An Innovative Method in SAliva Samples for the Early Differential Diagnosis of High-impact NeuroDegenerative Diseases Through Raman Spectroscopy (SANDY)

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Parkinson Disease; Parkinsonian Disorders; Amyotrophic Lateral Sclerosis; Alzheimer Disease; Neurodegenerative Disorders; Fronto-temporal Dementia

• Study Type: Observational
• Enrollment (Estimated): 310

Contacts and Locations

Study Locations

• Italy
  • Cagliari, Italy
    • Azienda Ospedaliera Universitaria di Cagliari
  • Florence, Italy
    • IRCCS Fondazione Don Carlo Gnocchi
  • Florence, Italy
    • Laboratorio Congiunto di Ricerca DON GNOCCHI - UNIFI neurogenetica in riabilitazione - NGR
  • Milano, Italy
    • IRCCS Fondazione Don Carlo Gnocchi, Milano

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
control subjects; They are subjects admitted to IRCCS Don Gnocchi Florence in the cardiology, pulmonology, and orthopedics departments who have no neurological symptoms or diagnosis of neurological or psychiatric diseases, in the absence of positive family history (relatives I and II degree) for NDDs. Control subjects should be in a clinically stable condition at inclusion, and will be enrolled at least 15 days after the acute event causing hospitalization.
cases; They are individuals with a diagnosis of alzheimer's dementia, diagnosis of fronto-temporal dementia(behavioral variant), diagnosis of Parkinson's disease, clinical diagnosis of Parkinsonisms, and clinical diagnosis of amyotrophic lateral sclerosis.
prodromal cases; Subjects with Parkinson's or Alzheimer's disease or Frontotemporal dementia (behavioral variant) in the prodromal stage according to Berg's criteria.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Illness Rating Scale (CIRS)	it's a scale that records the comorbidity	at enrollment
Neurological Clinical informations	Presence/absence of symptoms/signs such as presence of speech disorder, hearing loss, low vision, dysphagia, oculomotricity disorder, disorientation, decreased insight, fatuity, perseveration/affacceleration, dx/sn recognition inability, gait disorder, instability/falls, neglect, ideomotor apraxia, signs of frontal release, rigidity/spasticity, bradykinesia, tremor or other involuntary movements, signs of first or second motor neuron, need for use of aids/presence of medical aids.	at enrollment
Genetic test	genetic testing will lead in NDDs and CTRL to the determination of the ApoE polymorphism (categorical variable). In NDDs, diagnostic investigation will aim to confirm/exclude a mutation in one of the disease-causing genes (APP, PS1, PS2, MAPT, PGRN, C9ORF72, SOD 1, TARDBP, VCP) in accordance with the pathological phenotype	at enrollment
Plasma test	NfL and GFAP assay result on plasma (continuous numeric variables)	at enrollment
Salivary test	results of NfL and GFAP assay on saliva (continuous numeric variables)	at enrollment
nerological objective examination checklist	presence/absence of symptoms/signs such as presence of speech disorder, hearing impairment, low vision, dysphagia, oculomotor disorder, disorientation, decreased insight, fatuity, perseveration/affacility, dx/sn recognition inability, gait disorder, instability/falls, neglect, ideomotor apraxia, signs of frontal release, rigidity/spasticity, bradykinesia, tremor or other involuntary movements, signs of first or second motor neuron,need for use of aids/presence of medical aids (categorical variables)	at enrollment
UPDRS part III and IV	evaluation of motor symptoms only for subjects with parkinson's disease or parkinsonisms	at enrollment
Hoehn and Yahr Scale	evaluation of clinical status only for subjects with parkinson's disease	at enrollment
NON-MOTOR SYMPTOMS SCALE	evaluation of non motor symptoms only for subjects with parkinson's disease	at enrollment
Functional Rating Scale-Revised (ALSFRS-R)	evaluation of disability only for subjects with ALS	at enrollment
MONTREAL COGNITIVE ASSESSMENT (MOCA)	Cognitive screening test for all except control subjects	at enrollment
denomination test of SAND	denomination of visual stimuli for all subjects except control cases	at enrollment
semantic, phonemic and alternate fluency Test	semantic, phonemic and alternate fluency Test for all subjects except control cases	at enrollment
TRAIL MAKING TEST part A and B	evaluation of attentional skills for all subjects except control cases	at enrollment
STROOP TEST	evaluation of inhibitory control for all subjects except control cases	at enrollment
REY'S 15-WORD TEST	evaluation of long term memory for all subjects except control cases	at enrollment
REY OSTERRIETH COMPLEX FIGURE	evaluation of visuospatial skills for all subjects except control cases	at enrollment
FACE TEST	evaluation of ability to recognize mental states of others for all subjects except control cases	at enrollment
NEUROPSYCHIATRICH INVENTORY (NPI)	interview assessing behavioral of others for all subjects except control cases	at enrollment
FRONTAL ASSESSMENT BATTERY (FAB)	evaluation of executive functions; for all subjects except control cases	at enrollment
MINIMENTAL STATE EXAMINATION (MMSE)	cognitive screening only for subjects with ADD and with Mild Cognitive Impairment (MCI)	at enrollment

Collaborators and Investigators

• Sponsor: Fondazione Don Carlo Gnocchi Onlus
• Collaborators: University of Cagliari, Cagliari, Italy

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2025
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: March 7, 2025
• First Submitted That Met QC Criteria: March 11, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 11, 2025
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Synucleinopathies; Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neuromuscular Diseases; Metabolic Diseases; Neurobehavioral Manifestations; Neurocognitive Disorders; Dementia; Tauopathies; Movement Disorders; Basal Ganglia Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Communication Disorders; Language Disorders; Aphasia; Speech Disorders; Frontotemporal Lobar Degeneration; Alzheimer Disease; Parkinson Disease; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain; Parkinsonian Disorders
• Other Study ID Numbers: SANDY - POC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No