University of Groningen

The Dysregulated BrainHaarman, Bartholomeus Cornelius Maria

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Bartholomeus C.M. Haarman

Adapted from Haarman BCM, Riemersma - Van der Lek RF, Ruhé HG,

Groot JC, Nolen WA, Doorduin J. Bipolar Disorders. In: Dierckx RAJO,

Otte A, de Vries EFJ, Waarde A, den Boer JA, editors. PET and SPECT in

Psychiatry. Heidelberg: Springer Berlin Heidelberg; 2014. p. 223–51.

General background

CHAPTER 1

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IntroductionBipolar disorder: diagnostic descriptionBipolar disorder (BD)1 is a mood disorder characterized by episodic pathologic distur-bances in mood: (hypo)manic episodes and depressive episodes which alternate with euthymic periods, i.e. with normal mood. BD has to be distinguished from (unipolar) major depressive disorder (MDD), which is characterized by only depressive episodes. According to DSM-IV, the core criterion of a (hypo)manic episode is the occurrence of a pathologically elated (euphoria), expansive or irritable mood. DSM-5 added increased energy or activity to this list. In addition to these core criteria, there are other symptoms such as inflated self-esteem or grandiosity, decreased need for sleep, being more talkative than usual, flight of ideas, distractibility, increase in goal-directed activity or psychomotor agitation and excessive involvement in plea-surable activities that have a high potential for painful consequences. A depressive episode consists of at least one of the core symptoms: depressed mood and loss of interest or pleasure, completed with symptoms such as sleep problems, psychomotor changes, fatigue or loss of energy, feelings of worthlessness or excessive feelings of guilt, difficulty concentrating or making decisions and recurrent thoughts of death1. Two types of BD are recognized: bipolar I disorder (BD-I) and bipolar II disorder (BD-II), characterized by the occurrence of manic episode(s) or by only hypomanic episode(s), respectively. The difference between manic and hypomanic episodes (and thus between BD-I and BD-II) is that manic episodes are associated with marked impairment in occupational, relational or social functioning, which can lead to hospitalization, while hypomanic episodes do not have this marked impairment and do not lead to hospitalization. When manic and depressive symptoms co-occur (or alternate very quickly) in the same episode, in DSM-IV it is labeled as a mixed episode and in DSM-5 as a bipolar disorder, manic or depressive episode with mixed features. Manic, depressive and mixed episodes can also be complicated by the presence of concurrent psychotic symptoms. Besides the mood symptoms, many patients with BD also show cognitive dysfunctions which may persist during euthymic periods, and which involve disturbances in various domains such as attention, verbal memory and executive functioning2,3.

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General background

1Epidemiology and burden of diseaseThe lifetime prevalence of BD is about 2% across different countries, women being affected as frequently as men4,5. Across the world, the disorder is sixth among all health conditions in terms of causing disability6 with poor clinical and functional outcome7, increased risk for suicidality8 and significant societal costs9. It has been calculated that in the United States the average cost per case ranged from $11,720 to $624,785, based on the severity of the illness9. In the European countries societal costs for managing BD are considered to be high as well10–12.

Risk factorsEstablished risk factors for BD include history of BD, and interestingly also other psychiatric disorders, in parents or siblings; severe childhood adversities; and excessive alcohol use, although the last two are viewed as triggers rather than causes in the presence of biological vulnerability13,14. A recent systematic review concluded that it is still unclear whether perinatal infection has a role in the etiology of BD15. This is particularly relevant in view of the present thesis.

Diagnostic and treatment complicationsAlthough the clinical picture seems clear at first glance, making the diagnosis is more complicated in practice. On average, there is a time lag of about 6 years between the first episode and the making of the right diagnosis, and another six years before the start of adequate treatment. This is in most cases partly impeded by the precedence of depressive episodes without obvious (hypo)manic symptoms at the beginning of the disease16. Because antidepressants appear less effective for the treatment of bipolar depressive episodes than for unipolar MDD17, delayed diagnosis often leads to prolonged illness and dysfunction.

Current pathophysiological modelsIt is generally accepted that the cause of BD is multifactorial, with multiple genes making someone vulnerable, and with psychological and social factors causing the genes to be expressed. Moreover, somatic factors are assumed to play a role. To unravel the complex interplay between genotype and phenotype researchers have tried to find intermediary processes that are related to both the underlying geno-type and the ultimate phenotype. Over the last 50 years several pathophysiological theories have been proposed for BD. Of these, we will shortly address the monoamine theory, the neuroinflammation theory, the white matter tract integrity disruption theory and the mitochondrial dysfunction theory.

