Huntington's Disease (HD) is a progressive neurodegenerative disease caused by a mutation in the huntingtin gene. The mutation leads to a toxic gain of function of the mutant huntingtin (mHtt)... Show moreHuntington's Disease (HD) is a progressive neurodegenerative disease caused by a mutation in the huntingtin gene. The mutation leads to a toxic gain of function of the mutant huntingtin (mHtt) protein resulting in cellular malfunction, aberrant huntingtin aggregation and eventually neuronal cell death. Patients with HD show impaired motor functions and cognitive decline. Elevated levels of glucocorticoids have been found in HD patients and in HD mouse models, and there is a positive correlation between increased glucocorticoid levels and the progression of HD. Therefore, antagonism of the glucocorticoid receptor (GR) may be an interesting strategy for the treatment of HD. In this study, we evaluated the efficacy of the selective GR antagonist CORT113176 in the commonly used R6/2 mouse model. In male mice, CORT113176 treatment significantly delayed the loss of grip strength, the development of hindlimb clasping, gait abnormalities, and the occurrence of epileptic seizures. CORT113176 treatment delayed loss of DARPP-32 immunoreactivity in the dorsolateral striatum. It also restored HD -related parameters including astrocyte markers in both the dorsolateral striatum and the hippocampus, and microglia markers in the hippocampus. This suggests that CORT113176 has both cell -type and brain regionspecific effects. CORT113176 delayed the formation of mHtt aggregates in the striatum and the hippocampus. In female mice, we did not observe major effects of CORT113176 treatment on HD -related symptoms, with the exception of the anti -epileptic effects. We conclude that CORT113176 effectively delays several key symptoms related to the HD phenotype in male R6/2 mice and believe that GR antagonism may be a possible treatment option. Show less
This thesis aims to further unravel the role of the stress-systems in the pathophysiology of stress-related psychiatric disorders, by exploring elements of regulation and dysregulation of the two... Show moreThis thesis aims to further unravel the role of the stress-systems in the pathophysiology of stress-related psychiatric disorders, by exploring elements of regulation and dysregulation of the two major stress systems (i.e. the ANS and the HPA-axis), and their relation with psychological and psychiatric characteristics. Show less
Wiebenga, J.X.M.; Heering, H.D.; Eikelenboom, M.; Hemert, A.M. van; Oppen, P. van; Penninx, B.W.J.H. 2022
Background: People with depressive and/or anxiety disorders are at increased risk of suicidal ideation and suicide attempts, but biological correlates signaling such risk remain unclear.... Show moreBackground: People with depressive and/or anxiety disorders are at increased risk of suicidal ideation and suicide attempts, but biological correlates signaling such risk remain unclear. Independent and cumulative dysregulations in physiological stress systems, in particular the hypothalamic-pituitaryadrenal axis (HPA-axis), immune inflammatory system, and autonomous nervous system (ANS), may contribute to this risk. However, findings have either been heterogeneous or absent thus far.Methods: Associations between individual markers and cumulative indices of the HPA-axis (cortisol awakening response and evening cortisol), immune-inflammatory system (C-reactive protein, interleukin-6 (IL-6), and tumor necrosis factor-alpha), and the ANS (heart rate, respiratory sinus arrhythmia, and pre-ejection period) and the outcomes no suicide ideation with suicide attempt (SI-SA+), suicide ideation without suicide attempt (SI+SA-) and suicide ideation with suicide attempt (SI+SA+) were investigated in 1749 persons with depressive and/or anxiety disorders from the Netherlands Study of Depression and Anxiety (NESDA).Results: High levels of CRP and IL-6 were associated with SI-SA+ and SI+SA+ respectively when compared to non-suicidal patients after adjusting for confounders and multiple testing. Also, cumulative immune inflammatory dysregulations were positively associated with SI+SA+, suggesting a dose-response effect. No significant associations were found between HPA-axis or ANS indicators and suicide-outcomes and between immune-inflammatory system markers or cumulative stress system dysregulations and SI+SA-.Conclusion: Although stress system markers could not differentiate between SI+SA-and non-suicidal patients, findings indicate that dysregulations of individual and cumulative immune-inflammatory markers are associated with suicide attempts in depressive and/or anxiety patients. Thus, immune-inflammatory system dysregulation may be involved in the pathophysiology of suicidal behavior, supporting further examination of the effects of anti-inflammatory interventions on suicidality. Show less
