Blood, CSF Marker Detects Parkinsonian Disorders

A novel blood and cerebrospinal fluid (CSF) measure showed promise as a biomarker for Parkinsonian disorders.

CSF levels of DOPA decarboxylase (DDC) -- an enzyme that converts levodopa into dopamine -- accurately identified patients with Lewy body disease with an area under the curve (AUC) of 0.89, reported Oskar Hansson, MD, PhD, of Lund University in Sweden, and co-authors in a Nature Aging research letter.

In an independent replication cohort, plasma DDC levels identified both Lewy body disease and atypical Parkinsonian disorders (AUC 0.92).

"This study shows for the first time that DDC is elevated in both cerebrospinal fluid and blood in patients with Parkinsonian disorders, including Parkinson's disease, Lewy body dementia, progressive supranuclear palsy, and multiple system atrophy," Hansson told MedPage Today. "We even found that the levels were increased before symptom onset and could predict subsequent development of clinical disease."

DDC, also known as aromatic L-amino acid decarboxylase, identified preclinical Lewy body disease in unimpaired individuals who had a positive alpha-synuclein seed amplification assay (AUC 0.81), the researchers said. It predicted progression to clinical Lewy body disease over a 3-year period in preclinical cases (HR 3.7 per standard deviation change, 95% CI 1.1–12.7, P=0.035).

DDC levels were increased in atypical Parkinsonian disorders but not in other neurodegenerative disorders like Alzheimer's disease, frontotemporal dementia, or vascular dementia.

"Parkinsonian disorders are often difficult to diagnose accurately based on clinical assessments alone, especially during early disease stages," Hansson noted.

"PET imaging of the dopaminergic neurons is often helpful, but it's expensive and requires a complex infrastructure," he said. "Accurate fluid biomarkers, especially if they can be measured in blood, would be much more cost-effective and scalable."

Hansson and colleagues studied 682 individuals from the Swedish BioFINDER 2 cohort. The sample included 81 patients with Lewy body disease (Parkinson's disease or dementia with Lewy bodies), 40 with atypical Parkinsonian disorders, 214 with other neurodegenerative disorders like Alzheimer's disease, and 347 clinically unimpaired controls.

The researchers measured a panel of 2,943 proteins in CSF and 92 proteins in plasma using a highly sensitive, specific multiplex immunoassay. The primary goal was to identify biomarkers that could detect clinical Lewy body disease and atypical Parkinsonian disorders. The secondary aim was to find markers of preclinical Lewy body disease, defined as clinically unimpaired individuals with a positive alpha-synuclein seed amplification assay (SAA).

The researchers replicated their findings in an independent sample of 152 people to assess generalizability and measured candidate biomarkers in blood samples from 174 people.

Because the most common medication to treat Lewy body disease is levodopa combined with a DDC inhibitor (carbidopa), the researchers repeated their analyses in 45 people with early clinical disease who had not yet received dopaminergic drugs and found DDC levels were upregulated in this subgroup compared with controls (AUC 0.92).

DDC was not a good biomarker to discriminate atypical Parkinsonian disorders from Lewy body disease, Hansson and co-authors noted.

The alpha-synuclein SAA is an accurate biomarker for Lewy body disease but not always for atypical Parkinsonian disorders (which lack Lewy bodies), the researchers observed. "We suggest that DDC and alpha-synuclein SAA may be combined in clinical practice in the future, where high DDC and abnormal alpha-synuclein SAA would indicate Lewy body disease, whereas high DDC and normal alpha-synuclein SAA would indicate an atypical Parkinsonian disorder," they wrote.

A similar idea combining SAA with neurofilament light chain (NfL) has been proposed, Hansson and colleagues said. But unlike DDC, NfL is a "rather unspecific neurodegeneration biomarker that is affected across several neurodegenerative disorders, such as amyotrophic lateral sclerosis and frontotemporal dementia, among many others," they pointed out.

The study investigated only one technique to measure DDC protein levels in CSF or plasma, the researchers acknowledged.

"We need to develop laboratory tests that can be more easily used in research, and later on in clinical practice and trials," Hansson said. "Further, the results -- especially in blood -- need to be validated in further clinical relevant cohorts."

Comment