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Monoamine theorySince the 1960s, after the discovery of the first antipsychotic and antidepressant drugs, the monoamine theory has been the leading pathophysiological theory for various psychiatric disorders, including MDD and BD18–20. Based on the working mechanism of these drugs, disruption of serotonergic and noradrenergic neurotrans-mission in mood disorders and dopaminergic neurotransmission in schizophrenia underlies these disorders. In this regard noradrenaline is related to alertness and energy as well as to anxiety and attention; lack of serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward19. Although the neurotransmitter theory originated in the discovery of psycho tropic medication and has also given rise to the development of new pharmacological treatments, this model has also been criticized. The model is often regarded to be (too) simple, not explaining all patients’ symptoms, and having an effect that likely depends more on indirect effects, e.g. receptor changes21.

Corticolimbic dysregulation theoryBased on extensive molecular imaging results (see chapter 6), complemented with functional MRI (fMRI) research, overall hyperactivation of limbic brain regions in BD patients relative to controls were displayed in a meta-analysis, along with an over-all hypoactivation of frontal regions22 (see figure 1). This corresponds to findings in other mood disorders, especially MDD, which is known as the corticolimbic theory of depression23. Hypo- and hyperactivity in frontal and limbic regions, respectively, was most pronounced in manic patients, although also present in depressed and euthymic ones. Depressed patients exhibit more pronounced hypoactivation of frontal regions than euthymic patients, whereas euthymic patients display, surprisingly, more hyper-activity in limbic regions than their depressed counterparts.The corticolimbic theory has some overlap with several neurological networks that have been described and are thought to lie at the basis of physiological emotional processing. These networks can be divided into circuits that lie within the cerebral cortex and those that extend to other parts of the brain24. The limbic-cortical-striatal-pallidal-thalamic (LCSPT) circuit connects the PFC to the limbic and subcortical areas of the brain25. This LCSPT circuit is thought to be particularly important in the mediation of emotional expression, because of its relation to visceral control structures26.The mood related cortico-cortical networks interact with and extend to the LCSPT27 via top-down inhibitory control28. The orbital prefrontal network consists of the central and caudal part of the orbital cortex and the ventrolateral PFC; it includes sensory association areas such as the visual associated areas in the inferior temporal cortex and somatic-sensory associated areas in the insula and frontal operculum, as well as the olfactory and taste areas. In addition to sensory integration, this system

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General background

1

codes for affective characteristics of stimuli such as reward, aversion and relative value (salience)26.The medial prefrontal network of cortical areas includes the ventromedial PFC, the dorsolateral PFC, the anterior and posterior cingulate cortex, anterior temporal cortex and the enthorhinal and posterior parahippocampal corteces. This system does not have substantial sensory connections, but is a visceromotor system that is particu-larly involved in introspective functions such as mood and emotion, and in visceral reactions to emotional stimuli24. It is widely known as the “default system”, because in fMRI imaging it appeared activated as a network of areas that become inactive in most tasks that involve external attention29. It has been proposed that the “ventral” orbital prefrontal network and the “dorsal” medial prefrontal network are reciprocally connected and that the orbital PFC may mediate connections between higher-order dorsolateral prefrontal regions and subcortical limbic regions such as the amygdala during emotion regulation30.

amygdala

anterior cingulate cortex

prefrontal cortex

subgenual cingulate

orbitofrontal cortex

hypothalamus

hippocampus

raphe nuclei

locus coeruleus

nervus vagus

ventral striatum

pituitary

FIGURE 1 Neuroanatomical regions important in mood disorders

Neuroanatomical regions important in mood disorders. (Adapted from Patrick J. Lynch, medical illustrator, and C. Carl Jaffe, MD, cardiologist76, under the Creative Commons Attribution 2.5 Generic license (CC BY 2.5)).

