Skin α-Synuclein Aggregation Seeding Activity: A Possible Biomarker for Parkinson Disease

This retrospective and prospective diagnostic study evaluated autopsy and biopsy skin samples from neuropathologically and clinically diagnosed patients with Parkinson Disease and controls without PD.

Skin α-synuclein (αSynP) seeding activity may allow for a better diagnosis of synucleinopathies. These findings, from a retrospective and prospective diagnostic study, were published in JAMA Neurology.

Skin samples were collected from the abdomen (n=130: Parkinson disease [PD; n=47], neurodegenerative diseases [n=40], tauopathies [n=20], and control [n=43] cadavers) and scalp (n=30: PD [n=20] and control [n=10] cadavers) at autopsy and from the leg or posterior cervical region (n=41: PD [n=21] and control [n=20] patients) by biopsy. All diagnoses of cadavers were confirmed by neuropathological examination of brain tissue during autopsy and for living patients, were confirmed by the Movement Disorder Society Clinical Criteria for PD. Samples were analyzed by real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) assays and by microscopy staining.

Postmortem skin samples were obtained from patients who were 60.7% men aged 76.8 (standard deviation [SD], 10.1) years at death. Antemortem skin samples were obtained from 66% men aged 65.3 (SD, 9.2) years at biopsy.

Phosphorylated αSynP presence was first confirmed through microscopy among samples, in which activity was detected at 10-5 serially diluted PD samples. No seeding activity was observed among non-PD samples at 10-3 to 10-6 dilutions.

The average maximal Thioflavin T fluorescence for abdominal skin was 82.6% (SD, 22.5%) among PD cadaver samples compared with 4.5% (SD, 0.7%) among non-PD samples (P <.001). In a blinded assay of cadaver scalp samples, PD was detected by RT-QuIC with a sensitivity of 100% (95% CI, 91%-100%) and specificity of 100% (95% CI, 87%-100%).

αSynP seeding activity was detected by PMCA among 83% of PD abdominal samples and 0% of the control samples; indicating an overall sensitivity of 83% (95% CI, 74%-92%) and specificity of 100% (95% CI, 84%-100%) for the PMCA assay.

Aggregated seeding activity was observed among samples from individuals with neurodegenerative diseases (multiple system atrophy and Lewy body dementia) with sensitivities of 67% (95% CI, 42%-92%) and 100% (95% CI, 94%-100%), respectively. The αSynP activity was observed among 5 of the 17 samples from cadavers with Alzheimer’s disease and none of the samples with progressive supranuclear palsy or corticobasal degeneration.

The RT-QuIC assay could differentiate between synucleinopathies from nonsynucleinopathies with an area under the receiver operating characteristic curve (AUC) of 0.9696 (95% CI, 0.9431-0.9961; P <.001).

Among samples obtained at biopsy, αSynP seeding activity could be observed in tissues obtained from the cervical sites, but leg biopsies exhibited weak activity. The maximum response of biopsied samples among patients with PD was 56.6% (SD, 19.2%) compared with 8.3% (SD, 4.4%) among control individuals (P <.001). Similarly, the PMCA assay successfully differentiated between PD and controls with an AUC of 0.9250 (95% CI, 0.8001-1.0000; P <.001).

The major limitation of this study was the imbalance of sample sizes. Further study among more individuals is needed.

This study was the first to detect evidence of αSynP aggregation seeding activity among skin samples from individuals with synucleinopathies and may be an effective biomarker for diagnoses.


Wang Z, Becker K, Donadio V, et al. Skin α-synuclein aggregation seeding activity as a novel biomarker for Parkinson disease. JAMA Neurol. 2020;e203311. doi:10.1001/jamaneurol.2020.3311.