PRedicting the EVolution of SubjectIvE Cognitive Decline to Alzheimer's Disease With Machine Learning

NCT05569083 | Unknown

• 1 other identifier: 20RSVB
• Study Type: observational
• Target: 350
• Locations: 1 country
• Sites: 4

Brief Summary

Alzheimer's disease (AD) has a presymptomatic course which can last from several years to decades. Identification of subjects at an early stage is crucial for therapeutic intervention and possible prevention of cognitive decline. Current research is focused on identifying characteristics of the early stages of AD and several concepts have been developed to that end. Subjective cognitive decline (SCD) is defined as a self-experienced persistent decline in cognitive capacity in comparison with the subject's previously normal status, during which the subject has normal age-, gender-, and education-adjusted performance on standardized cognitive tests. SCD is not related to current cognitive impairment, however it has been considered for its potential role as risk factors for AD. The aim of this study is to evaluate, through machine learning tools, the accuracy data, neuropsychological assessment, personality traits, cognitive reserve, genetic factors, cerebrospinal fluid (CSF) neurodegeneration biomarkers, EEG and Event Related Potential recordings in predicting conversion from SCD condition, to Mild Cognitive Impairment (MCI) and AD.

Conditions

Cognitive Decline; Mild Cognitive Impairment; Alzheimer Disease

Keywords

Dementia; Cognitive reserve; machine learning; deep learning; precision medicine; Electroencephalogram; Event Related Potential; Cerebrospinal Fluid biomarker; Apolipoprotein E; Brain-derived neurotrophic factor

Outcome Measures

Primary Outcomes (2)

• Clinical diagnosis of MCI in patients diagnosed with SCD

  Patients diagnosed with SCD at baseline will be followed-up every six months by neurological evaluation and every twelve months by neuropsychological examination in order to detect progression to MCI according to National Institute on Aging and Alzheimer's Association (NIA-AA) criteria (Albert et al. 2011)

  three years

• Clinical diagnosis of AD in patients diangosed with SCD and MCI

  Patients diagnosed with SCD or MCI at baseline will be followed-up every six months by neurological evaluation and every twelve months by neuropsychological examination in order to detect progression to AD according to NIA-AA criteria (Mc Khann et al. 2011)

  three years

Secondary Outcomes (1)

• Variations in neuropsychological scores

  three years

Study Arms (3)

Patients with Subjective Cognitive Decline

Patients complaining about cognitive decline with normal functioning on the activities of daily living and unsatisfied criteria for MCI or dementia at baseline.

Genetic: Genetic analysis of APOE and BDNF genes.; Diagnostic Test: EEG recording; Diagnostic Test: CSF collection and AD biomarker measurement; Diagnostic Test: Neuropsychological evaluation; Diagnostic Test: Assessment of cognitive reserve, depression, personality traits and leisure activities; Diagnostic Test: Clinical-neuropsychological follow-up; Diagnostic Test: ERP recording

Patients with Mild Cognitive Impairment

Patients diagnosed with MCI

Genetic: Genetic analysis of APOE and BDNF genes.; Diagnostic Test: EEG recording; Diagnostic Test: CSF collection and AD biomarker measurement; Diagnostic Test: Neuropsychological evaluation; Diagnostic Test: Assessment of cognitive reserve, depression, personality traits and leisure activities; Diagnostic Test: Clinical-neuropsychological follow-up; Diagnostic Test: ERP recording

Healthy controls

Diagnostic Test: EEG recording; Diagnostic Test: ERP recording

Interventions

Genetic analysis of APOE and BDNF genes. GENETIC

The three SNPs (rs429358, rs7412 and rs6265 on APOE and BDNF genes respectively) will be analyzed by the polymerase chain reaction (PCR) on genomic DNA and with the analysis of melting curves (HRMA) using the Rotor-Gene 6,000 (Rotor-Gene, Corbett Research, Mortlake, Australia).

Patients with Mild Cognitive Impairment; Patients with Subjective Cognitive Decline

EEG recording DIAGNOSTIC_TEST

The EEG activity will be recorded continuously from 19 sites by using electrodes set in an elastic cap and positioned according to the 10-20 international system. The recording will be referenced to the common average of all electrodes, excluding Fp1 and Fp2. Re-referencing will be done prior to the EEG artifact detection and analysis. Data will be recorded with a band-pass filter of 0.3-70 Hz and digitized at a sampling rate of 512 Hz and analogue-digital precision was 16 bits (Gal-Nt, EbNeuro®, Florence, Italy). Horizontal and vertical eye movements will be detected by electrooculogram (EOG). Subjects will be sat in a reclined chair for approximately 20 min. Data will be collected at a sampling rate of 256 Hz, with a common mode rejection ratio of 105 dB (decibel), and the following band pass characteristics: 0.1 Hz high-pass filter, 100 Hz fifth order low-pass filter.

