Neuroendocrine Dysfunction Research Articles

Understanding the Physiological Links Between Physical Frailty and Cognitive Decline.

Declines in both physical and cognitive function are associated with increasing age. Understanding the physiological link between physical frailty and cognitive decline may allow us to develop interventions that prevent and treat both conditions. Although there is significant epidemiological evidence linking physical frailty to cognitive decline, a complete understanding of the underpinning biological basis of the two disorders remains fragmented. This narrative review discusses insights into the potential roles of chronic inflammation, impaired hypothalamic-pituitary axis stress response, imbalanced energy metabolism, mitochondrial dysfunction, oxidative stress, and neuroendocrine dysfunction linking physical frailty with cognitive decline. We highlight the importance of easier identification of strategic approaches delaying the progression and onset of physical frailty and cognitive decline as well as preventing disability in the older population.

Combined HIV-1 Tat and oxycodone activate the hypothalamic-pituitary-adrenal and -gonadal axes and promote psychomotor, affective, and cognitive dysfunction in female mice

The majority of HIV+ patients present with neuroendocrine dysfunction and ~50% experience co-morbid neurological symptoms including motor, affective, and cognitive dysfunction, collectively termed neuroHIV. In preclinical models, the neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat), promotes neuroHIV pathology that can be exacerbated by opioids. We and others find gonadal steroids, estradiol (E2) or progesterone (P4), to rescue Tat-mediated pathology. However, the combined effects of Tat and opioids on neuroendocrine function and the subsequent ameliorative capacity of gonadal steroids are unknown. We found that conditional HIV-1 Tat expression in naturally-cycling transgenic mice dose-dependently potentiated oxycodone-mediated psychomotor behavior. Tat increased depression-like behavior in a tail-suspension test among proestrous mice, but decreased it among diestrous mice (who already demonstrated greater depression-like behavior); oxycodone reversed these effects. Combined Tat and oxycodone produced apparent behavioral disinhibition of anxiety-like responding which was greater on diestrus than on proestrus. These mice made more central entries in an open field, but spent less time there and demonstrated greater circulating corticosterone. Tat increased the E2:P4 ratio of circulating steroids on diestrus and acute oxycodone attenuated this effect, but repeated oxycodone exacerbated it. Corticotropin-releasing factor was increased by Tat expression, acute oxycodone exposure, and was greater on diestrus compared to proestrus. In human neuroblastoma cells, Tat exerted neurotoxicity that was ameliorated by E2 (1 or 10 nM) or P4 (100, but not 10 nM) independent of oxycodone. Oxycodone decreased gene expression of estrogen and κ-opioid receptors. Thus, neuroendocrine function may be an important target for HIV-1 Tat/opioid interactions.

Prevalence of growth hormone deficiency in middle-age adults recovering from stroke

ABSTRACTObjective: The prevalence of chronic growth hormone deficiency (GHD) and its association with other hormonal deficiencies was determined in middle-aged patients post-stroke with and without consideration of body mass index (BMI).Methods: Clinical records were reviewed to determine pituitary function at least 3 months post-stroke. Patients with a history of endocrine anomalies were excluded. GHD was determined by utilizing standard peak GH cutoffs following the glucagon stimulation test. A secondary analysis was conducted with stricter BMI-adjusted cutoffs. The accuracy of IGF-1 in predicting GHD was also examined.Results: GHD was diagnosed in 54% of patients (≥5.0 μg/L), with 32% falling into the severe (≤3 μg/L) category. Patients with GHD had lower levels of FSH, T3, LH, and SHBG. Analyzes of BMI-adjusted GH levels, revealed that 14% of patients were GHD. These patients had higher prolactin. IGF-1 values were not predictive of GHD. Latency to be admitted to post-acute rehabilitation was greater in patients with GHD.Conclusions: Evidence suggests patients with stroke may be at risk for developing GHD. GHD was associated with decreased levels of other hormones. Co-morbidities for stroke and neuroendocrine dysfunction overlap and may have implications for recovery following stroke.

Stress Triggers Flare of Inflammatory Bowel Disease in Children and Adults.

