Patients with isolated REM-sleep behavior disorder have elevated levels of alpha-synuclein aggregates in stool

Abstract

Misfolded and aggregated α-synuclein is a neuropathological hallmark of Parkinson’s disease (PD). Thus, α-synuclein aggregates are regarded as a biomarker for the development of diagnostic assays. Quantification of α-synuclein aggregates in body fluids is challenging, and requires highly sensitive and specific assays. Recent studies suggest that α-synuclein aggregates may be shed into stool. We used surface-based fluorescence intensity distribution analysis (sFIDA) to detect and quantify single particles of α-synuclein aggregates in stool of 94 PD patients, 72 isolated rapid eye movement sleep behavior disorder (iRBD) patients, and 51 healthy controls. We measured significantly elevated concentrations of α-synuclein aggregates in stool of iRBD patients versus those of controls (p = 0.024) or PD patients (p < 0.001). Our results show that α-synuclein aggregates are excreted in stool and can be measured using the sFIDA assay, which could support the diagnosis of prodromal synucleinopathies.

Disrupted‐in‐schizophrenia 1 protein aggregates in cerebrospinal fluid are elevated in patients with first‐episode psychosis

“…A limitation is that these protein aggregates were in the femtomolar range and require highly sensitive methods such as sFIDA which are able to count single protein aggregates. sFIDA has been previously developed to exploit pathological oligomers and aggregates as a biomarker for neurodegeneration 12,14–16 . sFIDA has the capacity to measure single particles through fluorescence imaging, thereby making it possible to determine the size of aggregates larger than ~200 nm.…”

“…sFIDA has been previously developed to exploit pathological oligomers and aggregates as a biomarker for neurodegeneration. 12,[14][15][16] sFIDA has the capacity to measure single particles through fluorescence imaging, thereby making it possible to determine the size of aggregates larger than $200 nm. However, due to the constraints posed by diffraction-limited optics, it is not feasible to directly analyze the size distribution of subresolution particles, including small protein aggregates and oligomers.…”

“…The method has been applied more recently to quantify α‐synuclein and Tau oligomers in CSF of patients diagnosed with tauopathies and synucleinopathies 14 . Furthermore, sFIDA has been employed to determine levels of α‐synuclein aggregates in stool samples obtained from patients with idiopathic rapid eye movement sleep disorder and Parkinson disease, 15 as well as Aβ aggregate levels in ex vivo brain samples from patients with Alzheimer disease 16 …”

“…The method has been applied more recently to quantify α-synuclein and Tau oligomers in CSF of patients diagnosed with tauopathies and synucleinopathies. 14 Furthermore, sFIDA has been employed to determine levels of α-synuclein aggregates in stool samples obtained from patients with idiopathic rapid eye movement sleep disorder and Parkinson disease, 15 as well as Aβ aggregate levels in ex vivo brain samples from patients with Alzheimer disease. 16 The main aim of our study was to use sFIDA to quantitatively compare DISC1 protein aggregates in CSF between patients with FEP versus HCs and to explore the presence and the potential diagnostic significance of DISC1 aggregate detection for clinical use.…”

Evaluation of α‐synuclein in CNS‐originating extracellular vesicles for Parkinsonian disorders: A systematic review and meta‐analysis

“…Ultimately, this meta-analysis highlights the necessity for standardized blood collection and EV isolation techniques/methodologies and underscores the importance of exploring additional biomarkers using the same approach such as Clusterin 19 or a specific microRNA such as Linc-POU3F3, 41 as well as considering other biofluids such as cerebrospinal fluid, 62 urine, 63 skin 64 stool 65 or tears. 66 It also suggests the exploration of other techniques for biomarker discovery such as protein seeding assays, 20,67 measurements of neurophysiological factors 68 or kinematic fluctuations, 69 among other potential approaches.…”