An enzyme biomarker could act as an early warning sign for common neurodegenerative disorders and predict the progression to clinical disease, research suggests.
Levels of DOPA decarboxylase (DDC) in cerebrospinal fluid (CSF) and blood plasma were raised in Parkinsonian disorders and dementia with Lewy bodies, which together are called Lewy body disease (LBD).
The enzyme, which is also known as aromatic l-amino acid decarboxylase, could be a marker of the reduced dopamine signaling in the brain, the researchers suggested.
The findings could help aid in early detection and diagnosis of these disorders, as well as provide opportunities to develop therapeutic strategies to delay their progression.
“Collectively, our findings show that DDC is a unique and very promising biomarker for LBD and atypical Parkinsonian disorders,” reported Oskar Hansson, PhD, a professor of clinical memory research at Lund University in Sweden, and colleagues in the journal Nature Aging.
Parkinsonian disorders are among the most common neurodegenerative disorders, affecting approximately 6% of the global population.
They include LBD, together with atypical syndromes such as multiple system atrophy.
Traditionally, diagnosis occurs with clinical symptoms, but prior research indicates that the neurodegenerative processes can begin years earlier.
Molecular changes in the brain are reflected in CSF, making it a valuable source of biomarkers for the early diagnosis of neurodegenerative disorders.
This has already been shown in Alzheimer’s disease, where amyloid-β and phosphorylated tau isoforms reliably detect underlying pathology even in preclinical disease.
In an attempt to identify similar biomarkers for LBD, Hansson and the team studied 428 people using a multiplex proteomic approach, which enables the identification and quantification of proteins.
The researchers measured an extensive panel of 2,943 proteins in the CSF using a highly sensitive and specific immunoassay.
They found that DDC levels in cerebrospinal fluid levels were highly accurate in identifying participants with LBD and were also significantly associated with impaired cognitive function.
DDC also had value in preclinical individuals who had a positive α-synuclein seed amplification assay (SAA), reflecting underlying abnormal α-synuclein aggregation.
Enzyme levels were significantly increased among 35 individuals in these early disease stages compared with 310 without abnormal α-synuclein aggregation.
The biomarker could also predict progression to clinical disease among clinically normal cases with abnormal α-synuclein aggregation, who were assessed every 1–2 years.
Higher DDC levels were significantly associated with subsequent progression to clinical LBD over an average follow-up of 2.53 years, with a hazard ratio of 3.7 per standard deviation change.
DDC levels were associated with worse global cognition, low memory performance, worse cognitive speed, and visuospatial abilities in cognitive assessments among individuals with clinical LBD.
Levels of DDC were also raised among individuals with atypical Parkinsonian disorders, such as multiple system atrophy, suggesting that DDC might be a marker of dopaminergic dysfunction rather than α-synuclein-based Lewy body pathology.
This is not the case with people who had non-Parkinsonian neurodegenerative diseases.
The results were replicated in an independent cohort of 152 individuals. Preliminary studies in 174 individuals indicated the potential of DDC in blood plasma to accurately identify LBD and atypical Parkinsonian disorders among 92 plasma proteins investigated.
“When combined with the specific α-synuclein SAA used in our study, DDC might improve the diagnostic workup of Parkinsonian disorders in clinical practice,” the researchers said.
They explained: “Since α-synuclein SAA is an accurate biomarker for LBD but not always for atypical Parkinsonian disorders (which lack Lewy bodies), we suggest that DDC and α-synuclein SAA may be combined in clinical practice in the future, where high DDC and abnormal α-synuclein SAA would indicate LBD, whereas high DDC and normal α-synuclein SAA would indicate an atypical Parkinsonian disorder.”
