DDC enzyme may be biomarker of Parkinson’s, related diseases
Measuring its levels may help differentiate disease from unrelated conditions
Measuring levels of an enzyme called DOPA decarboxylase (DDC) in the blood or fluid around the brain and spinal cord may help distinguish Parkinson’s disease and related disorders from non-Parkinsonian neurodegenerative diseases, a study reports.
“Since the symptoms of various neurodegenerative brain diseases resemble each other, there is a significant risk of misdiagnosis and thus improper treatment,” Oskar Hansson, MD, PhD, the study’s senior author at Lund University, Sweden, said in a university press release. “Therefore, it is crucial to find safer diagnostic tools and methods, and we are focusing on that in our research.”
“Our findings suggest that … DDC is a highly promising biomarker for Parkinsonian disorders,” the researchers wrote, adding it might be “important for early and even preclinical detection of Parkinsonian disorders and predict future conversion to clinical [disease].”
The study, “DOPA decarboxylase is an emerging biomarker for Parkinsonian disorders including preclinical Lewy body disease,” was published in Nature Aging.
Parkinsonism describes any disease that features a set of symptoms similar to Parkinson’s, such as slow movements, rigidity or stiffness, tremors, and mobility issues. Parkinson’s disease is the most common form of parkinsonism and atypical parkinsonism types include dementia with Lewy bodies (DLB), progressive supranuclear palsy, and multiple system atrophy.
While Parkinson’s and atypical parkinsonism are marked by reduced dopamine signaling in the brain, they’re associated with distinct biological changes and the conditions have different clinical symptom profiles. Dopamine is a major brain signaling molecule involved in controlling movement. Parkinson’s and Lewy body disease (LBD) are characterized by the formation of Lewy bodies, complex, toxic aggregates of the alpha-synuclein protein inside nerve cells in the brain.
Diagnosing Parkinson’s and the risk of misdiagnosis
The diagnosis of parkinsonism “is primarily based on clinical criteria,” the researchers wrote, but “even when clinical criteria are correctly applied, the frequency of misdiagnosis is high due to considerable symptom overlap with other disorders.”
Given the “growing evidence indicating that the neurodegenerative processes underlying [parkinsonism] begin several years before the onset of clinical symptoms,” identifying early disease biomarkers is crucial to improving its diagnosis, said the researchers who looked for possible biomarkers of clinical parkinsonism and subclinical Lewy body disease (LBD), including Parkinson’s and DLB, and analyzed whether these could distinguish parkinsonism from non-Parkinsonian neurodegenerative diseases.
They first analyzed samples of cerebrospinal fluid (CSF) — the liquid that surrounds the brain and spinal cord — from 81 people with LBD (48 with Parkinson’s disease, 33 with DLB) and 347 people with no disease.
“We have used advanced techniques that allow us to measure thousands of proteins simultaneously in a small amount of sample … to identify biomarkers that can indicate whether a patient with motor disturbances or cognitive difficulties has damage to the dopamine system in the brain,” Hansson said.
Levels of DDC enzyme
The levels of 10 proteins were significantly increased in the LBD group relative to the healthy people, while the levels of four were significantly reduced. Of the increased proteins, DDC, which brain cells use to produce dopamine, showed the best ability to discriminate between the two groups.
DDC levels could distinguish between people with or without LBD with an area under receiver operating characteristic curve (AUC) of 0.89. Values of AUC, a statistical metric, range from 0 to 1, with higher values reflecting a better discriminating ability.
DDC levels were elevated regardless of treatment with dopamine-modulating medications and no significant differences were found between Parkinson’s patients and those with DLB.
Among the healthy people, DDC levels were significantly higher in those positive on seed amplification assays (SAA), a test that looks for toxic alpha-synuclein clumping. The 35 SAA-positive people were followed for an average of more than two years, during which time 12 developed clinical symptoms of LBD.
Statistical tests suggested that elevated DDC levels increased the risk of clinical LBD by nearly four times. “We found that DDC predicted conversion from preclinical to clinical LBD, indicating that it has an important prognostic value,” the researchers wrote.
“We found that if a patient has a disorder in the dopamine system, the levels of the biomarker DDC increase, regardless of where they are in the course of the disease,” Hansson said.
Rising DDC levels were also associated with worse global cognition.
Distinguishing atypical Parkinson’s, non-Parkinsonian disorders
The researchers also analyzed CSF samples of 40 people with atypical parkinsonism other than DLB and 214 people with non-Parkinsonian neurodegenerative disorders.
They found that DDC levels were significantly higher in atypical Parkinsonism patients relative to healthy people, suggesting “DDC might be a marker of [dopamine] dysfunction rather than [alpha-synuclein-based] Lewy body [disease],” wrote the researchers, who noted LBD patients also had significantly higher DDC levels compared with those with non-Parkinsonian diseases, “indicating that changes in this biomarker are specific for Parkinsonian diseases.”
All the CSF results were replicated in a new group of patients and healthy people, whose blood data revealed that DDC levels could accurately identify both LBD (AUC of 0.92), and atypical Parkinsonian disorders (AUC of 0.85).
“DDC was unable to accurately discriminate LBD from atypical Parkinsonian disorders,” however, the researchers wrote, adding future research is needed to verify whether DDC can reliably predict disease before symptoms appear. Research that tracks DDC levels over time is also needed, they said.