A Study of the Behavioral Variant of Frontotemporal Dementia and Bipolar Disorder: a Neuroimaging and Epigenetics Integrated Approach (DISBAND)

November 22, 2024 updated by: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

The aim of this study is to investigate the selective epigenetic modifications and their effect on brain's morphology and functionality in the frontotemporal dementia behavioral variant and bipolar disorder. The open-label, multicentric, interventional case-control study involves the analysis of 3 separate cohorts of patients, partly selected over the course of the past 10 years. More specifically, 80 behavioral variant Frontotemporal Dementia (bvFTD) patients (40, of whom 20 carry G4C2 expansion in the C9orf72 gene, are already available, while 40 will be prospectively recruited), 80 Bipolar Disorder (BD) patients (40, including 20 with early onset and 20 with late onset, are already available, while 40 will be prospectively recruited) and 50 healthy control (HC) subjects (20 of whom are already available from other previously approved studies), will be enrolled in this study.

For each participant a blood sample will be collected, processed, and studied in order analyze the expression of miRNA. Every participant will also undergo Nuclear Magnetic Resonance Imaging (NMR), Nuclear Magnetic Resonance Spectroscopy (1H-MRS), and Positron Emission Tomography (PET) and, lastly, a battery of behavioral scales to explore different cognitive domains will be administered to all participants by a team of psychologists and physicians. The overall estimated duration of the study is 36 months.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Following the inclusion and exclusion criteria, the participants will be recruited and subdivided into three groups:

  • bvFTD patients, followed prospectively for at least 2 years. These include bvFTD carriers of G4C2 expansion in the C9orf72 gene (best model of the two diseases because such expansion is widely associated with the development of psychosis)
  • BD patients who are part of a cohort of multi affected families (MAF) followed since January 2017 at the Psychiatry Operating Unit of the Policlinico di Milano and who have positive family history of neurodegenerative diseases.
  • Healthy subjects who underwent neurocognitive tests at baseline that excluded the presence of dementia and psychiatric diseases.

The investigators will be collecting participants blood samples, which will be processed and analyzed. More specifically, total exosomes will be isolated from 500 microliters of plasma by ExoQuick precipitation solution (SBI). Isolation and purification of NDEs will be performed by ExoFlow purification kit using biotinylated anti-human CD171 (L1CAM) antibody (clone 5G3, Ebiosciences). Total RNA contained in NDEs will be extracted by Total Exosome RNA and Protein Isolation Kit and miRNA expression analysis by TaqMan OpenArray Human Advanced MicroRNA Panel (Thermo Fisher Scientific). Expression analysis of lncRNAs will be conducted by LincFinder Array and inflammatory and autoimmunity arrays (Qiagen).

The participants will also undergo a neuroimaging session, where structural MRI and 1H-MRS sessions will be performed using a 3T MRI scanner available at the Neuroradiology Unit. The 1H-MRS will provide sensitive and reliable assessment of neurochemical changes in specific brain areas. The acquisition voxels will be palced in the dorso- and ventrolateral prefrontal cortex (DLPFC/VLPFC), amygdala, and hippocampus. Finally, an FDG-PET scan will be performed with a Biograph Truepoint 64 PET/TC scanner. T1-weighted and FDG-PET images will be used to explore brain morphological/metabolic differences between the groups. Gray matter and white matter volumes will be estimated locally and compared between groups using voxel-based morphometry. A parallel region of interest comparison (ROIs) will be performed to estimate regional volumes using the Automated Anatomical Labelling (AAL) atlas as a reference, again focusing on the DLPFC/VLPFC, amygdala and hippocampus. Finally, an additional regional analysis based on Freesurfer software will allow the investigators to estimate the cortical thickness, cortical surface area, and cortical gyrification of the Desikan-Killiany atlas regions. All MRI and PET analyses will be performed in the context of a general linear model using a specific software implementation in MATLAB called Statistical Parametric Mapping (SPM).

Lastly, neuroimaging data and ncRNA expression profiles will be used as predictors in the ML analysis. Given the small sample size, initially linear models (e.g., Support Vector Machine) will be used. Later, to improve the predictive power of our models, the investigators will apply the ML method called random forest, a more versatile and powerful classification algorithm, and the XGBoost (eXtreme Gradient Boosting) algorithm. To avoid overfitting of the learning process, a "grid" search of model hyperparameters will be performed. A 5-fold cross-validation will be used to validate the results, with a split between training-tests of 80%-20%.