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Neuroinflammation theoryThe “macrophage theory of depression” postulates an aberrant pro-inflammatory state of monocytes/macrophages in patients with mood disorder, and considers this aberrant state of the cells as a driving force behind the illness31. The theory is founded on a higher frequency of autoimmune diseases in mood disorders, aberrant pro-inflammatory cytokines and elevated pro-inflammatory gene expression in monocytes. Autoimmune thyroiditis is considered to be an endophenotype of BD32. Patients with BD and MDD have a raised prevalence of autoimmune thyroiditis33–35. Not only BD patients, but also their offspring (affected as well as non-affected) and their monozygotic (affected and non-affected) and dizygotic (affected, but not as much unaffected) co-twins have a raised prevalence of autoimmune thyroiditis32,36. It was hypothesized that an activated inflammatory response system in monocytes consti-tutes the shared genetic susceptibility factor for both BD and thyroid autoimmunity; this has led to the extensive investigations of neopterine, IL-1β, IL-6 and TNF-α in mood disorders, and in particular in MDD. With regard to the serum concentration of these compounds, increased levels were also described in BD when compared to controls, although not in all studies37,38. To investigate the pro-inflammatory state of monocytes in a more precise and robust manner, a Q-PCR analysis of CD14+ purified monocytes was performed in which 22 mRNAs for inflammatory, chemokinesis/mo-tility, cell survival/apoptosis and MAP kinases pathway molecules were found to have an increased expression in BD patients compared to controls39. Interactions between the immune system and the HPA-axis, as well as interactions between the immune system and the neuronal system via indoleamine 2,3 dioxygen-ase (IDO) pathways have been suggested to result in mood disorder symptomatology. The HPA-axis is a complex set of direct influences and feedback interactions among the hypothalamus, the pituitary gland, and the adrenal glands that controls reactions to stress and regulates many body processes. The adrenal glands produce cortisol, which is a major stress hormone and has effects on many tissues in the body, includ-ing the brain, where it binds to glucocorticoid receptors in the PFC, the amygdala and the hippocampus40. Moreover, glucocorticoid insensitivity has been associated with a higher risk of developing a depressive episode40. In various in vivo and ex vivo studies a strong association between the activation of the inflammatory response system and glucocorticoid insensitivity has been demonstrated, linking at least in part the overproduction of pro-inflammatory cytokines to the HPA-axis disturbances in major mood disorders41–43. Tryptophan, the precursor amino acid of serotonin, can also be metabolized to downstream metabolites, known as kynurenines, via an alternative pathway. IDO is an oxygenase that catabolizes the first and rate-limiting step in this oxidative degradation. The IDO activity in monocytes/macrophages is enhanced by proin-

13

General background

1flammatory cytokines, e.g. during infections and when there is physical or mental stress44. Under such circumstances tryptophan breakdown is increased, making it less available for serotonin synthesis. When tryptophan is degraded, the next in vivo product is kynurenine, which is the first metabolite of tryptophan45. This kynurenine is again broken down into two pathways: (1) a neuroprotective, kynurenic acid, NMDA receptor antagonist pathway and (2) a neurotoxic 3-hydroxy kynurenine and quinolinic acid, NMDA receptor agonist pathway46. In the brain, this latter part of tryptophan catabolism, the kynurenine pathway, occurs in the astrocytes and microglia where astrocytes produce mainly neuroprotective kynurenic acid while macrophages produce mainly neurotoxic metabolites like quinolinic acid. Normally, formation of quinolinic acid is faster, while kynurenic acid has a counteractive pro-tective role against quinolinic acid47. Based on the above, a hypothesis was proposed, that an imbalance between the neurodegenerative and neuroprotective pathways leads to neurodegeneration and brings a person to a chronically depressive episode. This imbalance might be due either to a highly increased neurodegenerative pathway activity or to a lack of sufficient neuroprotective factor activity48. Tryptophan levels and the neuroprotective kynurenic acid were significantly decreased in MDD patients when compared to controls49. Also, in IFN-α treatment of hepatitis C patients, associated with depression and fatigue, IFN-α was found to up-regulate the expression of IDO50. Furthermore, the decrease of plasma tryptophan and the increase of kynurenine and neopterine during IFN-α treatment were found to correlate with the development of depression51,52.Molecular imaging can be of added importance in investigating the neuroinflam-mation theory. Microglia are the central cells involved in immune regulation in the brain. When activated, these cells present the translocator protein (TSPO) on their mitochondrial membrane53. Using the positron emission tomography (PET) ligand 11C-PK11195, areas of microglia activation in the brain can be visualized. Besides in various neurological disorders, microglia activation has been found in schizophrenia, where a clear focus of neuroinflammation was found in the hippocampus54,55.