Inflammatory bowel disease (IBD) is an idiopathic inflammatory disease characterized by chronic and relapsing manifestations. It is noteworthy that the prevalence of IBD is gradually increasing in both children and adults. Currently, the pathogenesis of IBD remains to be completely elucidated. IBD is believed to occur through interactions among genetics, environmental factors, and the gut microbiota. However, the relapsing and remitting course of IBD underlines the importance of other modifiers, such as psychological stress. Growing evidence from clinical and experimental studies suggests that stress acts as a promoting or relapsing factor for IBD. Importantly, recent studies have reported an increasing incidence of anxiety or depression in both children and adults with IBD. In this article, we review the mechanisms by which stress affects IBD, such as via impaired intestinal barrier function, disturbance of the gut microbiota, intestinal dysmotility, and immune and neuroendocrine dysfunction. With regard to both children and adults, we provide recent evidence to describe how stress can affect IBD at various stages. Furthermore, we emphasize the importance of mental healing and discuss the value of approaches targeting stress in clinical management to develop enhanced strategies for the prevention and treatment of IBD.

Intranasal Neuropeptide Y Blunts Lipopolysaccharide-Evoked Sickness Behavior but Not the Immune Response in Mice

Neuropeptide Y (NPY) has been demonstrated to exert stress buffering effects and promote resilience. Non-invasive intranasal (IN) application of NPY to rodents is able to mitigate traumatic stress-induced behavioral changes as well as dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. However, it is unknown whether IN NPY could prevent the behavioral, pro-inflammatory and neurochemical responses to peripheral immune activation by the Toll-like receptor 4 (TLR4) stimulant lipopolysaccharide (LPS). Therefore, we analyzed the effects of IN NPY (100 μg) on the behavioral sickness response (reduced locomotion and exploration) and the underlying molecular mechanisms, 3 h and 21 h after intraperitoneal injections of LPS (0.03 mg/kg) in male C57BL/6N mice. The acute behavioral sickness response was significantly dampened by pretreatment with IN NPY 3 h after LPS injection. This effect was accompanied by diminished weight loss and lowered plasma corticosterone (CORT) levels 21 h after LPS injection. In contrast, acute circulating cytokine levels and hypothalamic cytokine mRNA expression remained unaltered by IN NPY, which indicates that the peripheral and cerebral immune response to LPS was left undisturbed. Our findings are in agreement with the reported activity of NPY to dampen the response of the HPA axis to stress. We propose that IN NPY ablates sickness behavior at a site beyond the peripheral and cerebral cytokine response, an action that is associated with reduced activity of the HPA axis as determined by decreased plasma CORT.These results indicate that IN NPY administration may be relevant to the management of neuropsychiatric disorders arising from immune-induced neuroendocrine dysfunction.

Abstract 3113: Regulation of TOR complex 1 by the BRAFV600EMutant determines response and development of resistance to MEK inhibition by trametinib in glioma models

Abstract Pediatric Low-Grade glioma (PLGG) is the most common brain tumor in children. Current treatment protocols, particularly those involving high dose radiation therapy are associated with neurocognitive and neuroendocrine dysfunction. Genomic studies have revealed that PLGG are characterized by activation of the MAPK cascade. Recently, the value of selumetinib, an allosteric inhibitor of MEK1/2 has been demonstrated in PLGG. However, drug resistance will inevitably limit the efficacy. Trametinib is a more potent MEK1/2 inhibitor with better brain penetration than selumetinib. Here we have attempted to identify the mechanism/s of the resistance to trametinib that PLGG developes, and to explore combination treatments that may retard or prevent emergence of trametinib resistance in animal models. In BT-40 (childhood anaplastic astrocytoma with BRAFV600E mutation) xenografts, trametinib caused complete tumor regressions, followed by tumor regrowth at the end of treatment. Trametinib treatment rapidly induced pSTAT3(Y705), that was blocked by the JAK1/2 inhibitor, ruxolitinib. Agaist BT-40 xenografts, ruxolitinib slightly enhanced the antitumor response to trametinib. The combination of trametinib with rapamycin was more active in each xenograft line than either single agent alone and in both subcutaneous and intracranial BT-40 models. In BT-40 xenografts, resistance to trametinib was consistently induced within 3 or 4 6-week cycles of treatment similar to that for the trametinib + ruxolitinib combination. In contrast, resistance to combined trametinib and rapamycin was not developed. Rapamycin prevented emergence of trametinib resistance, but did not reverse resistance to trametinib, once acquired. Inhibition of MAPK signaling by trametinib was similar in parental and trametinib-resistant BT-40 xenografts, however, trametinib reistant tumor cells failed to undergo apoptosis. Cells freshly isolated from trametinib resistant BT-40 xenografts had a higher apoptotic threshhold, whereas cells isolated from BT-40 xenografts after 3 cycles of trametinib + rapamycin, remained equally sensitive to parental BT-40 cells, as determined by BH3 profiling. This study reveals a potential new therapeutic use of rapamycin, preventing emergence of resistance to trametinib. Potentially, addition of rapamycin to MEK inhibitor therapy children with BRAF-driven low-grade glioma may be of value. Citation Format: Fuyang Li. Regulation of TOR complex 1 by the BRAFV600EMutant determines response and development of resistance to MEK inhibition by trametinib in glioma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3113.

