Immune Cells in Blood May Help with Diagnosis Years Before Motor Onset

Immune cells targeting the alpha-synuclein protein are common in Parkinson’s patients, and new research shows that these cells can be present in the blood up to 10 years before diagnosis, long before disease symptoms are evident.

This finding carries important implications for people at risk, such as those carrying genetic factors associated with Parkinson’s or displaying pre-motor symptoms. They may benefit from immunotherapies that prevent these immune cells from further damaging neurons.

The study, “α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease,” was published in Nature Communications.

Decades before a definitive diagnosis, before symptoms are present, people with Parkinson’s start showing molecular changes in the body that are followed by such non-motor symptoms as difficulty sleeping, constipation, mood changes, and loss of a sense of smell.

These changes are usually not enough to diagnose the disease — that is usually done only when motor symptoms of Parkinson’s are evident. But at that time, a large proportion of dopaminergic neurons — those that produce dopamine — have already been irreversibly lost, limiting the effectiveness of treatment.

Researchers are trying to identify early changes in Parkinson’s patients that can help in a definitive diagnosis before extensive nerve cell damage has taken place.

“Once these cells are gone, they’re gone. So if you are able to diagnose the disease as early as possible, it could make a huge difference,” Cecilia Lindestam Arlehamn, PhD, the study’s first author, said in a press release.

A team led by David Sulzer, PhD, at Columbia University Medical Center, and Alessandro Sette, at La Jolla Institute for Allergy and Immunology, reported in a 2017 study that some Parkinson’s patients have immune T-cells that react against the alpha-synuclein protein, known to form toxic clumps in dopamine-producing neurons of Parkinson’s patients.

This was the first direct evidence that autoimmunity could contribute to Parkinson’s development, with some immune T-cells mistakenly attacking nerve cells.

To understand how these cells were contributing to the disease, the team now set out to explore how these immune cells changed over time, both before and after diagnosis.

Researchers first examined blood samples from a single patient spanning 11 years prior to his Parkinson’s diagnosis, and then nine years after diagnosis. Each year, the patient underwent two blood collections, one in March and another in September.

They found that T-cells reacting against alpha-synuclein were detectable 10 years before the diagnosis and start of motor symptoms, reached a peak shortly before disease onset, and then declined in the years that followed.

Sulzer and Sette then collaborated with a team at the University of Alabama at Birmingham to examine how alpha-synuclein immune responses in blood samples from a group of Parkinson’s patients compared to age-matched healthy individuals serving as controls.

Regardless of time from diagnosis, patients overall exhibited significantly stronger responses (T-cell reactivity) to alpha-synuclein than controls. This response also appeared to be specific to Parkinson’s, as a group of Alzheimer’s disease patients showed a reactivity to alpha-synuclein similar to controls.

As noted in the first patient, these Parkinson’s patients also showed stronger reactivity responses closer to their diagnosis, which then weaned over time. In a group of 96 patients, about 40% of those diagnosed within 10 years had such strong responses, compared with 8.6% of those diagnosed more than 10 years ago.

An analysis of the pro-inflammatory molecules being produced in response to alpha-synuclein allowed the researchers to identify CD4-positive T-cells as the main players in this immune response. These immune cells do not directly neutralize a threat, instead they trigger other cells of the immune system to fight it.

In addition to a shorter time since diagnosis, older age and low doses of levodopa were also associated with increased responses to alpha-synuclein. Together, these three factors best identified patients with immune responses, though its sensitivity (or true positive rate) was still low.

“In conclusion, the present study confirms an association of [alpha-synuclein]-specific T cells and PD [Parkinson’s disease], and demonstrates that the presence of these T cells is a feature of preclinical and early motor PD,” the researchers wrote.

“This tells us that detection of T cell responses could help in the diagnosis of people at risk or in early stages of disease development, when many of the symptoms have not been detected yet,” Sette said.

These findings suggest that monitoring immune reactivity against alpha-synuclein may help to identify quickly those in need of preventive treatments that stop or delay nerve cell degeneration in earlier stages of disease.

Such treatments, like anti-TNF therapies, have already been associated with a lower incidence of Parkinson’s.

“Importantly, we could dream of a scenario where early interference with T cell responses could prevent the disease from manifesting itself or progressing,” Sette added.