BARCELONA – The ratio of total tau over total alpha-synuclein gave a sensitivity of 89% and a specificity of 61% for discriminating Parkinson’s disease from other neurodegenerative diseases in a prospective study of 181 patients.

This is the first time a combination biomarker has been used to identify Parkinson’s disease patients among a group with related disorders, including Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, Dr. Omar El-Agnaf said in an interview at the international conference on Alzheimer’s and Parkinson’s diseases. The findings’ implications could be important in both the clinic and the lab.

"It isn’t perfect, and it’s not yet clinically usable, but it’s better than anything else we have at this point," Dr. El-Agnaf said. The ability to discriminate Parkinson’s disease patients from those with other neurodegenerative disorders could allow earlier detection and earlier and possibly more effective treatment, as well as provide an enriched research pool with the potential to speed up drug development.

The study, which will soon appear in the journal Movement Disorders, was conducted by a group of researchers involved in the Parkinson’s Progression Markers Initiative (PPMI), a 5-year project seeking to identify and validate biochemical and imaging markers for the disease. The Michael J. Fox Foundation for Parkinson’s Research is sponsoring the $40 million project.

Healthy neurons normally release the alpha-synuclein protein into interstitial fluid; it’s thought to be important in presynaptic signaling. Decreasing levels may be related to neuronal damage, and in previous studies they have been associated with Parkinson’s disease and dementia with Lewy bodies, said Dr. El-Agnaf, a biochemist and professor at the United Arab Emirates University, Al Ain. But these prior studies found conflicting evidence that alpha-synuclein alone adequately identifies Parkinson’s disease.

This is partially a result of the wide reference range for normal alpha-synuclein levels (5-40 ng/mL) and to its natural, age-related decline. Other factors might be different methods of sample collection, different antibodies used in the immunoassay, and even the age of the samples. "Storage can affect the levels of alpha-synuclein. If a sample has been stored more than 120 months, the level goes down significantly. So we cannot compare fresh samples with those that have been stored for a long period of time."

Those earlier studies confirmed that Parkinson’s disease patients tended to cluster in the lowest level of alpha-synuclein, but "there were huge overlaps" with other disorders, and even with normal controls, which Dr. El-Agnaf said negated any significant association with Parkinson’s. "If this was going to become a clinically useful tool, we needed a better way to measure" the potential biomarker.

Dr. El-Agnaf and his colleagues have been pursuing alpha-synuclein as a Parkinson’s biomarker since 2002. In 2010, the group found that, in addition to decreased levels of total alpha-synuclein, Parkinson’s disease patients also expressed increased levels of the protein’s oligomeric form. Oligomers usually form before more complex molecules, and their increased presence suggested that these species might be particularly useful in detecting Parkinson’s in its earliest stages, he said.

The 2010 paper found that a ratio of alpha-synuclein oligomers to total alpha-synuclein had 89% sensitivity and 91% specificity for Parkinson’s patients, compared with those with progressive supranuclear palsy (Neurology 2010;75:1766-72). "The ratio measurement was a much better indicator, but there was still a large overlap" with Alzheimer’s disease patients and normal controls. That study also found a progression-related association: Alpha-synuclein oligomers were increased in patients with mild and early Parkinson’s, "suggesting that this could be an early or possibly presymptomatic diagnostic marker."

His current study, still in press, sought to identify any clinically useful relationship between alpha-synuclein and the biomarkers used in Alzheimer’s research (amyloid beta 42, total tau, and phosphorylated tau). The study cohort comprised subjects with Parkinson’s (38), Alzheimer’s (48), dementia with Lewy bodies (32), frontotemporal dementia (31), and other neurologic disorders (32). All of these patients donated cerebral spinal fluid, which underwent the same immunoassay.

All patients with a disorder had significantly lower alpha-synuclein than did control subjects, again showing its inability to adequately discriminate Parkinson’s disease from other conditions. The story was no different with the other individual biomarkers tested; the group overlap was still too great for clinical usefulness.

"We then tried ratios again: amyloid beta 42, total tau, and phosphorylated tau over alpha-synuclein," Dr. El-Agnaf said. "Both forms of tau over alpha-synuclein distinguished the Parkinson’s patients, who had significantly lower ratios than the other groups." Total tau over alpha-synuclein gave the best results, with a sensitivity of 89% and a specificity of 61%.

Although not yet specific enough for a diagnostic tool, the research strengthens the link between alpha-synuclein and Parkinson’s, and suggests that if a disease-modifying drug is created, it would probably be most effective in patients at the very earliest stage because up to 70% of dopaminergic neurons have been lost by the time symptoms are clinically apparent.

"The earlier you start treatment, presumably the more effective it would be," Dr. El-Agnaf said. "Halting disease progression can only be effective if you start the drugs as early as possible."

Dr. El-Agnaf had no financial disclosures.

Biomarker Ratio Improves Ability to Distinguish Parkinson's