Power estimation for non-standardized multisite studies

A concern for researchers planning multisite studies is that scanner and T1-weighted sequence-related biases on regional volumes could overshadow true effects, especially for studies with a heterogeneous set of scanners and sequences. Current approaches attempt to harmonize data by standardizing hardware, pulse sequences, and protocols, or by calibrating across sites using phantom-based corrections to ensure the same raw image intensities. We propose to avoid harmonization and phantom-based correction entirely. We hypothesized that the bias of estimated regional volumes is scaled between sites due to the contrast and gradient distortion differences between scanners and sequences. Given this…

Translational value of choroid plexus imaging for tracking neuroinflammation in mice and humans.

Neuroinflammation is a pathophysiological hallmark of multiple sclerosis and has a close mechanistic link to neurodegeneration. Although this link is potentially targetable, robust translatable models to reliably quantify and track neuroinflammation in both mice and humans are lacking. The choroid plexus (ChP) plays a pivotal role in regulating the trafficking of immune cells from the brain parenchyma into the cerebrospinal fluid (CSF) and has recently attracted attention as a key structure in the initiation of inflammatory brain responses. In a translational framework, we here address the integrity and multidimensional characteristics of the ChP under inflammatory conditions and question w…

Multimodal quantitative MRI assessment of cortical damage in relapsing-remitting multiple sclerosis

Purpose To investigate magnetization transfer ratio (MTR), T1 relaxation time, and proton density (PD) as indicators of gray matter damage in relapsing-remitting multiple sclerosis (RRMS), reflecting different aspects of microstructural damage and as imaging correlates of clinical disability. We aimed to determine which of these parameters may optimally quantify cortical damage, and serve as an imaging surrogate of clinical disability. In this study, cortical values of MTR, a surrogate for demyelination in MS, of PD, reflecting replacement of neural tissue by water, and of T1 , indicating a complex array of microstructural changes, were assessed in a group of RRMS patients in comparison to …

Sex-specific signatures of intrinsic hippocampal networks and regional integrity underlying cognitive status in multiple sclerosis

Abstract The hippocampus is an anatomically compartmentalized structure embedded in highly wired networks that are essential for cognitive functions. The hippocampal vulnerability has been postulated in acute and chronic neuroinflammation in multiple sclerosis, while the patterns of occurring inflammation, neurodegeneration or compensation have not yet been described. Besides focal damage to hippocampal tissue, network disruption is an important contributor to cognitive decline in multiple sclerosis patients. We postulate sex-specific trajectories in hippocampal network reorganization and regional integrity and address their relationship to markers of neuroinflammation, cognitive/memory per…

Longitudinal quantitative MRI assessment of cortical damage in multiple sclerosis: A pilot study

PURPOSE Quantitative MRI (qMRI) allows assessing cortical pathology in multiple sclerosis (MS) on a microstructural level, where cortical damage has been shown to prolong T1 -relaxation time and increase proton density (PD) compared to controls. However, the evolution of these changes in MS over time has not been investigated so far. In this pilot study we used an advanced method for the longitudinal assessment of cortical tissue change in MS patients with qMRI in comparison to cortical atrophy, as derived from conventional MRI. MATERIALS AND METHODS Twelve patients with relapsing-remitting MS underwent 3T T1 /PD-mapping at two timepoints with a mean interval of 12 months. The respective co…

Supplement_TAND_050219 – Supplemental material for Longitudinal cortical network reorganization in early relapsing–remitting multiple sclerosis

Supplemental material, Supplement_TAND_050219 for Longitudinal cortical network reorganization in early relapsing–remitting multiple sclerosis by Vinzenz Fleischer, Nabin Koirala, Amgad Droby, René-Maxime Gracien, Ralf Deichmann, Ulf Ziemann, Sven G. Meuth, Muthuraman Muthuraman, Frauke Zipp and Sergiu Groppa in Therapeutic Advances in Neurological Disorders

NfL predicts relapse-free progression in a longitudinal multiple sclerosis cohort study

Background: Easily accessible biomarkers enabling the identification of those patients with multiple sclerosis (MS) who will accumulate irreversible disability in the long term are essential to guide early therapeutic decisions. We here examine the utility of serum neurofilament light chain (sNfL) for forecasting relapse-free disability progression and conversion to secondary progressive MS (SPMS) in the prospective Neurofilament and longterm outcome in MS (NaloMS) cohort. Methods: The predictive ability of sNfL at Baseline and sNfL follow-up (FU)/ Baseline (BL) ratio with regard to disability progression was assessed within a development cohort (NaloMS, n=196 patients with relapsing-remitt…

