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Pathological data showed focal inflammation and regions of diffuse neuronal loss in the cortex of people with multiple sclerosis (MS). In this work, we applied a novel model (“soma and neurite density imaging (SANDI)”) to multishell diffusion-weighted MRI data acquired in healthy subjects and people with multiple sclerosis (pwMS), in order to investigate inflammation and degeneration-related changes in the cortical tissue of pwMS. We aimed to (i) establish whether SANDI is applicable in vivo clinical data; (ii) investigate inflammatory and degenerative changes using SANDI soma fraction ( f soma )—a marker of cellularity—in both cortical lesions and in the normal-appearing-cortex and (iii) correlate SANDI f soma with clinical and biological measures in pwMS. We applied a simplified version of SANDI to a clinical scanners. We then provided evidence that pwMS exhibited an overall decrease in cortical SANDI f soma compared to healthy subjects, suggesting global degenerative processes compatible with neuronal loss. On the other hand, we have found that progressive pwMS showed a higher SANDI f soma in the outer part of the cortex compared to relapsing–remitting pwMS, possibly supporting current pathological knowledge of increased innate inflammatory cells in these regions. A similar finding was obtained in subpial lesions in relapsing–remitting patients, reflecting existing pathological data in these lesion types. A significant correlation was found between SANDI f soma and serum neurofilament light chain—a biomarker of inflammatory axonal damage—suggesting a relationship between SANDI soma fraction and inflammatory processes in pwMS again. Overall, our data show that SANDI f soma is a promising biomarker to monitor changes in cellularity compatible with neurodegeneration and neuroinflammation in the cortex of MS patients.

Progressive neurological decline in multiple sclerosis is associated with axonal loss and synaptic dysfunction in the non-demyelinated normal appearing gray matter (NAGM) and prominently in the cerebellum. In contrast to early disease stages, where synaptic and neuro-axonal pathology correlates with the extent of T cell infiltration, a prominent role of the innate immune system has been proposed for progressive MS. However, the specific contribution of microglia and astrocytes to synaptic cerebellar pathology in the NAGM– independent of an adaptive T cell response - remains largely unexplored. In the present study, we quantified synaptic changes in the cerebellar NAGM distant from demyelinated lesions in a mouse model of toxic demyelination. Proteomic analysis of the cerebellar cortex revealed differential regulation of synaptic and glutamate transport proteins in the absence of evident structural synaptic pathology or local gray matter demyelination. At the functional level, synaptic changes manifested as a reduction in frequency-dependent facilitation at the parallel fiber– Purkinje cell synapse. Further, deficiency of MyD88, an adaptor protein of the innate immune response, associated with a functional recovery in facilitation, reduced changes in the differential expression of synaptic and glutamate transport proteins, and reduced transcription levels of inflammatory cytokines. Nevertheless, the characteristics of demyelinating lesions and their associated cellular response were similar to wild type animals. Our work brings forward an experimental paradigm mimicking the diffuse synaptic pathology independent of demyelination in late stage MS and highlights the complex regulation of synaptic pathology in the cerebellar NAGM. Moreover, our findings suggest a role of astrocytes, in particular Bergmann glia, as key cellular determinants of cerebellar synaptic dysfunction.

Postmortem magnetic resonance imaging (MRI) of the fixed healthy and diseased human brain facilitates spatial resolutions and image quality that is not achievable with in vivo MRI scans. Though challenging—and almost exclusively performed at 7 T field strength—depicting the tissue architecture of the entire brain in fine detail is invaluable since it enables the study of neuroanatomy and uncovers important pathological features in neurological disorders. The objectives of the present work were (1) to develop a 3D isotropic ultra-high-resolution imaging approach for human whole-brain ex vivo acquisitions working on a standard clinical 3 T MRI system; and (2) to explore the sensitivity and specificity of this concept for specific pathoanatomical features of multiple sclerosis. The reconstructed images demonstrate unprecedented resolution and soft tissue contrast of the diseased human brain at 3 T, thus allowing visualization of sub-millimetric lesions in the different cortical layers and in the cerebellar cortex, as well as unique cortical lesion characteristics such as the presence of incomplete/complete iron rims, and patterns of iron accumulation. Further details such as the subpial molecular layer, the line of Gennari, and some intrathalamic nuclei are also well distinguishable.

