The burden of recurrence acute pancreatitis and annual event rates are underestimated because of high rates of home self-management.

BACKGROUND/OBJECTIVES: The event-rate of recurrent acute pancreatitis (RAP) in patient populations is critical for powering research studies. We hypothesize that some patients manage RAP attacks at home, reducing event rate estimations based on counting emergency department (ED) visits and hospitalizations only. The aim of this study was to determine the rates of home self-management of recurrent acute pancreatitis compared to ED visits and hospitalizations. METHODS: An anonymous 8-question survey was sent to 1825 individuals on an email list of individuals with a history of acute pancreatitis (AP) or chronic pancreatitis or interest in pancreatic diseases. Question were designed to identify subjects with RAP within the past 2 years and to subdivide patients based on having a chronic pain syndrome or not. RESULTS: After an initial email request and one reminder a total of 194 subjects responded with 98 RAP subjects suitable for analysis. Annual AP events included an average of 1.44 hospitalizations, 1.37 ED visits, 2.46 disrupted work/school/social engagements, and 3.95 pancreatitis-like pain attacks per year. Patients with RAP average 6.8 RAP events per year with 58.4 % managed at home. CONCLUSIONS: The burden of disease in patients with RAP is significantly underestimated, especially for patients with chronic pain. Future studies should include measures to capture RAP events managed at home and utilize methods of documenting RAP events.

Relationship of circulating levels of long-chain fatty acids to persistent organ failure in acute pancreatitis.

During acute pancreatitis (AP), free fatty acids (FFAs) are liberated from circulating triglycerides (TG) and injured adipocytes by pancreatic lipase. Circulating FFAs have been suspected as a source of systemic lipotoxicity in AP. However, assessment of FFAs is difficult and time-consuming, and little is known about relative levels of FFAs between patients with different severities of AP and controls. This study's aims were to assess early circulating levels of FFAs, (both saturated and unsaturated) in patients with AP vs. controls, and associations between FFA levels and AP severity. Serum samples from patients with AP were collected at enrollment (day 1 of hospital stay); serum samples were also collected from controls. FFAs including palmitic, palmitoleic, stearic, oleic, and linoleic acid were extracted and quantitated using gas chromatography separation. Severity of AP was determined by Revised Atlanta Classification. Differences in FFA levels and percentages of total FFAs were assessed between patients with AP and controls and patients with AP of different severity grades. A total of 93 patients with AP (48 female, 52%) and 29 controls (20 female, 69%) were enrolled. Of the patients with AP, 74 had mild/moderate and 19 had severe AP. Serum levels of all FFAs except stearic acid were significantly higher in patients with AP compared with controls. A strong and independent association between elevated palmitoleic acid levels and severe AP was found. Serum unsaturated FFA levels, specifically palmitoleic acid, appear to correlate with severe AP. These findings have potential clinical implications for targeted AP therapies.NEW & NOTEWORTHY Drivers of the inflammatory response in acute pancreatitis remain incompletely understood. Unsaturated fatty acids, specifically palmitoleic, appear to have an association with more severe acute pancreatitis. This finding presents a new clinical understanding of fatty acid toxicity and highlights a potential future target for treatment in severe acute pancreatitis.

Severe acute pancreatitis exhibits distinct cytokine signatures and trajectories in humans: a prospective observational study.

