Abstract
The clinical diagnosis of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), is challenging, especially at an early disease stage, due to the heterogeneous and often non-specific clinical manifestations. The discovery of reliable specific markers for synucleinopathies would consequently be of great aid to the diagnosis and management of these disorders. Real-Time Quaking-Induced Conversion (RT-QuIC) is an ultrasensitive technique that has been previously used to detect self-templating amyloidogenic proteins in the cerebrospinal fluid (CSF) and other biospecimens in prion disease and synucleinopathies. Using a wild-type recombinant α-synuclein as a substrate, we applied RT-QuIC to a large cohort of 439 CSF samples from clinically well-characterized, or post-mortem verified patients with parkinsonism or dementia. Of significance, we also studied patients with isolated REM sleep behavior disorder (iRBD) (n = 18) and pure autonomic failure (PAF) (n = 28), representing clinical syndromes that are often caused by a synucleinopathy, and may precede the appearance of parkinsonism or cognitive decline. The results show that our RT-QuIC assay can accurately detect α-synuclein seeding activity across the spectrum of Lewy Body (LB)-related disorders (LBD), including DLB, PD, iRBD, and PAF, with an overall sensitivity of 95.3%. In contrast, all but two patients with MSA showed no α-synuclein seeding activity in the applied experimental setting. The analysis of the fluorescence response reflecting the amount of α-synuclein seeds revealed no significant differences between the clinical syndromes associated with LB pathology. Finally, the assay demonstrated 98% specificity in a neuropathological cohort of 101 cases lacking LB pathology. In conclusion, α-synuclein RT-QuIC provides an accurate marker of synucleinopathies linked to LB pathology and may have a pivotal role in the early discrimination and management of affected patients. The finding of no α-synuclein seeding activity in MSA seems to support the current view that MSA and LBD are associated with different conformational strains of α-synuclein.
Highlights
Synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are neurodegenerative diseases characterized by the intracellular accumulation of toxic α-synuclein1 3 Vol.:(0123456789)Acta Neuropathologica (2020) 140:49–62(α-Syn) aggregates [62, 67]
In the neuropathologically verified cohort (Fig. 2a), the cerebrospinal fluid (CSF) α-Syn Real-Time Quaking-Induced Conversion (RT-QuIC) yielded an overall specificity of 98.0% and a sensitivity of 95.2% (100% in definite DLB), whereas the specificity calculated on the clinical controls was 98.4% (61/62 negatives), or 97.6% (40/41 negatives) when only the subgroup of controls age-matched (64.0 ± 6.2 years) with the isolated REM sleep behavior disorder (iRBD), pure/isolated autonomic failure (PAF), and PD groups was considered
More details about the patients who underwent phenoconversion from prodromic syndromes to MSA, PD, and DLB are shown in Supplementary Table 5, online resource. These results indicate that RT-QuIC can reliably detect pathogenic species of α-Syn in the CSF of patients affected by PAF and iRBD, and can discriminate them from RBD associated with narcolepsy or MSA
Summary
Synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are neurodegenerative diseases characterized by the intracellular accumulation of toxic α-synuclein1 3 Vol.:(0123456789)Acta Neuropathologica (2020) 140:49–62(α-Syn) aggregates [62, 67]. Given its capacity of identifying misfolded forms of prion protein (PrP) from Creutzfeldt–Jakob disease (CJD) CSF with a specificity of 100% and a sensitivity of 95–98%, RT-QuIC has already been included in the diagnostic criteria for the clinical diagnosis of sporadic(s) CJD, the most common human prion disease [70] By showing that this assay may accurately discriminate between LBD and other parkinsonisms or dementias unrelated to α-Syn, more recent studies strongly suggested that CSF RT-QuIC can be applied successfully to synucleinopathies [9, 20, 28, 55, 64], especially to those associated with LB pathology. We tested for the first time a significant number of patients affected by iRBD and PAF
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