Gray matter integrity predicts white matter network reorganization in multiple sclerosis

Abstract Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease leading to gray matter atrophy and brain network reconfiguration as a response to increasing tissue damage. We evaluated whether white matter network reconfiguration appears subsequently to gray matter damage, or whether the gray matter degenerates following alterations in white matter networks. MRI data from 83 patients with clinically isolated syndrome and early relapsing–remitting MS were acquired at two time points with a follow‐up after 1 year. White matter network integrity was assessed based on probabilistic tractography performed on diffusion‐weighted data using graph theoretical analyses. We ev…

Testing different ICA algorithms and connectivity analyses on MS patients.

Multiple sclerosis (MS) is a progressive neurological disorder that affects the central nervous system. Functional magnetic resonance imaging (fMRI) has been employed to track the course and disease progression in patients with MS. The two main aims of this study were to apply in a data-driven approach the independent component analysis (ICA) in the spatial domain to depict the active sources and to look at the effective connectivity between the identified spatial sources. Several ICA algorithms have been proposed for fMRI data analysis. In this study, we aimed to test two well characterized algorithms, namely, the fast ICA and the complex infomax algorithms, followed by two effective conne…

Increased cerebrospinal fluid albumin and immunoglobulin A fractions forecast cortical atrophy and longitudinal functional deterioration in relapsing-remitting multiple sclerosis.

Background: Currently, no unequivocal predictors of disease evolution exist in patients with multiple sclerosis (MS). Cortical atrophy measurements are, however, closely associated with cumulative disability. Objective: Here, we aim to forecast longitudinal magnetic resonance imaging (MRI)-driven cortical atrophy and clinical disability from cerebrospinal fluid (CSF) markers. Methods: We analyzed CSF fractions of albumin and immunoglobulins (Ig) A, G, and M and their CSF to serum quotients. Results: Widespread atrophy was highly associated with increased baseline CSF concentrations and quotients of albumin and IgA. Patients with increased CSFIgA and CSFIgM showed higher functional disabilit…

Linking Microstructural Integrity and Motor Cortex Excitability in Multiple Sclerosis

Motor skills are frequently impaired in multiple sclerosis (MS) patients following grey and white matter damage with cortical excitability abnormalities. We applied advanced diffusion imaging with 3T magnetic resonance tomography for neurite orientation dispersion and density imaging (NODDI), as well as diffusion tensor imaging (DTI) in 50 MS patients and 49 age-matched healthy controls to quantify microstructural integrity of the motor system. To assess excitability, we determined resting motor thresholds using non-invasive transcranial magnetic stimulation. As measures of cognitive-motor performance, we conducted neuropsychological assessments including the Nine-Hole Peg Test, Trail Makin…

Selective Brain Network and Cellular Responses Upon Dimethyl Fumarate Immunomodulation in Multiple Sclerosis

Background: Efficient personalized therapy paradigms are needed to modify the disease course and halt gray (GM) and white matter (WM) damage in patients with multiple sclerosis (MS). Presently, promising disease-modifying drugs show impressive efficiency, however, tailored markers of therapy responses are required. Here, we aimed to detect in a real-world setting patients with a more favorable brain network response and immune cell dynamics upon dimethyl fumarate (DMF) treatment. Methods: In a cohort of 78 MS patients we identified two thoroughly matched groups, based on age, disease duration, disability status and lesion volume, receiving DMF (n = 42) and NAT (n = 36) and followed them ove…

Increased structural white and grey matter network connectivity compensates for functional decline in early multiple sclerosis

Background: The pathology of multiple sclerosis (MS) consists of demyelination and neuronal injury, which occur early in the disease; yet, remission phases indicate repair. Whether and how the central nervous system (CNS) maintains homeostasis to counteract clinical impairment is not known. Objective: We analyse the structural connectivity of white matter (WM) and grey matter (GM) networks to understand the absence of clinical decline as the disease progresses. Methods: A total of 138 relapsing–remitting MS patients (classified into six groups by disease duration) and 32 healthy controls were investigated using 3-Tesla magnetic resonance imaging (MRI). Networks were analysed using graph the…

The impact of isolated lesions on white-matter fiber tracts in multiple sclerosis patients

