Parkinson's disease (PD) is a synucleinopathy and the most common neurodegenerative disease involving disabling motor deficits. PD is clinically heterogeneous; motor symptoms may be accompanied by nonmotor symptoms such as cognitive impairment. Many molecular processes may underlie the phenotypic heterogeneity of PD, among which synaptic and axonal degeneration, neuroinflammation, and the co-occurrence of different proteinopathies. The definition of robust biomarkers that reflect distinct pathophysiological pathways taking place in PD may favor the selection of more homogeneous cohorts of patients in clinical trials, thus increasing the chance of success of a targeted disease-modifying therapy. The possibility of measuring these markers in biological matrices suitable for repeated sampling could provide objective measures of the effectiveness of a therapeutic approach. In this proposal we will combine the expertise of three different Italian medical research centers to establish a molecular profile of PD based on biomarkers reflecting different biological pathways, in different biological matrices, by applying immunoassays, proximity extension assays (PEA) and seed amplification assays (SAA). Two easily accessible biological matrices, i.e., blood plasma and olfactory mucosa (OM), has been/will be collected in each center for PD patients, controls and patients affected by Alzheimer's disease (AD) as other neurodegenerative disease controls. OM will be collected by a non-invasive procedure known as nasal brushing which is already operational and standardized among the three participating centers. The project will include both a prospective and retrospective cohort composed of 200 PD patients, 100 controls and 40 AD. All PD patients that will be recruited will undergo a thorough clinical and neuropsychological evaluation. The control group will be constituted by healthy volunteers as well as by cognitively unimpaired subjects with subjective memory complaints or patients affected by minor neurological symptoms (i.e., headache, peripheral neuropathy, etc.). The above-mentioned clinical information has been already collected for the retrospective cohort. Plasma amyloid-ß (Aß) 42/Aß40 ratio and phosphorylated at threonine 181 tau (p-tau) will be measured with the Lumipulse automated platform for all collected plasma samples. In a subset of 80 PD patients and 40 AD the CSF levels of this markers have been already measured and will be used to assess the robustness of these markers as well as the correlation between their CSF and plasma levels. SAA will be applied in OM for the detection of misfolded a-synuclein. Phosphorylated a-synuclein (p-a-syn) will be measured in a subset of PD patients and controls to compare the diagnostic accuracy of p-a-syn in skin biopsies and a-synuclein seeding activity in OM. In a subset of 30 PD and 30 AD/CTRL with paired OM and CSF samples the CSF SAA protocol of Amprion Inc. will be applied to verify the concordance of the results between CSF and OM. CNBP will be specifically responsible for collecting clinical and biomarker data from the three centers and for assessing their relationships. For the sake of measurements uniformity, the PEA analyses will be instead centralized at Olink (Uppsala, Sweden), at which the Olink Explore 384 Inflammation and Olink Explore 384 Neurology panels will be measured in all plasma samples.
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clinical or CSF-based diagnosis
Timeframe: 3 months
Biological signature of Parkinson's disease
Timeframe: 12 months