Clinical trial NCT06846658: Exploring the Olfactory Mucosa, Blood and Urine for the Identification of Early Biomarkers of Parkinson's Disease, Atypical Parkinsonisms and Neurocognitive Disorders Due to Lewy Body Disease
Official title: Exploring the Olfactory Mucosa, Blood and Urine for the Identification of Early Biomarkers of Parkinson's Disease, Atypical Parkinsonisms and Neurocognitive Disorders Due to Lewy Body Disease
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Parkinson Disease
MSA - Multiple System Atrophy
Lewy Body Dementia (LBD)
Neurodegenerative Disease
Healthy Subjects (HS)
Keywords: Parkinson&#39;s disease (PD)
multiple system atrophy (MSA)
dementia with Lewy bodies (DLB)
misfolded alpha-synuclein
new biomarkers
peripheral tissues
Real-Time Quaking-Induced Conversion (RT-QuIC)
single-molecule array (Simoa)
circulating neurofilament light chain (NfL)
Nanoparticle Tracking Analysis (NTA)
blood-derived extracellular vesicles (EVs)
multi-omics analyses
transmission electron microscopy (TEM) and protein-NMR
protein misfolding
early diagnosis
Lead sponsor: Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
Sponsor class: OTHER
First posted: 2025-02-26
Enrollment: 180
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: PD (n=20), MSA (n=20), DLB (n=20), OND (n=10, including acquired and hereditary ataxic syndrome with known etiology, progressive supranuclear palsy, corticobasal degeneration, and motor neuron disease) and HS (n=10).

Brief summary: Clinical diagnosis of Parkinson's disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) is challenging, especially in the early stages. Each disease is associated with distinct conformers of misfolded alpha-synuclein (maS) which form typical protein aggregates in the brain and represent key disease biomarkers. Thus, detection and characterization of intracerebral maS aggregates allow a definite diagnosis. The recent development of ultrasensitive assays enabled the detection of maS and other potential new biomarkers in peripheral tissues, although with several limitations. Here, the investigators propose to combine the expertise of leading and young researchers in the field of neurology, structural and molecular biology, biophysics and machine learning to perform ultrasensitive and multi-omics analyses of olfactory mucosa (OM), blood and urine of PD, MSA and DLB patients for detecting and characterizing key peripheral biomarkers allowing accurate disease recognition.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* PD (Postuma et al., 2015), MSA (Palma et al., 2018), DLB (McKeith et al., 2017), OND including acquired and hereditary ataxic syndrome with known etiology, progressive supranuclear palsy, corticobasal degeneration, and motor neuron disease.

Exclusion Criteria:

* na

Primary outcomes:
measure: Identify a predictive model for the diagnosis of PD, MSA and DLB
timeFrame: 3 years
Secondary outcomes:
measure: Analysis of olfactory functions.
timeFrame: 12 months
measure: Evaluation of RT-QuIC accuracy in detecting maS in OM, blood- and urine-derived EVs
timeFrame: 21 months
measure: Ultrasensitive detection and measurement of known or potential new biomarkers in OM, blood and urine of enrolled patients by Simoa SR-X.
timeFrame: 18 months
measure: Ultrasensitive detection and measurement of known or potential new biomarkers in OM, blood and urine of enrolled patients by ELISA.
timeFrame: 18 months
measure: NTA Nano-Sight NS300 analysis of concentration and size of EVs circulating in blood and urine.
timeFrame: 24 months
measure: Biochemical, morphological and structural characterization of selected RT-QuIC end products by Western blot and dot blot solution NMR and solid-state NMR analysis
timeFrame: 21 months
Other outcomes:
Locations:
city: Sesto Fiorentino
country: Italy
facility: Consorzio Interuniversitario Risonanze Magnetiche Metallo Proteine (CIRMMP)
state: FI
city: Brescia
country: Italy
facility: IRCCS Centro San Giovanni di Dio
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Neurologico Carlo Besta
Study officials:
affiliation: Fondazione IRCCS Istituto Neurologico Carlo Besta
name: Fabio Moda, PHD
role: PRINCIPAL_INVESTIGATOR
References: