Volume, metabolites and neuroinflammation of the hippocampus in bipolar disorder - A combined magnetic resonance imaging and positron emission tomography study.
BACKGROUND
The hippocampus is one of the brain regions that is involved in several pathophysiological theories about bipolar disorder (BD), such as the neuroinflammation theory and the corticolimbic metabolic dysregulation theory. We compared hippocampal volume and hippocampal metabolites in bipolar I disorder (BD-I) patients versus healthy controls (HCs) with magnetic resonance imaging (MRI) and spectroscopy (MRS). We post hoc investigated whether hippocampal volume and hippocampal metabolites were associated with microglial activation and explored if potential illness modifying factors affected these hippocampal measurements and whether these were associated with experienced mood and functioning.


METHODS
Twenty-two BD-I patients and twenty-four HCs were included in the analyses. All subjects underwent psychiatric interviews as well as an MRI scan, including a T1 scan and PRESS magnetic resonance spectroscopy (MRS). Volumetric analysis was performed with Freesurfer. MRS quantification was performed with LC Model. A subgroup of 14 patients and 11 HCs also underwent a successful [(11)C]-(R)-PK11195 neuroinflammation positron emission tomography scan.


RESULTS
In contrast to our hypothesis, hippocampal volumes were not decreased in patients compared to HC after correcting for individual whole-brain volume variations. We demonstrated decreased N-acetylaspartate (NAA)+N-acetyl-aspartyl-glutamate (NAAG) and creatine (Cr)+phosphocreatine (PCr) concentrations in the left hippocampus. In the explorative analyses in the left hippocampus we identified positive associations between microglial activation and the NAA+NAAG concentration, between alcohol use and NAA+NAAG concentration, between microglial activation and the depression score and a negative relation between Cr+PCr concentration and experienced occupational disability. Duration of illness associated positively with volume bilaterally.


CONCLUSIONS
Compared to HCs, the decreased NAA+NAAG concentration in the left hippocampus of BD-I patients suggests a decreased neuronal integrity in this region. In addition we found a positive relation between microglial activation and neuronal integrity in vivo, corresponding to a differentiated microglial function where some microglia induce apoptosis while others stimulate neurogenesis.
University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands; Radiology Morphological Solutions, Berkel en Rodenrijs, The Netherlands. Electronic address: b.c.m.haarman@umcg.nl.
Bartholomeus C M 'Benno'
BC
Haarman
University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of General Practice, Groningen, The Netherlands.
Huibert
H
Burger
University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen, The Netherlands.
Janine
J
Doorduin
University of Groningen, Neuroimaging Center, Groningen, The Netherlands.
Remco J
RJ
Renken
University of Groningen, Neuroimaging Center, Groningen, The Netherlands.
Anita J
AJ
Sibeijn-Kuiper
University of Groningen, Neuroimaging Center, Groningen, The Netherlands.
Jan-Bernard C
JB
Marsman
University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen, The Netherlands.
Erik F J
EF
de Vries
University of Groningen, University Medical Center Groningen, Department of Radiology, Groningen, The Netherlands.
Jan Cees
JC
de Groot
Erasmus MC, Department of Immunology, Rotterdam, The Netherlands.
Hemmo A
HA
Drexhage
Radiology Morphological Solutions, Berkel en Rodenrijs, The Netherlands.
Richard
R
Mendes
University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands.
Willem A
WA
Nolen
University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands.
Rixt F
RF
Riemersma-Van der Lek
D000328:Adult; D000368:Aged; D001714:Bipolar Disorder / Q000000981:diagnostic imaging* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002250:Carbon Radioisotopes / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000000981:diagnostic imaging* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000000981:diagnostic imaging* / Q000378:metabolism; D007546:Isoquinolines / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D017628:Microglia / Q000378:metabolism*; D008875:Middle Aged; D064847:Multimodal Imaging; D049268:Positron-Emission Tomography / Q000379:methods*; D055815:Young Adult
D002250:Carbon Radioisotopes; C000615233:Carbon-11; D007546:Isoquinolines; C037850:PK 11195
Bipolar disorder; MRI; MRS; Microglial activation; Morphology; Neuroinflammation; PET