White matter microstructure integrity disturbancesInterest in the white matter tracts in BD started with the observation of diffuse cor-tical and callosal white matter pathology in structural MRI studies in BD patients56,57. With the development of diffusion tensor imaging (DTI), a MRI technique allowing for the investigation of the preferred direction and rate of water diffusion, the integ-rity of the white matter microstructure can be investigated in more detail, because in the physiological situation water diffusion is restricted by the axonal structures58. The main parameters derived from DTI are the fractional anisotropy (FA) and mean diffusivity (MD). MD measures the magnitude of water molecule diffusion and FA is an index of the degree of directionality of water diffusivity. FA is reduced in diseased

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states known to be associated with axonal loss and destruction of myelin sheaths in several diseases, e.g. multiple sclerosis, leukoencephalopathies and Alzheimer’s disease59. In BD most studies reported reduced FA and/or elevated MD, compared to controls, involving the prefrontal lobe, corpus callosum, internal capsule, uncinate fasciculus and superior and inferior longitudinal fasciculi, and suggesting a role for white matter microstructure disturbances in BD pathophysiology60. The studies focusing on the specific mood states of BD patients revealed FA to be altered in the different mood states61. In the euthymic state FA was usually found to be increased in the genu of corpus callosum, internal capsule, anterior thalamic radiation and uncinate fasciculus compared to controls, whereas during depressive episodes a lower FA has been shown in the genu of the corpus callosum and in corona radiate compared controls. In mixed samples, higher and lower FA values were found in different brain regions62. The place of white matter microstructure disturbances in the pathophysiology, with regard to other disease mechanisms, is still controversial. It has been suggested that FA changes could be related to inflammation related processes in BD, analogous to multiple sclerosis61.

Mitochondrial dysfunctionUsing various techniques, scientific evidence for a cellular energy metabolism disturbance has been presented. When observed in cell biological research, abnormal mitochondrial morphology is often linked to altered energy metabolism. In BD patients, compared to controls, mitochondria in neurons and fibroblasts have been reported to be smaller and concentrated proportionately more within the perinuclear region than in distal processes of the cells63. Conversely, patients with mitochondrial diseases have a higher lifetime prevalence of MDD (54%) or BD (17%) than the aver-age population64.Magnetic resonance spectroscopy (MRS) is a neuroimaging technique that allows the investigation of the metabolism on a cellular level. This MRI technique provides additional biochemical information of a selected voxel compared to a regular T1 or T2 image. The cellular metabolites are presumed to represent different cell func-tions: N-acetyl-aspertate (NAA) relates to cell viability and choline to cell membrane phospholipid integrity, and creatine is a measure of cellular metabolism65. Creatine plays an important role as a cell energy buffer, especially in high energy consum-ing cells such as muscular and brain cells. Using the creatine energy buffer reaction (figure 2), cells with an abundance of ATP can store energy by converting creatine to phosphocreatine. When in energy demanding circumstances the ATP stock becomes depleted, ATP can temporarily be supplied by reconverting phosphocreatine to creatine until the phosphocreatine stock is also depleted or energy is resupplied

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General background

1

via other routes such as the oxidative phosphorylation. With 31P-MRS, creatine and phosphocreatine concentrations can be measured separately, as can the total concentration of both metabolites. The total concen-tration can also be measured with 1H-MRS, but the separate concentrations to a lesser degree when advanced quantification tools are being used. In BD patients a decreased phosphocreatine66 and reduced total creatine67,68 were described, when compared to controls, supporting the mitochondrial dysfunction theory. Findings in other MRS metabolites such as a reduced pH and increased lactate, exponents of cell metabolism exhaustion, add indirectly to this theory66,69. A study of the nature of the metabolic dysfunction revealed a paradoxical down-regulation of mitochondria-related genes to glucose deprivation in fresh lymphocytes derived from BD patients, whereas control subjects showed an upregulation. This finding would suggest that patients with BD might have impairment in molecular adaptation to energy stress70. However, there is still debate as to whether this dys-regulation is based on mitochondrial DNA disturbances, mitochondria-related nuclear DNA disturbances, or the effects of other mechanisms71.

FIGURE 2 Creatine energy buffer reaction

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Aim and outline of this thesisAlthough multiple pathophysiological theories on BD exist, a comprehensive pathophysiological framework, integrating the various illness models for BD, is still lacking. Since immune cells play an important role, not only protecting neurons from pathogens but as microglia cells also helping in maintaining homeostasis in the brain72,73, they may play a key role in such a framework.This thesis aims to clarify the role of the immune system in the pathophysiology of BD via several different approaches, using bio-assay and neuroimaging techniques. The immune system consists of two parts: the peripheral immune system and the neuroimmune system. Structurally distinct from the peripheral immune system, the neuroimmune system is a system of structures and processes, involving the biochem-ical and electrophysiological interactions between the nervous system and immune system, which protect neurons from pathogens. Unlike the peripheral system, the neuroimmune system is composed primarily of glial cells, in particular microglia72–74.