Severe acute pancreatitis (SAP) is associated with substantial morbidity and mortality. Several cytokines have been identified to have pathophysiological significance in SAP, but studies characterizing their early trajectories are lacking. Here we characterize the early trajectories of seven key cytokines associated with SAP and compare them with non-SAP subjects. Five proinflammatory cytokines (angiopoietin-2, interleukin-6, interleukin-8, monocyte chemoattractant protein-1, resistin) and two anti-inflammatory cytokines (hepatocyte growth factor, and soluble tumor necrosis factor-α receptor-1A) were measured in a prospective cohort of acute pancreatitis subjects (2012-2016) at the time of enrollment and then every 24 h for 5 days or until discharge. The cytokines' levels and trajectories were calibrated based on date of pain onset and were compared between healthy controls and three severity categories (mild, moderate, and severe). The cohort (n = 170) consisted of 27 healthy controls, 65 mild, 38 moderate, and 40 SAP. From day 1 of symptom onset, SAP subjects exhibited significantly higher levels of both pro- and anti-inflammatory cytokines compared with non-SAP and healthy subjects. But in SAP subjects, all proinflammatory cytokines' levels trended downward after day 2 (except for a flat slope for angiopoeitin-2) whereas for non-SAP subjects, the trajectory was upward: this trajectory difference between SAP versus non-SAP subjects resulted in narrowing of the differences initially seen on day 1 for proinflammatory cytokines. For anti-inflammatory cytokines, the trajectories were uniformly upward for both SAP and non-SAP subjects. Proinflammatory cytokine response is an early and time-sensitive event in SAP that should be accounted for when designing future biomarker studies and/or therapeutic trials.NEW & NOTEWORTHY In this study, we showed that the proinflammatory cytokine response in SAP is an early event, with subsequent downregulation of proinflammatory cytokines beginning at day 1 of symptom onset. Our findings underscore the importance of enrolling subjects very early in the disease course when conducting studies to investigate early immune events of SAP; this current study also serves as an important reference for the design of future biomarker studies and therapeutic trials in SAP.

Circulating eNAMPT as a biomarker in the critically ill: acute pancreatitis, sepsis, trauma, and acute respiratory distress syndrome.

BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT) exhibits dual functionality - as an intracellular enzyme regulating nicotinamide adenine dinucleotide metabolism and as an extracellular secreted protein (eNAMPT) to function as a cytokine regulator of innate immunity via binding to Toll-Like receptor 4 and NF-κB activation. In limited preclinical and clinical studies, eNAMPT was implicated in the pathobiology of acute respiratory distress syndrome (ARDS) suggesting that eNAMPT could potentially serve as a diagnostic and prognostic biomarker. We investigated the feasibility of circulating eNAMPT levels to serve as a biomarker in an expanded cohort of patients with ARDS and ARDS-predisposing conditions that included acute pancreatitis, sepsis, and trauma with comparisons to controls. METHODS: A total of 671 patients and 179 healthy controls were included in two independent cohorts. Plasma and serum eNAMPT levels were quantified using one of two complementary Enzyme-linked Immunosorbent Assays. After log base 2 variance stabilizing transformation of plasma/serum eNAMPT measurements, differences between healthy controls and each disease cohort were compared using linear regression or a generalized estimating equation (GEE) model where applicable. Complementary analyses included sensitivity, specificity, positive predictive values, negative predictive values, and the area under the receiver operating curve. RESULTS: Compared to controls, circulating eNAMPT levels were significantly elevated in subjects with acute pancreatitis, sepsis, trauma, and ARDS (all p < 0.01). In the acute pancreatitis cohort, circulating eNAMPT levels positively correlated with disease severity (p < 0.01). CONCLUSIONS: Circulating eNAMPT levels are novel biomarker in the critically ill with acute pancreatitis, sepsis, trauma, and/or ARDS with the potential to reflect disease severity.

Acute and Chronic Pancreatitis Disease Prevalence, Classification, and Comorbidities: A Cohort Study of the UK BioBank.

INTRODUCTION: Pancreatitis is a complex syndrome that results from many etiologies. Large well-characterized cohorts are needed to further understand disease risk and prognosis. METHODS: A pancreatitis cohort of more than 4,200 patients and 24,000 controls were identified in the UK BioBank (UKBB) consortium. A descriptive analysis was completed, comparing patients with acute (AP) and chronic pancreatitis (CP). The Toxic-metabolic, Idiopathic, Genetic, Autoimmune, Recurrent, and severe pancreatitis and Obstructive checklist Version 2 classification was applied to patients with AP and CP and compared with the control population. RESULTS: CP prevalence in the UKBB is 163 per 100,000. AP incidence increased from 21.4/100,000 per year from 2001 to 2005 to 48.2/100,000 per year between 2016 and 2020. Gallstones and smoking were confirmed as key risk factors for AP and CP, respectively. Both populations carry multiple risk factors and a high burden of comorbidities, including benign and malignant neoplastic disorders. DISCUSSION: The UKBB serves as a rich cohort to evaluate pancreatitis. Disease burden of AP and CP was high in this population. The association of common risk factors identified in other cohort studies was confirmed in this study. Further analysis is needed to link genomic risks and biomarkers with disease features in this population.