Early neglect is a key determinant of adult hair cortisol concentration and is associated with increased vulnerability to trauma in a transdiagnostic sample

BackgroundChildhood adversities and traumatic events have each been associated with hypothalamus-pituitary-adrenal (HPA) axis dysregulation and trauma-related symptoms in adulthood. Hair cortisol concentration (HCC) reflects cumulative cortisol levels over the course of months and is discussed as a potential marker between trauma-induced neuroendocrine dysfunction and trauma-related symptoms. The present study examines this hypothetical link by delineating the impact of exposure to categories of abuse and neglect during development and lifetime traumatic experiences on HCC and trauma-related symptoms. MethodsThe Maltreatment and Abuse Chronology Exposure (MACE) scale, Life Events Checklist, and predictive analytics were used to evaluate the importance of type and timing of maltreatment and trauma load on HCC in inpatients (n = 183) with different psychiatric diagnoses. Additionally, a comparison group of n = 75 controls were recruited from the community. The extent to which the relationship between trauma load and trauma-related symptoms was influenced by childhood adversities and HCC was determined by analysis of variance. ResultsEarly neglect, in particular neglect at 3 years, emerged as the most important predictor of adult HCC. Post-hoc explanatory analysis showed that patients with high neglect at age 3 had lower HCC compared to patients with low neglect at age 3 and controls. Patients with high neglect at age 3 and low cortisol reported increased trauma-related symptoms upon trauma exposure. ConclusionResults strengthen evidence that inadequate care and neglect during critical periods alter HPA axis biology towards enduring reduction in cortisol, the latter being associated with augmented trauma-related symptoms upon trauma exposure. If validated by longitudinal assessments these cross-sectional findings suggest biological mechanisms of childhood adversities into psychopathology in adulthood.

Neuroendocrine Whiplash: Slamming the Breaks on Anabolic-Androgenic Steroids Following Repetitive Mild Traumatic Brain Injury in Rats May Worsen Outcomes

Sport-related concussion is an increasingly common injury among adolescents, with repetitive mild traumatic brain injuries (RmTBI) being a significant risk factor for long-term neurobiological and psychological consequences. It is not uncommon for younger professional athletes to consume anabolic-androgenic steroids (AAS) in an attempt to enhance their performance, subjecting their hormonally sensitive brains to potential impairment during neurodevelopment. Furthermore, RmTBI produces acute neuroendocrine dysfunction, specifically in the anterior pituitary, disrupting the hypothalamic-pituitary adrenal axis, lowering cortisol secretion that is needed to appropriately respond to injury. Some AAS users exhibit worse symptoms post-RmTBI if they quit their steroid regime. We sought to examine the pathophysiological outcomes associated with the abrupt cessation of the commonly abused AAS, Metandienone (Met) on RmTBI outcomes in rats. Prior to injury, adolescent male rats received either Met or placebo, and exercise. Rats were then administered RmTBIs or sham injuries, followed by steroid and exercise cessation (SEC) or continued treatment. A behavioral battery was conducted to measure outcomes consistent with clinical representations of post-concussion syndrome and chronic AAS exposure, followed by analysis of serum hormone levels, and qRT-PCR for mRNA expression and telomere length. RmTBI increased loss of consciousness and anxiety-like behavior, while also impairing balance and short-term working memory. SEC induced hyperactivity while Met treatment alone increased depressive-like behavior. There were cumulative effects whereby RmTBI and SEC exacerbated anxiety and short-term memory outcomes. mRNA expression in the prefrontal cortex, amygdala, hippocampus, and pituitary were modified in response to Met and SEC. Analysis of telomere length revealed the negative impact of SEC while Met and SEC produced changes in serum levels of testosterone and corticosterone. We identified robust changes in mRNA to serotonergic circuitry, neuroinflammation, and an enhanced stress response. Interestingly, Met treatment promoted glucocorticoid secretion after injury, suggesting that maintained AAS may be more beneficial than abstaining after mTBI.

