Alpha-synuclein seeds in olfactory mucosa of patients with isolated rapid-eye-movement sleep behaviour disorder

Abstract

Isolated REM sleep behaviour disorder is an early-stage alpha-synucleinopathy in most, if not all, affected subjects. Detection of pathological alpha-synuclein in peripheral tissues of isolated REM sleep behaviour disorder patients may identify those progressing to Parkinson's disease, dementia with Lewy bodies or multiple system atrophy, with the ultimate goal of testing preventive therapies. Real-Time Quaking-Induced Conversion provided evidence of alpha-synuclein seeding activity in cerebrospinal fluid and olfactory mucosa of patients with alpha-synucleinopathies. Aim of this study was to explore Real-Time Quaking-Induced Conversion detection of alpha-synuclein aggregates in olfactory mucosa of large cohort of subjects with isolated REM sleep behavior disorder compared to Parkinson's disease and controls. This prospective bicentric case-control study was performed between October 2017 and December 2018 at the Medical University of Innsbruck, Austria, and the Hospital Clinic de Barcelona, Spain. Olfactory mucosa samples obtained by nasal swab in 63 patients with isolated REM sleep behavior disorder, 31 matched Parkinson's disease patients and 59 matched controls were analysed by alpha-synuclein Real-Time Quaking-Induced Conversion in a blinded fashion at the University of Verona, Italy. Median age of isolated REM sleep behavior disorder patients was 70 years, 85.7% were male. All participants were tested for smell, autonomic, cognitive and motor functions. Olfactory mucosa was alpha-synuclein Real-Time Quaking-Induced Conversion positive in 44.4% isolated REM sleep behavior disorder patients, 41.9% Parkinson's disease and 10.2% controls. While the sensitivity for isolated REM sleep behavior disorder plus Parkinson's disease versus controls was 40.9%, specificity was high (89.8%). Among isolated REM sleep behavior disorder patients with positive alpha-synuclein Real-Time Quaking-Induced Conversion, 78.6% had olfactory dysfunction as compared to 21.4% with negative alpha-synuclein Real-Time Quaking-Induced Conversion, p<0.001. The extent of olfactory dysfunction was more severe in positive than in negative alpha-synuclein Real-Time Quaking-Induced Conversion olfactory mucosa isolated REM sleep behavior disorder patients (p<0.001). We provide evidence that alpha-synuclein Real-Time Quaking-Induced Conversion assay enables the molecular detection of neuronal alpha-synuclein aggregates in olfactory mucosa of patients with isolated REM sleep behavior disorder and Parkinson's disease. Although the overall sensitivity was moderate in this study, nasal swabbing is attractive as simple, non-invasive test, with a potential of use as screening test to identify subjects in the prodromal stages of alpha-synucleinopathies. Further studies are needed to enhance sensitivity, and better understand the temporal dynamics of alpha-synuclein seeding in the olfactory mucosa and spreading to other brain areas during the progression from isolated REM sleep behavior disorder to overt alpha-synucleinopathy.

Alpha-synuclein seeds in olfactory mucosa and cerebrospinal fluid of patients with dementia with Lewy bodies

“…Compared to the previously reported RT-QuIC results in OM of patients with PD and MSA, and iRBD, the RT-QuIC sensitivity in DLB is apparently higher. 20 , 21 This finding might be related to the detection of α-syn deposition in the olfactory neuroepithelium of DLB individuals. 34 …”

“…We performed α-syn RT-QuIC assay as reported previously for CSF and OM except where indicated. 12 , 21 …”

“… 20 More recently, we showed that RT-QuIC assay is positive in OM of 44.4% of patients with iRBD. 21 However, at present no data are available on α-syn RT-QuIC testing in OM samples from patients with DLB.…”

Soluble Triggering Receptor Expressed on Myeloid Cells 2 From Cerebrospinal Fluid in Sleep Disorders Related to Parkinson’s Disease

“…Another key factor related to sleep disorders is α-syn ( Dolores et al, 2016 ). Abnormal α-syn, normally localized to presynaptic terminals of neurons, forms pathological amyloid aggregates deposited in multiple brain regions and induces abnormal neurotransmitter release, such as sleep-related interleukins ( Dolores et al, 2016 ; Doppler et al, 2017 ; Garrido et al, 2020 ; Stefani et al, 2021 ). Phosphorylated α-syn deposits in the colon, saliva, glands, and skin can be used to differentiate subjects with isolated rapid eye movement sleep behavior disorder (RBD) from controls with 24–89% sensitivity and 78–100% specificity ( Doppler et al, 2017 ).…”

“…The regulation of sleep depends on the comprehensive functions of multiple brain regions and a series of neurotransmitters, including dopamine, 5-hydroxytryptamine, norepinephrine, and other PD-related molecules ( Alexandre et al, 2006 ; Meles et al, 2017 ; Oh et al, 2018 ; Hayat et al, 2020 ). The mechanism of sleep disorders in PD patients may involve the loss of DA neurons and the deposition of α-syn in the brain stem, basal ganglia and hypothalamus ( Dolores et al, 2016 ; Doppler et al, 2017 ; Garrido et al, 2020 ; Stefani et al, 2021 ). It has been suggested that sleep disorders have a certain value for the prediction and diagnosis of PD ( Barasa et al, 2021 ).…”