By Antonella Macerolo
For November 2020, we have selected: Wang Z. 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. Online ahead of print.
There is still an unmet need of early diagnosis of synucleinopathies including Parkinson disease (PD), Lewy body dementia (LBD), and multiple system atrophy (MSA). Indeed, a definite diagnosis is only post-mortem on brain biopsy available.
Our paper of the month is a retrospective and prospective diagnostic study focused on the development of sensitive and specific skin biomarkers for antemortem diagnosis of PD and other synucleinopathies.
The study analysed samples of 57 cadavers with synucleinopathies and 73 cadavers with nonsynucleinopathies as well as 20 skin samples of patients with PD and 21 controls without PD from three institutions.
The authors performed a total of 160 (130 abdominal, 30 scalp) autopsy skin samples from 130 cadavers, including 47 PD; 40 cadavers with other neurodegenerative [7 LBD, 3 MSA, 17 Alzheimer disease (AD), 8 progressive supranuclear palsy (PSP), and 5 with corticobasal degeneration (CBD)]; and 43 non-neurodegenerative control (NNC) cadavers. Moreover, 41 antemortem skin biopsies (20 PD and 21 controls) were analysed.
There were two techniques to analyse Skin αSynP seeding activity: Real-Time Quaking-Induced Conversion (RT-QuIC) and Protein Misfolding Cyclic Amplification (PMCA) assays.
RT-QuIC analysis of αSynP seeding activity in autopsy abdominal skin samples from 47 PD cadavers and 43 NNCs revealed 94% sensitivity and 98% specificity. As groups, RT-QuIC also yielded 93% sensitivity and 93% specificity among 57 cadavers with synucleinopathies (PD, LBD, and MSA) and 73 cadavers without synucleinopathies (AD, PSP, CBD, and NNCs).
PMCA assays showed 82% sensitivity and 96% specificity with autopsy abdominal skin samples from PD cadavers.
From posterior cervical and leg skin biopsy tissues from patients with PD and controls without PD, the sensitivity and specificity were 95% and 100%, respectively, for RT-QuIC and 80% and 90% for PMCA.
Overall, this study showed a statistically significant increase in αSynP seeding activity in individuals with PD and synucleinopathies compared with controls with tauopathies and non-neurodegenerative diseases.
Given that skin punch biopsy is relatively easy to perform and much less invasive, skin αSynP seeding activity may be a practical antemortem diagnostic biomarker for PD and synucleinopathies allowing clinicians to make an early differential diagnosis between synucleopathies and taupathies. Consequentially, this biomarker will improve the management of these patients.
Indeed, an easy skin test would aide in treatment planning, prognostication and
guiding enrollment in clinical trials. Of note, the authors highlighted some study limitations including a smaller number of cases with non-PD synucleinopathies (MSA,LBD) or tauopathies (PSP and CBD) compared to PD cases and controls and a limited number of skin biopsy samples. Therefore, further studies on larger numbers of cases are necessary to validate these results as well as follow-up neuropathological autopsies of each case are critical to validate the sensitivity and specificity of the biopsy skin samples.