The outcome of chronic meningitis depends to a large degree on the causative pathogen and the interval between onset of symptoms and diagnosis. We present a patient with a delayed diagnosis and several complications, for whom adequate therapy resulted in a favorable outcome. In a 76‐year‐old male patient, Candida albicans meningitis was diagnosed 4 months after the onset of symptoms. CSF findings (protein >1000 mg/L, predominance of intrathecal immunoglobulin A synthesis, lactate concentrations of approx. 10 mmol/L, leukocyte counts around 1000/μl, variable differential leukocyte counts) resembled tuberculous meningitis. In spite of the long interval without treatment, voriconazole 200 mg every 12 h for 7 weeks followed by fluconazole 300 mg/day maintenance therapy for 7 months led to a recovery with only mild deficits. The case illustrates that 1. C. albicans can cause chronic meningitis in patients without severe immune defects, 2. patients can survive C. albicans meningitis with mild long‐term sequelae even when diagnosis and adequate treatment are delayed, and 3. voriconazole as a sole agent may be suitable for treatment of C. albicans meningitis. We present a chronic Candida albicans meningitis patient initially misdiagnosed with polymyalgia rheumatica who recovered with only mild sequelae after appropriate therapy with voriconazole had been initiated 4 months after symptom onset.

Autoimmune pathology of acute disseminated encephalomyelitis (ADEM) is generally restricted to the brain. Our objective is to expand the phenotype of ADEM. A four-year-old girl was admitted to the pediatric emergency room of a university medical center five days after a common upper respiratory tract infection. Acute symptoms were fever, leg pain, and headaches. She developed meningeal signs, and her level of consciousness dropped rapidly. Epileptic seizure activity started, and she became comatose, requiring intubation and mechanical ventilation. Serial brain magnetic resonance imaging (MRI) illustrated the fulminant development of ADEM. Treatment escalation with high-dose corticosteroids, immunoglobulins, and plasma exchange did not lead to clinical improvement. On day ten, the patient developed treatment-refractory cardiogenic shock and passed away. The postmortem assessment confirmed ADEM and revealed acute lymphocytic myocarditis, likely explaining the acute cardiac failure. Human metapneumovirus and picornavirus were detected in the tracheal secrete by PCR. Data sources–medical chart of the patient. This case is consistent with evidence from experimental findings of an association of ADEM with myocarditis as a postinfectious systemic autoimmune response, with life-threatening involvement of the brain and heart.

Quantitative MRI (qMRI) probes the microstructural properties of the central nervous system (CNS) by providing biophysical measures of tissue characteristics. In this work, we aimed to (i) identify qMRI measures that distinguish histological lesion types in postmortem multiple sclerosis (MS) brains, especially the remyelinated ones; and to (ii) investigate the relationship between those measures and quantitative histological markers of myelin, axons, and astrocytes in the same experimental setting. Three fixed MS whole brains were imaged with qMRI at 3T to obtain magnetization transfer ratio (MTR), myelin water fraction (MWF), quantitative T1 (qT1), quantitative susceptibility mapping (QSM), fractional anisotropy (FA) and radial diffusivity (RD) maps. The identification of lesion types (active, inactive, chronic active, or remyelinated) and quantification of tissue components were performed using histological staining methods as well as immunohistochemistry and immunofluorescence. Pairwise logistic and LASSO regression models were used to identify the best qMRI discriminators of lesion types. The association between qMRI and quantitative histological measures was performed using Spearman's correlations and linear mixed‐effect models. We identified a total of 65 lesions. MTR and MWF best predicted the chance of a lesion to be remyelinated, whereas RD and QSM were useful in the discrimination of active lesions. The measurement of microstructural properties through qMRI did not show any difference between chronic active and inactive lesions. MWF and RD were associated with myelin content in both lesions and normal‐appearing white matter (NAWM), FA was the measure most associated with axon content in both locations, while MWF was associated with astrocyte immunoreactivity only in lesions. Moreover, we provided evidence of extensive astrogliosis in remyelinated lesions. Our study provides new information on the discriminative power of qMRI in differentiating MS lesions ‐especially remyelinated ones‐ as well as on the relative association between multiple qMRI measures and myelin, axon and astrocytes. Examples of histopathological lesion types and their correspondent quantitative MRI.

In the past 2-3 years before the latest admission, the patient had developed a progressive left-sided hemiparesis concomitant with an increase of T2-hyperintensities in the white matter of the right hemisphere, ipsilateral to the PHA (B-D). [...]MRI scans illustrated ipsilateral cerebral atrophy (B-D).

