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 comparison to HC, pointing towards a network structure with densely interconnected nodes within one module, while the number of connections with other modules outside decreases. This higher decomposable network favours cost-efficient local information processing and promotes long-range disconnection. In addition, at the regional anatomical level, the network parameters clustering coefficient and local efficiency were increased in the insula, the superior parietal gyrus and the temporal pole. Our study indicates that modularity as derived from fMRI can be seen as a characteristic connectivity feature that is increased in MS patients compared to HC. Furthermore, specific anatomical regions linked to perception, motor function and cognition were mainly involved in the enhanced local information processing

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

Background and Purpose: The 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. Methods: Within 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. Results: None of the patients developed symptomatic congestive heart failure. However, the frequency of patients experiencing cardiac dysfunction of milder forms after mitoxantrone therapy was 4.1% (26 patients) among all patients. Analyses of the risk for cardiotoxicity revealed that cumulative dose exposure was the only statistically relevant risk factor associated with cardiac dysfunction. Conclusions: The number of patients developing subclinical cardiac dysfunction below the maximum recommended cumulative dose is higher than was initially assumed. Interestingly, a subgroup of patients was identified who experienced cardiac dysfunction shortly after initiation of mitoxantrone and who received a low cumulative dose. Therefore, each administration of mitoxantrone should include monitoring of cardiac function to enhance the treatment safety for patients and to allow for early detection of any side effects, especially in potential high-risk subgroups (as determined genetically)

Impact of dietary intervention on serum neurofilament light chain in multiple sclerosis

BACKGROUND AND OBJECTIVES: Adapted ketogenic diet (AKD) and caloric restriction (CR) have been suggested as alternative therapeutic strategies for multiple sclerosis (MS), but information on their impact on neuroaxonal damage is lacking. Thus, we explored the impact of diets on serum neurofilament light chain (sNfL) levels in patients with relapsing-remitting MS. METHODS: We retrospectively evaluated a prospective randomized controlled trial of 60 patients with MS who were on a common diet or ketogenic diet or fasting. We examined sNfL levels of 40 participants at baseline and at the end of the study after 6 months using single molecule array assay. RESULTS: sNfL levels were investigated in 9 controls, 14 participants on CR, and 17 participants on AKD. Correlation analysis showed an association of sNfL with age and disease duration; an association was also found between sNfL and the Multiple Sclerosis Functional Composite. AKD significantly reduced sNfL levels at 6 months compared with the common diet group (p = 0.001). DISCUSSION: For clinical or study use, consider that AKD may incline sNfL levels independent of relapse activity up to 3 months after initiation. At 6 months, AKD, which complements current therapies, reduced sNfL levels, therefore suggesting potential neuroprotective effects in MS. A single cycle of seven-day fasting did not affect sNfL. AKD may be an addition to the armamentarium to help clinicians support patients with MS in a personalized manner with tailored diet strategies. TRIAL REGISTRATION INFORMATION: Clinical trial registration number NCT01538355

Continuous short-term structural network reorganisation beyond atrophy in patients with RRMS [Abstract]

Background and aim: Longitudinal assessment of structural brain changes is important to track the clinical course of multiple sclerosis (MS), but an exact quantification of the diffuse tissue damage is highly challenging. We aimed to identify short-term structural dynamics by measuring grey matter (GM) network connectivity patterns and comparing these with established morphological measures of GM integrity. Methods: For our prospectively designed study, we collected data from January 2013 through December 2014. In total, forty-five structural MRI datasets from relapsing-remitting MS patients in the relapse free phase of the disease (mean age: 42 ± 12.1 years; median EDSS 1.5 (0 - 2.5); mean disease duration 3.5 ± 6.5 years) were acquired using 3T MRI. Each patient was followed up every 8 weeks for 8 months and all patients were enrolled at two German university hospitals. Longitudinal brain atrophy was analyzed using SIENA (part of FSL), while FreeSurfer was used to investigate cortical thickness changes over time. GM connectivity patterns were reconstructed from cortical thickness correlation matrix between anatomical regions, as derived from the AAL atlas, and a network analysis was conducted using graph theoretical approaches. Results: Our study shows a significant longitudinal structural network reorganisation in the absence of cortical thinning and brain atrophy already over a period of 4 months. We demonstrate an increased local (clustering coefficient (F(4,41) = 3.547, p < 0.001), local efficiency (F(4,41) = 3.0874, p < 0.01)) and modular connectivity pattern (modularity (F(4,41) =2.612, p < 0.01)). Conversely a concomitant break-down of long-range connectivity occurred (assortativity (F(4,41) = 3.0654, p < 0.01) and small-world index (F(4,41) = 3.687, p < 0.001)). No regional or global atrophy signs were detected in the applied morphometric analysis. Conclusions and relevance: Our GM network analysis demonstrates a short-term increase in local connectivity and a decrease in long-range paths in MS patients in the relapse free state of the disease, in the absence of atrophy or clinical progression. Structural reorganisation patterns with co-occurrence of detrimental and adaptive reorganisation processes might be important sensitive measurable fingerprints of the disease that can be used in clinical practice

