Inflammatory cytokines influence measures of white matter integrity in Bipolar Disorder
Abstract
Background Bipolar Disorder (BD) is associated with elevated biomarkers of cell-mediated immune activation and inflammation and with signs of widespread disruption of white matter (WM) integrity in adult life. Consistent findings in animal models link WM damage in inflammatory diseases of the brain and serum levels of cytokines.Methods With an exploratory approach, we tested the effects of 22 serum analytes, including pro- and anti-inflammatory cytokines and neurotrophic/hematopoietic factors, on DTI measures of WM microstructure in a sample of 31 patients with a major depressive episode in course of BD. We used whole brain tract-based spatial statistics in the WM skeleton with threshold-free cluster enhancement of DTI measures of WM microstructure: axial (AD), radial (RD), and mean diffusivity (MD), and fractional anisotropy (FA).Results The inflammation-related cytokines TNF-α, IL-8, IFN-γ and IL-10, and the growth factors IGFBP2 and PDGF-BB, shared the same significant associations with lower FA, and higher MD and RD, in large overlapping networks of WM fibers mostly located in the anterior part of the brain and including corpus callosum, cingulum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi, uncinate, forceps, corona radiata, thalamic radiation, internal capsule.Conclusions Higher RD is thought to signify increased space between fibers, suggesting demyelination or dysmyelination. The pattern of higher RD and MD with lower FA suggests that inflammation-related cytokine and growth factor levels inversely associate with integrity of myelin sheaths. The activated inflammatory response system might contribute to BD pathophysiology by hampering structural connectivity in critical cortico-limbic networks.
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In patients with a depressive episode in major depressive disorder or bipolar disorder, IL-8, IL-10, TNF-α, and IFN-γ are associated with white matter microstructure.
“and of IL-8, IL-10, TNF-α, IFN-γ with white matter (WM) microstructure, with levels of inflammatory cytokines being inversely related with measures of WM integrity (Benedetti et al., 2016)”
From Persistent psychopathology and neurocognitive impairment in COVID-19 survivors: effect of inflammatory biomarkers at three-month follow-up (2021) · cites this paper as Benedetti et al., 2016
In the same patient group, inflammatory cytokine levels are inversely related to measures of white matter integrity.
“with levels of inflammatory cytokines being inversely related with measures of WM integrity (Benedetti et al., 2016)”
From Persistent psychopathology and neurocognitive impairment in COVID-19 survivors: effect of inflammatory biomarkers at three-month follow-up (2021) · cites this paper as Benedetti et al., 2016
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Self-citationCorticolimbic connectivity as a possible biomarker for bipolar disorder
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Self-citationVai, B., Poletti, S., Radaelli, D., Dallaspezia, S., Bulgarelli, C., Locatelli, C., Bollettini, I., Falini, A., Colombo, C., Smeraldi, E., et al. (2015) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2015.07.015 · Cited by 42 · see citing works
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Disruption of white matter integrity marks poor antidepressant response in bipolar disorder
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BIOLOGICAL ACTIVITY OF INTERLEUKIN-10 IN THE CENTRAL NERVOUS SYSTEM
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Mazza, M. G., Palladini, M., De Lorenzo, R., Magnaghi, C., Poletti, S., Furlan, R., Ciceri, F., Rovere-Querini, P., & Benedetti, F. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2021.02.021 · Cited by 513 · see citing works
“, 2020a); and of IL-8, IL-10, TNF-α, IFN-γ with white matter (WM) microstructure, with levels of inflammatory cytokines being inversely related with measures of WM integrity (Benedetti et al., 2016).”
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Schlaaff, K., Dobrowolny, H., Frodl, T., Mawrin, C., Gos, T., Steiner, J., & Bogerts, B. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.04.021 · Cited by 107 · see citing works
Mao, R., Zhang, C., Chen, J., Zhao, G., Zhou, R., Wang, F., Xu, J., Yang, T., Su, Y., Huang, J., et al. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2018.04.115 · Cited by 68 · see citing works
Benedetti, F., Poletti, S., Locatelli, C., Mazza, E., Lorenzi, C., Vitali, A., Riberto, M., Brioschi, S., Vai, B., Bollettini, I., et al. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.10.011 · Cited by 64 · see citing works
Higher Baseline Interleukin-1β and TNF-α Hamper Antidepressant Response in Major Depressive Disorder
Benedetti, F., Poletti, S., Vai, B., Mazza, M. G., Lorenzi, C., Brioschi, S., Aggio, V., Branchi, I., Colombo, C., Furlan, R., et al. (2021) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2020.11.009 · Cited by 62 · see citing works
Self-citationMarkers of neuroinflammation influence measures of cortical thickness in bipolar depression
Poletti, S., Leone, G., Hoogenboezem, T. A., Ghiglino, D., Vai, B., de Wit, H., Wijkhuijs, A. J. M., Locatelli, C., Colombo, C., Drexhage, H. A., et al. (2019) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2019.01.009 · Cited by 54 · see citing works
Self-citationAntidepressant psychopharmacology: is inflammation a future target?
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Self-citationMelloni, E. M. T., Poletti, S., Vai, B., Bollettini, I., Colombo, C., & Benedetti, F. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.02.015 · Cited by 34 · see citing works
- Authors
- Benedetti, F., Poletti, S., Hoogenboezem, T. A., Mazza, E., Ambrée, O., de Wit, H., Wijkhuijs, A. J. M., Locatelli, C., Bollettini, I., Colombo, C., Arolt, V., & Drexhage, H. A.
- Affiliations
- Vita-Salute San Raffaele University (IT)
- Erasmus MC (NL)
- University of Münster (DE)
- Corresponding author
- Benedetti, Francesco
- ORCID
- Venue
- Journal of Affective Disorders
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 202
- Pages
- 1-9
- ISSN
- 0165-0327 (ISSN-L)
- OpenAlex
- W2254802873
- Cited by
- 151
- References
- 102
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 21 · 2023: 15 · 2022: 18 · 2021: 19 · 2020: 16 · 2019: 18 · 2018: 9 · 2017: 7 · 2016: 6
- FWCI
- 11.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Affective Disorders (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Keywords
- bipolar disorder, inflammatory cytokines, white matter integrity, major depressive episode, diffusion tensor imaging, fractional anisotropy, radial diffusivity, mean diffusivity, TNF-α, interleukin-8, interferon-gamma, IL-10, IGFBP-2, PDGF-BB, demyelination, myelin sheath, structural connectivity, cortico-limbic network, serum biomarkers, neuroinflammation
- MeSH terms
- Adult, Bipolar Disorder, Major Depressive Disorder, Depressive Disorder, Major, Female, Humans, Male, Middle Aged, Cytokines, Anisotropy, Internal Capsule, Diffusion Tensor Imaging, White Matter
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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