Background: Childhood trauma (CT) is a risk factor for depressive and anxiety disorders. Although dysregulated biological stress systems may underlie the enduring effect of CT, the relation between... Show moreBackground: Childhood trauma (CT) is a risk factor for depressive and anxiety disorders. Although dysregulated biological stress systems may underlie the enduring effect of CT, the relation between CT and separate and cumulative activity of the major stress systems, namely, the hypothalamic-pituitary-adrenal (HPA)-axis, the immune-inflammatory system, and the autonomic nervous system (ANS), remains inconclusive.Methods: In the Netherlands Study of Depression and Anxiety (NESDA, n = 2778), we determined whether self-reported CT (as assessed by the Childhood Trauma Interview) was associated with separate and cumulative markers of the HPA-axis (cortisol awakening response, evening cortisol, dexamethasone suppression test cortisol), the immune-inflammatory system (C-reactive protein, interleukin-6, tumor necrosis factor-alpha), and the ANS (heart rate, respiratory sinus arrhythmia, pre-ejection period) in adulthood.Results: Almost all individuals with CT (n = 1330) had either current or remitted depressive and/or anxiety disorder (88.6%). Total-sample analyses showed little evidence for CT being significantly associated with the separate or cumulative stress systems' activity in adulthood. These findings were true for individuals with and without depressive and/or anxiety disorders. To maximize contrast, individuals with severe CT were compared to healthy controls without CT. This yielded slight, but significantly higher levels of cortisol awakening response (AUCg, beta =.088, p =.007; AUCi, beta =.084, p =.010), cumulative HPA-axis markers (beta =.115, p =.001), Creactive protein (beta =.055, p =.032), interleukin-6 (beta =.053, p =.038), cumulative inflammation (beta =.060, p =.020), and cumulative markers across all systems (beta =.125, p =.0003) for those with severe CT, partially explained by higher rates of smoking, body mass index, and chronic diseases.Conclusion: While our findings do not provide conclusive evidence on CT directly dysregulating stress systems, individuals with severe CT showed slight indications of dysregulations, partially explained by an unhealthy lifestyle and poorer health. Show less
Glucocorticoids mediate numerous essential processes in the human body via binding to the glucocorticoid receptor (GR). Excessive GR signaling can cause disease, and GR antagonists can be used to... Show moreGlucocorticoids mediate numerous essential processes in the human body via binding to the glucocorticoid receptor (GR). Excessive GR signaling can cause disease, and GR antagonists can be used to treat many symptoms of glucocorticoid-induced pathology. The purpose of this study was to characterize the tissue-specific properties of the selective GR antagonist CORT125281. We evaluated the antagonistic effects of CORT125281 upon acute and subchronic corticosterone exposure in mice. In the acute corticosterone setting, hypothalamus-pituitary-adrenal-axis activity was investigated by measurement of basal- and stress-induced corticosterone levels, adrenocorticotropic hormone levels and pituitary proopiomelanocortin expression. GR signaling was evaluated by RT-PCR analysis of GR-responsive transcripts in liver, muscle, brown adipose tissue (BAT), white adipose tissue (WAT) and hippocampus. Pretreatment with a high dose of CORT125281 antagonized GR activity in a tissue-dependent manner. We observed complete inhibition of GR-induced target gene expression in the liver, partial blockade in muscle and BAT and no antagonism in WAT and hippocampus. Tissue distribution only partially explained the lack of effective antagonism. CORT125281 treatment did not disinhibit the hypothalamus-pituitary-adrenal neuroendocrine axis. In the subchronic corticosterone setting, CORT125281 partially prevented corticosterone-induced hyperinsulinemia, but not hyperlipidemia and immune suppression. In conclusion, CORT125281 antagonizes GR transcriptional activity in a tissue-dependent manner and improves corticosterone-induced hyperinsulinemia. Tailored dosing of CORT125281 may allow tissue-specific inhibition of GR transcriptional activity. Show less
Glucocorticoids mediate numerous essential processes in the human body via binding to the glucocorticoid receptor (GR). Excessive GR signaling can cause disease, and GR antagonists can be used to... Show moreGlucocorticoids mediate numerous essential processes in the human body via binding to the glucocorticoid receptor (GR). Excessive GR signaling can cause disease, and GR antagonists can be used to treat many symptoms of glucocorticoid-induced pathology. The purpose of this study was to characterize the tissue-specific properties of the selective GR antagonist CORT125281. We evaluated the antagonistic effects of CORT125281 upon acute and subchronic corticosterone exposure in mice. In the acute corticosterone setting, hypothalamus-pituitary-adrenal-axis activity was investigated by measurement of basal- and stress-induced corticosterone levels, adrenocorticotropic