Pain Experience in Pancreatitis: Strong Association of Genetic Risk Loci for Anxiety and PTSD in Patients With Severe, Constant, and Constant-Severe Pain.

INTRODUCTION: Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) are progressive inflammatory syndromes with variable features. Pain is the primary feature that contributes to low physical and mental quality of life with a third of patients reporting severe pain. Pain experience is worsened by depression. Here, we tested the hypothesis that genetic risk of the psychiatric conditions of anxiety and post-traumatic stress disorder (PTSD) is associated with pain in CP and RAP + CP subjects. METHODS: The study cohort included phenotyped and genotyped RAP and CP patients from the North American Pancreatitis Study II of European Ancestry. Candidate genetic association studies were based on the absence of pain vs pain that is constant, constant-severe, or severe. Twenty-eight candidate genetic loci for anxiety and PTSD risk were identified in the literature and were the focus of this study. RESULTS: We identified 24 significant pain-associated single nucleotide polymorphisms within 13 loci across the 3 pain patterns in CP and RAP + CP (P < 0.002). Thirteen anxiety or PTSD genes were within these pain loci indicating nonrandom associations (P < 4.885 × 10-23). CTNND2 was associated with all pain categories and all pancreatitis etiologies. Implicated systems include neuronal signaling (HTR2A, DRD3, NPY, and BDNF), hypothalamic-pituitary-adrenal axis (NR3C1 and FKBP5), and cell-cell interaction (CTNND2 and THBS2). DISCUSSION: A component of constant and severe pain in patients with RAP and CP is associated with genetic predisposition to anxiety and PTSD. Identification of patients at risk eligible for trials of targeted treatment as a component of a multidisciplinary pain management strategy should be formally evaluated.

Dynamic changes in the pancreatitis activity scoring system during hospital course in a multicenter, prospective cohort.

BACKGROUND AND AIM: The primary aim was to validate the Pancreatitis Activity Scoring System (PASS) in a multicenter prospectively ascertained acute pancreatitis (AP) cohort. Second, we investigated the association of early PASS trajectories with disease severity and length of hospital stay (LOS). METHODS: Data were prospectively collected through the APPRENTICE consortium (2015-2018). AP severity was categorized based on revised Atlanta classification. Delta PASS (ΔPASS) was calculated by subtracting activity score from baseline value. PASS trajectories were compared between severity subsets. Subsequently, the cohort was subdivided into three LOS subgroups as short (S-LOS): 2-3 days; intermediate (I-LOS): 3-7 days; and long (L-LOS): ≥7 days. The generalized estimating equations model was implemented to compare PASS trajectories. RESULTS: There were 434 subjects analyzed including 322 (74%) mild, 86 (20%) moderately severe, and 26 (6%) severe AP. Severe AP subjects had the highest activity levels and the slowest rate of decline in activity (P = 0.039). Focusing on mild AP, L-LOS subjects (34%) had 28 points per day slower decline; whereas, S-LOS group (13%) showed 34 points per day sharper decrease compared with I-LOS (53%; P < 0.001). We noticed an outlier subset with a median admission-PASS of 466 compared with 140 in the rest. Morphine equivalent dose constituted 80% of the total PASS in the outliers (median morphine equivalent dose score = 392), compared with only 25% in normal-range subjects (score = 33, P value < 0.001). CONCLUSIONS: This study highlighted that PASS can quantify AP activity. Significant differences in PASS trajectories were found both in revised Atlanta classification severity and LOS groups, which can be harnessed in AP monitoring/management (ClincialTrials.gov number, NCT03075618).

Low serum trypsinogen levels in chronic pancreatitis: Correlation with parenchymal loss, exocrine pancreatic insufficiency, and diabetes but not CT-based cambridge severity scores for fibrosis.

