Conference Agenda

Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), collectively known as alpha-synucleinopathies, are characterized by the deposition of misfolded alpha-synuclein in the central nervous system (Alafuzoff et al, 2017). Achieving accurate and early clinical diagnosis of these diseases remains challenging, emphasizing the crucial need for specific and easily accessible diagnostic biomarkers. Seed amplification assays (SAAs) have become increasingly used in alpha-synucleinopathies, enabling the detection of pathological alpha-synuclein in various tissues, including cerebrospinal fluid (CSF), olfactory mucosa (OM) and skin (Bellomo et al, 2022). Among these tissues, the OM holds promise as a diagnostic tool, as it can be easily and periodically collected with non-invasive procedures. Furthermore, several studies have successfully applied SAAs to the analysis of OM samples obtained from patients with PD, MSA, DLB, as well as individuals with isolated REM-sleep behavior disorder (iRBD) (De Luca et al, 2019; Bargar et al, 2021; Perra et al, 2021; Stefani et al, 2021). iRBD is recognized as an early non-motor manifestation of alpha-synucleinopathies, with over 80% of iRBD patients likely to progress to PD, followed by DLB (Galbiati et al, 2019). The detection of pathological alpha-synuclein in the OM and CSF of iRBD individuals (Stefani et al, 2021; Concha-Marambio L et al, 2023; Kuzkina et al, 2023) offers the potential to identify subjects at higher risk of developing alpha-synucleinopathies and initiating early interventions, when available. Thus, OM analysis using SAA shows great potential as a non-invasive and accessible tool for the clinical and early diagnosis of alpha-synucleinopathies. However, further research efforts are needed to refine and validate this approach, ultimately contributing to early detection, accurate diagnosis and improved management of these devastating neurodegenerative disorders.

The diagnosis of Parkinson's disease (PD) is often prone to inaccuracies because the clinical manifestations on which diagnosis is based can overlap with those of other degenerative disorders. Moreover, symptoms occur when neuronal loss is in a very advanced stage and the treatments are ineffective.

Therefore, the study of mechanisms of disease development is crucial for the identification of early biomarkers that are PD specific. In vivo molecular imaging has so far played a key role in this assessment throughout tomographic techniques as PET and SPECT that take advantage of radiopharmaceuticals specific for different targets including neurotransmission systems and neuroinflammation.

Here we describe all the improvements obtained in the last few years in PD diagnosis using Nuclear Medicine imaging applied to the identification of new potential biomarkers of disease. In particular, we explored different animal models of PD and advanced analysis techniques for biomarkers validation.

The recent development of high sensitivity detection techniques enable the evaluation of plasma markers in blood potentially able to quantify in vivo alpha-synuclein, neuronal and gliagl pathology with fair correlation with CSF-based analyses. The role of such markers, including NfL, GFAP, alpha-synucelin, p-tau are still debated in the clinical spectrum of alpha-synucleinopathies includin parkinson's disase, dementia with lewy bodies and multiple system atrophy. Furthermore, there is an urgent need of an application of such markers In prodromal phases of neurodegeneration, including idiopathic REM sleep behavioral disorders. The assessment of prodromal neurodegeneration using advanced dopaminergic analyses and digital markers might enable the stratification of subjects at different risk for neurodegeneration and possible relationship with biological markers.

Parkinson’s disease (PD) has been recently redefined as a multisystem disorder. The search of a peripheral biomarker for PD is crucial for diagnosis in alive patients and improves patient stratification for clinical trials. Recently, we identified α-synuclein oligomers in skin biopsy, an easily and accessible biosample, and demonstrated that these aggregates are a reliable biomarker for distinguishing PD from healthy controls. Thus, this study looks at an unexplored cohort of GBA-PD (n=29) and aims to: i) understand if α-synuclein oligomers accumulation is a common peripheral pathway in PD pathology, ii) investigate whether GCase expression changes in synaptic terminals of autonomic structures in skin biopsies, and iii) unravel indicators that could differentiate patients with specific GBA mutations. PLA score can distinguish GBA-PD patients from age- and sex-matched control subjects (P<0.0001). We obtained a high sensitivity (92%) and a good specificity (85%). Notably, no difference was found between GBA-PD patients and iPD, suggesting a common pathological pathway. Furthermore, a significant increase of the synaptic density was observed in GBA-PD compared to both iPD and controls. After controlling in multivariate regression analysis for the effect of age, sex, disease duration, UPDRS-III scores, and Hoehn and Yahr stage, the effect of genetic status was confirmed as a predictor for synaptic density (beta=0.645, 95% CI 0.298-0.752, p<0.001). Interestingly, GBA-PD carrying the N409S mutation displayed higher synaptic density compared with L483P-mutated patients, whereas α-synuclein oligomers did not differ between these groups. All together, this work reinforces the value of PLA score as a reliable biomarker for PD and the increase of the synaptic density could mark the milder form of GBA-PD.

This work was supported by “Fondazione Grigioni per il Morbo di Parkinson” (Italian “5 x 1000” funding).