A Study of the Behavioral Variant of Frontotemporal Dementia and Bipolar Disorder: a Neuroimaging and Epigenetics Integrated Approach
NCT ID: NCT06706687
Last Updated: 2024-11-26
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
NA
210 participants
INTERVENTIONAL
2021-05-19
2025-04-30
Brief Summary
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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.
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Detailed Description
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* 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%.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
OTHER
NONE
Study Groups
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Frontotemporal Dementia, Behavioral Variant (bvFTD)
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.
Bipolar Disorder (BD)
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.
Healthy controls (HC)
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.
Interventions
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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.
Eligibility Criteria
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Inclusion Criteria
* 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
* 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
18 Years
ALL
Yes
Sponsors
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Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
OTHER
Responsible Party
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Principal Investigators
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Elio Scarpini, Professor
Role: PRINCIPAL_INVESTIGATOR
UOSD Malattie Neurodegenerative
Locations
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Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
Milan, MI, Italy
Countries
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Central Contacts
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Facility Contacts
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References
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Galimberti D, Fenoglio C, Serpente M, Villa C, Bonsi R, Arighi A, Fumagalli GG, Del Bo R, Bruni AC, Anfossi M, Clodomiro A, Cupidi C, Nacmias B, Sorbi S, Piaceri I, Bagnoli S, Bessi V, Marcone A, Cerami C, Cappa SF, Filippi M, Agosta F, Magnani G, Comi G, Franceschi M, Rainero I, Giordana MT, Rubino E, Ferrero P, Rogaeva E, Xi Z, Confaloni A, Piscopo P, Bruno G, Talarico G, Cagnin A, Clerici F, Dell'Osso B, Comi GP, Altamura AC, Mariani C, Scarpini E. Autosomal dominant frontotemporal lobar degeneration due to the C9ORF72 hexanucleotide repeat expansion: late-onset psychotic clinical presentation. Biol Psychiatry. 2013 Sep 1;74(5):384-91. doi: 10.1016/j.biopsych.2013.01.031. Epub 2013 Mar 7.
Vieta E, Popovic D, Rosa AR, Sole B, Grande I, Frey BN, Martinez-Aran A, Sanchez-Moreno J, Balanza-Martinez V, Tabares-Seisdedos R, Kapczinski F. The clinical implications of cognitive impairment and allostatic load in bipolar disorder. Eur Psychiatry. 2013 Jan;28(1):21-9. doi: 10.1016/j.eurpsy.2011.11.007. Epub 2012 Apr 24.
Baez S. et al., Neuropsychologia. 2017 Feb 17; S0028-3932(17)30058-1. doi: 10.1016/j.neuropsychologia.2017.02.012.
Delvecchio G. et al., Aust N Z J Psychiatry. 2018 Dec 13:4867418815976. doi: 10.1177/0004867418815976
Neueder A. et al, J Mol Biol. 2018 Dec 29; S0022-2836(18)31287-7. doi: 10.1016/j.jmb.2018.12.012.
Belzil VV, Gendron TF, Petrucelli L. RNA-mediated toxicity in neurodegenerative disease. Mol Cell Neurosci. 2013 Sep;56:406-19. doi: 10.1016/j.mcn.2012.12.006. Epub 2012 Dec 29.
Rademakers R, Eriksen JL, Baker M, Robinson T, Ahmed Z, Lincoln SJ, Finch N, Rutherford NJ, Crook RJ, Josephs KA, Boeve BF, Knopman DS, Petersen RC, Parisi JE, Caselli RJ, Wszolek ZK, Uitti RJ, Feldman H, Hutton ML, Mackenzie IR, Graff-Radford NR, Dickson DW. Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Hum Mol Genet. 2008 Dec 1;17(23):3631-42. doi: 10.1093/hmg/ddn257. Epub 2008 Aug 21.
Galimberti D, Villa C, Fenoglio C, Serpente M, Ghezzi L, Cioffi SM, Arighi A, Fumagalli G, Scarpini E. Circulating miRNAs as potential biomarkers in Alzheimer's disease. J Alzheimers Dis. 2014;42(4):1261-7. doi: 10.3233/JAD-140756.
Fenoglio C, Ridolfi E, Galimberti D, Scarpini E. An emerging role for long non-coding RNA dysregulation in neurological disorders. Int J Mol Sci. 2013 Oct 14;14(10):20427-42. doi: 10.3390/ijms141020427.
Ludwig B, Dwivedi Y. Dissecting bipolar disorder complexity through epigenomic approach. Mol Psychiatry. 2016 Nov;21(11):1490-1498. doi: 10.1038/mp.2016.123. Epub 2016 Aug 2.
Jin XF, Wu N, Wang L, Li J. Circulating microRNAs: a novel class of potential biomarkers for diagnosing and prognosing central nervous system diseases. Cell Mol Neurobiol. 2013 Jul;33(5):601-13. doi: 10.1007/s10571-013-9940-9. Epub 2013 Apr 30.
Fries GR, Walss-Bass C, Soares JC, Quevedo J. Non-genetic transgenerational transmission of bipolar disorder: targeting DNA methyltransferases. Mol Psychiatry. 2016 Dec;21(12):1653-1654. doi: 10.1038/mp.2016.172. Epub 2016 Oct 4. No abstract available.
Ghidoni R, Paterlini A, Albertini V, Glionna M, Monti E, Schiaffonati L, Benussi L, Levy E, Binetti G. Cystatin C is released in association with exosomes: a new tool of neuronal communication which is unbalanced in Alzheimer's disease. Neurobiol Aging. 2011 Aug;32(8):1435-42. doi: 10.1016/j.neurobiolaging.2009.08.013. Epub 2009 Sep 20.
Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012 Jan;62(1):63-77. doi: 10.1016/j.neuropharm.2011.07.036. Epub 2011 Aug 3.
Jun C, Choi Y, Lim SM, Bae S, Hong YS, Kim JE, Lyoo IK. Disturbance of the glutamatergic system in mood disorders. Exp Neurobiol. 2014 Mar;23(1):28-35. doi: 10.5607/en.2014.23.1.28. Epub 2014 Mar 27.
Other Identifiers
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DISBAND
Identifier Type: -
Identifier Source: org_study_id
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