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NCT07480187

Toward Molecular Profiling of Parkinson's Disease in Easily Accessible Biological Matrices

Sponsor: Azienda Ospedaliera di Perugia

View on ClinicalTrials.gov

Summary

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.

Key Details

Gender

All

Age Range

30 Years - Any

Study Type

INTERVENTIONAL

Enrollment

340

Start Date

2023-05-20

Completion Date

2026-05-20

Last Updated

2026-03-18

Healthy Volunteers

Yes

Conditions

Parkinson Disease Synucleinopathy Alzheimer Disease

Interventions

DIAGNOSTIC_TEST

biomarkers

Comparison of biomarkers measured in matched and unmatched biomatrices (blood, cerebrospinal fluid, skin biopses, brain metabolites by MRS, olfactory mucosa) in patients with Parkinson's disease, Alzheimer's disease, and controls. These biomarkers include cerebrospinal fluid biomarkers of Alzheimer's disease, proximity-extension assay proteomic biomarkers, alpha-synuclein seed amplification assay performed in olfactory mucosa, cerebrospinal fluid and skin, and brain magnetic resonance spectroscopy.

Inclusion Criteria: patients with clinical diagnosis of Parkinson's disease, atypical parkinsonisms, Alzheimer's disease, healthy volunteers, people with subjective cognitive decline. Exclusion Criteria: Other acute neurological diseases or neurodegenerative diseases such as Frontotemporal dementia, vascular dementia, and stroke Relevant comorbidities: chronic kidney disease (significant alteration of blood biomarkers) Skin biopsy: local skin infection at biopsy site, severe dermatologic disease at sampling area, known bleeding disorder, significant thrombocytopenia, anticoagulation not safely manageable, allergy to local anesthetics, poor wound healing, severe peripheral vascular disease, high-risk immunosuppression, inability to consent or cooperate, extensive scarring at intended site Magnetic resonance spectroscopy: non-MRI-compatible implanted device, ferromagnetic intracranial clip, metallic foreign body, severe claustrophobia not manageable, inability to remain still, MRI-conditional device not meeting safety conditions, pregnancy per institutional policy, severe agitation or confusion, body size exceeding scanner limits, severe motion disorder affecting acquisition Venipuncture: refusal or inability to consent, local infection at puncture site, severe coagulopathy, marked thrombocytopenia, high bleeding risk anticoagulation, severe anemia relative to planned blood volume, difficult venous access, history of severe vasovagal syncope Eligibility Criteria Inclusion Criteria: Adults able to provide informed consent Clinical diagnosis of Parkinson's disease Clinical diagnosis of atypical parkinsonism Clinical diagnosis of Alzheimer's disease Individuals with subjective cognitive decline Healthy volunteers Exclusion Criteria: Acute neurological diseases Other neurodegenerative diseases not included in the study groups (e.g., frontotemporal dementia, vascular dementia) History of stroke with significant neurological sequelae Chronic kidney disease with significant alteration of blood biomarkers Procedure-specific exclusion criteria Skin biopsy: Local skin infection at biopsy site Severe dermatologic disease at sampling area Known bleeding disorder Significant thrombocytopenia Anticoagulation not safely manageable Allergy to local anesthetics Poor wound healing Severe peripheral vascular disease High-risk immunosuppression Inability to consent or cooperate Extensive scarring at intended biopsy site Magnetic resonance spectroscopy (MRS): Non-MRI-compatible implanted device Ferromagnetic intracranial clip Metallic foreign body incompatible with MRI Severe claustrophobia not manageable with standard procedures Inability to remain still during MRI acquisition MRI-conditional device not meeting safety conditions Pregnancy according to institutional MRI safety policy Severe agitation or confusion preventing examination Body size exceeding scanner limits Severe motion disorder affecting acquisition Venipuncture: Refusal or inability to provide consent Local infection at puncture site Severe coagulopathy Marked thrombocytopenia High bleeding risk due to anticoagulation Severe anemia relative to planned blood draw volume Difficult venous access History of severe vasovagal syncope during venipuncture Lumbar puncture: Signs of increased intracranial pressure due to mass lesion Local infection at puncture site Uncorrected coagulopathy Severe thrombocytopenia Anticoagulation not safely interruptible Spinal cord compression Unstable spine Refusal or inability to cooperate with the procedure Severe spinal deformity Prior lumbar surgery complicating access Severe anxiety or intolerance to the procedure Pregnancy requiring procedural precautions Nasal brushing: Significant nasal polyposis Severe septal deviation preventing access to the olfactory cleft Active acute or chronic rhinosinusitis Recent epistaxis or bleeding-prone nasal mucosa Nasal lesions, ulcers, or tumors Recent nasal surgery Nasal brushing: Significant nasal polyposis, Severe septal deviation preventing access to the olfactory cleft, Active acute or chronic rhinosinusitis, Recent epistaxis or bleeding-prone nasal mucosa, Nasal lesions, ulcers, tumors, or recent nasal surger

Locations (3)

Centro Neurolesi Bonino Pulejo

Messina, Messina, Italy

Istituto Neurologico Carlo Besta

Milan, Milano, Italy

Azienda Ospedaliera di Perugia

Perugia, Italy