SUN-427 Hypopituitarism as a Rare Manifestation in a Patient with Neurosarcoidosis

Introduction: Sarcoidosis is a systemic disease of unknown cause that is characterised by the formation of immune granulomas in various organs, mainly the lungs and lymphatic system. 5-10% of patients with sarcoidosis present with neurological involvement [1,2]. Neuroendocrine dysfunction is uncommon with hypothalamic-pituitary dysfunction occurring in 2-8% of patients with neurosarcoidosis [3]. Clinical case: A 47 year old caucasian male presented with a ten month history of severe fatigue, weight gain, loss of libido, erectile dysfunction and polyuria. Past medical history was significant for sarcoidosis for which he had been lost to follow up for many years. On examination, body mass index was 31.1kg/m2 with central obesity and loss of secondary sexual characteristics and gynaecomastia were noted. Initial endocrine investigations confirmed central hypothyroidism ((TSH: 1.87mIU/L (0.35-4.94), fT4: 8.6 Pmol/L (9.0-20.0)) and hypogonadotropic hypogondism ((FSH: 1.5 IU/L (1.4-10.8), LH: <0.5 IU/L (1.4-6.5), AM Testosterone: 0.7nmol/L (7.1-407)). IGF-1 and prolactin concentrations were normal. Short synacthen® test was abnormal with peak cortisol at 60 mins of 445 nmol/L and ACTH 15ng/L (7-63). Water deprivation testing confirmed partial Diabetes Insipidus. Chest Xray showed mediastinal and bihilar lymphadenopathy consistent with sarcoidosis. MRI brain and pituitary with gadolinium revealed a normal sized pituitary gland, pituitary infundibulum at the upper limit of normal thickness (3mm) and signal abnormality of the periaqueductal grey matter and tectal plate which demonstrated enhancement following contrast administration, and the presence of abnormal enhancement of the optic chiasm/hypothalamus, consistent with neurosarcoidosis. A diagnosis of hypopituitarism secondary to neurosarcoidosis was made. The patient was commenced on steroid and testosterone replacement with the later addition of levothyroxine and ddAVP, with marked improvement in symptoms. He required a Multidisciplinary team approach with respiratory and neurology input. Conclusion: This case illustrates a rare presentation of hypopituitarism secondary to neurosarcoidosis in a young patient lost to medical care. It is important that patients with sarcoidosis have long-term follow up with consideration given to rare endocrine manifestations in the appropriate clinical setting.

SUN-406 Complete Recovery of Central Diabetes Insipidus Associated with Isolated Stalk Thickening in a Neurosarcoidosis Patient

Background: Neurosarcoidosis (NS) affects ~15% of patients with sarcoidosis. Hypothalamic-pituitary (HP) involvement is even rare and occurs in <1% of sarcoidosis. Clinically, NS presents as neuroendocrine dysfunction in 2.5% and radiologically, it typically manifests as HP lesion with parenchymal disease. The literature review demonstrates increased pituitary volume as the most frequent MRI abnormality observed in more than a half patients with HP involvement. Pituitary stalk thickening (PST) has been reported in combination with parenchymal abnormality but not in isolation. Central diabetes insipidus (CDI) is a known manifestation of stalk involvement. The exact mechanism of anti-diuretic hormone (ADH) dysfunction is not well understood, however CDI is mostly attributed to defective ADH release with direct infiltration of the stalk. Hormonal deficiencies are considered to be irreversible even in the setting of normalization of MRI findings after treatment. We herein report a case of NS associated with isolated PST presenting as CDI, where complete recovery was observed. Case: A 54-year-old male with pulmonary and gastrointestional (GI) sarcoidosis confirmed by gastric biopsy, developed abrupt onset of polyuria-polydipsia [Intake: 11-12 L/d, Output: 8-10 L/d] while treated with prednisone 5 mg/d. Urine osmolality (osm) was 64 mosm/kg, urine sodium (Na) 10 meq/l, serum osm 292 mosm/kg and serum Na 143 mmol/l. MRI of the Sella revealed 3.5 mm PST, absent posterior pituitary bright spot and partial empty sella. Anterior pituitary evaluation showed: Testosterone 122ng/dl, FSH 9.8mIU/ml, LH 3.3mIU/ml, Prolactin 17.8ng/ml, TSH 1.07 mcIU/ml, FT4; 0.7ng/dl, Cortisol 11.3mcg/dl, ACTH 12pg/ml and IGF-1; 129ng/ml. DDAVP 0.2mg bid controlled DI well. GI symptoms were treated with increased prednisone 40 mg/d and hydroxychloroquine. MRI showed decreased PST at 2.6 mm in 1 year and normal stalk thickness 1.8 mm in 2 years. He was successfully weaned off DDAVP, along with a slow taper of steroid. Four years since presentation, symptoms are well controlled on prednisone 3mg/d. Testosterone improved (213 ng/dl) and other anterior pituitary hormones remained in normal range. He has no polyuria, stalk measures 1.9 mm and posterior pituitary bright spot is absent. Conclusion: This case demonstrates a rare manifestation of NS presenting with isolated PST associated with CDI, without parenchymal disease. Furthermore, this is the first case report of complete resolution of CDI that correlated with normalization of MRI finding. In general hormonal deficits with HP sarcoidosis is considered irreversible and no correlation has been reported between the hormonal dysfunction and radiologic outcomes. Hence, in similar patients with isolated PST as the only manifestation of NS a trial off DDAVP may be offered, if improvement in MRI finding is noted over the course of the treatment.

