Daniel M. Keller, PhD

March 24, 2015

NICE, France — Using an unbiased approach to investigate biomarkers in cerebrospinal fluid (CSF) from patients with parkinsonian symptoms, a study was able to differentiate patients with Parkinson's disease (PD) from healthy controls and from those with atypical parkinsonian syndromes (APS), which include progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal syndrome (CBS).

Presenting his work here at the AD/PD 2015: International Conference on Alzheimer's and Parkinson's Diseases, Johan Gobom, PhD, from the University of Gothenberg, Sweden, explained that by looking at all proteins in the CSF, rather than by looking for specific ones a priori, a wide picture of differences between disease groups emerged.

He used isobaric labeling of the proteins, a mass spectrometry (MS) technique that allows not only identification of peptides but also information about the relative quantities of the peptides in a sample during liquid chromatography-MS analysis. "This identified some 5000 peptides in our samples, and it came from about 700 proteins," he said.

The study was divided into an initial discovery phase of the technique and a validation phase. A total of 28 CSF samples were obtained from healthy controls; 26 from patients with PD; and 82 from patients with APS who had PSP, MSA, or CBS. About half of each sample set was used in the discovery phase and half for validation.

Using OPLS-DA (orthogonal projections to latent structures-discriminant analysis) statistics to analyze the large data sets, Dr Gobom could differentiate APS CSF from healthy control samples with 100% sensitivity and 70% specificity.

"Typical Parkinson's patients, they fall in between the healthy controls and the APS, which probably reflects the slower and less widespread neurodegeneration in the typical Parkinson's patients," he said. "There are many proteins that underlie this group separation."

He found some of the largest differences between groups in the proteins involved in acute phase signaling and in inflammatory proteins.

Complement component C7 and α-1-antichymotrypsin concentrations were lowest in healthy controls, intermediate in PD, and highest in APS. Complement component 7 was lowest in healthy controls but about equally elevated in the CSF from patients with PD and APS. Dr Gobom said that inappropriate activation of the complement system may contribute to disease.

Several neuronal and synaptic proteins were highest in the healthy control samples, intermediate in PD, and lowest in APS. Among these were neuronal pentraxin receptor, neuronal pentraxin-1, and amyloid precursor protein.

Technical Problems

Session moderator Irina Alafuzoff, MD, PhD, professor of neuropathology at Uppsala University in Sweden, commented to Medscape Medical News that Dr Gobom's approach and findings could have important clinical utility.

"It's may be difficult technically today, but if you solve all the technical problems it might be of interest," she said. "Both PD and atypical PD are difficult diseases to diagnose, and there are always those which will be also impossible to identify."

She mentioned some of the limitations of this small study. "You had the PSP, and then PD, and controls, and from neurodegenerative points they are different diseases. So what they need is more cases, and they need postmortem verification," she said.

Dr Gobom said he plans to "dig deeper into the CSF proteome" and to establish targeted assays for the identified candidate biomarkers that can distinguish the different conditions.

There was no commercial funding for the study. Dr Gobom and Dr Alafuzoff have disclosed no relevant financial relationships.

AD/PD 2015: International Conference on Alzheimer's and Parkinson's Diseases. Abstract #256. Presented March 19, 2015.

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