The followings make me wonder if Karen's suicide was caused by a parasite, as odd as that sounds.
I highlight the CSF related items, of a lengthy article, in the following:
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Dwivedi Y, editor. The Neurobiological Basis of Suicide. Boca Raton (FL): CRC Press; 2012.
Chapter 19 “Toxoplasma gondii, the Immune System, and Suicidal Behavior” - Olaoluwa Okusaga and Teodor T. Postolache.
… if allergy (a misdirected immune response against innocuous substances that were “misperceived” by the immune system as invasive pathogens) is associated with suicidal behavior, one would expect real neurotropic parasites to also be associated with suicide behavior. This led us to investigate Toxoplasma gondii and the anti-T. gondii immune response. A possible connection between T. gondii and suicidal behavior was suggested by the relatively high seroprevalence, its neurotropism (Flegr 2007), the immune activation involved in the defense against the parasite leading to elevation of cytokines previously found related to suicidal behavior (see Section 19.3.2), the occurrence of induced self-destructive behavior in rodent models (Lamberton et al. 2008; Vyas et al. 2007; Webster 2007), behavioral changes in humans (Flegr et al. 2002), and the parasite’s association with mental illness (Niebuhr et al. 2008; Torrey et al. 2007). …
19.2.2.1. Monocytes and Macrophages
Both originate from myeloid stem cells and ingest microbes and particles bound to immunoglobulin, complement, or both (i.e., microbes and particles marked for clearance from the body). They produce nitric oxide, which is very effective in killing microbial pathogens, and are involved in both acute inflammatory responses and granulomatous processes. Activated macrophages produce large amounts of tumor necrosis factor (TNF), interferon gamma (IFN-γ), and interleukins 6 and 12 (IL-6 and IL-12). …
[Anyone happen to know what Beetroot, from the health food store, does to CSF pressure? Beetroot changes nitric oxide levels. http://jn.nutrition.org/content/143/9/1399.abstract among many other related documents.]
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19.3.1. Neuroimmune Interactions in Mood Disorders
Through their modulation of neuronal anatomy and function, cytokines and other immune molecules have been found to impact neuropsychiatric functions such as mood and cognition. For example TNF-α and IL-1β, when present at pathophysiologically elevated levels, have the tendency to inhibit long-term potentiation and impair neuronal plasticity (Loftis et al. 2010). Neuronal synaptic plasticity describes the phenomenon whereby postsynaptic neurons are able to vary their response to presynaptic stimulation and long-term potentiation is a long-term increase in synaptic strength. Both synaptic plasticity and long-term potentiation are generally believed to be the basis for learning and memory (Berretta et al. 2008).
[Problems with memory. A common complaint of Leakers.]
An accumulating body of evidence now supports the notion that neuroimmune interactions play a significant role in the pathogenesis of depressive disorders and other psychiatric conditions. An immune (inflammatory) activation consequence is “sickness behavior,” which is characterized by fatigue, sleep disturbance, appetite disturbance, decreased social interaction, and loss of interest in usual activities—all of which are also seen in major depressive disorder (MDD) (Dantzer 2009). Sickness behavior is mediated by proinflammatory cytokines such as IL-1, IL-6, TNF-α, and IFN-γ. Several studies have reported elevated levels of proinflammatory cytokines in patients with MDD even without any apparent infection or inflammation (Raison et al. 2006). A corollary to this is the finding that most antidepressant medication as well as electroconvulsive therapy (ECT) inhibit the production of proinflammatory cytokines (Müller et al. 2009).