BACKGROUND: Chronic pancreatitis (CP) is a complex inflammatory disorder of the pancreas affecting acinar cells, duct cells, islet cells and inflammatory cells including fibrosis-producing stellate cells. Serum trypsinogen is a biomarkers of acinar cell function. AIM: To define the degree of correlation between low trypsinogen levels as a marker of acinar cell function and variable features of CP. METHODS: Serum samples from previously ascertained and well phenotyped case and control subjects from the North American Pancreatitis Study II (NAPS2) were used to measure serum trypsinogen levels in a commercial laboratory. Control samples were used to define normal ranges and compared with levels in CP patients with defined features. RESULTS: A final cohort of 279 CP patients and 262 controls from the NAPS2 studies were evaluated. In controls trypsinogen had a mean of 34.96 ng/ml and SD = 11.99. Cut-off values for low trypsinogen ranged from <20 to 10 ng/ml and very low trypsinogen at <10 ng/ml. Compared to controls, CP was associated with very low trypsinogen levels (p < 0.0001). Within CP, very low trypsinogen levels correlated with parenchymal loss (pancreatic surgery [p < 0.05]; atrophy with calcifications, [p < 0.001]), EPI (p < 0.01, trend p < 0.001) and diabetes (trend p < 0.01) but not CT-based criteria for fibrosis (pancreatic duct dilation, irregularity, strictures). CONCLUSIONS: Very low serum trypsinogen levels correlate with measures of acinar cell loss including surgical resection, atrophic-calcific CP, diabetes and functional symptoms EPI but not duct morphology criteria. Serum trypsinogen levels correlate with decreased acinar cell function and therefore have biomarker utility clinical management.

Severe acute pancreatitis: capillary permeability model linking systemic inflammation to multiorgan failure.

Severe acute pancreatitis (SAP) includes persistent systemic inflammation (SIRS) and multiorgan failure (MOF). The mechanism of transition from SIRS to MOF is unclear. We developed a fluid compartment model and used clinical data to test predictions. The model includes vascular, interstitial and "third-space" compartments with variable permeability of plasma proteins at the capillaries. Consented patients from University of Pittsburgh Medical Center Presbyterian Hospital were studied. Preadmission and daily hematocrit (HCT), blood urea nitrogen (BUN), creatine (Cr), albumin (Alb), and total protein (TP) were collected, and nonalbumin plasma protein (NAPP = TP minus the Alb) was calculated. Subjects served as their own controls for trajectory analysis. Of 57 SAP subjects, 18 developed MOF (5 died), and 39 were non-MOF (0 died). Compared with preadmission levels, admission HCT increased in MOF +5.00 [25%-75% interquartile range, IQR] versus non-MOF -0.10 [-1.55, 1.40] (P < 0.002) with HCT > +3 distinguishing MOF from non-MOF (odds ratio 17.7, P = 0.014). Preadmission Alb fell faster in MOF than non-MOF (P < 0.01). By day 2, TP and NAPP dropped in MOF but not non-MOF (P < 0.001). BUN and Cr levels increased in MOF (P = 0.001), but BUN-to-Cr ratios remained constant. Pancreatic necrosis was more common in MOF (56%) than non-MOF (23%). Changing capillary permeability to allow loss of NAPP in this model predicts loss of plasma oncotic pressure and reduced vascular volume, hypotension with prerenal azotemia and acute kidney dysfunction, pancreas necrosis, and pulmonary edema from capillary leak in the lung with acute respiratory distress syndrome. Sequential biomarker analysis in humans with or without MOF is consistent with this model. This study is registered on https://clinicaltrials.gov at NCT03075605.NEW & NOTEWORTHY Acute pancreatitis is a sudden inflammatory response to pancreatic injury that may spread to systemic inflammation, multiorgan failure, and death in some patients. With the use of the predictions of a new mechanistic model, we compared patients with severe acute pancreatitis with or without multiorgan failure. All biomarkers of capillary leak and clinical features of multiorgan failure were accurately predicted. This provides a new paradigm for understanding and developing new treatments for patients with severe acute pancreatitis.

Constant-severe pain in chronic pancreatitis is associated with genetic loci for major depression in the NAPS2 cohort.