Longitudinal structural network reorganisation in early relapsing-remitting multiple sclerosis [Abstract]

Background: Multiple sclerosis (MS) is characterized by relapses and remissions indicating damage and compensatory processes occurring early in the disease. Over time, cortical pathology is highly relevant for disability, while brain networks evolve towards a disconnected organization as the disease progresses. However, it is poorly understood how and when pathology impacts cortical networks and in particular, how the network responds to damage in the very beginning of the disease. Aim: To address cortical pathology by quantifying structural connectivity patterns over 12 months in patients with early relapsing-remitting MS. Methods: Here we investigated cortical grey matter networks longitudinally as derived from structural 3 Tesla MRI in 92 patients in the initial phase of the disease (65 female / 27 male; mean age: 32.9 ± 9.9 years; mean disease duration: 12.1 ± 14.5 months) and in 101 healthy controls (59 female / 42 male; mean age: 19.7 ± 0.9 years). Longitudinal brain volume atrophy was analyzed using SIENA and cortical thickness changes were quantified using FreeSurfer. Brain networks were computed based on cortical thickness inter-regional correlations between anatomical regions and fed into graph theoretical analysis. Finally, subgroup analyses were performed between patients with “no evidence of disease activity” (NEDA) during this period and those with disease activity (EDA). Results: Over one year, increased local cortical connectivity and an emerging modular-constructed network were detected in patients - a pattern reported to be associated with adaptation, efficiency and compensation. These longitudinal dynamics were attested in both patients with NEDA and EDA, indicating continuous cortical reorganisation independent of disease activity. This local and modular cortical reorganisation was not detected in healthy controls over the same period of time and emerged beyond measureable signs of atrophy using established morphometric tools. Conclusion: Our findings demonstrate that despite initiation of neuroinflammatory damage, substantial structural adaptation processes emerge cortically in the early disease stage. This subtle reorganisation of the cortex architecture is quantifiable by structural MRI in patients with and without disease activity, suggesting a principal response of the network evolving from the onset of this chronic disease. Disclosure: The authors declare no conflict of interests

Continuous reorganisation of cortical information flow in MS patients: a longitudinal effective connectivity study [Abstract]

Background: Brain reorganisation processes are essential for the long-term outcome in patients with multiple sclerosis (MS). Effective connectivity (EC) as derived from functional MRI, can be analysed to estimate reorganisation processes and directional information flows between cortical regions. These measures could provide the missing link for modelling the long-term disease course between tissue damage and repair or adaptation. Aim: To obtain longitudinal measurements of EC and information flows in MS patients at short-term intervals focusing on the main anatomical brain regions and to investigate the link between the connectivity strength and clinical impairment. Methods: Twelve MS patients (mean age: 41.7 ± 11.5 years) underwent 3 Tesla structural and resting state functional MRI at five different time points over one year (approximately every 12 weeks). Twelve healthy subjects (mean age: 33.5 ± 9.6 years) served as controls (HC). For the analytical framework, two novel approaches for EC quantification were used. Causal Bayesian Network (CBN) and Time Domain Partial Directed Coherence (TPDC) were applied for the description of the information flows between frontal, prefrontal, temporal, occipital, and parietal lobe; cerebellum and deep grey matter nuclei (DGMN) were also analysed. Results: Specific longitudinal EC patterns have been attested in the studied regions. Information flows from DGMN, frontal, prefrontal and temporal to the other studied regions showed a continuous increase over time, whereas the directed connections from parietal and occipital lobes and from the cerebellum did not change over time as confirmed by both applied methods. No longitudinal changes of EC were attested in HC. The longitudinal connectivity increase in the prefrontal-frontal and fronto-cerebellar pathway showed a significant inverse correlation to EDSS (Expanded Disability Status Scale). Moreover, the EC change from the frontal lobe to the cerebellum showed a significant inverse correlation to patients’ fatigue score. Conclusion: Our data depicts a continuous longitudinal increase in EC in patients with MS substantiated by two novel methodological approaches. Furthermore, the dynamics of the fronto-cerebellar connections are linked to clinical impairment and possibly essential for the long-term outcome

