Measuring alpha-synuclein in skin, nose could detect Parkinson’s

Nasal swabs, skin biopsies also may distinguish disease subtypes, study finds

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Testing for the presence of misfolded alpha-synuclein — the protein that toxically builds up in Parkinson’s disease — in both the nasal passages and skin samples could serve as a sensitive way to detect Parkinson’s early pathology and distinguish its subtypes, according to a small recent study.

By using both tests, the scientists identified a few Parkinson’s patients who had alpha-synuclein buildup only in the nasal passages, but not the skin.  Researchers believe that reflects a so-called “brain first” type of Parkinson’s in which symptoms start in the brain or olfactory system and only spread later to the rest of the nervous system.

“Assaying [alpha-synuclein] of diverse origins … could increase diagnostic accuracy and allow better stratification [classification] of patients,” the authors wrote.

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The study, “Combining skin and olfactory α-synuclein seed amplification assays (SAA) towards biomarker-driven phenotyping in synucleinopathies,” was published in npj Parkinson’s Disease.

The toxic clumps of alpha-synuclein that characterize Parkinson’s can be found in the central nervous system (CNS) — the brain and spinal cord — as well as outside those regions in the peripheral nervous system.

Measuring alpha-synuclein aggregation via a test called a seed amplification assay (SAA) can be used to help diagnose the neurodegenerative disease. This can be done in a variety of tissues, although the diagnostic utility of such tests is not clearly established.

For example, given the fact that a diminished sense of smell (hyposmia) is a common early Parkinson’s symptom, it is possible that cells from the nasal passages (olfactory epithelium) could be used for SAA testing. However, previous studies found that the test wasn’t very sensitive at doing so.

Now, the researchers set out to investigate the distribution of alpha-synuclein aggregates in the nasal passages and skin of 27 Parkinson’s patients, 30 healthy adults (a control group), and 18 people with idiopathic REM sleep behavior disorder (iRBD), a sleep disorder that’s commonly an early, or prodromal, sign of Parkinson’s.

Swabs and biopsies

Participants underwent a nasal swab to obtain cells from the olfactory epithelium, as well as a skin biopsy, which were used to perform the SAA test. Of note, because of its proximity to nerves of the CNS, the olfactory epithelium is considered a CNS tissue, whereas the skin served as a peripheral tissue.

The test was found to be less sensitive at measuring alpha-synuclein aggregation in nasal cells, which the researchers believe was related to technical issues that should be addressed in future studies.

Overall, iRBD patients showed a higher burden of alpha-synuclein aggregation across both the nasal passages and the skin relative to Parkinson’s patients. In the nose, misfolded alpha-synuclein was detected in 48% of Parkinson’s patients, 67% of iRBD patients, and 10% of controls, whereas the the toxic protein was found in the skin of all iRBD patients and 79% of Parkinson’s patients.

A higher overall alpha-synuclein burden across the nose and skin was linked to worse smell function in both patient groups, as well as RBD and gastrointestinal problems in the Parkinson’s group.

Notably, for a small subset of three Parkinson’s patients, misfolded alpha-synculein was found only in nasal cells, but not skin cells.

These patients had a lower burden of non-motor symptoms than the rest of the Parkinson’s patients, and none reported signs of RBD or gastrointestinal problems.

‘Body first’ versus ‘brain first’

Researchers believe that finding overall supports a recent model describing two types of Parkinson’s. “Body first” Parkinson’s is marked by alpha-synuclein aggregation that starts in the peripheral nervous system and spreads later to the brain, with the earliest symptoms being non-motor. In “brain first” disease, the process is reversed, starting in the brain or olfactory tissues, with early motor symptoms.

In patients where aggregates are found in the nasal passages only, the pathology is likely “brain first” and hasn’t yet spread throughout the body, the team noted. On the other hand, iRBD, is likely a prodromal stage of the body-first type, the scientists added.

“Taken together, although nasal SAA does not allow subtyping the patients on its own, it might become feasible in combination with a skin biopsy if confirmed in a larger cohort,” the researchers wrote.

Three people in the healthy control group tested positive for alpha-synuclein in the nasal passages. All three were found to be anosmic, or lacking a sense of smell, and one screened positive for iRBD.

While these symptoms could reflect prodromal Parkinson’s, these findings alone are not sufficient to diagnose those patients, the researchers noted.

Detect Parkinson’s subtypes more precisely

Altogether, the researchers believe that a combination of biomarkers, including skin biopsies and nasal swabs, “would not only result in more efficient [alpha-synuclein] detection but could lead to more precise … subtyping of patients.”

Larger and more comprehensive studies are needed to “shed more light on the usefulness of combined sampling for clinical practice and subtyping of [Parkinson’s],” the scientists concluded.