BACKGROUND: Pain is the most debilitating symptom of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) and often requires chronic opioids or total pancreatectomy with islet autotransplantation to manage. Pain is a complex experience that can be exacerbated by depression and vice versa. Our aim was to test the hypothesis that depression-associated genes are associated with a constant-severe pain experience in RAP/CP patients. STUDY: A retrospective study was done using North American Pancreatitis Study II (NAPS2) genotyped RAP and CP patients with completed case report forms (n = 1,357). Subjects were divided based on pattern of pain and pain severity as constant-severe pain (n = 787) versus not constant-severe pain (n = 570) to conduct a nested genome-wide association study. The association between reported antidepressant medication use and depression gene loci was tested. RESULTS: Constant-severe pain was reported in 58% (n = 787) of pancreatitis patients. No differences in sex or alcohol consumption were found based on pain severity. Antidepressant use was reported in 28% (n = 223), and they had lower SF-12 mental quality of life (MCS, p < 2.2 × 10- 16). Fifteen loci associated with constant-severe pain (p < 0.00001) were found to be in or near depression-associated genes including ROBO2, CTNND2, SGCZ, CNTN5 and BAIAP2. Three of these genes respond to antidepressant use (SGCZ, ROBO2, and CTNND2). CONCLUSION: Depression is a major co-factor in the pain experience. This genetic predisposition to depression may have utility in counseling patients and in instituting early antidepressant therapy for pain management of pancreatitis patients. Prospective randomized trials are warranted. CLINICAL TRIALS REGISTRATION: Clinicaltriasl.gov.# NCT01545167.

Assessment of Weight Loss and Gastrointestinal Symptoms Suggestive of Exocrine Pancreatic Dysfunction After Acute Pancreatitis.

INTRODUCTION: Studies evaluating the natural history of exocrine pancreatic dysfunction (EPD) after acute pancreatitis (AP) are sparse. This study aims to assess incidence and predictors of weight loss and gastrointestinal (GI) symptoms suggestive of EPD 12 months after an AP episode. METHODS: Patients enrolled in the Pancreatitis-associated Risk of Organ Failure Study at the time of an AP episode were included. Weight and GI symptom data were prospectively collected by self-report at enrollment and at 3- and 12-month (windows 2-7 and 8-20) telephone follow-ups. Multivariable logistic regression was used to assess factors associated with ≥10% total body weight loss (EPD surrogate) at 12 months. A generalized estimating equation was used to measure each factor's population effect (in pounds) over 12 months after AP. RESULTS: Follow-up at 12 months in 186 patients (median age = 54 years, 46% men, 45% biliary, 65% first AP attack) revealed weight loss ≥10% from baseline, occurring in 44 patients (24%). Risk of weight loss increased with higher baseline body mass index, previous diagnosis of diabetes mellitus, and worsening AP severity (all P < 0.010). GI symptoms were reported in 13/31 (42%) patients at 12 months. AP severity was independently associated with ≥10% weight loss at 12 months. Over 12 months, men lost more weight than women (average 9.5 lbs); patients with severe AP lost, on average, 14 lbs. DISCUSSION: Weight loss after AP occurs in one-quarter of patients and is associated with AP severity. EPD incidence after AP is likely underappreciated. Further work is needed to assess EPD and potential for pancreatic enzyme supplementation.

Germline Variants and Risk for Pancreatic Cancer: A Systematic Review and Emerging Concepts.

Pancreatic cancer requires many genetic mutations. Combinations of underlying germline variants and environmental factors may increase the risk of cancer and accelerate the oncogenic process. We systematically reviewed, annotated, and classified previously reported pancreatic cancer-associated germline variants in established risk genes. Variants were scored using multiple criteria and binned by evidence for pathogenicity, then annotated with published functional studies and associated biological systems/pathways. Twenty-two previously identified pancreatic cancer risk genes and 337 germline variants were identified from 97 informative studies that met our inclusion criteria. Fifteen of these genes contained 66 variants predicted to be pathogenic (APC, ATM, BRCA1, BRCA2, CDKN2A, CFTR, CHEK2, MLH1, MSH2, NBN, PALB2, PALLD, PRSS1, SPINK1, TP53). Pancreatic cancer risk genes were organized into key biological mechanisms that promote pancreatic oncogenesis within an oncogenic model. Development of precision medicine approaches requires updated variant information within the framework of an oncogenic progression model. Complex risk modeling may improve interpretation of early biomarkers and guide pathway-specific treatment for pancreatic cancer in the future. Precision medicine is within reach.

Acute pancreatitis patient registry to examine novel therapies in clinical experience (APPRENTICE): an international, multicenter consortium for the study of acute pancreatitis.