Part 1: Peripheral immune systemThe first part of the thesis describes studies of the function of the peripheral immune system in BD, focusing on monocyte pro-inflammatory gene-expression and CRP, using bio assay techniques.

Association between monocyte gene-expression and clinical featuresChapter 2 discusses the associations between monocyte pro-inflammatory gene expression and illness characteristics. We a priori hypothesized that pro-inflammatory gene expression would be found more frequently in BD patients with a lifetime history of psychotic symptoms. We go on to explore the associations with the individual manic and depressive symptoms of BD. Then we elucidate the course of the pro-inflammatory gene expression by investigating in more detail the relation between the pro-inflammatory gene expression and age at onset, and duration of illness. Finally, in chapter 2, we examine the association between the current use of psychotropic medication and monocyte pro-inflammatory gene expression.The feature-expression heat map, an in-house developed method used in chapter 2 to visualize the complex associations between symptoms and gene-expression, is explained in more detail in chapter 3.

Monocyte gene-expression: state or trait?In chapter 4 we present the results of the study among the bipolar cohort of the MOODINFLAME project75, in which we investigated whether monocyte pro-inflammatory gene-expression is more a state or more a trait marker. We compare the monocyte pro-inflammatory gene-expression in euthymic BD patients

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General background

1with HC. Moreover, we present the results of a small additional study in which BD patients are compared during a mood episode and when euthymic.

Does CRP predict outcome in clinical practice?Chapter 5 describes a historic cohort study in which we investigate whether, in a clinical setting, higher CRP levels at baseline may predict a worse BD outcome, defined as a shorter time to relapse or a longer time to recover, depending on the mood state at baseline.

Part 2: Neuroimmune systemThe second part of the thesis investigates the function of the neuroimmune sys-tem, focusing on microglia activation, and using PET, MRI, MRS, DTI neuroimaging techniques.

Previous PET/SPECT studiesChapter 6 describes the findings of previous PET / single-photon emission computed tomography (SPECT) research efforts in BD, based on the literature. First, we discuss the cerebral blood flow and cerebral metabolism findings, followed by the neurotransmitter studies. Finally, we summarize the most important conclusions, and follow with remarks about the observed molecular imaging study designs specific for BD.

Microglial activation in the hippocampusIn chapter 7 we present the results of the first neuroinflammation PET study in BD. We aimed to demonstrate an increased [11C]-(R)-PK11195 binding to activated microglia in BD-I in comparison to a healthy control group. We a priori hypothesized the hippocampus to be the main focus of neuroinflammation in BD. In a second model we explore the presence of neuroinflammation in other brain regions.

Associations between volume, metabolites and microglial activationIn chapter 8 we investigate the relations between volume, metabolites and microglial activation of the hippocampus in a contemporaneously executed PET/MRI study. We compare hippocampal volume and metabolites in BD-I patients with HC, using MRI and MRS. We a priori hypothesized hippocampal volume and the N-acetylaspartate (NAA) metabolite to be decreased in BD patients, compared to HC. Subsequently, within the BD-I and HC groups, we post-hoc investigate whether hippocampal volume and metabolites were associated with microglial activation. Furthermore, we explore if potential illness modifying factors such as duration of illness, medication use, body mass index (BMI), exercise, smoking, number of caffeine consumptions and alcohol use did affect these hippocampal measurements within the BD-I group, and whether

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these hippocampal measurements were associated with experienced mood and functioning.

White matter microstructure disturbances and lithium usageUsing DTI, in chapter 9 we investigate the white matter microstructure in BD and HC, and differences among patients in relation to lithium usage. We first com-pare estimates of white matter microstructure (fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD)) between euthymic BD-I patients and HC. We a priori hypothesized that we would find a widespread decrease in FA in several white matter tracts of BD-I patients compared to HC, associated with reciprocal alterations of other white matter microstructural parameters. Subsequently, we divide the patient group into lithium-users and non-lithium-users and analyze the estimates of white matter microstructure across these three groups (non-lithium-users, lithium-users, healthy controls). In this analysis, supposing a restoring effect of lithium on myelination, we a priori hypothesized FA to be increased - and consistently a decrease of other white matter microstructural parameters - in lithium-using patients compared to non-lithium-using patients, possibly even attaining healthy control values.

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General background

1

Peripheral immune system

PART 1