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Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
Cerebrospinal fluid mtDNA concentration is elevated in multiple sclerosis disease and responds to treatment
Cyra E Leurs1, Petar Podlesniy2, Ramon Trullas2
1Department of Neurology, MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
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.
Insights
Levels of mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) were elevated in progressive multiple sclerosis (MS) patients. mtDNA levels responded to fingolimod treatment, suggesting potential for monitoring therapeutic effects in MS.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Mitochondrial dysfunction is implicated in multiple sclerosis (MS) pathology and disease progression.
- The role of mitochondrial DNA (mtDNA) levels in cerebrospinal fluid (CSF) concerning MS progression and treatment response remains unclear.
Purpose of the Study:
- To determine if CSF mtDNA concentrations in MS patients indicate neuropathology and can differentiate MS subtypes.
- To investigate the impact of disease-modifying therapies on CSF mtDNA levels.
Main Methods:
- Mitochondrial DNA (mtDNA) levels in CSF were quantified using digital polymerase chain reaction (PCR).
- Two independent MS cohorts were analyzed, including relapsing-remitting MS (RRMS), progressive MS (PMS), neurologic disease controls, and healthy controls.
Main Results:
- Progressive MS (PMS) patients exhibited significantly higher CSF mtDNA concentrations compared to controls.
- Elevated mtDNA levels correlated with increased T2 lesion volume and decreased normalized brain volume.
- Patients treated with fingolimod showed significantly reduced mtDNA levels post-treatment compared to baseline.
Conclusions:
- CSF mtDNA levels are non-specifically elevated in progressive MS (PMS) patients.
- mtDNA concentrations are responsive to fingolimod treatment and may serve as a biomarker for monitoring its biological effects in MS.
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