specific lesion topology does not fully explain the inhomogeneous CC atrophy.

Automatic deep learning multicontrast corpus callosum segmentation in multiple sclerosis.

BACKGROUND AND PURPOSE: Corpus callosum (CC) atrophy is predictive of future disability in multiple sclerosis (MS). However, current segmentation methods are either labor- or computationally intensive. We therefore developed an automated deep learning-based CC segmentation tool and hypothesized that its output would correlate with disability. METHODS: A cohort of 631 MS patients (449 females, baseline age 41 ± 11 years) with both 3-dimensional T1-weighted and T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI was used for the development. Data from 204 patients were manually segmented to train convolutional neural networks in extracting the midsagittal intracranial and CC areas. Remaining data were used to compare segmentations with FreeSurfer and benchmark the outputs with regard to clinical correlations. A 1.5 and 3 Tesla reproducibility cohort of 9 MS patients evaluated the segmentation robustness. RESULTS: The deep learning-based tool was accurate in selecting the appropriate slice for segmentation (98% accuracy within 3 mm of the manual ground truth) and segmenting the CC (Dice coefficient .88-.91) and intracranial areas (.97-.98). The accuracy was lower with higher atrophy. Reproducibility was excellent (intraclass correlation coefficient > .90) for T1-weighted scans and moderate-good for FLAIR (.74-.75). Segmentations were associated with baseline and future (average follow-up time 6-7 years) Expanded Disability Status Scale (ρ = -.13 to -.24) and Symbol Digit Modalities Test (r = .18-.29) scores. CONCLUSIONS: We present a fully automatic deep learning-based CC segmentation tool optimized to modern imaging in MS with clinical correlations on par with computationally expensive alternatives.

Quantitative 7-Tesla Imaging of Cortical Myelin Changes in Early Multiple Sclerosis.

Cortical demyelination occurs early in multiple sclerosis (MS) and relates to disease outcome. The brain cortex has endogenous propensity for remyelination as proven from histopathology study. In this study, we aimed at characterizing cortical microstructural abnormalities related to myelin content by applying a novel quantitative MRI technique in early MS. A combined myelin estimation (CME) cortical map was obtained from quantitative 7-Tesla (7T) T 2 * and T1 acquisitions in 25 patients with early MS and 19 healthy volunteers. Cortical lesions in MS patients were classified based on their myelin content by comparison with CME values in healthy controls as demyelinated, partially demyelinated, or non-demyelinated. At follow-up, we registered changes in cortical lesions as increased, decreased, or stable CME. Vertex-wise analysis compared cortical CME in the normal-appearing cortex in 25 MS patients vs. 19 healthy controls at baseline and investigated longitudinal changes at 1 year in 10 MS patients. Measurements from the neurite orientation dispersion and density imaging (NODDI) diffusion model were obtained to account for cortical neurite/dendrite loss at baseline and follow-up. Finally, CME maps were correlated with clinical metrics. CME was overall low in cortical lesions (p = 0.03) and several normal-appearing cortical areas (p < 0.05) in the absence of NODDI abnormalities. Individual cortical lesion analysis revealed, however, heterogeneous CME patterns from extensive to partial or absent demyelination. At follow-up, CME overall decreased in cortical lesions and non-lesioned cortex, with few areas showing an increase (p < 0.05). Cortical CME maps correlated with processing speed in several areas across the cortex. In conclusion, CME allows detection of cortical microstructural changes related to coexisting demyelination and remyelination since the early phases of MS, and shows to be more sensitive than NODDI and relates to cognitive performance.

COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin-aldosterone system.

SARS-CoV-2 uses ACE2, an inhibitor of the Renin-Angiotensin-Aldosterone System (RAAS), for cellular entry. Studies indicate that RAAS imbalance worsens the prognosis in COVID-19. We present a consecutive retrospective COVID-19 cohort with findings of frequent pulmonary thromboembolism (17%), high pulmonary artery pressure (60%) and lung MRI perfusion disturbances. We demonstrate, in swine, that infusing angiotensin II or blocking ACE2 induces increased pulmonary artery pressure, reduces blood oxygenation, increases coagulation, disturbs lung perfusion, induces diffuse alveolar damage, and acute tubular necrosis compared to control animals. We further demonstrate that this imbalanced state can be ameliorated by infusion of an angiotensin receptor blocker and low-molecular-weight heparin. In this work, we show that a pathophysiological state in swine induced by RAAS imbalance shares several features with the clinical COVID-19 presentation. Therefore, we propose that severe COVID-19 could partially be driven by a RAAS imbalance.

