Alpha-synuclein in Fluids and Tissues Not a Valid Parkinson’s Biomarker, Study Finds

The total amount of alpha-synuclein in certain fluids and tissues failed to accurately distinguish between people with Parkinson’s disease and healthy individuals, and cannot be used to help diagnose the disease earlier, a large study has now shown.

According to the study, levels of this protein in the cerebrospinal fluid (CSF) — the clear, colorless liquid that fills and surrounds the brain and spinal cord — were not specific enough, meaning they could not accurately rule out people without Parkinson’s.

At the same time, levels in skin and salivary gland biopsies were specific but not sensitive enough, meaning they were not able to consistently identify people with the disease. They only identified about half and one quarter, respectively, of Parkinson’s patients as actually having the disease.

The study, one of the most complete to examine this potential biomarker, is titled “In vivo distribution of α-synuclein in multiple tissues and biofluids in Parkinson disease” and published in Neurology.

A distinctive feature of Parkinson’s is the progressive degeneration of brain cells due to the accumulation of toxic clumps of alpha-synuclein. Given its role in the disease, this protein has been regarded as a lead candidate biomarker for Parkinson’s.

Biomarkers are urgently needed for these patients; they can help provide earlier diagnoses, monitor disease progression, and measure responses to treatment. But so far, studies examining levels of alpha-synuclein in bodily fluids have failed to validate it as an accurate biomarker of disease.

The Systemic Synuclein Sampling Study (S4; NCT02572713), an initiative from The Michael J. Fox Foundation, was therefore launched to compare the levels of alpha-synuclein in multiple fluids and tissues of patients and controls. Whether levels of this protein were correlated across samples from the same individual was also investigated.

A total of 59 patients with idiopathic Parkinson’s disease and without dementia were enrolled at six U.S. sites from October 2015 to August 2017. For controls, 21 healthy individuals were also included. Patients and controls both had a median age of 63 years, but the patient group had a significantly larger proportion of males (69% vs. 43%).

Participants provided blood, saliva, and CSF samples, as well as biopsies from the skin (both from the thigh and cervical region), colon, and submandibular gland, a salivary gland that sits beneath the floor of the mouth.

Results first showed that blood and saliva did not exhibit significantly different levels of alpha-synuclein between the groups. And while the total levels of this protein in the CSF were significantly lower in patients than controls, they could only distinguish the two groups with an accuracy of 69%.

In fact, CSF levels could identify about 87% of Parkinson’s patients as having the disease (sensitivity), but only 63.2% of controls were deemed negative for the condition (specificity) — meaning that nearly 1 in 4 controls would be wrongly diagnosed with Parkinson’s.

As for tissue samples, only skin and submandibular samples had a greater number of patients testing positive for alpha-synuclein than controls. While these were very good at identifying controls – only one of 21 controls tested positive for alpha-synuclein in tissue samples – only 56% of submandibular samples and 24% of skin samples tested positive in patients, meaning these were not good enough to identify people with Parkinson’s.

In submandibular gland tissue, the ability to identify Parkinson’s patients rose to 78.6% when only people with advanced disease were included in the analysis. Sensitivity remained low for skin samples.

Though examining all three tissues in one patient could theoretically improve the diagnostic accuracy of alpha-synuclein, the researchers noted that a large proportion of patients (14 of 39) tested negative for this protein in all three tissues, showing that combining data from multiple tissues does not improve diagnostic yield.

“We did not find a correlation between intraindividual measures of total [alpha]-synuclein across the various biofluids and tissues as we had hypothesized,” the researchers wrote.

Finally, the researchers examined if testing positive for alpha-synuclein in skin or gland tissue was associated with clinical characteristics. They found no significant differences between patients testing positive and those who tested negative in these tissue samples.

“These results provide critical information we and the broader Parkinson’s research community can use to move forward. We will continue to support the development of alpha-synuclein biomarkers that may prove to have higher accuracy,” Jamie Eberling, PhD, vice president of research programs at MJFF, said in a press release.

The team believes that measuring toxic alpha-synuclein clumps rather than all forms of alpha-synuclein may provide a better biomarker for the disease.

“Importantly, S4 also provides the research community with samples of fluids and tissues (accessible via michaeljfox.org), with which to assess promising new assays and stains,” the researchers wrote. “Ultimately, understanding the distribution of α-synuclein in biofluids and tissues will help advance development of [Parkinson’s] biomarkers and our understanding of [Parkinson’s] pathology including its progression.”