Hippocampal Neuroinflammation, Functional Connectivity, and Depressive Symptoms in Multiple Sclerosis

Alessandro Colasanti; Qi Guo; Paolo Giannetti; Matthew B Wall; Rexford D Newbould; Courtney Bishop; Mayca Onega; Richard Nicholas; Olga Ciccarelli; Paolo A Muraro; Omar Malik; David R Owen; Allan H Young; Roger N Gunn; Paola Piccini; Paul M Matthews; Eugenii A Rabiner

doi:10.1016/j.biopsych.2015.11.022

Hippocampal Neuroinflammation, Functional Connectivity, and Depressive Symptoms in Multiple Sclerosis

Alessandro Colasanti, Qi Guo, Paolo Giannetti, Matthew B Wall, Rexford D Newbould, Courtney Bishop, Mayca Onega, Richard Nicholas, Olga Ciccarelli, Paolo A Muraro, Omar Malik, David R Owen, Allan H Young, Roger N Gunn, Paola Piccini, Paul M Matthews, Eugenii A Rabiner

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Abstract

BACKGROUND: Depression, a condition commonly comorbid with multiple sclerosis (MS), is associated more generally with elevated inflammatory markers and hippocampal pathology. We hypothesized that neuroinflammation in the hippocampus is responsible for depression associated with MS. We characterized the relationship between depressive symptoms and hippocampal microglial activation in patients with MS using the 18-kDa translocator protein radioligand [(18)F]PBR111. To evaluate pathophysiologic mechanisms, we explored the relationships between hippocampal neuroinflammation, depressive symptoms, and hippocampal functional connectivities defined by resting-state functional magnetic resonance imaging.

METHODS: The Beck Depression Inventory (BDI) was administered to 11 patients with MS and 22 healthy control subjects before scanning with positron emission tomography and functional magnetic resonance imaging. We tested for higher [(18)F]PBR111 uptake in the hippocampus of patients with MS relative to healthy control subjects and examined the correlations between [(18)F]PBR111 uptake, BDI scores, and hippocampal functional connectivities in the patients with MS.

RESULTS: Patients with MS had an increased hippocampal [(18)F]PBR111 distribution volume ratio relative to healthy control subjects (p = .024), and the hippocampal distribution volume ratio was strongly correlated with the BDI score in patients with MS (r = .86, p = .006). Hippocampal functional connectivities to the subgenual cingulate and prefrontal and parietal regions correlated with BDI scores and [(18)F]PBR111 distribution volume ratio.

CONCLUSIONS: Our results provide evidence that hippocampal microglial activation in MS impairs the brain functional connectivities in regions contributing to maintenance of a normal affective state. Our results suggest a rationale for the responsiveness of depression in some patients with MS to effective control of brain neuroinflammation. Our findings also lend support to further investigation of the role of inflammatory processes in the pathogenesis of depression more generally.

Original language	English
Pages (from-to)	62-72
Journal	Biological psychiatry
Volume	80
Issue number	1
Early online date	5 Dec 2015
DOIs	https://doi.org/10.1016/j.biopsych.2015.11.022
Publication status	Published - 1 Jul 2016

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Hippocampal Neuroinflammation_COLASANTI_Accepted 25Nov2015_GOLD VoRFinal published version, 1.34 MBLicence: CC BY

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Colasanti, A., Guo, Q., Giannetti, P., Wall, M. B., Newbould, R. D., Bishop, C., Onega, M., Nicholas, R., Ciccarelli, O., Muraro, P. A., Malik, O., Owen, D. R., Young, A. H., Gunn, R. N., Piccini, P., Matthews, P. M., & Rabiner, E. A. (2016). Hippocampal Neuroinflammation, Functional Connectivity, and Depressive Symptoms in Multiple Sclerosis. Biological psychiatry, 80(1), 62-72. https://doi.org/10.1016/j.biopsych.2015.11.022