OR11-5 Early Prevalence of Neuroendocrine Dysfunction after Spontaneous Aneurysmal Subarachnoid Haemorrhage: Interim Findings from a Prospective Cohort Study

The prevalence of neuroendocrine dysfunction after aneurysmal subarachnoid haemorrhage (SAH) is highly varied between 0-55%, with little known of time of onset and recovery. We aimed to examine prevalence, time of onset, progression and predictors of neuroendocrine dysfunction in patients with aneurysmal SAH. All patients admitted with spontaneous aneurysmal SAH, without known prior pituitary dysfunction or recent exposure to glucocorticoids, were prospectively recruited. Serum cortisol at 8AM was measured on days 1, 3, 5, 7 and 10 of admission while serum free T4, TSH, LH/FSH, estradiol/testosterone, and prolactin were evaluated on day 7 post intervention (surgical or endovascular) or day 10 of admission if there was no intervention. Complete pituitary function including IGF-1, were re-evaluated at 3 months. 32 patients (mean age: 56.4 ±13.3 years, 66% female) were recruited. 19 were categorized as World Federation of Neurological Societies (WFNS) low-grade (1-3) on arrival and 13 were high-grade (4-5). 25 and 5 subjects had endovascular and surgical interventions respectively, while 2 had none. 30-day mortality rate was 9.4% (3/32), with death occurring within a week in all 3 patients. Of the 29 who survived beyond a week, none developed early corticotroph deficiency. Mean cortisol levels were 876.9 (±406.9), 770.4 (±329.7), 674.1 (±278.7), 668.1 (±269.0) and 643.0 (±350.1) nmol/L on days 1,3,5,7, and 10 respectively. A homogenous control group of critically ill post coronary bypass patients were recruited to compare values of cortisol during the acute phase. There were no significant differences in mean serum cortisol between SAH patients and controls apart from day 1 levels, with controls having a higher mean cortisol level, 1109.1 ±410.1 nmol/L (p=0.03). 9.4% (3/29) and 41.4% (12/29) had early thyrotroph and gonadotroph deficiency respectively. Prolactin was normal in all patients. There was no significant association between WFNS grade and type of intervention on development of pituitary dysfunction. The mortality rate at 3 months was 18.8% (6/32), and there was no significant association between early cortisol levels, thyrotroph or gonadotroph deficiency and mortality status at this point. At 3 months, repeat testing revealed normal pituitary function (including IGF-1) in all patients except one with persistent gonadotroph deficiency. Pituitary dysfunction after aneurysmal SAH is uncommon. Early gonadotroph and thyrotroph deficiencies that occur are likely due to acute illness that recovers on follow up. However acute Day 1 basal cortisol post SAH while not deficient, is significantly lower than that in non-neurological critical illness.