In MDD, cellular, molecular, and morphological studies in animals and human subjects have demonstrated an imbalance between neuroprotection and neurotoxicity in favor of the latter (Duman 2009). Neuroimmune interactions are involved in the neurotoxic mechanisms of depressive disorder. Proinflammatory cytokines such as IL-2, IFN-γ, and TNF-α increase the activity of indoleamine 2,3-dioxygenase (IDO) and kynurenine monooxygenase (KMO), two enzymes involved in the metabolism of tryptophan. Tryptophan is an amino acid that serves as “raw material” for the synthesis of serotonin (a neurotransmitter). IDO catalyzes the breakdown of tryptophan to kynurenine, thus resulting in a relative tryptophan depletion. The shunting of tryptophan toward production of kynurenine makes tryptophan unavailable for serotonin synthesis ultimately resulting in low serotonin levels in the brain. Low serotonin has been implicated in the pathogenesis of depression (Dursun et al. 2001). IN ADDITION, SUICIDE ATTEMPTERS (ESPECIALLY THOSE WITH VIOLENT ATTEMPTS) HAVE BEEN FOUND TO HAVE SIGNIFICANTLY LOWER CEREBROSPINAL FLUID (CSF) LEVELS OF 5-HYDROXYINDOLEACETIC ACID (5-HIAA), A KEY METABOLITE OF SEROTONIN, RELATIVE TO HEALTHY VOLUNTEERS (TRÄSKMAN ET AL. 1981). Kynurenine crosses freely from the periphery to the brain and from the brain to the periphery. It has recently been implicated in depression and depressive-like behaviors (Dantzer et al. 2011; Raison et al. 2010). Kynurenine metabolites are potent immunomodulators (Schwarcz and Pellicciari 2002); specifically under the influence of KMO, kynurenine is catalyzed to 3-hydroxykynurenine (3-OH-kynurenine) and quinolinic (QUIN) acid in a two-step process. Both 3-OH-kynurenine and QUIN can induce neurodegeneration through the induction of excitotoxicity and generation of neurotoxic radicals (Müller et al. 2009). These pathways have specific cellular substrate. For instance, the microglia are the cells responsible for the rate-limiting pathway of transformation of kynurenine via kynurenine 3-monooxygenase (KMO) to QUIN. Astrocytes are responsible for the transformation of kynurenine via kynurenine aminotransferases (KAT) I and II to kynurenine acid (KA) (Wonodi and Schwarcz 2010).
19.3.2. Immune Activation and Suicidal Behavior
In contrast to the number of published studies on immune dysregulation and mood disorders, only a few studies have identified a possible link between immune mechanisms and suicidal behavior. In one study (Nassberger and Traskman-Bendz 1993), the plasma concentrations of soluble interleukin-2 receptor (S-IL-2R) in medication-free suicide attempters were significantly higher than those found in healthy controls. Most recently, Janelidze et al. (2010) evaluated blood cytokine levels in 47 suicide attempters, 17 non-suicidal depressed patients, and 16 healthy controls, and found increased levels of IL-6 and TNF-α in suicide attempters relative to non-suicidal depressed patients and healthy controls. WHILE THIS CYTOKINE ACTIVATION WAS FOUND IN THE “PERIPHERY,” IL-6 LEVELS HAVE ALSO BEEN REPORTED TO BE ELEVATED IN THE CSF OF SUICIDE ATTEMPTERS RELATIVE TO CONTROLS (LINDQVIST ET AL. 2009). Another study found elevated levels of Th2 cytokine mRNAs in postmortem brain tissue samples within the orbitofrontal cortex of suicide victims (Tonelli et al. 2008b). Microglia cells in the brain are capable of expressing cytokines, and significant microgliosis has been observed in the brains of patients who committed suicide (Steiner et al. 2008).
19.4. Toxoplasma gondii AND SUICIDE
T. gondii, a widespread neurotropic protozoan parasite (Ajioka and Soldati 2007), affects approximately one-third of all humans worldwide. …
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In the brain, the parasite will hide within neurons and glial cells, intracellularly, ultimately in cystic structures. These structures have minimal exposure to cellular and molecular mediators of the immune system that contain the infection successfully, but fail to eradicate it. Previous research in rodents has revealed that T. gondii localizes in multiple structures of the brain, including the prefrontal cortex and predominantly the amygdala (Vyas et al. 2007). These areas have a primary role in emotional and behavioral regulation, and they show major histopathological changes in suicide victims (Mann 2003). It is possible that because T. gondii occupies these areas, T. gondii infection may disrupt the balance of affective and behavioral modulation and in turn elevate risk of suicide.