Study Type

Interventional

Enrollment (Estimated)

210

Phase

  • Not Applicable

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
    • MI
      • Milan, MI, Italy, 20100
        • Recruiting
        • Fondazione Irccs Ca' Granda - Ospedale Maggiore Policlinico
        • 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

Yes

Description

Inclusion Criteria:

  • byFTD group: patients of either sex; 18 years of age or older; diagnosis of behavioral variant Frontotemporal Dementia according to current diagnostic criteria; presence of a signed informed consent.
  • BD group: patients of either sex; 18 years of age or older; diagnosis of bipolar disorder according to DSM-V criteria; presence of a signed informed consent.
  • HC group: patients of either sex; 18 years of age or older; subjects who have gone through the same diagnostic process as patients under suspicion of a central nervous system and/or psychiatric disorder, resulting in the absence of cognitive deficits and mood disorders; presence of a signed informed consent.

Exclusion Criteria:

  • Diagnosis of Alzheimer's disease
  • Comorbidities interfering with the studied condition (e.g. other neurological diseases or history of substance or alcohol abuse)
  • Diseases with an inflammatory component (e.g. autoimmune diseases, tumors)
  • Pregnancy

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

  • Primary Purpose: Other
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Frontotemporal Dementia, Behavioral Variant (bvFTD)
Diagnostic test: DISBAND protocol
For each participant blood samples will be collected, processed and studied to analyse microRNA expression, more specifically investigating non-coding RNA (ncRNA). Each participant will undergo a multimodal neuroimaging session, composed of structural MRI, 1H-MRS and PET.
Other: Bipolar Disorder (BD)
Diagnostic test: DISBAND protocol
For each participant blood samples will be collected, processed and studied to analyse microRNA expression, more specifically investigating non-coding RNA (ncRNA). Each participant will undergo a multimodal neuroimaging session, composed of structural MRI, 1H-MRS and PET.
Other: Healthy controls (HC)
Diagnostic test: DISBAND protocol
For each participant blood samples will be collected, processed and studied to analyse microRNA expression, more specifically investigating non-coding RNA (ncRNA). Each participant will undergo a multimodal neuroimaging session, composed of structural MRI, 1H-MRS and PET.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Identification of ncRNA transcripts and a specific noncoding RNA profile in neuron-derived exosomes
Time Frame: 36 months
Identification of ncRNA transcripts and a specific noncoding RNA profile in neuron-derived exosomes in patients with bvFTD and BD
36 months
Differences in brain structure in terms of white matter volumes
Time Frame: 36 months
Evaluation of the differences in brain structure in terms of white matter volumes comparing the three groups, using structural MRI
36 months
Differences in brain structure in terms of gray matter volumes
Time Frame: 36 months
Evaluation of the differences in brain structure in terms of gray matter volumes comparing the three groups, using structural MRI
36 months
Differences in brain structure in terms of cortical gyrification
Time Frame: 36 months
Evaluation of the differences in brain structure in terms of cortical gyrification comparing the three groups, using structural MRI
36 months
Differences in brain structure in terms of superficial cortical area
Time Frame: 36 months
Evaluation of the differences in brain structure in terms of superficial cortical area comparing the three groups, using structural MRI
36 months
Differences in brain structure in terms of cortical thickness
Time Frame: 36 months
Evaluation of the differences in brain structure in terms of cortical thickness comparing the three groups, using structural MRI
36 months
Differences in brain metabolism
Time Frame: 36 months
Evaluation of the differences in brain metabolism comparing the three groups, using FDG/PET
36 months
Differences in glutamatergic neurotransmission in the prefrontal-limbic cortex
Time Frame: 36 months
Evaluation of the differences in the glutamatergic neurotransmission of the prefrontal-limbic cortex, comparing the three groups, using 1H-MRS
36 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Creation of a machine learning model
Time Frame: 36 months
Creation of a machine learning model that could integrate neuroimaging data and miRNA expression data to validate the best candidates identified combining imaging and epigenetic data
36 months

Collaborators and Investigators

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

Sponsor

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Investigators

  • Principal Investigator: Elio Scarpini, Professor, UOSD Malattie Neurodegenerative

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 19, 2021

Primary Completion (Estimated)

January 1, 2025

Study Completion (Estimated)

April 1, 2025

Study Registration Dates

First Submitted

November 22, 2024

First Submitted That Met QC Criteria

November 22, 2024

First Posted (Estimated)

November 26, 2024

Study Record Updates

Last Update Posted (Estimated)

November 26, 2024

Last Update Submitted That Met QC Criteria

November 22, 2024

Last Verified

November 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DISBAND

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

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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