Innovative Blood Test Can Detect Parkinson’s in Its Very Initial Stages
1 September 2023
Researchers at Duke University School of Medicine have developed a groundbreaking blood test, Mito DNADX, that can detect Parkinson's disease by identifying mitochondrial DNA damage. This early detection method could revolutionize the diagnosis process, currently based on clinical symptoms that appear after significant neurological damage.
The test also highlighted a mutation in the LRRK2 kinase enzyme gene, commonly associated with Parkinson's. The assay offers hope for not just early detection, but also potential treatments targeting mitochondrial DNA damage. Parkinson’s, which affects about 10 million people globally, is currently diagnosed based largely on clinical symptoms.
However, by the time these symptoms manifest, significant neuronal damage has already happened. The new PCR-based assay, named Mito DNADX, zeroes in on mitochondrial DNA (mtDNA) damage to pinpoint the presence of the disease. This could not only expedite diagnosis but also improve treatment efficacy.
“Currently, Parkinson’s disease is diagnosed largely based on clinical symptoms after significant neurological damage has already occurred. A simple blood test would allow us to diagnose the disease earlier and start therapies sooner. Additionally, a clear-cut diagnosis would accurately identify patients who could participate in drug studies, leading to the development of better treatments and potentially even cures,” said Professor Laurie Sanders, PhD, member of the Duke Center for Neurodegeneration and Neurotherapeutics.
Mitochondria, often dubbed the "powerhouses" of cells, contain their own DNA, separate from the organism's main genome. Previous studies have linked mitochondrial DNA damage to an elevated risk of Parkinson’s disease. Notably, Duke's team has found notable mtDNA damage in post-mortem brain tissues from Parkinson's patients. This diagnostic tool could prove invaluable.
The early symptoms of Parkinson's are varied and include sleep disturbances, mood changes, constipation, and movement difficulties. As a result, up to 25% of people are misdiagnosed initially, according to a Parkinson's UK poll. A definitive diagnostic test would be a giant leap in addressing this issue, ensuring patients receive the support and treatment they need much sooner.
Of particular interest is test the blood test's sensitivity to a mutation in the LRRK2 kinase enzyme gene, a prevalent known cause of Parkinson's. Remarkably, the test has detected heightened mtDNA damage in individuals without a Parkinson's diagnosis but who carry the LRRK2 mutation. This suggests that such damage might occur before any clinical diagnosis is possible. Additionally, the assay hints at potential treatments.
When the LRRK2 enzyme was inhibited using the experimental molecule MLi-2, DNA damage decreased in a Parkinson's rat model. These findings indicate that treatments targeting the LRRK2 enzyme could be beneficial, even for patients without the LRRK2 mutation.
“Our hope is that this assay could not only diagnose Parkinson’s disease, but also identify drugs that reverse or halt mitochondrial DNA damage and the disease process. It’s important to get new, effective treatments over the finish line,” Professor Sanders added.
In conclusion, this development holds the promise of a brighter future for Parkinson's patients. With early and definitive diagnoses, plus potentially transformative treatments on the horizon, the medical community is taking crucial steps towards conquering this challenging condition.
Abstract of research
A blood-based marker of mitochondrial DNA damage in Parkinson’s disease
Abstract: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region–specific accumulation of mitochondrial DNA (mtDNA) damage in PD neuronal culture and animal models, as well as in human PD postmortem brain tissue. To investigate mtDNA damage as a potential blood-based marker for PD, we describe herein a PCR-based assay (Mito DNADX) that allows for the accurate real-time quantification of mtDNA damage in a scalable platform. We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation in comparison with age-matched controls. In addition, mtDNA damage was elevated in non–disease-manifesting LRRK2 mutation carriers, demonstrating that mtDNA damage can occur irrespective of a PD diagnosis. We further established that Lrrk2 G2019S knock-in mice displayed increased mtDNA damage, whereas Lrrk2 knockout mice showed fewer mtDNA lesions in the ventral midbrain, compared with wild-type control mice. Furthermore, a small-molecule kinase inhibitor of LRRK2 mitigated mtDNA damage in a rotenone PD rat midbrain neuron model and in idiopathic PD patient–derived lymphoblastoid cell lines. Quantifying mtDNA damage using the Mito DNADX assay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.
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