Therapeutic Inhibition of MicroRNA‐124‐3p Induces Histone Modification Changes in the Hippocampus in a Rat Model of Gulf War Illness

Gulf War Illness (GWI) is a chronic, multisymptomillness that continues to affect 30% of the 700,000 US veterans deployed to the Persian Gulf during the 1990–1991 Gulf War. Memory dysfunction and depression are common symptoms. Epidemiological studies have consistently identified neurotoxic chemical exposures as the strongest risk factors for GWI, but after 28 years, useful treatments are lacking and underlying cellular and molecular mechanisms involved in its pathobiology remain poorly understood. Using an established rat model of GWI, we previously identified chronic elevation of microRNA‐124‐3p(miR‐124) levels in the hippocampus whose gene targets are involved in cognition‐associated pathways and neuroendocrine function. We further showed that intracerebro ventricular (icv) infusion of locked nucleic acid (LNA)‐miR‐124 inhibitor increased hippocampal expression of downstream target genes important for synaptic plasticity, glucocorticoid signaling, and neurogenesis compared to LNA‐scrambled oligonucleotide, suggesting that miR‐124 inhibition may be a promising therapeutic approach to improve cognition and neuroendocrine dysfunction in GWI. This strategy has also been proposed to improve memory deficits and/or depression in patients with multiple sclerosis, major depressive disorder, amyotrophic lateral sclerosis, and Alzheimer's disease. Because histone post‐translational modifications are critical for gene expression during memory processes, the aim of this study was to determine whether miR‐124 inhibition alters histone modifications in the hippocampus of GWI rats. Nine months after a 28‐day exposure regimen of GW chemicals and stress, rats underwent icv infusion of LNA‐miR‐124 inhibitor or LNA‐scrambled control from implanted osmotic pumps delivering 0.1 nmol/day for 28 days (n=5 per group). Hippocampi were harvested and underwent extraction of histones. Targeted analysis of &gt;80 unmodified and modified histone peptides was performed in triplicate using mass spectrometry (Active Motif). LNA‐miR‐124 inhibitor induced 11 histone modification changes, with histone H3 methylationat lysine (K) residues 18, 27, 36, and 79 being the most predominant changes observed. These included a 22% decrease (p&lt;0.001) in H3K27me3, a marker of gene repression known to be elevated in neuro degenerative diseases and during aging, and a 20% increase (p=0.008) in H3K36me3, a marker of transcriptional activation known to increase during object recognition memory and decrease during aging. Results suggest that miR‐124 inhibition induces histone modifications in the hippocampus that likely correspond with enhanced transcription of genes important for synaptic plasticity and neuroendocrine signaling shown previously to occur in GWI rats treated with LNA‐miR‐124 inhibitor. Future work is needed to identify the transcriptional targets of these histone markers to better understand the potential therapeutic benefits of miR‐124inhibition for GWI and other cognitive disorders.Support or Funding InformationDoD CDMRP Gulf War Illness Research Program grant award GW150132. Content is that of the authors and does not reflect the official policy or position of the Department of the Army, Department of Defense, or the US government.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

REST: An epigenetic regulator of neuronal stress responses in the young and ageing brain.

The transcriptional repressor REST (Repressor Element-1 Silencing Transcription factor) is a key modulator of the neuronal epigenome and targets genes involved in neuronal differentiation, axonal growth, vesicular transport, ion channel conductance and synaptic plasticity. Whilst its gene expression-modifying properties have been examined extensively in neuronal development, REST's response towards stress-induced neuronal insults has only recently been explored. Overall, REST appears to be an ideal candidate to fine-tune neuronal gene expression following different forms of cellular, neuropathological, psychological and physical stressors. Upregulation of REST is reportedly protective against premature neural stem cell depletion, neuronal hyperexcitability, oxidative stress, neuroendocrine system dysfunction and neuropathology. In contrast, neuronal REST activation has also been linked to neuronal dysfunction and neurodegeneration. Here, we highlight key findings and discrepancies surrounding our current understanding of REST's function in neuronal adaptation to stress and explore its potential role in neuronal stress resilience in the young and ageing brain.

Clinical picture and the treatment of TBI-induced hypopituitarism.