CSF markers of blood-brain barrier integrity forecast disease progression in early MS [Abstract]

Background and aim: Cortical atrophy, reflecting neuronal loss, is highly associated with long-term disability in patients with multiple sclerosis (MS). In this longitudinal study we link cerebrospinal fluid (CSF) markers of blood-brain barrier (BBB) integrity to longitudinal cortical atrophy and clinical disability. Methods: 71 relapsing-remitting multiple sclerosis (RRMS) patients (31.2 ± 9.4 (mean ± SD), 25 males) were included in this longitudinal study. CSF and serum samples were obtained from each patient at the time of first clinical event. We analyzed CSF levels of albumin (AlbCSF), immunoglobulin A (IgACSF), IgG (IgGCSF) and IgM (IgMCSF). All patients underwent MR imaging twice with the same standardized protocol (follow-up after 12 ± 1 months) at 3T (Siemens Magnetom Trio). Longitudinal changes of cortical thickness (CT) were extracted using the FreeSurfer processing stream. The Expanded Disability Status Scale (EDSS) score at follow-up was used as a clinical outcome measure to quantify clinical disability. The rate of cortical atrophy was assessed in relation to CSF variables. Results: Baseline AlbCSF and IgACSF were highly associated with the rate of cortical atrophy over one year. Significant correlations were found in the precuneus (PrC), rostral middle frontal, precentral and inferior parietal gyri of both hemispheres. The regions with the highest atrophy rates were the right PrC (R = 0.604, p < 0.001) and left fusiform gyrus (R = 0.539, p < 0.001). IgACSF and IgMCSF (IgA: 1.67 ± 0.69 mg/l vs 2.03 ± 0.71 mg/l, IgM: 9.87 ± 2.38 mg/l vs 11.5 ± 2.03 mg/l; p = 0.04 and p = 0.003, respectively) significantly differed between patients with no disability (EDSS 0 - 1.5) and those with mild to moderate disability (EDSS 2 - 6) at the second time point. Conclusion: Our data show that widespread cortical atrophy is highly associated with increased baseline CSF Albumin and IgA mirroring a permeable BBB. Patients with this BBB pattern showed higher functional disability at follow-up. These parameters could be addressed to dichotomize patients at risk of rapid disease progression

Activation of Microglial Poly(ADP-Ribose)-Polymerase-1 by Cholesterol Breakdown Products during Neuroinflammation: a Link between Demyelination and Neuronal Damage

Multiple sclerosis (MS) is a chronic demyelinating disease in which it has only recently been suggested that damage to neuronal structures plays a key role. Here, we uncovered a link between the release of lipid breakdown products, found in the brain and cerebrospinal fluid (CSF) of MS patients as well as in experimental autoimmune encephalomyelitis, and neuronal damage mediated by microglial activation. The concentrations of the breakdown product 7-ketocholesterol detected in the CSF of MS patients were capable of inducing neuronal damage via the activation and migration of microglial cells in living brain tissue. 7-ketocholesterol rapidly entered the nucleus and activated poly(ADP-ribose)-polymerase (PARP)-1, followed by the expression of migration-regulating integrins CD11a and intercellular adhesion molecule 1. These findings reveal a novel mechanism linking demyelination and progressive neuronal damage, which might represent an underlying insidious process driving disease beyond a primary white matter phenomenon and rendering the microglial PARP-1 a possible antiinflammatory therapeutic target

Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL

Here, we provide evidence for a detrimental role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in neural death in T cell-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Clinical severity and neuronal apoptosis in brainstem motor areas were substantially reduced upon brain-specific blockade of TRAIL after induction of EAE through adoptive transfer of encephalitogenic T cells. Furthermore, TRAIL-deficient myelin-specific lymphocytes showed reduced encephalitogenicity when transferred to wild-type mice. Conversely, intracerebral delivery of TRAIL to animals with EAE increased clinical deficits, while naive mice were not susceptible to TRAIL. Using organotypic slice cultures as a model for living brain tissue, we found that neurons were susceptible to TRAIL-mediated injury induced by encephalitogenic T cells. Thus, in addition to its known immunoregulatory effects, the death ligand TRAIL contributes to neural damage in the inflamed brain