Cerebrospinal fluid evidence of increased extra-mitochondrial glucose metabolism implicates mitochondrial dysfunction in multiple sclerosis disease progression

Background: Mitochondrial dysfunction is increasingly recognized as an important feature of multiple sclerosis (MS) pathology and may be relevant for clinical disease progression. However, it is unknown whether mitochondrial DNA (mtDNA) levels in the cerebrospinal fluid (CSF) associate with disease progression and therapeutic response. Objectives: To evaluate whether CSF concentrations of mtDNA in MS patients can serve as a marker of ongoing neuropathology and may be helpful to differentiate between MS disease subtypes. To explore the effect of disease-modifying therapies on mtDNA levels in the CSF. Methods: CSF mtDNA was measured using a digital polymerase chain reaction (PCR) CSF mtDNA in two independent MS cohorts. The cohorts included 92 relapsing-remitting multiple sclerosis (RRMS) patients, 40 progressive multiple sclerosis (PMS) patients (27 secondary progressive and 13 primary progressive), 50 various neurologic disease controls, and 5 healthy controls. Results: Patients with PMS showed a significant increase in CSF mtDNA compared to non-inflammatory neurologic disease controls. Patients with higher T2 lesion volumes and lower normalized brain volumes showed increased concentration of mtDNA. Patients treated with fingolimod had significantly lower mtDNA copy levels at follow-up compared to baseline. Conclusion: Our results showed a non-specific elevation of concentration of mtDNA in PMS patients. mtDNA concentrations respond to fingolimod and may be used to monitor biological effect of this treatment.

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Cerebrospinal fluid lactate is associated with multiple sclerosis disease progression

Journal of Neuroinflammation ◽

10.1186/s12974-016-0502-1 ◽

2016 ◽

Vol 13 (1) ◽

Cited By ~ 28

Author(s):

Maria Albanese ◽

Sara Zagaglia ◽

Doriana Landi ◽

Laura Boffa ◽

Carolina G. Nicoletti ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Disease Progression ◽

Multiple Sclerosis Disease

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Experimental design and sample size considerations in longitudinal magnetic resonance imaging-based biomarker detection for multiple sclerosis

Statistical Methods in Medical Research ◽

10.1177/0962280220904392 ◽

2020 ◽

Vol 29 (9) ◽

pp. 2617-2628 ◽

Cited By ~ 1

Author(s):

Menghan Hu ◽

Matthew K Schindler ◽

Blake E Dewey ◽

Daniel S Reich ◽

Russell T Shinohara ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Multiple Sclerosis ◽

Clinical Trials ◽

Magnetic Resonance ◽

Sample Size ◽

Disease Progression ◽

Multiple Sclerosis Lesion ◽

Resonance Imaging ◽

Study Duration ◽

Multiple Sclerosis Disease

Several modeling approaches have been developed to quantify differences in multiple sclerosis lesion evolution on magnetic resonance imaging to identify the effect of treatment on disease progression. These studies have limited clinical applicability due to onerous scan frequency and lengthy study duration. Efficient methods are needed to reduce the required sample size, study duration, and sampling frequency in longitudinal magnetic resonance imaging studies. We develop a data-driven approach to identify parameters of study design for evaluation of longitudinal magnetic resonance imaging biomarkers of multiple sclerosis lesion evolution. Our design strategies are considerably shorter than those described in previous studies, thus having the potential to lower costs of clinical trials. From a dataset of 36 multiple sclerosis patients with at least six monthly magnetic resonance imagings, we extracted new lesions and performed principal component analysis to estimate a biomarker that recapitulated lesion recovery. We tested the effect of multiple sclerosis disease modifying therapy on the lesion evolution index in three experimental designs and calculated sample sizes needed to appropriately power studies. Our proposed methods can be used to calculate required sample size and scan frequency in observational studies of multiple sclerosis disease progression as well as in designing clinical trials to find effects of treatment on multiple sclerosis lesion evolution.

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Cerebrospinal fluid detection of interleukin-1β in phase of remission predicts disease progression in multiple sclerosis

Journal of Neuroinflammation ◽

10.1186/1742-2094-11-32 ◽

2014 ◽

Vol 11 (1) ◽

pp. 32 ◽

Cited By ~ 41

Author(s):

Silvia Rossi ◽

Valeria Studer ◽

Caterina Motta ◽

Giorgio Germani ◽

Giulia Macchiarulo ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Disease Progression ◽

Interleukin 1Β ◽

Fluid Detection

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Cerebrospinal fluid B cells and disease progression in multiple sclerosis - A longitudinal prospective study

PLoS ONE ◽

10.1371/journal.pone.0182462 ◽

2017 ◽

Vol 12 (8) ◽

pp. e0182462 ◽

Cited By ~ 10

Author(s):