BACKGROUND: We have established a multicenter international consortium to better understand the natural history of acute pancreatitis (AP) worldwide and to develop a platform for future randomized clinical trials. METHODS: The AP patient registry to examine novel therapies in clinical experience (APPRENTICE) was formed in July 2014. Detailed web-based questionnaires were then developed to prospectively capture information on demographics, etiology, pancreatitis history, comorbidities, risk factors, severity biomarkers, severity indices, health-care utilization, management strategies, and outcomes of AP patients. RESULTS: Between November 2015 and September 2016, a total of 20 sites (8 in the United States, 5 in Europe, 3 in South America, 2 in Mexico and 2 in India) prospectively enrolled 509 AP patients. All data were entered into the REDCap (Research Electronic Data Capture) database by participating centers and systematically reviewed by the coordinating site (University of Pittsburgh). The approaches and methodology are described in detail, along with an interim report on the demographic results. CONCLUSION: APPRENTICE, an international collaboration of tertiary AP centers throughout the world, has demonstrated the feasibility of building a large, prospective, multicenter patient registry to study AP. Analysis of the collected data may provide a greater understanding of AP and APPRENTICE will serve as a future platform for randomized clinical trials.

Prospective reports of chronic life stress predict decreased grey matter volume in the hippocampus.

Chronic stress in non-human animals decreases the volume of the hippocampus, a brain region that supports learning and memory and that regulates neuroendocrine activity. In humans with stress-related psychiatric syndromes characterized by impaired learning and memory and dysregulated neuroendocrine activity, surrogate and retrospective indicators of chronic stress are also associated with decreased hippocampal volume. However, it is unknown whether chronic stress is associated with decreased hippocampal volume in those without a clinical syndrome. We tested whether reports of life stress obtained prospectively over an approximate 20-year period predicted later hippocampal grey matter volume in 48 healthy postmenopausal women. Women completed the Perceived Stress Scale repeatedly from 1985 to 2004; in 2005 and 2006, their hippocampal grey matter volume was quantified by voxel-based morphometry. Higher Perceived Stress Scale scores from 1985 to 2004 - an indicator of more chronic life stress - predicted decreased grey matter volume in the right orbitofrontal cortex and right hippocampus. These relationships persisted after accounting for age, total grey matter volume, time since menopause, use of hormone therapy, subclinical depressive symptoms, and other potentially confounding behavioral and age-related cerebrovascular risk factors. The relationship between chronic life stress and regional grey matter volume - particularly in the hippocampus and orbitofrontal cortex - appears to span a continuum that extends to otherwise healthy individuals. Consistent with animal and human clinical evidence, we speculate that chronic-stress-related variations in brain morphology are reciprocally and functionally related to adaptive and maladaptive changes in cognition, neuroendocrine activity, and psychiatric vulnerability.

Higher blood pressure predicts lower regional grey matter volume: Consequences on short-term information processing.

Hypertension is a risk factor for diffuse brain atrophy. Yet, there is little evidence that higher blood pressure predicts focal brain atrophy, as indicated by a lower volume of regional brain tissue. This voxel-based morphometry study tested (a) whether higher blood pressure predicts lower regional grey or white matter volume and (b) whether a blood-pressure-related reduction in regional brain tissue volume predicts poorer neuropsychological test performance. Participants were 76 men (M age = 61.33, SD = 4.95 years) and 58 women (M age = 59.86, SD = 5.10 years) without a cardiovascular, cerebrovascular, or neuropsychiatric disease. Results showed that among men, higher resting systolic blood pressure predicted lower grey matter volume in the supplementary motor area and adjacent superior frontal gyrus, the anterior cingulate cortex, and middle temporal gyrus. Among men, lower grey matter volume in the supplementary motor area also predicted a slower time to complete the Trail Making Part B Test of executive control and a poorer recall of items from the Four-word Short-term Memory Test of working memory. These relationships were independent of age, total brain tissue volume, educational history, severity of carotid atherosclerosis, and the extent of periventricular and subcortical white matter lesions. Among women, no statistically significant relationships were found between blood pressure, regional brain tissue volume, and cognitive function. These findings suggest a functional relationship among men between higher blood pressure, lower regional grey matter volume, and poorer cognitive function that is independent of other risk factors and confounding medical conditions.

Gender differences in a fenfluramine-activated FDG PET study of borderline personality disorder.

