Autoimmune Dementia: Predictors of Neuronal Synaptic Antibodies in Patients With New-ONset Cognitive Impairment (ADONIS)

March 22, 2024 updated by: Azienda Usl di Bologna

Autoimmune Dementia: Predictors of Neuronal Synaptic Antibodies in Patients With New-ONset Cognitive Impairment and Their Relevance in Non-encephalitic formS: The ADONIS Study

The goal of this observational study is to investigate the frequency and the possible pathogenic role of neuronal synaptic antibodies (NSAb) in patients with cognitive impairment (CI). The main questions it aims to answer are:

  1. the frequency and associated features of NSAb in patients with CI and the usefulness of a clinical score in improving autoimmune dementia (AID) diagnosis;
  2. the clinical significance of NSAb in patients with CI not fulfilling the autoimmune encephalitis (AE) criteria and serum NSAb (NSAb-pos-CI);
  3. the impact of blood-brain-barrier (BBB) dysfunction on their pathogenicity.

Study Overview

Status

Recruiting

Conditions

Detailed Description

AE can mimic dementia and, contrarily to neurodegenerative dementia syndromes, affected patients can improve with timely immunotherapies. Consensus-based diagnostic criteria for AE help to select patients for antibody testing. However, encephalitis signs can be absent, particularly in the elderly, and AE can present with slowly progressing CI mimicking classical neurodegenerative diseases, misleading the diagnostic process. Data on the prevalence of NSAb and AE in unselected patients with CI are sparse and mostly affected by retrospective design, small cohorts, and antibody assay shortcomings. There is an urgent need to define the frequency of NSAb and AE in CI patients and elucidate the associated clinical, laboratory and imaging features. Filling these gaps is the first aim of this project. This will allow the early identification and the best management of patients with AID. On the other hand, a proportion of CI patients have NSAb and do not fit the AE criteria (NSAb-pos-CI).

These NSAb are often in the serum, and not in the Cerebrospinal Fluid (CSF), or belong to the Immunoglobulin A/M (Ig A/M) subclasses, as opposite to the AE-associated Immunoglobulin G (IgG) subclass, thus triggering questions about their clinical and therapeutic implications. As NSAb can be found at low titers in the serum of healthy controls, a hypothesis explaining their pathogenicity relies on dysfunctions of the BBB, in a context of indolent inflammation, that might allow the antibodies to reach the Central Nervous System (CNS). Alternatively, NSAb may not be directly pathogenic and could even be secondary to an ongoing neurodegenerative process. However, even in this context, known and unknown NSAb, could still contribute to the clinical phenotype, modulating the disease progression or the presence of additional clinical features (i.e. psychiatric symptoms). Understanding if these serum NSAb, along with other factors such as inflammation and BBB alterations, have a role in modifying the disease trajectory, i.e. accelerating the neurodegeneration and CI progression, is the other main goal. This project will represent a chance to clarify the role of NSAb in NSAb-pos-CI and potentially help to identify a subgroup of patients with specific phenotypes, who could benefit from immunotherapies. The identification of such patients will allow their best clinical management.

Study Type

Observational

Enrollment (Estimated)

300

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Italy
      • Bologna, Italy, 40139
      • Milano, Italy, 20133
        • Recruiting
        • Fondazione IRCCS Istituto Neurologico Carlo Besta
        • Contact:
      • Milano, Italy, 20095
        • Recruiting
        • Istituto Auxologico Italiano IRCCS
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

N/A

Sampling Method

Non-Probability Sample

Study Population

patients with a diagnosis of new-onset neurocognitive disorders (major and minor)

Description

Inclusion Criteria:

  • both sexes
  • adult (aged between 40 and 90 years)
  • patients with a diagnosis of new-onset neurocognitive disorders (major and minor), as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, with onset within the previous 24 months

Exclusion Criteria:

- presence of a history of seizures within 4 weeks from onset.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
retrospective cohort
patients with a diagnosis of new-onset neurocognitive disorders (major and minor) with onset within the previous 24 months
prospective cohort
patients with a diagnosis of new-onset neurocognitive disorders (major and minor) with onset within the previous 24 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
frequency of antibodies against neuronal antigens
Time Frame: at baseline
NSAb frequency will be calculated by dividing the number of patients with NSAb with the total number of patients
at baseline
frequency of antibodies against neuronal antigens
Time Frame: 12 months (54 weeks)
NSAb frequency will be calculated by dividing the number of patients with NSAb with the total number of patients
12 months (54 weeks)
creation of a score that predicts the presence of NSAb
Time Frame: 24 months (108 weeks)
Based on logistic regression models including the clinical, imaging and biomarkers data. The minimum and maximum score is to be defined on the bases of the analyses of the clinical data at 24 months milestone.An higher score is expected to be associated with the antibody presence.
24 months (108 weeks)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
changes of neuroanatomy
Time Frame: at baseline
comparison of Brain MRI from baseline to one year follow up in seropositive versus seronegative patients
at baseline
changes of neuroanatomy
Time Frame: 1 year (54 weeks)
comparison of Brain MRI from baseline to one year follow up in seropositive versus seronegative patients
1 year (54 weeks)
changes of neurodegeneration biomarkers
Time Frame: at baseline
comparison of blood biomarkers from baseline to one year follow up in seropositive versus seronegative patients. The blood biomarkers are: phosphorylated tau protein 181 (p-tau 181) (pg/mL), Neurofilament Light chain (NfL) (pg/mL), Glial Fibrillary Acidic Protein (GFAP) (pg/mL).
at baseline
changes of neurodegeneration biomarkers
Time Frame: 1 year (54 weeks)
comparison of blood biomarkers from baseline to one year follow up in seropositive versus seronegative patients. The blood biomarkers are: phosphorylated tau protein 181 (p-tau 181) (pg/mL), Neurofilament Light chain (NfL) (pg/mL), Glial Fibrillary Acidic Protein (GFAP) (pg/mL).
1 year (54 weeks)
changes of inflammatory biomarkers
Time Frame: at baseline
comparison of inflammatory biomarkers from baseline to one year follow up in seropositive versus seronegative patients. The inflammatory biomarkers are: Interferon alpha (IFN alpha) (pg/mL), Interferon gamma (IFN gamma) (pg/mL), Interleukin-1 beta (IL-1 beta) (pg/mL), Interleukin-2 (IL-2) (pg/mL), Interleukin-4 (IL-4) (pg/mL), Interleukin-5 (IL-5) (pg/mL), Interleukin-6 (IL-6) (pg/mL), Interleukin-8 (IL-8) (pg/mL), Interleukin-17A (IL-17A) (pg/mL), Tumor necrosis factor alpha (TNF alpha) (pg/mL), Interferon gamma-induced protein 10 (IP-10) known as C-X-C motif chemokine 10(CXCL10) (pg/mL), Monocyte chemoattractant protein-1 (MCP-1) known as C-C motif chemokine ligand 2 (CCL2) (pg/mL).
at baseline
changes of inflammatory biomarkers
Time Frame: 1 year (54 weeks)
comparison of inflammatory biomarkers from baseline to one year follow up in seropositive versus seronegative patients. The inflammatory biomarkers are: Interferon alpha (IFN alpha) (pg/mL), Interferon gamma (IFN gamma) (pg/mL), Interleukin-1 beta (IL-1 beta) (pg/mL), Interleukin-2 (IL-2) (pg/mL), Interleukin-4 (IL-4) (pg/mL), Interleukin-5 (IL-5) (pg/mL), Interleukin-6 (IL-6) (pg/mL), Interleukin-8 (IL-8) (pg/mL), Interleukin-17A (IL-17A) (pg/mL), Tumor necrosis factor alpha (TNF alpha) (pg/mL), Interferon gamma-induced protein 10 (IP-10) known as C-X-C motif chemokine 10(CXCL10) (pg/mL), Monocyte chemoattractant protein-1 (MCP-1) known as C-C motif chemokine ligand 2 (CCL2) (pg/mL).
1 year (54 weeks)
changes of brain blood barrier biomarkers
Time Frame: at baseline
comparison of brain blood barrier biomarkers from baseline to one year follow up in seropositive versus seronegative patients. The biomarkers are: S100 calcium-binding protein B (S-100b) (pg/mL), Glial Fibrillary Acidic Protein (GFAP) (pg/mL).
at baseline
changes of brain blood barrier biomarkers
Time Frame: 1 year (54 weeks)
comparison of brain blood barrier biomarkers from baseline to one year follow up in seropositive versus seronegative patients. The biomarkers are: S100 calcium-binding protein B (S-100b) (pg/mL), Glial Fibrillary Acidic Protein (GFAP) (pg/mL).
1 year (54 weeks)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Azienda Usl di Bologna

Investigators

  • Principal Investigator: Maria Pia Giannoccaro, Dr., IRCCS Istituto delle Scienze Neurologiche di Bologna

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 10, 2023

Primary Completion (Estimated)

June 30, 2026

Study Completion (Estimated)

June 30, 2026

Study Registration Dates

First Submitted

March 14, 2024

First Submitted That Met QC Criteria

March 19, 2024

First Posted (Actual)

March 20, 2024

Study Record Updates

Last Update Posted (Actual)

March 25, 2024

Last Update Submitted That Met QC Criteria

March 22, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GR-2021-12373134

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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