Infratentorial lesions have been assigned an equivalent weighting to supratentorial plaques in the new McDonald criteria for diagnosing multiple sclerosis. Moreover, their presence has been shown to have prognostic value for disability. However, their spatial distribution and impact on network damage is not well understood. As a preliminary step in this study, we mapped the overall infratentorial lesion pattern in relapsing–remitting multiple sclerosis patients (N = 317) using MRI, finding the pons (lesion density, 14.25/cm3) and peduncles (13.38/cm3) to be predilection sites for infratentorial lesions. Based on these results, 118 fiber bundles from 15 healthy controls and a subgroup of 23 …

Clinical implications of serum neurofilament in newly diagnosed MS patients: a longitudinal multicentre cohort study

Abstract Background We aim to evaluate serum neurofilament light chain (sNfL), indicating neuroaxonal damage, as a biomarker at diagnosis in a large cohort of early multiple sclerosis (MS) patients. Methods In a multicentre prospective longitudinal observational cohort, patients with newly diagnosed relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers. Clinical parameters, MRI, and sNfL levels (measured by single molecule array) were assessed at baseline and up to four-year follow-up. Findings Of 814 patients, 54.7% (445) were diagnosed with RRMS and 45.3% (369) with CIS when applying 2010 McDonald criteria (R…

Serum neurofilament levels reflect outer retinal layer changes in multiple sclerosis

Background: Serum neurofilament light chain (sNfL) and distinct intra-retinal layers are both promising biomarkers of neuro-axonal injury in multiple sclerosis (MS). We aimed to unravel the association of both markers in early MS, having identified that neurofilament has a distinct immunohistochemical expression pattern among intra-retinal layers. Methods: Three-dimensional (3D) spectral domain macular optical coherence tomography scans and sNfL levels were investigated in 156 early MS patients (female/male: 109/47, mean age: 33.3 ± 9.5 years, mean disease duration: 2.0 ± 3.3 years). Out of the whole cohort, 110 patients had no history of optic neuritis (NHON) and 46 patients had a previous…

Cardiotoxicity of mitoxantrone treatment in a german cohort of 639 multiple sclerosis patients

Background and PurposezzThe aim of this study was to elucidate the role of therapy-related cardiotoxicity in multiple sclerosis (MS) patients treated with mitoxantrone and to identify potential predictors for individual risk assessment. MethodszzWithin a multicenter retrospective cohort design, cardiac side effects attributed to mitoxantrone were analyzed in 639 MS patients at 2 MS centers in Germany. Demographic, disease, treatment, and follow-up data were collected from hospital records. Patients regularly received cardiac monitoring during the treatment phase. ResultszzNone of the patients developed symptomatic congestive heart failure. However, the frequency of patients experiencing car…

Gray matter network reorganization in multiple sclerosis from 7‐Tesla and 3‐Tesla MRI data

[Objective]: The objective of this study was to determine the ability of 7T‐MRI for characterizing brain tissue integrity in early relapsing‐remitting MS patients compared to conventional 3T‐MRI and to investigate whether 7T‐MRI improves the performance for detecting cortical gray matter neurodegeneration and its associated network reorganization dynamics.

Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis

Background: The course of multiple sclerosis (MS) shows substantial inter-individual variability. The underlying determinants of disease severity likely involve genetic and environmental factors. Objective: The aim of this study was to assess the impact of APOE and HLA polymorphisms as well as smoking and body mass index (BMI) in the very early MS course. Methods: Untreated patients ( n = 263) with a recent diagnosis of relapsing-remitting (RR) MS or clinically isolated syndrome underwent standardized magnetic resonance imaging (MRI). Genotyping was performed for single-nucleotide polymorphisms (SNPs) rs3135388 tagging the HLA-DRB1*15:01 haplotype and rs7412 (Ɛ2) and rs429358 (Ɛ4) in APOE. …

Covarying patterns of white matter lesions and cortical atrophy predict progression in early MS

ObjectiveWe applied longitudinal 3T MRI and advanced computational models in 2 independent cohorts of patients with early MS to investigate how white matter (WM) lesion distribution and cortical atrophy topographically interrelate and affect functional disability.MethodsClinical disability was measured using the Expanded Disability Status Scale Score at baseline and at 1-year follow-up in a cohort of 119 patients with early relapsing-remitting MS and in a replication cohort of 81 patients. Covarying patterns of cortical atrophy and baseline lesion distribution were extracted by parallel independent component analysis. Predictive power of covarying patterns for disability progression was tes…

The Relationship between Gray Matter Quantitative MRI and Disability in Secondary Progressive Multiple Sclerosis