Neuroimaging studies of impulsive-aggressive subjects with borderline personality disorder (BPD) demonstrate hypometabolism in areas of prefrontal and frontal cortex, and a blunted cortical metabolic response to challenge with serotonergic agonists. Neuroendocrine responses to serotonergic challenge are known to vary greatly by gender, and may be related to sex differences in expression of impulsive aggression. We conducted single-blind, placebo-controlled fenfluramine-activated positron emission tomography (PET) studies in impulsive male and female subjects with BPD to look for gender differences in cortical response. The sample comprised 22 BPD (15 female, 7 male) and 24 control subjects (10 female, 14 male) who received placebo on Day 1 and d,l-fenfluramine on Day 2 before PET neuroimaging. In response to placebo, female, but not male, controls had areas of increased uptake of fluorodeoxyglucose-F18 in prefrontal cortex compared with BPD subjects, with greatest uptake in the medial orbital frontal cortex, bilaterally. Male, but not female, BPD subjects, showed areas of increased glucose utilization compared with controls in large areas of parietal and occipital cortex, bilaterally. In response to fenfluramine (relative to placebo), significant decreases in glucose uptake were found in male, but not female, BPD subjects, centered in the left temporal lobe. Female, but not male, control subjects showed significantly decreased uptake in areas of right frontal and temporal cortex. Covarying for impulsive-aggression rendered nonsignificant the gender differences in responses to placebo or fenfluramine. Gender differences in serotonergic function may mediate differences in behavioral expression of impulsive aggression in subjects with BPD.

Widespread increases of cortical serotonin type 2A receptor availability after hormone therapy in euthymic postmenopausal women.

OBJECTIVE: To use statistical parametric mapping to determine the extent of previously reported serotonin type 2A (5HT(2A)) receptor binding potential (BP) increases in postmenopausal women following hormone therapy. DESIGN: Repeated measures positron emission tomography (PET) study. SETTING: Academic research environment. PATIENT(S): Five healthy, postmenopausal women. INTERVENTION(S): Serial PET images of [(18)F]altanserin uptake were acquired to measure 5HT(2A) receptor BP at menopausal baseline, following estradiol (E(2)), and following combined E(2) + micronized progesterone (P(4)). MAIN OUTCOME MEASURE(S): 5HT(2A) receptor BP. RESULT(S): Combined E(2) + P(4) treatment was associated with significant increases in the 5HT(2A) receptor BP increases in widespread areas of cerebral cortex. Treatment with E(2) alone was also associated with widespread cortical BP increases, although these changes reached statistical significance in fewer regions. The rate of [(18)F]altanserin metabolism was significantly decreased in the E(2) + P(4) condition relative to menopausal baseline, but this difference did not appear to correlate with changes in 5HT(2A) receptor BP. CONCLUSION(S): Estradiol priming followed by combined E(2) + P(4) is associated with widespread increases in 5HT(2A) receptor BP in the cerebral cortex, consistent with the E(2)-associated increases in 5HT(2A) receptor density previously observed in experimental animals.

Impulsivity and prefrontal hypometabolism in borderline personality disorder.

Prefrontal hypoperfusion and decreased glucose uptake in the prefrontal cortex (PFC) are found in violent criminal offenders, murderers and aggressive psychiatric patients. These abnormalities may be independent of diagnosis and associated with impulsive-aggression as a personality trait. Impulsive-aggression is a clinical characteristic of borderline personality disorder (BPD) where it is associated with assaultive and suicidal behaviors. We conducted FDG-PET studies in 13 non-depressed, impulsive female subjects with BPD and 9 healthy controls to look for abnormalities in glucose metabolism in areas of the PFC associated with regulation of impulsive behavior. Statistical Parametric Mapping-99 (SPM99) was used to analyze the PET data with Hamilton depression scores as covariate. Significant reductions in FDG uptake in BPD subjects relative to healthy controls were found bilaterally in medial orbital frontal cortex, including Brodmann's areas 9, 10 and 11. There were no significant areas of increased uptake in BPD subjects compared to control subjects. Covarying for measures of impulsivity or impulsive-aggression rendered insignificant the differences between groups. Decreased glucose uptake in medial orbital frontal cortex may be associated with diminished regulation of impulsive behavior in BPD.