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The role of neural derived extracellular vesicles micro-ribonucleic acid cargo in white matter integrity in early-onset and late-onset bipolar disorder

Molecular Psychiatry (2026)Cite this article

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Abstract

Bipolar disorder (BD) shows different clinical manifestations according to illness onset (early vs late onset). Its etiology is multifaceted and no reliable biomarkers are available. However, clinical manifestations of BD may stem from disruption in white matter (WM) integrity within brain networks or selective epigenetic alterations, including plasma neural derived extracellular vesicles (NDEVs). In this context, this study further explores the existence of similar epigenetic expression patterns in NDVEs, such as micro-ribonucleic acid (miRNA), and seeks to correlate them with biological markers obtained through Diffusion Tensor Imaging and with clinical data. 23 early onset BD (35% males) (EOBD), 15 late-onset BD (47% males) (LOBD), and 18 healthy controls (44% males) (HC) were recruited. Fractional anisotropy (FA) was investigated through Tract-Based Spatial Statistics. NDEVs were isolated from plasma, and their miRNA content was profiled using real-time polymerase chain reaction. Compared to HC, miR-20a and miR-299-5p were upregulated in EOBD, while miR-323-3p expression was reduced in both EOBD and LOBD patients relative to HC. Moreover, compared to HC, EOBD and LOBD showed decreased FA in the left posterior thalamic radiation and the left anterior corona radiata, respectively. Finally, after Bonferroni correction, EOBD patients showed a negative correlation between miR-323-3p and FA in the left tapetum. Our results shed light on a possible interaction between miRNA expression and WM modifications in BD. However, further research is needed to better characterize the role of miRNA by FA interaction in BD pathophysiology.

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Fig. 1: EL differences in miR-20a, mi-R-299-5p and miR-323-3p among the three groups.
Fig. 2: FA differences in the six regions surviving Bonferroni correction.

Data availability

The data will be made available upon reasonable request to the corresponding author.

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Acknowledgements

This study was supported by the Italian Ministry of Health (GR-2019-12369100 to Maria Serpente and Giuseppe Delvecchio). Andrea Arighi and Daniela Galimberti were supported by Centro Dino Ferrari". Paolo Brambilla was partially supported by grants from the Italian Ministry of Education and Research - MUR (‘Dipartimenti di Eccellenza’ Programme 2023–27 - Dept. of Pathophysiology and Transplantation, Università degli Studi di Milano), the Italian Ministry of Health (Hub Life Science- Diagnostica Avanzata, HLS-DA, PNC-E3-2022-23683266– CUP: C43C22001630001 / MI-0117; Ricerca Corrente 2026), by the ERANET Neuron JTC 2023 (ERP-2023-23684211-ResilNet) and Eranet Neuron JTC 2024 (ER-2024-23684536 - BRAWO Project).

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  1. These authors contributed equally: Giuseppe Delvecchio, Giovanni Videtta.

Authors and Affiliations

  1. Department of Neurosciences and Mental Health, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy

    Giuseppe Delvecchio, Giovanni Videtta, Camilla Pansitta, Lorena Di Consoli, Adele Ferro, Antonio Callari, Cecilia Prunas & Paolo Brambilla

  2. Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

    Giuseppe Delvecchio, Letizia Squarcina, Fabio Maria Triulzi & Paolo Brambilla

  3. Department of Biomedical Sciences for Health, University of Milan, Milan, Italy

    Giovanni Videtta

  4. Neurodegenerative Diseases Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy

    Maria Serpente, Chiara Fenoglio, Elio Scarpini, Andrea Arighi & Daniela Galimberti

  5. Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy

    Chiara Fenoglio & Daniela Galimberti

  6. Department of Neuroradiology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy

    Elisa Scola & Fabio Maria Triulzi

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  1. Giuseppe Delvecchio
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Contributions

GD designed this particular study. GD and GV prepared the first version of the manuscript. GD, GV and LS carried out the data analysis. MS and CF extracted miRNA content from NDEVs. AA, ES and DG coordinated the blood sample extraction. LDC, AF and PB coordinated subject recruitment and sample collection. PB coordinated data management. AC and CP were involved in patient enrolment and assessment. ES and FMT were involved in MRI data acquisition. All authors revised and approved the final version of the manuscript.

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Correspondence to Giuseppe Delvecchio or Paolo Brambilla.

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Delvecchio, G., Videtta, G., Serpente, M. et al. The role of neural derived extracellular vesicles micro-ribonucleic acid cargo in white matter integrity in early-onset and late-onset bipolar disorder. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03449-y

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