Healthy controls; Patients with Mild Cognitive Impairment; Patients with Subjective Cognitive Decline

CSF collection and AD biomarker measurement DIAGNOSTIC_TEST

The CSF samples will be collected by lumbar puncture, immediately centrifuged and stored at -80 °C until performing the analysis. Aβ42, Aβ42/Aβ40 ratio, t-tau, and p-tau will be measured using a chemiluminescent enzyme immunoassay (CLEIA) analyzer LUMIPULSE® G600 (Fujirebio, Tokyo, Japan).

Patients with Mild Cognitive Impairment; Patients with Subjective Cognitive Decline

Neuropsychological evaluation DIAGNOSTIC_TEST

For extensive neuropsychological evaluation the investigators will use the following tools: global measurements (MMSE, Information-Memory-Concentration Test), tasks exploring verbal and spatial short- and long-term memory (Digit Span, Corsi Tapping Test, Five Words and Paired Words Acquisition and Recall after 10 min and 24 hr, Short Story Immediate and Delayed Recall), prospective memory (Rivermead Behavioral Memory Test), attention (Trail Making Test A, Dual Task), language (Token Test, naming pictures, Category Fluency Task, Phonemic Fluency Task), constructional praxis (Copying Drawings and Rey-Osterrieth complex figure) and executive function (Trail Making Test B, Stroop Test, Frontal Assessment Battery, Weigl Test). To assess independent living skills, the investigators will use two structured interview: Activities of Daily Living Scale (ADL) and Instrumental Activities of Daily Living Scale (IADL).

Patients with Mild Cognitive Impairment; Patients with Subjective Cognitive Decline

Assessment of cognitive reserve, depression, personality traits and leisure activities DIAGNOSTIC_TEST

In order to estimate premorbid intelligence, all cases will perform TIB test (Test di Intelligenza Breve), an Italian version of the National Adult Reading Test (NART). To assess personality traits of the subjects, the investigators will use the Big Five Factors Questionnaire (BFFQ), that measures the five factors of emotional stability, energy, conscientiousness, agreeableness and openness to culture and experience. For cognitive reserve. subjects will perform structured interviewed regarding participation in intellectual, sporting and social activities, in the course of their life. The presence of depressive symptoms will be evaluated by means of the 22-item Hamilton Depression Rating Scale (HDRS).

Patients with Mild Cognitive Impairment; Patients with Subjective Cognitive Decline

Clinical-neuropsychological follow-up DIAGNOSTIC_TEST

For follow-up assessment, each subject will perform a complete clinical evaluation, an extensive neuropsychological evaluation (27 test), assessment of independent living skills (ADL and IADL), estimation of premorbid intelligence (TIB test) and scale for depression (Hamilton Depression Rating Scale - HDRS).

Patients with Mild Cognitive Impairment; Patients with Subjective Cognitive Decline

ERP recording DIAGNOSTIC_TEST

For ERP acquisition the same EEG system that was used for EEG data acquisition will be used. The participants will be administered an ERP test battery with concurrently recorded EEG consisting of a 3-choice vigilance task (3CVT) designed to evaluate sustained attention and standard image recognition memory task (SIR) designed to evaluate attention, encoding, and image recognition memory. In the SIR, images will be chosen as stimuli to distinguish short term from semantic memory loss and extend previous results of image recognition ERP effects.

Healthy controls; Patients with Mild Cognitive Impairment; Patients with Subjective Cognitive Decline

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The investigators will include in the study, consecutive spontaneous subjects who self-referred to the Centre for Alzheimer's Disease and Adult Cognitive Disorders of Careggi Hospital in Florence. The investigators will include in the study 300 patients with SCD already selected and evaluated one time (baseline) or more (follow-up) in our clinic, and they will increase the baseline sample by adding new subjects with SCD or MCI.

You may qualify if:

• Complaining of cognitive decline with a duration of ≥ 6 months;
• Normal functioning on the Activities of Daily Living and the Instrumental Activities of Daily Living scales (Lawton and Brody, 1969);
• Unsatisfied criteria for dementia at baseline (DSM-V, American Psychiatric Association, 2013).