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title = "Hippocampal Neuroinflammation, Functional Connectivity, and Depressive Symptoms in Multiple Sclerosis",

abstract = "BACKGROUND: Depression, a condition commonly comorbid with multiple sclerosis (MS), is associated more generally with elevated inflammatory markers and hippocampal pathology. We hypothesized that neuroinflammation in the hippocampus is responsible for depression associated with MS. We characterized the relationship between depressive symptoms and hippocampal microglial activation in patients with MS using the 18-kDa translocator protein radioligand [(18)F]PBR111. To evaluate pathophysiologic mechanisms, we explored the relationships between hippocampal neuroinflammation, depressive symptoms, and hippocampal functional connectivities defined by resting-state functional magnetic resonance imaging.METHODS: The Beck Depression Inventory (BDI) was administered to 11 patients with MS and 22 healthy control subjects before scanning with positron emission tomography and functional magnetic resonance imaging. We tested for higher [(18)F]PBR111 uptake in the hippocampus of patients with MS relative to healthy control subjects and examined the correlations between [(18)F]PBR111 uptake, BDI scores, and hippocampal functional connectivities in the patients with MS.RESULTS: Patients with MS had an increased hippocampal [(18)F]PBR111 distribution volume ratio relative to healthy control subjects (p = .024), and the hippocampal distribution volume ratio was strongly correlated with the BDI score in patients with MS (r = .86, p = .006). Hippocampal functional connectivities to the subgenual cingulate and prefrontal and parietal regions correlated with BDI scores and [(18)F]PBR111 distribution volume ratio.CONCLUSIONS: Our results provide evidence that hippocampal microglial activation in MS impairs the brain functional connectivities in regions contributing to maintenance of a normal affective state. Our results suggest a rationale for the responsiveness of depression in some patients with MS to effective control of brain neuroinflammation. Our findings also lend support to further investigation of the role of inflammatory processes in the pathogenesis of depression more generally.",

author = "Alessandro Colasanti and Qi Guo and Paolo Giannetti and Wall, {Matthew B} and Newbould, {Rexford D} and Courtney Bishop and Mayca Onega and Richard Nicholas and Olga Ciccarelli and Muraro, {Paolo A} and Omar Malik and Owen, {David R} and Young, {Allan H} and Gunn, {Roger N} and Paola Piccini and Matthews, {Paul M} and Rabiner, {Eugenii A}",

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month = jul,

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Colasanti, A , Guo, Q, Giannetti, P, Wall, MB, Newbould, RD, Bishop, C, Onega, M, Nicholas, R, Ciccarelli, O, Muraro, PA, Malik, O, Owen, DR, Young, AH, Gunn, RN, Piccini, P, Matthews, PM & Rabiner, EA 2016, 'Hippocampal Neuroinflammation, Functional Connectivity, and Depressive Symptoms in Multiple Sclerosis', Biological psychiatry, vol. 80, no. 1, pp. 62-72. https://doi.org/10.1016/j.biopsych.2015.11.022

TY - JOUR

T1 - Hippocampal Neuroinflammation, Functional Connectivity, and Depressive Symptoms in Multiple Sclerosis

