The aim of the study is to validate a salivary test that allows for rapid and accurate objective diagnosis in the context of neurodegenerative diseases, a complex of diseases that includes Alzheimer's Dementia, Frontotemporal Dementia, Parkinson's Disease, Atypical Parkinsonisms, and Amyotrophic Lateral Sclerosis. In particular, the study aims to validate the salivary method against methods already in use (CSF method) or better studied (blood-based method) to allow early recognition of the disease condition and a distinction between the various diseases in order to receive appropriate therapy when possible.

In fact, the term neurodegenerative diseases is a broad term that includes disorders characterized by predominantly cognitive, motor, or mixed disorders for which early and accurate diagnosis of the disease is often difficult given also the variability with which these diseases can present. Ab initio recognition of a specific neurodegenerative disease would allow better pharmacological management of this disorder and facilitate the planning of care and rehabilitation interventions. In general, the recognition of neurodegenerative diseases could be facilitated by the use of a biomarker, which is a biological indicator that can be related to the onset or development of a disease. For this reason, it is necessary to compare the biomarker assay of patients with that of controls, so you were asked to participate as a "Control Subject" precisely because you do not have neurodegenerative disease.

Participation in the study involves, in addition to the collection of clinical-demographic data, the performance of a cognitive screening test to attest that your cognitive performance is in the normal range and the collection of biological blood and salivary samples, to be compared with those of participants with neurodegenerative diseases. Apolipoprotein E (ApoE) polymorphism study will be performed on the blood. A genetic polymorphism is a variation in the DNA sequence present in at least 1% of the population, the determination of ApoE polymorphism will allow to define a His genetic characteristic related to a higher or lower risk of developing Alzheimer's Disease. Two specific biomarkers, called neurofilament light chain (NfL) and gliofibrillary acidic protein (GFAP), namely a marker of neurodegeneration and one of neuroinflammation, will also be assayed on blood. Analysis of some inflammatory proteins called cytokines will also be performed.

On saliva, the biochemical composition will be evaluated with the analysis of particles present within it called vesicles by a method called Raman Spectroscopy, and the assay of specific biomarkers called NfL and GFAP will also be performed on saliva. The diagnosis of pathology made according to clinical diagnostic criteria and supported, when necessary, by the presence of recognized biomarkers (molecular imaging/liquid markers) will be used as a reference to evaluate the diagnostic capabilities of salivary methodology to detect different pathologies and to differentiate a pathological condition from Controls. Finally, the study will also include a comparison of salivary study methods on a group of people who are at a very early stage of disease, in order to detect whether the study performed with portable instrumentation is as good a method as that with laboratory instrumentation. In fact, the use of portable instrumentation would make it even easier to acquire a biomarker quickly directly from the clinic.

Inclusion Criteria:

FOR ALL SUBJECTS: between 60 and 85 years old

FOR CASE:

1. ADD: diagnosis of dementia due to AD according to clinical criteria and supported by amyloid biomarkers (biomarkers in CSF or brain PET scan with amyloid-specific tracer) according to the definition biological or neurochemical definition of disease.
2. FTD: diagnosis of FTD-bv (behavioral variant) according to current clinical criteria.
3. PD: diagnosis according to MDS criteria; stable drug treatment (last 4 weeks).
4. APs: clinical diagnosis of Progressive Supranuclear Palsy according to the criteria of Hoglinger 2017, Corticobasal Degeneration according to the criteria of Armostrong 2013, Multisystem Atrophy according to the criteria of Wenning 2022.
5. ALS: clinical diagnosis according to the criteria of Brooks (2000) and subsequent revisions.

FOR CONTROL SUBJECTS

1. subjects admitted to IRCCS Don Gnocchi Florence in the departments of cardiology, pulmonology, orthopedics
2. ABSENCE of neurological symptoms
3. ABSENCE OF diagnosis of neurological or psychiatric diseases.
4. absence of positive family history (relatives I and II degree) for NDDs.
5. condition of clinical stability
6. at least 15 days after the acute event causing hospitalization.

FOR PRODROMAL CASE

1. Prodromal PD according to Berg's criteria.
2. prodromal FTD-bv according to Barker's criteria
3. prodromal AD according to the criteria of Dubois and Albert

Exclusion Criteria:

FOR CASE

1. Vascular Parkinsonism and other forms of secondary Parkinsonism such as drug-induced, other known or suspected causes (metabolic, brain tumor, etc.).
2. MoCA<15 for subjects with PD
3. cases with validated biomarkers (CSF and PET) in diagnostic conflict.

FOR ALL SUBJECTS

1. significant comorbidities
2. presence of severe systemic diseases or previously diagnosed psychiatric illnesses
3. patients unable to express consent for participation in the study themselves
4. presence of clinically unstable oral cavity disease (inflammatory/infectious)
5. time since acute event (if it occurred) <15 days
6. presence of local or systemic infection/inflammation detected on routine examinations.

Patients with NDDs will be recruited from participating centers through enrollment. We plan to recruit at least 52 subjects per experimental group (52 ADDs, 52 FTDs, 52 PDs, 52 APs, 52 ALS) and 50 CTRLs. An additional 50 prodromal cases belonging to the PD, FTD behavioral variant, and AD categories.