Editors' ChoiceNeurodegenerative Disease

A QuICR test to diagnose Parkinson’s disease

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Science Translational Medicine  13 Jan 2021:
Vol. 13, Issue 576, eabg1761
DOI: 10.1126/scitranslmed.abg1761


Refined conditions permit rapid detection of proteopathic α-synuclein seeds in cerebrospinal fluid from patients with Parkinson’s disease.

Parkinson’s disease (PD) is one of several neurodegenerative diseases characterized by accumulation of fibrillar aggregates of α-synuclein (αSyn) protein, termed synucleinopathies. Although there are currently no definitive laboratory or imaging diagnostic tests for PD in clinical practice, advances in fluorescence-based protein amplification assays have enabled the detection of minute quantities of pathologically misfolded αSyn “seeds” in biological tissues based on the phenomenon that misfolded αSyn seeds trigger the polymerization of recombinant αSyn monomer protein in the reaction vessel. This approach has been used in multiple paradigms, including real-time quaking–induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), and showed high sensitivity and specificity for distinguishing cerebrospinal fluid (CSF) from patients with PD versus controls. One major limitation so far has been the long incubation time required to obtain results, ranging from 5–13 days. Now, Orru et al. report that optimization of reaction conditions can shorten this time to 1 to2 days while maintaining comparable sensitivity and specificity, a method they termed rapid real-time quaking–induced conversion or RT-QuICR.

Using CSF samples from the Bio-FIND database obtained from participants with moderate to advanced PD and healthy controls, the authors optimized conditions including αSyn substrate, reaction temperature, buffer composition, and shaking parameters to achieve 97% sensitivity and 87% specificity for a binary positive/negative decision after 48 hours of incubation, with high concordance compared with first-generation RT-QuIC and PMCA. Additional analyses using the participants clinical data demonstrated an inverse relationship between the lag time to develop fluorescence signal and questionnaire scores for REM sleep behavior disorder, a recognized prodromal condition that often progresses to PD. This suggests that RT-QuICR may be able to distinguish between clinical subtypes of synucleinopathy, presumably due to differences in seeding characteristics of the αSyn aggregates present in distinct patient groups.

As the authors note, additional studies are warranted to further define the diagnostic utility of RT-QuICR not only for prodromal, early, and advanced stages of PD, but for other synucleinopathies including PD dementia, dementia with Lewy bodies, and multiple system atrophy. Going forward, detailed characterization of the fluorescence signature obtainable from αSyn amplification assays will need to be carefully correlated with clinical and neuropathological features in order to maximize their utility for diagnostic purposes and to guide disease-modifying therapeutic trials for synucleinopathies.

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