Purpose: In secondary progressive Multiple Sclerosis (SPMS), global neurodegeneration as a driver of disability gains importance in comparison to focal inflammatory processes. However, clinical MRI does not visualize changes of tissue composition outside MS lesions. This quantitative MRI (qMRI) study investigated cortical and deep gray matter (GM) proton density (PD) values and T1 relaxation times to explore their potential to assess neuronal damage and its relationship to clinical disability in SPMS. Materials and Methods: 11 SPMS patients underwent quantitative T1 and PD mapping. Parameter values across the cerebral cortex and deep GM structures were compared with 11 healthy controls, and…

Lack of efficacy of mitoxantrone in primary progressive Multiple Sclerosis irrespective of pharmacogenetic factors: A multi-center, retrospective analysis

Abstract Background Mitoxantrone is used on an off-label basis in primary progressive MS (PPMS). ABC -transporter-genotypes are associated with therapeutic response in relapsing/secondary progressive MS (RP/SPMS). Objective To evaluate potential pharmacogenetic response markers for mitoxantrone in PPMS. Methods 41 mitoxantrone-treated PPMS-patients, 155 mitoxantrone-treated RP/SPMS-patients and 43 PPMS-controls were retrospectively assessed for clinical therapy-response and in correlation with four single-nucleotide-polymorphisms in ABCB1 - and ABCG2 -genes. Results 53.7% PPMS-patients were mitoxantrone-responders, in comparison to 78.1% of RP/SPMS-patients (p = 0.039). There was no associa…

Graph Theoretical Framework of Brain Networks in Multiple Sclerosis: A Review of Concepts.

Abstract Network science provides powerful access to essential organizational principles of the human brain. It has been applied in combination with graph theory to characterize brain connectivity patterns. In multiple sclerosis (MS), analysis of the brain networks derived from either structural or functional imaging provides new insights into pathological processes within the gray and white matter. Beyond focal lesions and diffuse tissue damage, network connectivity patterns could be important for closely tracking and predicting the disease course. In this review, we describe concepts of graph theory, highlight novel issues of tissue reorganization in acute and chronic neuroinflammation an…

Flow cytometric analysis of T cell/monocyte ratio in clinically isolated syndrome identifies patients at risk of rapid disease progression.

Background: Multiple sclerosis is a chronic inflammatory central nervous system disease diagnosed by clinical presentation and characteristic magnetic resonance imaging findings. The role of cerebrospinal fluid (CSF) analysis has been emphasized in particular in the context of differential diagnosis in patients with a first episode suggestive of multiple sclerosis. Objective: We investigated here the potential additional value of analysis of CSF cellularity by fluorescence activated cell sorting (FACS) in the setting of a routine diagnostic work-up in our inpatient clinic. Methods: CSF cells from back-up samples from patients with suspected chronic inflammatory central nervous system disord…

MSJ763541_supplementary_material – Supplemental material for Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis

Supplemental material, MSJ763541_supplementary_material for Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis by Christiane Graetz, Adriane Gröge, Felix Luessi, Anke Salmen, Daniela Zöller, Janine Schultz, Nelly Siller, Vinzenz Fleischer, Barbara Bellenberg, Achim Berthele, Viola Biberacher, Joachim Havla, Michael Hecker, Reinhard Hohlfeld, Carmen Infante-Duarte, Jan S Kirschke, Tania Kümpfel, Ralf Linker, Friedemann Paul, Steffen Pfeuffer, Philipp Sämann, Gerrit Toenges, Frank Weber, Uwe K Zettl, Antje Jahn-Eimermacher, Gisela Antony, Sergiu Groppa, Heinz Wiendl, Bernhard Hemmer, Mark Mühlau, Carsten Lukas, Ralf Gold, Chri…

A "kissing lesion": In-vivo 7T evidence of meningeal inflammation in early multiple sclerosis

Background: The role of cortical lesions (CLs) in disease progression and clinical deficits is increasingly recognized in multiple sclerosis (MS); however the origin of CLs in MS still remains unclear. Objective: Here, we report a para-sulcal CL detected two years after diagnosis in a relapsing-remitting MS (RRMS) patient without manifestation of clinical deficit. Methods: Ultra-high field (7T) MR imaging using magnetization-prepared 2 rapid acquisition gradient echoes (MP2RAGE) sequence was performed. Results: A para-sulcal CL was detected which showed hypointense rim and iso- to hyperintense core. This was detected in the proximity of the leptomeninges in the left precentral gyrus extendi…

Role of IL-17-producing lymphocytes in severity of multiple sclerosis upon natalizumab treatment.