hormone levels and pituitary proopiomelanocortin expression. GR signaling was evaluated by RT-PCR analysis of GR-responsive transcripts in liver, muscle, brown adipose tissue (BAT), white adipose tissue (WAT) and hippocampus. Pretreatment with a high dose of CORT125281 antagonized GR activity in a tissue-dependent manner. We observed complete inhibition of GR-induced target gene expression in the liver, partial blockade in muscle and BAT and no antagonism in WAT and hippocampus. Tissue distribution only partially explained the lack of effective antagonism. CORT125281 treatment did not disinhibit the hypothalamus-pituitary-adrenal neuroendocrine axis. In the subchronic corticosterone setting, CORT125281 partially prevented corticosterone-induced hyperinsulinemia, but not hyperlipidemia and immune suppression. In conclusion, CORT125281 antagonizes GR transcriptional activity in a tissue-dependent manner and improves corticosterone-induced hyperinsulinemia. Tailored dosing of CORT125281 may allow tissue-specific inhibition of GR transcriptional activity. Show less
Purpose To assess the reliability and safety of a postsurgical evaluation strategy of adrenal function using CRH stimulation and basal cortisol concentrations after transsphenoidal pituitary... Show morePurpose To assess the reliability and safety of a postsurgical evaluation strategy of adrenal function using CRH stimulation and basal cortisol concentrations after transsphenoidal pituitary surgery.Methods Retrospective cohort study of all patients undergoing endoscopic transsphenoidal surgery from 2010 to 2017, in whom early postoperative basal cortisol and/or CRH-stimulated cortisol secretion were available, including confirmation of adrenal function during follow-up. Patients with Cushing's disease were excluded. Optimal test performances were assessed using ROC analysis.Results A total of 156 patients were included. Sensitivity and specificity of the CRH test were 78% and 90%, respectively, and 86% and 92% for basal cortisol, respectively, using an optimal cutoff of 220 nmol/L. Eight patients had false-negative test results with the CRH test (normal test but adrenal insufficient at follow-up), and six patients with basal cortisol, the majority of which had multiple pituitary hormone deficiencies and fluid imbalances. No clinical adverse events occurred in patients with false-negative test results. The diagnostic performance of a single basal cortisol measurement was superior to the CRH test.Conclusions The early postoperative basal cortisol is a safe and simple measurement to guide (dis)continuation of hydrocortisone replacement. However, disturbing factors, e.g., sodium balance disorders, contraceptives, untreated hypopituitarism, and illness impact the interpretation and in those cases this measure is unreliable. We propose an algorithm in which hydrocortisone replacement at discharge is based on basal cortisol <220 nmol/L on postoperative day 2 or 3 in a stable condition. Show less
During this research we wanted to gain more insight into the potential gene repertoire that is involved in the hippocampus when coping with stress and regulating learning and memory... Show more During this research we wanted to gain more insight into the potential gene repertoire that is involved in the hippocampus when coping with stress and regulating learning and memory processes. To investigate this further we aimed to answer the question:""What are the primary genomic binding sites of the by stress and thus cortisol stimulated protein receptors MR and GR in the hippocampus?" To answer this question, new methods have been applied to determine where exactly MR and GR bind to the DNA, to find out which genes are potentially involved during stress management. As a result we have identified thousands of GR-binding sites at the DNA of which we have analyzed a selection in further detail. One of the identified pathways that have been found to be sensitive for activated GR and corticosteroids is the mTOR pathway. This pathway is involved in neuronal plasticity, which is the fundament for resilience. We have found that expression of the mTOR protein is decreased after exposure to acute stress when the organism has a history of chronic stress. Our results indicate that the reduced resilience after experiencing chronic stress is likely to be mediated by mTOR. Show less
The overall hypothesis of the Switchbox study is that maintenance of homeostasis is pivotal for maintenance of health in old age. Therefore, the aim of this thesis as part of the Switchbox study,... Show moreThe overall hypothesis of the Switchbox study is that maintenance of homeostasis is pivotal for maintenance of health in old age. Therefore, the aim of this thesis as part of the Switchbox study, was to expand our knowledge of homeostatic mechanisms at old age, thus trying to unravel underlying mechanisms of healthy human longevity. The focus of this thesis will be on analysis of the HPT-axis and HPA-axis in participants who have the propensity to reach old age in good health compared to age-matched controls. In humans, we are able to assess the 'function' of the HPT- and HPA- axes by measuring the key hormones involved as well as physiological parameters that are affected by these systems (heart rate, metabolism) under different conditions (in rest and during stress). Show less
Dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis is hypothesized to underlie stress-related psychiatric disorders such as the posttraumatic stress disorder (PTSD). Some studies have... Show moreDysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis is hypothesized to underlie stress-related psychiatric disorders such as the posttraumatic stress disorder (PTSD). Some studies have reported HPA-axis dysregulation in trauma-exposed adults in the absence of psychiatric morbidity. In this dissertation we set out to unravel part of the mechanism that underlies the complex relation between trauma exposure, stress regulation, and psychopathology. Mentally healthy trauma-exposed subjects were compared with non-trauma-exposed healthy controls. To distinguish between the potential effects of childhood trauma as opposed to adulthood trauma, we included women exposed to childhood trauma as well as men who were exposed to trauma during adulthood. Basal HPA-axis functioning was assessed with salivary cortisol samples. HPA-axis reactivity was assessed with the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. The results show that childhood trauma exposure is associated with an attenuated cortisol response after the Dex/CRH challenge test in women. In contrast, trauma exposure during adulthood was not associated with alterations in HPA-axis regulation after the Dex/CRH test. Neither childhood trauma nor adulthood trauma were associated with basal HPA-axis functioning. Childhood trauma rather than adulthood trauma may chronically affect HPA-axis functioning. Since the association between adulthood trauma and resilience to psychopathology cannot be explained by HPA-axis functioning alone, other factors must play a role. Show less
In this thesis, we report on our investigations regarding the involvement of several neurotransmitter and hormonal systems in generalized social anxiety disorder (gSAD), one of the most common... Show moreIn this thesis, we report on our investigations regarding the involvement of several neurotransmitter and hormonal systems in generalized social anxiety disorder (gSAD), one of the most common psychiatric disorders. We found evidence of the involvement of serotonin, dopamine, and noradrenaline/the autonomic nervous system, but not the hypothalamic-pituitary-adrenal-axis, in the neurobiology of gSAD. As a result of our studies, we hypothesize that serotonin and dopamine function is decreased in gSAD, that there is hyperfunctioning of the autonomic nervous system, and that the other part of the stress system, the hypothalamic-pituitary-adrenal-axis function is not concordant with autonomic nervous system activation, as we saw in basal conditions, and in stress conditions following manipulation of the serotonergic system. We also think that there are indications that the female gonadal hormones also have a modulatory role in gSAD in a subgroup of women. This exploration of the neurobiology of gSAD leads to the conclusion that a variety of brain systems are involved in gSAD in a complex way.involvement of several neurotransmitter and hormonal systems in gSAD. Show less
We investigated the role of cortisol (an important stress-hormone) in the regulation of social fear and avoidance behavior in socially anxious individuals, which are characterized by extreme fear... Show moreWe investigated the role of cortisol (an important stress-hormone) in the regulation of social fear and avoidance behavior in socially anxious individuals, which are characterized by extreme fear and avoidance of social situations. Previous studies in animals and children showed a relation between increased fearfulness and avoidance and elevated cortisol levels, but the causal role of cortisol in these processes is not known. We found that, only in high socially anxious participants, cortisol administration or stress induction increased avoidance of social threat on an affect-evaluation computer task. Concurrent event-related potentials (brain activity measured with electrodes on the scalp) showed an associated increase in early processing of social threat. Another experiment indicated that the effects of cortisol on early threat processing are task dependent. We conclude that cortisol increases avoidance and facilitates or inhibits early processing of social threat in an adaptive manner, in line with the task goal. This effect is strongest in high anxious individuals, which are particularly sensitive to these threat signals. This knowledge can be relevant for the treatment of SAD, as cortisol levels may increase during exposure therapy, and also because cortisol administration has recently been proposed as a treatment for this disorder. Show less
