Parkinson’s disease, a brain disorder that gradually leads to difficulty moving, tremors, and usually dementia by the end, is often difficult to diagnose early in its yearslong progression. That makes testing experimental treatments challenging and slows people from getting existing drugs, which can’t stop the ongoing death of brain cells but temporarily improve many of the resulting symptoms. Now, a study using rodents and tissue from diagnosed Parkinson’s patients suggests DNA damage spotted in blood samples offers a simple way to diagnose the disease early.
Although the potential test needs to be validated in clinical studies, the detected DNA damage joins a “flurry” of other biomarkers recently identified for Parkinson’s and “adds to our ability to state confidently that an individual has Parkinson’s disease or not,” says neurodegeneration researcher Mark Cookson of the National Institute on Aging, whose grantmaking arm helped fund the new work, published today in Science Translational Medicine. A blood test based on the findings could also help patients go on existing treatments earlier and boost clinical trials evaluating new therapies, the study’s authors say.
“It’s really exciting because it’s something [physicians] could use to detect [Parkinson’s] before the clinical symptoms emerge,” says neuroscientist Malú Tansey of the University of Florida, who also was not involved with the research.
Parkinson’s occurs when the death of certain neurons in the brain causes levels of the neurotransmitter dopamine to drop, leading to muscle stiffness, balance problems, speech and cognitive problems, and other symptoms over time. The disorder, tied to both environmental and genetic factors, afflicts up to 1 million people in the United States.
The new test is built on observations that Parkinson’s often involves malfunctioning mitochondria, powerhouse organelles inside cells that have their own DNA. Several teams, including neuroscientist Laurie Sanders’s group at the Duke University School of Medicine, have reported that brain tissue from some Parkinson’s patients carries signs of mitochondrial DNA (mtDNA) damage. Some studies have also found defective mitochondria in patients’ blood cells, suggesting mtDNA damage in blood “could be a surrogate for what’s happening in the brain,” Sanders says.
Her lab and collaborators recently developed a novel assay that assesses the amount of damaged mtDNA in a blood sample. The test was able to distinguish several sets of up to about 50 people with Parkinson’s disease from healthy control subjects. The researchers also found higher levels of mtDNA damage in the blood of a diagnosed Parkinson’s patient who had been born with a rare, mutated form of a gene called LRRK2 that raises the risk for the condition. Sanders’s team had previously tied the mutation to mtDNA damage in brain tissue.
Most intriguing, the test picked up this damage in people with the disease-promoting variant of LRRK2 but no symptoms. That suggests it could flag people before they develop serious disease, perhaps even in the more than 90% lacking the LRRK2 mutation or other Parkinson’s-linked mutations, Sanders says.
The assay could also help determine who may benefit from an experimental Parkinson’s compound that targets LRRK2. In cultured cells from Parkinson’s patients and neurons from rats with the disease induced by a neurotoxin, treatment with the compound reduced levels of mtDNA damage, Sanders’s team reports. The compound is now in clinical testing and Sanders suggests her team’s assay could indicate whether it is helping patients.
So far, the assay has only been retrospectively tested on stored blood samples; researchers will need to prove it can accurately and sensitively detect Parkinson’s early through a prospective trial. Researchers also need to better understand why blocking LRRK2 appears to reduce mtDNA damage, Cookson says. “Understanding the mechanism involved is critical so we can properly understand what this promising biomarker is telling us about disease pathogenesis,” he says.
The mtDNA test isn’t the only candidate blood test for Parkinson’s. Earlier this year, researchers reported that analyzing spinal fluid for a misfolded form of a neural protein called alpha-synuclein could have potentially diagnosed 88% of 545 current patients. Researchers are making progress on a blood test for the protein, which is known to build up in the brains of people with Parkinson’s.
But the mtDNA and alpha-synuclein tests “are measuring slightly different things” and might reflect different forms of Parkinson’s disease, Sanders says. She envisions giving people suspected of having Parkinson’s both tests. “That could give us the power to really understand what’s happening in this disease so that we can then treat it better.”
