OM, blood and urine likely contain key specific biomarkers of PD, MSA and DLB detectable
with specialized ultrasensitive techniques, perhaps in the early disease stages.
Therefore, by combining for the first time the RT-QuIC, Simoa SR-X, ELISA and NTA
analyses of OM, blood and urine and by exploiting TEM and solution/solid-state NMR
analyses, the investigators will attempt at identifying specific fingerprints of
alpha-synucleinopathies usefult to stratify living patients. Supported by statistical
analyses and customized machine learning algorithms that will combine clinical (including
the analysis of olfactory functions) and experimental data, the investigators project
could significantly impact the clinical diagnosis of alpha-synucleinopathies.
The investigators project will combine innovative and ultrasensitive diagnostic
approaches to evaluate whether OM, blood and urine might serve as non-invasive and
easy-to-get samples for biomarkers detection, allowing recognition and stratification of
alpha-synucleinopathies. Multidisciplinary collaboration between researchers with
specific and complementary skills is required to achieve the goals of the project and to
have an impact on future scientific use, clinical applications and wellbeing of patients
suffering from these diseases. The investigators project will combine cutting-edge
technologies to improve the power of multidimensional biomarker patterns for the clinical
diagnosis of PD, MSA and DLB by using easily and periodically collectible tissues. In
particular, the investigators will determine unique insights into several key aspects of
alpha-synucleinopathies by assessing whether: (1) the OM, blood and urine of PD, MSA and
DLB patients contain peripheral maS exploitable to improve the patiens clinical
diagnosis/recognition; (2) the peripheral distribution of maS in OM, blood and urine
differs between diseases or even among tissues collected from the same patient; (3) the
biochemical, morphological and structural features of the RT-QuIC generated aggregates
enable discrimination of these diseases; (4) the levels of some key proteins (e.g. NfL,
alpha-synuclein, synapsin-3) or structures (e.g. EVs), known to be altered in the blood,
are also modified in the OM or urine and allow disease recognition, especially when
analyzed in combination with the other ultrasensitive assays; (5) the olfactory
impairment can be exploited as indicator of evolving alpha-synucleinopathy and whether it
correlates with maS accumulation in OM. The investigators research is transformative and
rapidly translatable into clinical practice. The possibility to accurately identify PD,
MSA and DLB will bring important advancements in patient selection for emerging
pharmacological treatments and clinical trials (better care for people). In addition, the
possibility to periodically collect OM, blood and urine samples could consent to monitor
disease progression and to evaluate the therapeutic effects in patients under
pharmacological treatments. The Investigators findings could also contribute to further
investigating whether PD, MSA and DLB are caused by distinct conformers of maS and verify
if these latter possess differential tropism for peripheral tissues, eventually unveiling
different molecular pathways involved in their pathogenesis. Finally, the investigators
approach could have a major impact on counseling and prevention strategies for patients
in the prodromal stages of alpha-synucleinopathies, representing a key goal on the path
to disease-modifying and neuroprotective therapies before full-blown phenotypes have
manifested.