Sebastian Wurth ◽

Bettina Kuenz ◽

Gabriel Bsteh ◽

Rainer Ehling ◽

Franziska Di Pauli ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

B Cells ◽

Prospective Study ◽

Disease Progression

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Plasma proteome in multiple sclerosis disease progression

Annals of Clinical and Translational Neurology ◽

10.1002/acn3.771 ◽

2019 ◽

Vol 6 (9) ◽

pp. 1582-1594

Author(s):

Arjan Malekzadeh ◽

Cyra Leurs ◽

Wessel Wieringen ◽

Martijn D. Steenwijk ◽

Menno M. Schoonheim ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Plasma Proteome ◽

Multiple Sclerosis Disease

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Brain TSPO-PET predicts later disease progression independent of relapses in multiple sclerosis

Brain ◽

10.1093/brain/awaa275 ◽

2020 ◽

Vol 143 (11) ◽

pp. 3318-3330

Author(s):

Marcus Sucksdorff ◽

Markus Matilainen ◽

Jouni Tuisku ◽

Eero Polvinen ◽

Anna Vuorimaa ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Disease Progression ◽

Cell Activation ◽

Immune Cell ◽

Innate Immune ◽

Innate Immune Cell ◽

Immune Cell Activation ◽

Normal Appearing White Matter ◽

Multiple Sclerosis Disease

Abstract Overactivation of microglia is associated with most neurodegenerative diseases. In this study we examined whether PET-measurable innate immune cell activation predicts multiple sclerosis disease progression. Activation of microglia/macrophages was measured using the 18-kDa translocator protein (TSPO)-binding radioligand 11C-PK11195 and PET imaging in 69 patients with multiple sclerosis and 18 age- and sex-matched healthy controls. Radioligand binding was evaluated as the distribution volume ratio from dynamic PET images. Conventional MRI and disability measurements using the Expanded Disability Status Scale were performed for patients at baseline and 4.1 ± 1.9 (mean ± standard deviation) years later. Fifty-one (74%) of the patients were free of relapses during the follow-up period. Patients had increased activation of innate immune cells in the normal-appearing white matter and in the thalamus compared to the healthy control group (P = 0.033 and P = 0.003, respectively, Wilcoxon). Forward-type stepwise logistic regression was used to assess the best variables predicting disease progression. Baseline innate immune cell activation in the normal-appearing white matter was a significant predictor of later progression when the entire multiple sclerosis cohort was assessed [odds ratio (OR) = 4.26; P = 0.048]. In the patient subgroup free of relapses there was an association between macrophage/microglia activation in the perilesional normal-appearing white matter and disease progression (OR = 4.57; P = 0.013). None of the conventional MRI parameters measured at baseline associated with later progression. Our results strongly suggest that innate immune cell activation contributes to the diffuse neural damage leading to multiple sclerosis disease progression independent of relapses.

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PET imaging of glucose metabolism, neuroinflammation and demyelination in the lysolecithin rat model for multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458514526941 ◽

2014 ◽

Vol 20 (11) ◽

pp. 1443-1452 ◽

Cited By ~ 23

Author(s):

Daniele de Paula Faria ◽

Erik FJ de Vries ◽

Jurgen WA Sijbesma ◽

Carlos A Buchpiguel ◽

Rudi AJO Dierckx ◽

...

Keyword(s):

Multiple Sclerosis ◽

Glucose Metabolism ◽

Corpus Callosum ◽

Disease Progression ◽

Pet Imaging ◽

Microglia Activation ◽

Sprague Dawley ◽

Positron Emission ◽

The Right

Background: Injection of lysolecithin in the central nervous system results in demyelination accompanied by local activation of microglia and recruitment of monocytes. Positron-emission tomography (PET) imaging, using specific tracers, may be an adequate technique to monitor these events in vivo and therefore may become a tool for monitoring disease progression in multiple sclerosis (MS) patients. Objectives: The objective of this paper is to evaluate the potential of PET imaging in monitoring local lesions, using [11C]MeDAS, [11C]PK11195 and [18F]FDG as PET tracers for myelin density, microglia activation and glucose metabolism, respectively. Methods: Sprague-Dawley rats were stereotactically injected with either 1% lysolecithin or saline in the corpus callosum and striatum of the right brain hemisphere. PET imaging was performed three days, one week and four weeks after injection. Animals were terminated after PET imaging and the brains were explanted for (immuno)histochemical analysis. Results: PET imaging was able to detect local demyelination induced by lysolecithin in the corpus callosum and striatum with [11C]MeDAS and concomitant microglia activation and monocyte recruitment with [11C]PK11195. [18F]FDG imaging demonstrated that glucose metabolism was maintained in the demyelinated lesions. Conclusion: PET imaging with multiple tracers allows simultaneous in vivo monitoring of myelin density, neuroinflammation and brain metabolism in small MS-like lesions, indicating its potential to monitor disease progression in MS patients.

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