title: Hippocampal Neuroinflammation, Functional Connectivity, and Depressive Symptoms in Multiple Sclerosis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom; Centre for Affective Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Imanova Centre for Imaging Sciences, London, United Kingdom. Electronic address: alessandro.colasanti@kcl.ac.uk.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Colasanti
authors.affiliation: Imanova Centre for Imaging Sciences, London, United Kingdom.
authors.forename: Qi
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Paolo
authors.initials: P
authors.lastname: Giannetti
authors.affiliation: Imanova Centre for Imaging Sciences, London, United Kingdom.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Wall
authors.affiliation: Imanova Centre for Imaging Sciences, London, United Kingdom.
authors.forename: Rexford D
authors.initials: RD
authors.lastname: Newbould
authors.affiliation: Imanova Centre for Imaging Sciences, London, United Kingdom.
authors.forename: Courtney
authors.initials: C
authors.lastname: Bishop
authors.affiliation: Imanova Centre for Imaging Sciences, London, United Kingdom.
authors.forename: Mayca
authors.initials: M
authors.lastname: Onega
authors.affiliation: Imperial College Healthcare National Health Service Trust, London, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Nicholas
authors.affiliation: Department of Neuroinflammation, University College London Institute of Neurology, London, United Kingdom; National Institute of Health Research Biomedical Research Centre at University College London Hospitals, London, United Kingdom.
authors.forename: Olga
authors.initials: O
authors.lastname: Ciccarelli
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Muraro
authors.affiliation: Imperial College Healthcare National Health Service Trust, London, United Kingdom.
authors.forename: Omar
authors.initials: O
authors.lastname: Malik
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: Owen
authors.affiliation: Centre for Affective Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
authors.forename: Allan H
authors.initials: AH
authors.lastname: Young
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom; Imanova Centre for Imaging Sciences, London, United Kingdom.
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Paola
authors.initials: P
authors.lastname: Piccini
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Matthews
authors.affiliation: Psychological Medicine, and Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Imanova Centre for Imaging Sciences, London, United Kingdom.
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
mesh_terms: D000328:Adult; D063132:Connectome / Q000379:methods*; D003863:Depression / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D017628:Microglia / Q000378:metabolism; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism; D015213:Neuroimmunomodulation; D049268:Positron-Emission Tomography; D011725:Pyridines
chemical_list: C550561:2-(6-chloro-2-(4-(3-fluoropropoxy)phenyl)imidazo(1,2-a)pyridin-3-yl)-N,N-diethylacetamide; D011725:Pyridines
keywords: Depression; Hippocampus; Multiple sclerosis; Neuroimaging; Neuroinflammation; TSPO
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