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19.4.6. Toxoplasma and Suicide Attempts: First Reported Association in Patients with Mood Disorders
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Patients with recurrent depression who previously attempted suicide had mean values for antibodies to T. gondii higher than either the patients with recurrent depression and no history of suicide attempts (p = 0.04), or the normal control group (p = 0.12). When adjusted for race, age, and gender, the suicidal patients with recurrent depression versus non-suicidal patients with recurrent depression had a greater mean IgG titer of 0.51 versus 0.37 (p = 0.017) (Figure 19.2). Logistic regression models revealed that serointensity predicted suicide attempts with OR of 1.55 (1.14–2.12), p = 0.006. However, there was a nonsignificant relation of seropositivity with suicide attempt, OR = 1.62 (0.72–3.65).
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19.4.8. Toxoplasma gondii IgG Antibodies and Suicide Attempts in Patients with Psychotic Disorders
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A question arises: Could this relationship be an artifact, the result of a general immune activation, or antibody elevation in patients at risk for suicide? We tested this hypothesis by analyzing antibodies to a number of neurotropic viruses as well as a food antigen, gliadin, and found no differences, using identical methods with those used for T. gondii antibodies analysis, for the cytomegalovirus (p = 0.22), herpes 1 virus (p = 0.36), and gliadin (p = 0.92). Thus, the increase in T. gondii IgG antibodies in patients who attempted suicide is unlikely to be attributed to a general nonspecific increase in antibody production.
All these results presented so far are cross-sectional associations. The following study will have a model of predictive association, as the determination of T. gondii antibodies will precede (often by many years) suicidal behavior.
19.4.10. National Suicide Rates Positively Correlate with Seroprevalence Rates for T. gondii in Women
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In conclusion, cross-sectional studies in mood disorders (Arling et al. 2009), psychiatric inpatients (Yagmur et al. 2010), schizophrenic patients (Okusaga et al. 2011), a prospective cohort study in mothers (Pedersen et al. 2012), and an ecological study in Europe (Ling et al. 2011) strongly support an association between T. gondii and suicidal behavior.
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What are possible mechanisms mediating the relationship between T. gondii and suicidal behavior? In addition to reactivation of the latent parasite (i.e., a direct effect), one of the important potential mechanisms is the host’s immune system activation in response to T. gondii infection. Previous studies have demonstrated that the production of proinflammatory cytokines (Aliberti 2005; Miller et al. 2009) is an integral part of containing T. gondii. IT IS POSSIBLE THAT THE ELEVATION OF INFLAMMATORY CYTOKINES IL-6 IN THE CSF (LINDQVIST ET AL. 2009) AND IL-6 AND TNF IN THE PLASMA (JANELIDZE ET AL. 2010) THAT HAVE BEEN FOUND PREVIOUSLY ELEVATED IN THOSE WHO ATTEMPT SUICIDE MAY MEDIATE THE ASSOCIATION OF T. GONDII AND SUICIDE BEHAVIOR. The growth of T. gondii is blocked by the production of inflammatory cytokines, particularly IFN-γ resulting in activation of macrophages and lymphocytes (Denkers and Gazzinelli 1998) as well as activation of the enzyme IDO. This results in relative tryptophan depletion (Miller et al. 2009) stemming from the IDO activation that starts a degradation tryptophan toward kynurenines. Local depletion of tryptophan decreases both the proliferation of T. gondii and the synthesis of serotonin, which may affect a number of suicide risk factors such as anxiety, impulsivity, and affective lability. Furthermore, IDO activation leads to production of kynurenine that further generates antagonists (kynurenic acid) or agonists (e.g., quinolinic acid) of the N-methyl-d-aspartate (NMDA) receptors and therefore alterations of glutaminergic neurotransmission (Dantzer et al. 2008). Recent findings on the activation of kynurenine pathways in suicidal behavior support this idea. NAMELY, VIOLENT SUICIDE ATTEMPTS, HISTORY OF MAJOR DEPRESSION, AND IL-6 LEVELS (LINDQVIST 2010) HAVE BEEN FOUND TO BE ASSOCIATED WITH KYNURENIC ACID CONCENTRATIONS IN THE CSF. Our collaborative study with Dr. Mann’s group at Columbia University has found that patients with mood disorders who have a history of suicide attempt relative to those without a history of attempts had an elevated level of kynurenine in plasma (Sublette et al. 2011) (Figure 19.5).