Traumatic brain injury (TBI) is an important public health problem with an increasing incidence in the last years. Relatively few cases are fatal; most individuals will survive and, in the long-term, the sequalae of TBI will include neuroendocrine dysfunctions with a much higher frequency than previously suspected. Patients who develop hypopituitarism after TBI present manifestations due to the number of deficient hormones, severity of hormonal deficiency, and the duration of hypopituitarism without diagnosis and treatment. The clinical spectrum of hypopituitarism is very large and many signs and symptoms of TBI survivors such as fatigue, concentration difficulties, depressive symptoms are nonspecific and overlap with symptoms of post-traumatic stress disorder and variably severe hypopituitarism related to brain damage remaining undiagnosed. This can explain why the diagnosis of hypopituitarism is often missed or delayed after this condition with potentially serious and hazardous consequences for the affected patients. Moreover, clinical experience cumulatively suggests that TBI-associated hypopituitarism is associated with poor recovery and worse outcome, since post-traumatic hypopituitarism is independently associated with cognitive impairment, poor quality of life, abnormal body composition, and adverse metabolic profile. In the present review, the current data related to clinical consequences of pituitary dysfunction after TBI in adult patients and therapeutic approaches are reported.

Neurorehabilitation of Traumatic Brain Injury (TBI): A Clinical Review.

Traumatic brain injury (TBI) and its potential long-term consequences are of major concern for public health. Neurorehabilitation of affected individuals has some specific characteristics in contrast to neurorehabilitation of patients with acquired brain lesions of other aetiology. This review will deal with the clinical consequences of the distinct lesions of TBI. In severe TBI, clinical course often follows a typical initial sequence of coma; followed by disturbed consciousness; later, post-traumatic agitation and amnesia; and finally, recovery of function occurs. In the different phases of neurorehabilitation, physicians should be aware of typical medical complications such as paroxysmal sympathetic hyperactivity, posttraumatic hydrocephalus, and posttraumatic neuroendocrine dysfunctions. Furthermore, we address questions on timing and on existing evidence for different rehabilitation programmes and for holistic neuropsychological rehabilitation approaches.

Neuroactive Steroids and GABAergic Involvement in the Neuroendocrine Dysfunction Associated With Major Depressive Disorder and Postpartum Depression

Stress and previous adverse life events are well-established risk factors for depression. Further, neuroendocrine disruptions are associated with both major depressive disorder (MDD) and postpartum depression (PPD). However, the mechanisms whereby stress contributes to the underlying neurobiology of depression remains poorly understood. The hypothalamic-pituitary-adrenal (HPA) axis, which mediates the body’s neuroendocrine response to stress, is tightly controlled by GABAergic signaling and there is accumulating evidence that GABAergic dysfunction contributes to the impact of stress on depression. GABAergic signaling plays a critical role in the neurobiological effects of stress, not only by tightly controlling the activity of the HPA axis, but also mediating stress effects in stress-related brain regions. Deficits in neuroactive steroids and neurosteroids, some of which are positive allosteric modulators of GABAA receptors (GABAARs), such as allopregnanolone and THDOC, have also been implicated in MDD and PPD, further supporting a role for GABAergic signaling in depression. Alterations in neurosteroid levels and GABAergic signaling are implicated as potential contributing factors to neuroendocrine dysfunction and vulnerability to MDD and PPD. Further, potential novel treatment strategies targeting these proposed underlying neurobiological mechanisms are discussed. The evidence summarized in the current review supports the notion that MDD and PPD are stress-related psychiatric disorders involving neurosteroids and GABAergic dysfunction.

The role of autoimmunity in pituitary dysfunction due to traumatic brain injury.

Traumatic brain injury (TBI) is one of the most common causes of mortality and long-term disability and it is associated with an increased prevalence of neuroendocrine dysfunctions. Post-traumatic hypopituitarism (PTHP) results in major physical, psychological and social consequences leading to impaired quality of life. PTHP can occur at any time after traumatic event, evolving through various ways and degrees of deficit, requiring appropriate screening for early detection and treatment. Although the PTHP pathophysiology remains to be elucitated, on the basis of proposed hypotheses it seems to be the result of combined pathological processes, with a possible role played by hypothalamic-pituitary autoimmunity (HPA). This review is aimed at focusing on this possible role in the development of PTHP and its potential clinical consequences, on the basis of the data so far appeared in the literature and of some results of personal studies on this issue. Scrutinizing the data so far appeared in literature on this topic, we have found only few studies evaluating the autoimmune pattern in affected patients, searching in particular for antipituitary and antihypothalamus autoantibodies (APA and AHA, respectively) by simple indirect immunofluorescence. The presence of APA and/or AHA at high titers was associated with an increased risk of onset/persistence of PTHP. HPA seems to contribute to TBI-induced pituitary damage and related PTHP. However, further prospective studies in a larger cohort of patients are needed to define etiopathogenic and diagnostic role of APA/AHA in development of post-traumatic hypothalamic/pituitary dysfunctions after a TBI.