You may not qualify if:

• \- History of head injury, current neurological and/or systemic disease, symptoms of psychosis, major depression, alcoholism or other substance abuse

Sponsors & Collaborators

• Azienda Ospedaliero-Universitaria Careggi: lead
• Fondazione Don Carlo Gnocchi Onlus: collaborator
• University of Florence: collaborator
• Scuola Superiore Sant'Anna di Pisa: collaborator

Study Sites (4)

AOU Careggi

Florence, Tuscany, 50134, Italy

RECRUITING

IRCCS Don Gnocchi

Florence, 50143, Italy

RECRUITING

Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence

Florence, Italy

RECRUITING

Istituto di Biorobotica e Dipartimento di Eccellenza in Robotica e AI, Scuola Superiore Sant'Anna

Pisa, Italy

RECRUITING

Related Publications (15)

• Giacomucci G, Mazzeo S, Bagnoli S, Casini M, Padiglioni S, Polito C, Berti V, Balestrini J, Ferrari C, Lombardi G, Ingannato A, Sorbi S, Nacmias B, Bessi V. Matching Clinical Diagnosis and Amyloid Biomarkers in Alzheimer's Disease and Frontotemporal Dementia. J Pers Med. 2021 Jan 14;11(1):47. doi: 10.3390/jpm11010047.

  PMID: 33466854 BACKGROUND

• Mazzeo S, Bessi V, Bagnoli S, Giacomucci G, Balestrini J, Padiglioni S, Tomaiuolo G, Ingannato A, Ferrari C, Bracco L, Sorbi S, Nacmias B. Dual Effect of PER2 C111G Polymorphism on Cognitive Functions across Progression from Subjective Cognitive Decline to Mild Cognitive Impairment. Diagnostics (Basel). 2021 Apr 18;11(4):718. doi: 10.3390/diagnostics11040718.

  PMID: 33919572 BACKGROUND

• Bessi V, Balestrini J, Bagnoli S, Mazzeo S, Giacomucci G, Padiglioni S, Piaceri I, Carraro M, Ferrari C, Bracco L, Sorbi S, Nacmias B. Influence of ApoE Genotype and Clock T3111C Interaction with Cardiovascular Risk Factors on the Progression to Alzheimer's Disease in Subjective Cognitive Decline and Mild Cognitive Impairment Patients. J Pers Med. 2020 May 29;10(2):45. doi: 10.3390/jpm10020045.

  PMID: 32485802 BACKGROUND

• Mazzeo S, Padiglioni S, Bagnoli S, Bracco L, Nacmias B, Sorbi S, Bessi V. The dual role of cognitive reserve in subjective cognitive decline and mild cognitive impairment: a 7-year follow-up study. J Neurol. 2019 Feb;266(2):487-497. doi: 10.1007/s00415-018-9164-5. Epub 2019 Jan 2.

  PMID: 30604054 BACKGROUND

• Giacomucci G, Mazzeo S, Padiglioni S, Bagnoli S, Belloni L, Ferrari C, Bracco L, Nacmias B, Sorbi S, Bessi V. Gender differences in cognitive reserve: implication for subjective cognitive decline in women. Neurol Sci. 2022 Apr;43(4):2499-2508. doi: 10.1007/s10072-021-05644-x. Epub 2021 Oct 8.

  PMID: 34625855 BACKGROUND

• Mazzeo S, Bessi V, Padiglioni S, Bagnoli S, Bracco L, Sorbi S, Nacmias B. KIBRA T allele influences memory performance and progression of cognitive decline: a 7-year follow-up study in subjective cognitive decline and mild cognitive impairment. Neurol Sci. 2019 Aug;40(8):1559-1566. doi: 10.1007/s10072-019-03866-8. Epub 2019 Apr 5.

  PMID: 30953258 BACKGROUND

• Bessi V, Mazzeo S, Padiglioni S, Piccini C, Nacmias B, Sorbi S, Bracco L. From Subjective Cognitive Decline to Alzheimer's Disease: The Predictive Role of Neuropsychological Assessment, Personality Traits, and Cognitive Reserve. A 7-Year Follow-Up Study. J Alzheimers Dis. 2018;63(4):1523-1535. doi: 10.3233/JAD-171180.