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In addition, previous research has suggested that infection with T. gondii may elevate testosterone levels (Flegr 2007), and in turn that elevation in testosterone may lead to an increase in aggression, which has been identified as an intermediate phenotype in suicide (Kovacsics et al. 2009; Mann et al. 2009). Testosterone has been linked to the suppression of neural circuitry that is related to both impulse control and emotional regulation (Mehta and Beer 2010). This could help explain why the association between T. gondii and suicide is observed in older women, but not in younger women, whose androgens are balanced by endogenous estrogen and progesterone.
[When Karen was in LA, she said 'I hate my hormones' because of issues she was having with them due to entering perimenopause.]
T. gondii infection may have the potential to heighten the risk factors that lead to attempting suicide. Joiner et al. (2009) presents a two-factor theory that states that there are two components that lead to attempting suicide when occurring simultaneously. The first domain is psychological, and it is expressed as a desire to die. This commonly results from a lack of the feeling of belongingness and a perception that one is a burden. The second domain is behavioral and is expressed as an acquired capability to attempt suicide through the habituation to the fear of death, dying, and the beyond; it is sometimes a result of witnessing or experiencing violence, or having painful and fearful occurrences.
[Karen though she was burden to me.]
T. gondii infection may contribute to the capability to engage in self-injurious behavior rather than just the increased wish to commit suicide. In experimentally infected immunocompetent rodents, T. gondii cysts are predominantly found in the amygdala, an area implicated in the expression of fear, of its host (Vyas et al. 2007), leading to a degree of atrophy of the dendritic tree and deafferentation. Furthermore, T. gondii contains two genes encoding tyrosine hydroxylase producing L-DOPA (Gaskell et al. 2009), which in turn may lead to an increase in dopamine and the ability to act on suicidal impulses and overcoming an innate fear of death. In additional to increased localization in the amygdala and olfactory bulb, T. gondii is localized in the prefrontal cortex (Vyas et al. 2007). Histopathological changes in certain areas of the prefrontal cortex, namely, the ventrolateral prefrontal cortex, have been implicated in suicidal behavior (Mann 2003). It is also possible that the ability of the prefrontal cortex to act as a behavioral “braking mechanism” on impulses and emotions produced in the subcortical structures of the limbic system is inhibited.
[On Karen's last day she tried all day long to get help. Clearly her final act was impulsive.]
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19.5. CONCLUSION
T. gondii is one of the most widespread parasites affecting approximately one-third of the population of the world (Montoya and Liesenfeld 2004), and ~60 million individuals in the United States (CDC 2010). Its unique ability to alter immune responses, to manipulate the immune system, and to alter behavior of the host could mediate an increased vulnerability to suicide attempts in those harboring the parasite. Not all individuals infected with T. gondii are at risk for suicide; most likely, a combination of predispositions, triggers, availability of means, and absence of protective factors and deterrents would be necessary. The intermediate mechanisms may include heightening of risk factors for suicide such as depression, impulsivity, aggression, arousal, and reduction of fear (especially fear of death). Considering the potential for new prognostic paradigms and etiological preventative interventions, this predictive association deserves future larger, longitudinal, and interventional studies.
Ref:
Lindqvist D, Janelidze S, Hagell P. et al. Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biol Psychiatry. 2009;66:287–292. [PubMed: 19268915]
Raison C.L, Dantzer R, Kelley K.W. et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: Relationship to CNS immune responses and depression. Mol Psychiatry. 2010;15:393–403. [PMC free article: PMC2844942] [PubMed: 19918244]
Träskman L, Åsberg M, Bertilsson L. et al. Monoamine metabolites in CSF and suicidal behavior. Arch Gen Psychiatry. 1981;38:631–634. [PubMed: 6166274]
[Seems like Lyme Syndrome would somehow be related here?]
See Also:
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