Hypopituitarism After Traumatic Brain Injury.

Acquired hypopituitarism is associated with traumatic brain injury. This neuroendocrine dysfunction can cause both short-term and long-term morbidity resulting in a cognitive, physiological, and behavioral decline, which increases the burden of the disease and the cost of care. Data in the trauma literature is derisory on this subject. The aim of this review is to edify clinicians on this condition, outline the screening criteria and methods for hypopituitarism after traumatic brain injury, and bring awareness to the chronic effects.

Dose-Constraint Model to Predict Neuroendocrine Dysfunction in Young Patients With Brain Tumors: Data From a Prospective Study

PurposeWe report on a possible dose-constraint model to predict long-term neuroendocrine dysfunction after cranial irradiation in children and young adults with benign and low-grade brain tumors treated with stereotactic conformal radiation therapy (RT) in a prospective clinical trial. Methods and materialsPatients treated with stereotactic conformal RT (54 Gy in 30 fractions) were included for analysis if their co-registered planning computed tomography and magnetic resonance imaging scans were available, along with baseline and post-RT endocrine assessment for at least 2 years. The hypothalamus–pituitary axis (HPA) was contoured on the fused computed tomography–magnetic resonance imaging data set. Worsening of endocrine function was defined biochemically as a new onset endocrine deficit or worsening of preexisting endocrine deficit. Dosimetric indices of HPA, extracted using cumulative dose-volume histograms, were correlated with worsening endocrine function using logistic regression analysis. ResultsA total of 51 patients (median age: 13 years; range, 5-25 years) were included. Worsening post-RT endocrine levels were seen in 27 of 51 patients (47%). Growth hormone was the most commonly affected (70%), followed by cortisol (44%), gonadotropin (40%), and thyroxine (7%). The mean of the maximum and minimum doses to HPA was 42.1 Gy and 35.7 Gy, respectively. For patients with worsening endocrine levels, the mean maximum dose to HPA was 46.6 Gy compared with 36.5 Gy in patients with stable functions. The mean minimum dose to HPA was also higher (40.5 Gy vs 29.6 Gy) in patients with endocrine dysfunction. Logistic regression analysis identified the volume of HPA receiving 50% of the prescribed dose as the only statistically significant parameter predicting endocrine dysfunction. A dose of ≥27 Gy to any volume of HPA was associated with a 4-fold increase in risk of endocrine dysfunction (odds ratio: 4.05; 95% confidence interval, 1.07-15.62; P = .038). ConclusionsOur prospective longitudinal study demonstrates the feasibility of HPA avoidance using modern, high-precision, conformal RT techniques and correlates HPA dosimetry with neuroendocrine dysfunction. We suggest restricting HPA doses to <27 Gy to minimize the risk of post-RT neuroendocrine deficits.

Abstract TP167: Prevalence of Growth Hormone Deficiency in the Chronic Phase of Recovery From Stroke

Introduction: The objective of the current retrospective study was to determine the prevalence of growth hormone deficiency (GHD) in middle-aged patients with ischemic and hemorrhagic stroke who were at least 3 months post-stroke. It was hypothesized a large percentage of patients with stroke would exhibit growth hormone deficiency, as well as, other hormone deficiencies. A secondary objective was to determine if chronic health conditions often associated with stroke were associated with neuroendocrine dysfunction. Methods: Clinical records from 139 adult patients (from 2009-2017), who were in the post-acute phase of their recovery, were obtained to analyze findings from standard endocrine blood tests. Patients with a pre-stroke history of endocrine anomalies were excluded from the study. Growth hormone was assessed by the glucagon stimulation test (GST). Results: GHD was identified in 54% of the patients with stroke during the chronic phase of recovery. Patients with GHD took longer to be admitted to post-acute rehabilitation compared to patients with normal GH levels. Patients with GHD also had lower levels of follicle stimulating hormone (FSH), triiodothyronine (T3), luteinizing hormone (LH) and sex hormone binding globulin. Body mass index was higher in patients with GHD. Conclusions: There is a considerable risk of developing hypopituitarism, particularly GHD, following ischemic or hemorrhagic stroke. In this relatively large sample of middle-aged stroke patients, GHD was associated with decreased levels of T3 and gonadotrophic hormones. Co-morbidities for stroke and neuroendocrine dysfunction overlap and may have implications for recovery following stroke and warrant further investigation.