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Background Perivascular spaces can become detectable on magnetic resonance imaging (MRI) upon enlargement, referred to as enlarged perivascular spaces (EPVS) or Virchow-Robin spaces. EPVS have been linked to small vessel disease. Some studies have also indicated an association of EPVS to neuroinflammation and/or neurodegeneration. However, there is conflicting evidence with regards to their potential as a clinically relevant imaging biomarker in multiple sclerosis (MS). Methods To perform a systematic review and meta-analysis of EPVS as visualized by MRI in MS. Nine out of 299 original studies addressing EPVS in humans using MRI were eligible for the systematic review and meta-analysis including a total of 457 MS patients and 352 control subjects. Results In MS, EPVS have been associated with cognitive decline, contrast-enhancing MRI lesions, and brain atrophy. Yet, these associations were not consistent between studies. The meta-analysis revealed that MS patients have greater EPVS prevalence (odds ratio = 4.61, 95% CI = [1.84; 11.60], p  = 0.001) as well as higher EPVS counts (standardized mean difference [SMD] = 0.46, 95% CI = [0.26; 0.67], p  < 0.001) and larger volumes (SMD = 0.88, 95% CI = [0.19; 1.56], p  = 0.01) compared to controls. Conclusions Available literature suggests a higher EPVS burden in MS patients compared to controls. The association of EPVS to neuroinflammatory or -degenerative pathology in MS remains inconsistent. Thus, there is currently insufficient evidence supporting EPVS as diagnostic and/or prognostic marker in MS. In order to benefit future comparisons of studies, we propose recommendations on EPVS assessment standardization in MS. PROSPERO No: CRD42019133946.

Multiple sclerosis is a chronic and progressive neuroinflammatory disease that leads to demyelination and neurodegeneration in the central nervous system (CNS). Previous research has identified a wide range of environmental, lifestyle and genetic factors which increase MS susceptibility. However, the pathomechanisms that influence the severity of MS are largely unknown, and adequate biomarkers of disease severity are consequently lacking. Therefore, the aim of my thesis was to; 1) assess associations between the nerve injury biomarker neurofilament light (NfL) and brain atrophy and lesion volumes; 2) assess which brain/lesion volume measuresshow the strongest longitudinal association with clinical MS disability measures and to what degree these associations were affected by age; and to 3) identify genetic variants associated with brain atrophy, lesion volumes and plasma NfL (pNfL) levels in persons with MS.In Study I, we assessed how cerebrospinal fluid (CSF) and pNfL levels were associated with T1- and T2-lesion volumes as well as whole-brain, cortical and subcortical grey matter, white matter and thalamic volume fractions of total intracranial volume based on magnetic resonance imaging (MRI). High baseline CSF and pNfL levels were associated with lower whole-brain, subcortical grey matter, thalamic, white matter and corpus callosal volume fractions over time. A further analysis showed that there was an association between baseline pNfL and baseline cortical grey matter fractions also in absence of radiological signs of inflammatory disease activity. A topographic analysis of cortical thickness showed that loss of cortical volume preferentially involved frontotemporal cortical regions. These findings indicate that NfL levels contribute information about MS severity not provided by traditional MRI lesion metrics.In Study II, we showed that associations between baseline MRI variables, and baseline physical disability and self-reported impact of MS rapidly increased in strength in individuals beyond approximately 40-50 years of age. In separate longitudinal analyses using linear mixed-effects models, we showed that among the recorded brain volume measures, cortical and subcortical grey matter and thalamic volume fractions at baseline were the strongest predictors of future worsening in clinical disability over a median of approximately ten years’ follow-up time. They were also stronger predictors than T1- and T2-lesion volumes.In Study III, we assessed if a weighted risk score comprising 12 known MS risk human leukocyte antigen (HLA) alleles was associated with baseline and longitudinal MRI measures as described in Studies I and II. While this risk score was not significantly associated with baseline MRI measures, we found that a high score was associated with lower cortical grey matter fractions longitudinally. A further analysis showed that this effect was primarily driven by the HLA-DRB1*15:01allele. These results suggest that MS HLA risk variants not only affect inflammatory, but also neurodegenerative aspects of the disease.In Studies IV and V, we performed genome-wide association studies of pNfL levels and whole-brain volume fractions, respectively, in persons with MS (and controls in Study IV). While no genome-wide significant associations were found in Study IV, gene set analyses highlighted a neural crest and odontogenesis development pathway in the regulation of pNfL levels, and a weighted MS susceptibility polygenic risk score was associated with higher pNfL levels in MS with statistical significance. These findings suggest that there is some degree of genetic regulation of pNfL levels, which partially overlap with MS risk. In Study V, we identified a genome-wide significant locus upstream of the glycerol kinase 2 (GK2) gene, previously implicated in the propensity for tobacco smoking, which is a known MS risk and severity factor. Gene set analyses in Study V also implicated Hypoxia Inducible Factor-1 (HIF1) in the regulation of whole-brain volume fractions, indicating that iron metabolism and response to hypoxia play a role in the neurodegenerative processes in MS.

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.

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) outcomes. 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.Competing Interest StatementThe authors have declared no competing interest.

Three new compounds ( 1 – 3 ) with unusual skeletons were isolated from the n -hexane extract of the air-dried aerial parts of Hypericum scabrum . Compound 1 represents the first example of an esterified polycyclic polyprenylated acylphloroglucinol that features a unique tricyclo-[4.3.1.1 1,4 ]-undecane skeleton. Compound 2 is a fairly simple MPAP, but with an unexpected cycloheptane ring decorated with prenyl substituents, and compound 3 has an unusual 5,5-spiroketal lactone core. Their structures were determined by extensive spectroscopic and spectrometric techniques (1D and 2D NMR, HRESI-TOFMS). Absolute configurations were established by ECD calculations, and the absolute structure of 2 was confirmed by a single crystal determination. Plausible biogenetic pathways of compounds 1 – 3 were also proposed. The in vitro antiprotozoal activity of the compounds against Trypanosoma brucei rhodesiense and Plasmodium falciparum and cytotoxicity against rat myoblast (L6) cells were determined. Compound 1 showed a moderate activity against T. brucei and P. falciparum , with IC 50 values of 3.07 and 2.25 μM, respectively.

This manuscript discusses the difficulties with magnetic position and orientation (MPO) system design and proposes a general method for finding optimal layouts. The formalism introduces a system quality measure through state separation and reduces the question “How to design an MPO system?” to a global optimization problem. The latter is then solved by combining differential evolution algorithms with magnet shape variation based on analytical computations of the field. The proposed formalism is then applied to study possible realizations of continuous three-axis joystick motion tracking, realized with just a single magnet and a single 3D magnetic field sensor. The computations show that this is possible when a specific design condition is fulfilled and that large state separations as high as 1mT/∘ can be achieved under realistic conditions. Finally, a comparison to state-of-the-art design methods is drawn, computation accuracy is reviewed critically, and an experimental validation is presented.