AU - Colasanti, Alessandro

AU - Guo, Qi

AU - Giannetti, Paolo

AU - Wall, Matthew B

AU - Newbould, Rexford D

AU - Bishop, Courtney

AU - Onega, Mayca

AU - Nicholas, Richard

AU - Ciccarelli, Olga

AU - Muraro, Paolo A

AU - Malik, Omar

AU - Owen, David R

AU - Young, Allan H

AU - Gunn, Roger N

AU - Piccini, Paola

AU - Matthews, Paul M

AU - Rabiner, Eugenii A

PY - 2016/7/1

Y1 - 2016/7/1

N2 - BACKGROUND: Depression, a condition commonly comorbid with multiple sclerosis (MS), is associated more generally with elevated inflammatory markers and hippocampal pathology. We hypothesized that neuroinflammation in the hippocampus is responsible for depression associated with MS. We characterized the relationship between depressive symptoms and hippocampal microglial activation in patients with MS using the 18-kDa translocator protein radioligand [(18)F]PBR111. To evaluate pathophysiologic mechanisms, we explored the relationships between hippocampal neuroinflammation, depressive symptoms, and hippocampal functional connectivities defined by resting-state functional magnetic resonance imaging.METHODS: The Beck Depression Inventory (BDI) was administered to 11 patients with MS and 22 healthy control subjects before scanning with positron emission tomography and functional magnetic resonance imaging. We tested for higher [(18)F]PBR111 uptake in the hippocampus of patients with MS relative to healthy control subjects and examined the correlations between [(18)F]PBR111 uptake, BDI scores, and hippocampal functional connectivities in the patients with MS.RESULTS: Patients with MS had an increased hippocampal [(18)F]PBR111 distribution volume ratio relative to healthy control subjects (p = .024), and the hippocampal distribution volume ratio was strongly correlated with the BDI score in patients with MS (r = .86, p = .006). Hippocampal functional connectivities to the subgenual cingulate and prefrontal and parietal regions correlated with BDI scores and [(18)F]PBR111 distribution volume ratio.CONCLUSIONS: Our results provide evidence that hippocampal microglial activation in MS impairs the brain functional connectivities in regions contributing to maintenance of a normal affective state. Our results suggest a rationale for the responsiveness of depression in some patients with MS to effective control of brain neuroinflammation. Our findings also lend support to further investigation of the role of inflammatory processes in the pathogenesis of depression more generally.

AB - BACKGROUND: Depression, a condition commonly comorbid with multiple sclerosis (MS), is associated more generally with elevated inflammatory markers and hippocampal pathology. We hypothesized that neuroinflammation in the hippocampus is responsible for depression associated with MS. We characterized the relationship between depressive symptoms and hippocampal microglial activation in patients with MS using the 18-kDa translocator protein radioligand [(18)F]PBR111. To evaluate pathophysiologic mechanisms, we explored the relationships between hippocampal neuroinflammation, depressive symptoms, and hippocampal functional connectivities defined by resting-state functional magnetic resonance imaging.METHODS: The Beck Depression Inventory (BDI) was administered to 11 patients with MS and 22 healthy control subjects before scanning with positron emission tomography and functional magnetic resonance imaging. We tested for higher [(18)F]PBR111 uptake in the hippocampus of patients with MS relative to healthy control subjects and examined the correlations between [(18)F]PBR111 uptake, BDI scores, and hippocampal functional connectivities in the patients with MS.RESULTS: Patients with MS had an increased hippocampal [(18)F]PBR111 distribution volume ratio relative to healthy control subjects (p = .024), and the hippocampal distribution volume ratio was strongly correlated with the BDI score in patients with MS (r = .86, p = .006). Hippocampal functional connectivities to the subgenual cingulate and prefrontal and parietal regions correlated with BDI scores and [(18)F]PBR111 distribution volume ratio.CONCLUSIONS: Our results provide evidence that hippocampal microglial activation in MS impairs the brain functional connectivities in regions contributing to maintenance of a normal affective state. Our results suggest a rationale for the responsiveness of depression in some patients with MS to effective control of brain neuroinflammation. Our findings also lend support to further investigation of the role of inflammatory processes in the pathogenesis of depression more generally.

U2 - 10.1016/j.biopsych.2015.11.022

DO - 10.1016/j.biopsych.2015.11.022

M3 - Article

C2 - 26809249

SN - 0006-3223

VL - 80

SP - 62

EP - 72

JO - Biological psychiatry

JF - Biological psychiatry

IS - 1

ER -

Hippocampal Neuroinflammation, Functional Connectivity, and Depressive Symptoms in Multiple Sclerosis

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