Deep Learning Corpus Callosum Segmentation as a Neurodegenerative Marker in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Corpus callosum atrophy is a sensitive biomarker of multiple sclerosis (MS) neurodegeneration but typically requires manual 2D or volumetric 3D-based segmentations. We developed a supervised machine learning algorithm, DeepnCCA, for corpus callosum segmentation and relate callosal morphology to clinical disability using conventional MRI scans collected in clinical routine. METHODS: In a prospective study of 553 MS patients with 704 acquisitions, 200 unique 2D T2 -weighted MRI scans were delineated to develop, train, and validate DeepnCCA. Comparative FreeSurfer segmentations were obtained in 504 3D T1 -weighted scans. Both FreeSurfer and DeepnCCA outputs were correlated with clinical disability. Using principal component analysis of the DeepnCCA output, the morphological changes were explored in relation to clinical disease burden. RESULTS: DeepnCCA and manual segmentations had high similarity (Dice coefficients 98.1 ± .11%, 89.3 ± .76%, for intracranial and corpus callosum area, respectively through 10-fold cross-validation). DeepnCCA had numerically stronger correlations with cognitive and physical disability as compared to FreeSurfer: Expanded disability status scale (EDSS) ±6 months (r = -.22 P = .002; r = -.17, P = .013), future EDSS (r = -.26, P<.001; r = -.17, P = .012), and future symbol digit modalities test (r = .26, P = .001; r = .24, P = .003). The corpus callosum became thinner with increasing cognitive and physical disability. Increasing physical disability, additionally, significantly correlated with a more angled corpus callosum. CONCLUSIONS: DeepnCCA (https://github.com/plattenmichael/DeepnCCA/) is an openly available tool that can provide fast and accurate corpus callosum measurements applicable to large MS cohorts, potentially suitable for monitoring disease progression and therapy response.

The relevance of multiple sclerosis cortical lesions on cortical thinning and their clinical impact as assessed by 7.0-T MRI.

OBJECTIVE: This study aimed to investigate at 7.0-T MRI a) the role of multiple sclerosis (MS) cortical lesions in cortical tissue loss b) their relation to neurological disability. METHODS: In 76 relapsing remitting and 26 secondary progressive MS patients (N = 102) and 56 healthy subjects 7.0-T T2*-weighted images were acquired for lesion segmentation; 3.0-T T1-weighted structural scans for cortical surface reconstruction/cortical thickness estimation. Patients were dichotomized based on the median cortical lesion volume in low and high cortical lesion load groups that differed by age, MS phenotype and degree of neurological disability. Group differences in cortical thickness were tested on reconstructed cortical surface. Patients were evaluated clinically by means of the Expanded Disability Status Scale (EDSS). RESULTS: Cortical lesions were detected in 96% of patients. White matter lesion load was greater in the high than in the low cortical lesion load MS group (p = 0.01). Both MS groups disclosed clusters (prevalently parietal) of cortical thinning relative to healthy subjects, though these regions did not show the highest cortical lesion density, which predominantly involved frontal regions. Cortical thickness decreased on average by 0.37 mm, (p = 0.002) in MS patients for each unit standard deviation change in white matter lesion volume. The odds of having a higher EDSS were associated with cortical lesion volume (1.78, p = 0.01) and disease duration (1.15, p < 0.001). CONCLUSION: Cortical thinning in MS is not directly related to cortical lesion load but rather with white matter lesion volume. Neurological disability in MS is better explained by cortical lesion volume assessment.

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.

Neurological manifestations of coronavirus infections - a systematic review.

To optimize diagnostic workup of the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, we systematically reviewed neurological and neuroradiological manifestations of SARS-CoV-2 and all other known human coronavirus species (HCoV). Which lessons can we learn? We identified relevant publications (until 26 July 2020) using systematic searches in PubMed, Web of Science, and Ovid EMBASE with predefined search strings. A total of 4571 unique publications were retrieved, out of which 378 publications were selected for in-depth analysis by two raters, including a total of 17549 (out of which were 14418 SARS-CoV-2) patients. Neurological complications and associated neuroradiological manifestations are prevalent for all HCoVs (HCoV-229E, HKU1, NL63, OC43, Middle East respiratory syndrome (MERS)-CoV, SARS-CoV-1, and SARS-CoV-2). Moreover there are similarities in symptomatology across different HCoVs, particularly between SARS-CoV-1 and SARS-CoV-2. Common neurological manifestations include fatigue, headache, and smell/taste disorders. Additionally, clinicians need to be attentive for at least five classes of neurological complications: (1) Cerebrovascular disorders including ischemic stroke and macro/micro-hemorrhages, (2) encephalopathies, (3) para-/postinfectious immune-mediated complications such as Guillain-Barré syndrome and acute disseminated encephalomyelitis, (4) (meningo-)encephalitis, potentially with concomitant seizures, and (5) neuropsychiatric complications such as psychosis and mood disorders. Our systematic review highlights the need for vigilance regarding neurological complications in patients infected by SARS-CoV-2 and other HCoVs, especially since some complications may result in chronic disability. Neuroimaging protocols should be designed to specifically screen for these complications. Therefore, we propose practical imaging guidelines to facilitate the diagnostic workup and monitoring of patients infected with HCoVs.

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.