Remyelination of cortical lesions in people with multiple sclerosis (pwMS) has been shown to be extensive. In this work, we aimed to assess whether postmortem quantitative MRI (qMRI) can help detect those areas. We imaged six fixed whole brains of deceased pwMS by 3T‐MRI using magnetization transfer ratio (MTR, 570 μm isotropic), myelin water fraction (MWF, 1000 μm isotropic), quantitative T1 (qT1, 670 μm isotropic), quantitative susceptibility mapping (QSM, 330 μm isotropic) and radial diffusivity (RD, 1300 or 1400 μm isotropic) maps. Immunohistochemistry for myelin proteins was performed in 129 tissue blocks including the cortex and enabled the detection of cortical demyelination (DM), cortical remyelination (RM), and normal‐appearing cortex (NAC). We identified 25 DM, 25 RM, and for each of these areas, a corresponding NAC near the lesion. Wilcoxon paired tests showed that: (a) qT1 and RD were higher and QSM lower in DM versus NAC (all p < 0.001), whereas RD was higher and QSM lower in RM versus NAC (p = 0.048 and p < 0.01 respectively); (b) mean qT1 in RM did not differ from mean qT1 in NAC (p = 0.074); (c) MWF and MTR were not different between DM and RM. We compared the delta between DM versus NAC (∆DM) and the delta between RM versus NAC (∆RM) using a Mann–Whitney test, in which RM showed a partial recovery of qT1 only (∆qT1 DM > ∆qT1 RM, p = 0.045). Mixed‐effect models confirmed the findings obtained using univariate analyses. qT1 and QSM, but not RD, correlated with MBP intensity (r = −0.28, p < 0.01 and r = 0.29, p < 0.01 respectively). A Bonferroni correction was performed for multiple testing. Our data show that qT1 is altered in demyelinated but not in remyelinated cortical areas, while QSM and RD are affected by any cortical abnormalities. Accordingly, qT1 might be considered a potential imaging biomarker of cortical RM. In a post‐mortem study using multiparametric qMRI of whole fixed human brains from people with multiple sclerosis (pwMS), we found evidence that quantitative T1 (qT1) is sensitive to remyelination in the cortex. In contrast, QSM and radial diffusivity were affected by cortical pathology independently of remyelination. Our data suggest that qT1 could be used to study myelin changes over time in the cortex of pwMS.

Autoimmune pathology of acute disseminated encephalomyelitis (ADEM) is generally restricted to the brain. Our objective is to expand the phenotype of ADEM. A four-year-old girl was admitted to the pediatric emergency room of a university medical center five days after a common upper respiratory tract infection. Acute symptoms were fever, leg pain, and headaches. She developed meningeal signs, and her level of consciousness dropped rapidly. Epileptic seizure activity started, and she became comatose, requiring intubation and mechanical ventilation. Serial brain magnetic resonance imaging (MRI) illustrated the fulminant development of ADEM. Treatment escalation with high-dose corticosteroids, immunoglobulins, and plasma exchange did not lead to clinical improvement. On day ten, the patient developed treatment-refractory cardiogenic shock and passed away. The postmortem assessment confirmed ADEM and revealed acute lymphocytic myocarditis, likely explaining the acute cardiac failure. Human metapneumovirus and picornavirus were detected in the tracheal secrete by PCR. Data sources-medical chart of the patient. This case is consistent with evidence from experimental findings of an association of ADEM with myocarditis as a postinfectious systemic autoimmune response, with life-threatening involvement of the brain and heart.

Abstract Postmortem magnetic resonance imaging (MRI) of the fixed healthy and diseased human brain facilitates spatial resolutions and image quality that is not achievable with in vivo MRI scans. Though challenging - and almost exclusively performed at 7T field strength - depicting the tissue architecture of the entire brain in fine detail is invaluable since it enables the study of neuroanatomy and uncovers important pathological features in neurological disorders. The objectives of the present work were (i) to develop a 3D isotropic ultra-high-resolution imaging approach for human whole-brain ex vivo acquisitions working on a standard clinical 3T MRI system, and (ii) to explore the sensitivity and specificity of this concept for specific pathoanatomical features of multiple sclerosis. The reconstructed images demonstrate unprecedented resolution and soft tissue contrast of the diseased human brain at 3T, thus allowing visualization of sub-millimetric lesions in the different cortical layers and in the cerebellar cortex, as well as unique cortical lesion characteristics such as the presence of incomplete / complete iron rims, and patterns of iron accumulation. Further details such as the subpial molecular layer, the line of Gennari, and some intrathalamic nuclei are also well distinguishable. Competing Interest Statement Matthias Weigel is funded by the Swiss National Science Fund (SNSF) grant PP00P3_176984 for multiple sclerosis MRI research and by Biogen Inc. for spinal cord MRI research, he has no conflicts of interest to declare for this work. Cristina Granziera is funded by the Swiss National Science Fund (SNSF) grant PP00P3_176984 for multiple sclerosis MRI research, she has no conflicts of interest to declare for this work. Peter Dechent, Riccardo Galbusera, Erik Bahn, Govind Nair, Ludwig Kappos, Wolfgang Brueck, and Christine Stadelmann have no conflicts of interest to declare for this work. * List of abbreviations (alphabetical) URI ultra-high-resolution imaging FLASH fast low-angle shot GM gray matter WM white matter