Objective: Natalizumab is known to prevent T-helper cells entering the central nervous system (CNS). We hypothesize that more pathogenic T-helper cells are present outside the CNS and a possible relationship to disease severity. Methods: Characterization and enrichment of human CD4+IL-17+ cells were performed ex vivo using peripheral blood mononuclear cells from natalizumab-treated relapsing-remitting multiple sclerosis (RRMS) patients ( n = 33), untreated RRMS patients ( n = 13), and healthy controls ( n = 33). Magnetic resonance imaging (MRI) scans were performed routinely for patients. Results: Lymphocytes were elevated in peripheral blood of natalizumab-treated patients compared to untr…

Assessment of cortical damage in early multiple sclerosis with quantitative T 2 relaxometry

T2 relaxation time is a quantitative MRI in vivo surrogate of cerebral tissue damage in multiple sclerosis (MS) patients. Cortical T2 prolongation is a known feature in later disease stages, but has not been demonstrated in the cortical normal appearing gray matter (NAGM) in early MS. This study centers on the quantitative evaluation of the tissue parameter T2 in cortical NAGM in a collective of early MS and clinically isolated syndrome (CIS) patients, hypothesizing that T2 prolongation is already present at early disease stages and variable over space, in line with global and focal inflammatory processes in MS. Additionally, magnetization transfer ratio (MTR) mapping was performed for furt…

Treatment response to dimethyl fumarate is characterized by disproportionate CD8+ T cell reduction in MS

Background: The effect of dimethyl fumarate (DMF) on circulating lymphocyte subsets and their contribution as predictors of clinical efficacy have not yet been investigated in multiple sclerosis (MS). Objective: To evaluate lymphocytes and lymphocyte subsets (analyzed 6 months after DMF start) in MS patients with and without disease activity after 1 year of treatment in a retrospective study. Methods: Peripheral blood lymphocyte subsets were analyzed by flow cytometry. Untreated MS patients ( n = 40) were compared to those 6 months after onset of DMF treatment ( n = 51). Clinical and magnetic resonance imaging (MRI) disease activity of DMF-treated patients were assessed in the first year un…

Network effects and pathways in Deep brain stimulation in Parkinson's disease.

Deep brain stimulation of subthalamic nucleus (STN-DBS) became a standard therapeutic option in Parkinson's disease (PD), even though the underlying modulated network of STN-DBS is still poorly described. Probabilistic tractography and connectivity analysis as derived from diffusion tensor imaging (DTI) were performed together with modelling of implanted electrode positions and linked postoperative clinical outcome. Fifteen patients with idiopathic PD without dementia were selected for DBS treatment. After pre-processing, probabilistic tractography was run from cortical and subcortical seeds of the hypothesized network to targets represented by the positions of the active DBS contacts. The …

Functional connectivity analysis using whole brain and regional network metrics in MS patients

In the present study we investigated brain network connectivity differences between patients with relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HC) as derived from functional resonance magnetic imaging (fMRI) using graph theory. Resting state fMRI data of 18 RRMS patients (12 female, mean age ± SD: 42 ± 12.06 years) and 25 HC (8 female, 29.2 ± 5.38 years) were analyzed. In order to obtain information of differences in entire brain network, we focused on both, local and global network connectivity parameters. And the regional connectivity differences were assessed using regional network parameters. RRMS patients presented a significant increase of modularity in comparis…

Translational Aspects of Immunotherapeutic Targets in Multiple Sclerosis

Dissecting task-specific plasticity capacity in patients with multiple sclerosis with transcranial magnetic stimulation.

Quantitative T 1 and proton density mapping with direct calculation of radiofrequency coil transmit and receive profiles from two-point variable flip angle data

Quantitative T1 mapping of brain tissue is frequently based on the variable flip angle (VFA) method, acquiring spoiled gradient echo (GE) datasets at different excitation angles. However, accurate T1 calculation requires a knowledge of the sensitivity profile B1 of the radiofrequency (RF) transmit coil. For an additional derivation of proton density (PD) maps, the receive coil sensitivity profile (RP) must also be known. Mapping of B1 and RP increases the experiment duration, which may be critical when investigating patients. In this work, a method is presented for the direct calculation of B1 and RP from VFA data. Thus, quantitative maps of T1 , PD, B1 and RP can be obtained from only two …