  PMID: 29782316 BACKGROUND

• Mazzeo S, Padiglioni S, Bagnoli S, Carraro M, Piaceri I, Bracco L, Nacmias B, Sorbi S, Bessi V. Assessing the effectiveness of subjective cognitive decline plus criteria in predicting the progression to Alzheimer's disease: an 11-year follow-up study. Eur J Neurol. 2020 May;27(5):894-899. doi: 10.1111/ene.14167. Epub 2020 Mar 8.

  PMID: 32043740 BACKGROUND

• Amoroso N, Diacono D, Fanizzi A, La Rocca M, Monaco A, Lombardi A, Guaragnella C, Bellotti R, Tangaro S; Alzheimer's Disease Neuroimaging Initiative. Deep learning reveals Alzheimer's disease onset in MCI subjects: Results from an international challenge. J Neurosci Methods. 2018 May 15;302:3-9. doi: 10.1016/j.jneumeth.2017.12.011. Epub 2017 Dec 26.

  PMID: 29287745 BACKGROUND

• Bansal D. et al. Comparative Analysis of Various Machine Learning Algorithms for Detecting Dementia - Procedia Computer Science (2018) 132: 1497-1502

  BACKGROUND

• Gouw AA, Alsema AM, Tijms BM, Borta A, Scheltens P, Stam CJ, van der Flier WM. EEG spectral analysis as a putative early prognostic biomarker in nondemented, amyloid positive subjects. Neurobiol Aging. 2017 Sep;57:133-142. doi: 10.1016/j.neurobiolaging.2017.05.017. Epub 2017 Jun 1.

  PMID: 28646686 BACKGROUND

• Guillem F, Rougier A, Claverie B. Short- and long-delay intracranial ERP repetition effects dissociate memory systems in the human brain. J Cogn Neurosci. 1999 Jul;11(4):437-58. doi: 10.1162/089892999563526.

  PMID: 10471850 BACKGROUND

• Mazzeo S, Lassi M, Padiglioni S, Vergani AA, Moschini V, Scarpino M, Giacomucci G, Burali R, Morinelli C, Fabbiani C, Galdo G, Amato LG, Bagnoli S, Emiliani F, Ingannato A, Nacmias B, Sorbi S, Grippo A, Mazzoni A, Bessi V. Towards the development of a management protocol for subjective cognitive decline: Insights from a cross-sectional and longitudinal analysis of multimodal data from a memory clinic. J Alzheimers Dis. 2026 Jan 28:13872877261416117. doi: 10.1177/13872877261416117. Online ahead of print.

  PMID: 41603334 DERIVED

• Amato LG, Lassi M, Vergani AA, Carpaneto J, Mazzeo S, Moschini V, Burali R, Salvestrini G, Fabbiani C, Giacomucci G, Galdo G, Morinelli C, Emiliani F, Scarpino M, Padiglioni S, Nacmias B, Sorbi S, Grippo A, Bessi V, Mazzoni A. Digital twins and non-invasive recordings enable early diagnosis of Alzheimer's disease. Alzheimers Res Ther. 2025 May 31;17(1):125. doi: 10.1186/s13195-025-01765-z.

  PMID: 40450374 DERIVED

• Mazzeo S, Lassi M, Padiglioni S, Vergani AA, Moschini V, Scarpino M, Giacomucci G, Burali R, Morinelli C, Fabbiani C, Galdo G, Amato LG, Bagnoli S, Emiliani F, Ingannato A, Nacmias B, Sorbi S, Grippo A, Mazzoni A, Bessi V. PRedicting the EVolution of SubjectIvE Cognitive Decline to Alzheimer's Disease With machine learning: the PREVIEW study protocol. BMC Neurol. 2023 Aug 12;23(1):300. doi: 10.1186/s12883-023-03347-8.

  PMID: 37573339 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

CSF biomarkers, whole blood

MeSH Terms

Conditions

Cognitive Dysfunction; Alzheimer Disease; Dementia

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases

Study Officials

• Valentina Bessi, MD, PhD

  Research and Innovation Centre for Dementia-CRIDEM, AOU Careggi, Florence, Italy

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Valentina Bessi, MD, PhD

CONTACT

+393496096308; valentina.bessi@unifi.it

Sonia Padiglioni, Psy, PhD

CONTACT

+393488512232; padiglionis@aou-careggi.toscana.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 24, 2022
• First Posted: October 6, 2022
• Study Start: October 1, 2020
• Primary Completion: September 30, 2023
• Study Completion: March 30, 2024
• Last Updated: October 7, 2022

Record last verified: 2022-10

Locations

IT (4)