Combining skin and olfactory α-synuclein RT-QuIC - towards biomarker-driven phenotyping in synucleinopathies

Abstract

Seeding assays, such as real-time quaking-induced conversion (RT-QuIC), are becoming commonly used in synucleinopathies to detect α-synuclein aggregates. Studies in Parkinson’s disease (PD) and isolated REM-sleep behavior disorder (iRBD) have shown a considerably lower sensitivity in the olfactory epithelium than in CSF or skin. To get an insight into α-synuclein (α-syn) distribution within the nervous system and reasons for low sensitivity, we compared RT-QuIC assessment of nasal brushings and skin biopsies in PD and iRBD patients and unaffected controls. We could show higher sensitivity of RT-QuIC in skin compared to nasal brushings and a higher deposition of misfolded α-synuclein across all sampled tissues in the iRBD cohort compared to PD, supporting the notion of RBD as a marker of a more malignant subtype of synucleinopathy. Interestingly, we identified a PD subgroup of patients with misfolded α-syn in the olfactory epithelium who did not show any dermal pathology, likely corresponding to the recently proposed brain-first subtype. Assaying α-syn of diverse origin (such as olfactory and peripheral nervous system) could allow better stratification of patients.

Seeding Activity of Skin Misfolded Tau as a Biomarker for Tauopathies

“…These ndings have been corroborated by independent research groups [39][40][41][42][43]. Motivated by these discoveries, we have expanded our inquiry to encompass the most prevalent neurodegenerative condition, AD, and other tauopathies.…”

Comparison of biospecimens for α‐synuclein seed amplification assays in Parkinson's disease: A systematic review and network meta‐analysis

“…The detected biofluids and peripheral tissues included CSF, skin, OM, saliva, GI tract, and NEs from plasma, serum and SMG. The characteristics of these studies are described in Table 1 [7–14, 16–49, 65]. The PRISMA flowchart is displayed in Figure 1.…”

“…In previous studies, CSF α‐syn SAAs displayed high sensitivity (84%–100%) and specificity (82.3%–100%) in the diagnosis of PD and other synucleinopathies [7–31]. With the advancement in detecting pathological α‐syn in biofluid, subsequent studies applied SAAs to detect α‐syn in various specimens such as skin (sensitivity 75%–100%; specificity 83%–100%) [11, 32–36], OM (sensitivity 46%–69%; specificity 90%–91%) [37–41], GI tract (sensitivity 10%–83%; specificity 75%–100%) [42–44], saliva (sensitivity 76%–84%; specificity 78%–94%) [45, 46], submandibular gland (SMG) (sensitivity 95%; specificity 100%) [26, 47], serum (sensitivity 94.6%; specificity 92.1%) [48] and neuron‐derived extracellular vesicles (NEs) from plasma (sensitivity 100%; specificity 100%) [49]. To date, some meta‐analyses have calculated the diagnostic efficacy of SAAs for PD, Lewy body dementia (DLB), multiple system atrophy (MSA) and prodromal α‐synucleinopathies.…”

Bidirectional relationship between olfaction and Parkinson’s disease

“…Influenza [5] and hospitalization due COVID-19 infection [31] have previously been identified as potential risk factors for PD. A recent study comparing α-synuclein seed amplification assays (SAA) of nasal brushings and skin biopsies found that the distribution of α-synuclein deposition is not uniform across PD patients [32]. The study supported a hypothesis based on two subtypes of PD: “body-first,” where pathogenic α-synuclein starts aggregation in the enteric nervous system and spreads to the brain, and “brain-first,” where it begins in the brain and then affects the rest of the body [33].…”