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Circulating cell-free mitochondrial DNA levels in Parkinson's disease are influenced by treatment
Hannah Lowes1, Angela Pyle2, Mauro Santibanez-Koref3
1Wellcome Centre for Mitochondrial Research, Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Abstract:
Several studies have linked circulating cell-free mitochondrial DNA (ccf-mtDNA) to human disease. In particular, reduced ccf-mtDNA levels in the cerebrospinal fluid (CSF) of both Alzheimer's and Parkinson's disease (PD) patients have raised the hypothesis that ccf-mtDNA could be used as a biomarker for neurodegenerative disease onset and progression. However, how a reduction of CSF ccf-mtDNA levels relates to neurodegeneration remains unclear. Many factors are likely to influence ccf-mtDNA levels, such as concomitant therapeutic treatment and comorbidities. In this study we aimed to investigate these factors, quantifying CSF ccf-mtDNA from the Parkinson's Progression Markers Initiative in 372 PD patients and 159 matched controls at two time points. We found that ccf-mtDNA levels appear significantly reduced in PD cases when compared to matched controls and are associated with cognitive impairment. However, our data indicate that this reduction in ccf-mtDNA is also associated with the commencement, type and duration of treatment. Additionally, we found that ccf-mtDNA levels are associated with comorbidities such as depression and insomnia, however this was only significant if measured in the absence of treatment. We conclude that in PD, similar to reports in HIV and sepsis, comorbidities and treatment can both influence ccf-mtDNA homeostasis, raising the possibility that ccf-mtDNA may be useful as a biomarker for treatment response or the development of secondary phenotypes. Given that, clinically, PD manifests often decades after neurodegeneration begins, predicting who will develop disease is important. Also, identifying patients who will respond to existing treatments or develop secondary phenotypes will have increased clinical importance as PD incidence rises.
Insights
Circulating cell-free mitochondrial DNA (ccf-mtDNA) is reduced in Parkinson's disease (PD) patients and linked to cognitive issues. Treatment and comorbidities significantly impact ccf-mtDNA levels, suggesting its potential as a biomarker for PD progression and treatment response.
Area of Science:
- Neuroscience
- Biochemistry
- Biomarker Discovery
Background:
- Circulating cell-free mitochondrial DNA (ccf-mtDNA) is implicated in various diseases.
- Reduced ccf-mtDNA in cerebrospinal fluid (CSF) of Alzheimer's and Parkinson's disease (PD) patients suggests potential as a neurodegenerative disease biomarker.
- The precise relationship between reduced CSF ccf-mtDNA and neurodegeneration, and influencing factors, remains unclear.
Purpose of the Study:
- To investigate factors influencing CSF ccf-mtDNA levels in Parkinson's disease.
- To quantify CSF ccf-mtDNA in PD patients and controls, assessing associations with disease, treatment, and comorbidities.
- To explore the potential of ccf-mtDNA as a biomarker in the context of PD.
Main Methods:
- Quantification of CSF ccf-mtDNA from 372 PD patients and 159 controls using data from the Parkinson's Progression Markers Initiative.
- Analysis of ccf-mtDNA levels in relation to PD diagnosis, cognitive status, treatment (commencement, type, duration), and comorbidities (depression, insomnia).
- Two-time point measurements were utilized for longitudinal assessment.
Main Results:
- CSF ccf-mtDNA levels were significantly reduced in PD patients compared to controls.
- Reduced ccf-mtDNA was associated with cognitive impairment in PD patients.
- ccf-mtDNA levels were influenced by the commencement, type, and duration of PD treatment.
- Comorbidities like depression and insomnia were associated with ccf-mtDNA levels, but only when treatment was absent.
Conclusions:
- In Parkinson's disease, both treatment and comorbidities significantly influence ccf-mtDNA homeostasis, similar to findings in HIV and sepsis.
- ccf-mtDNA may serve as a biomarker for treatment response or the development of secondary phenotypes in PD.
- Understanding these influences is crucial for biomarker development, especially given the long preclinical phase of PD and rising incidence.
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