Synucleinopathies are characterized by the abnormal misfolding and aggregation of α-synuclein. The mechanism of seeding, in which α-synuclein fibrils recruit soluble monomers that form visible aggregates, is an important part of the pathology of synucleinopathies. This fibrils have been detected in several tissued, including cerebrospinal fluid (CSF) and skin, through the amplification of abnormal α-synuclein aggregation using real-time quaking-induced conversion (RT-QuIC). However, there are no available assays to assess α-synuclein fibrils in the serum.
In a recently published study, Okuzumi et al. developed a modified RT-QuIC assay combined with immunoprecipitation to concentrate α-synuclein seeds from serum (IP/RT-QuIC assay). They further validated its usefulness as a diagnostic marker and evaluated if fibril morphology could discriminate among different synucleinopathies.
An initial main cohort included 270 patients with synucleinopathy (221 with Parkinson’s disease (PD), 39 with multiple systems atrophy (MSA) and 10 with dementia with Lewy bodies (DLB)), 9 with RBD, 30 with progressive supranuclear palsy (PSP), 25 with Alzheimer’s disease (AD), 17 with Parkin-linked PD (PRKN) and 128 non-neurodegenerative controls. A second internal cohort included 40 patients with synucleinopathy (34 PD and 6 MSA) and 9 non-neurodegenerative controls. Almost all participants’ diagnoses were based on clinicoradiological features without neuropathological confirmation.
Sensitivity and specificity were good for differentiating patients with PD from controls (94.6% and 92.1%, respectively, AUC 0.96) and patients with DLB from controls (96.4% and 92.2%, respectively, AUC 0.90) but more modest for differentiating patients with MSA from controls (64.1% and 11.0%, respectively, AUC 0.64). Analysis in an external cohort of 35 patients with synucleinopathies (20 PD and 15 MSA), 20 non-neurodegenerative controls and 6 patients with tauopathy as non-synucleinopathy controls produced relatively similar results (AUC 0.86 for PD and 0.80 for MSA). Interestingly, α-synuclein seeds were found in patients with AD and PSP but not in PRKN patients.
Transmission electron microscopy analysis of fibrils allowed to differentiate the morphology of PD/DLB seeds (paired filaments or bundled multiple filaments, with narrower width) from MSA seeds (twisted filaments and straight filaments). Moreover, there were no structural differences between serum-derived and CSF-derived fibrils in patients with PD or MSA.
Detection of α-synuclein seeds amplified from sera by IP/RT-QuIC appears to be a good biomarker to diagnose synucleinopathies and the structures of the amplified fibrils differed according to phenotype.
Key Points:
- Amplification assays have the potential to be a high-performance biomarker to diagnose synucleinopathies.
- Sensitivity and specificity were better in differentiating PD or DLB than MSA from controls.
- Amplified PD/DLB fibrils could be distinguished for MSA fibrils due to disease-specific structures assessed with transmission electron microscopy.
References:
- Okuzumi A, Hatano T, Matsumoto G, et al. Propagative α-synuclein seeds as serum biomarkers for synucleinopathies. Nat Med. 2023;29(6):1448-1455. doi:10.1038/s41591-023-02358-9 pubmed.ncbi.nlm.nih.gov/37248302/
Names of Co-author(s):
Michelangelo Mancuso, Neurological Institute, University of Pisa
Kailash Bhatia, UCL Queen Square Institute of Neurology, University College London
Publish on behalf of the Coordinating Panel on Rare Neurological Disease