Self-compassion training to improve well-being for surgical residents.

CONTEXT: Burnout remains prevalent among surgical residents. Self-compassion training may serve to improve their well-being. OBJECTIVE: To evaluate the impact on well-being of a self-compassion program modified for surgical residents. DESIGN: This is a 3-year, mixed-methods study using pre-post surveys and focus groups to identify areas for programmatic improvement and the subsequent impact of the modifications. SETTING: A single academic institution. PARTICIPANTS: Surgical residents participating in a self-compassion program. INTERVENTIONS: A self-compassion program adapted from a larger course to fit the needs of surgical residents. MAIN OUTCOME MEASURES: Themes relating to the program's strengths and weaknesses were identified through participant focus groups. Well-being was assessed through validated measurement tools, including The Maslach Burnout Inventory (MBI), Patient Health Questionnaire-9, Perceived Stress Scale, and Spielberger State-Trait Anxiety Inventory-6. RESULTS: 95 residents participated in the self-compassion program, of which 40 residents completed both surveys (total response rate: 42%). All participants demonstrated severe burnout pre-program, based on scores of at least one of the MBI subscales. Emotional exhaustion scores improved post-program, with larger improvements seen after program modifications (2018: 58% vs 2020: 71%). Focus group findings demonstrated that residents need a safe and distraction-free space to practice self-compassion, and program engagement improved following modifications.

All adverse childhood experiences are not equal: The contribution of synergy to adverse childhood experience scores.

The operationalization of childhood trauma and adversity into checklists commonly known as adverse childhood experiences, or ACEs, has become the most widely adopted methodology linking traumatic childhoods to adult outcomes. As the number of self-reported ACEs increase from 0 to 4 or more (4+), most studies find a roughly stepwise progression in risk for a wide range of negative medical and mental health outcomes. A score of 4+ ACEs, has become a de facto cutpoint, increasingly used clinically to define "high risk" status for a myriad of outcomes. Comparisons across studies using a 4+ cutpoint, however, find considerable heterogeneity in the degree of risk for the same outcomes. In addition to sample and methodological differences, certain pairs of ACEs comprising the cumulative ACE score interact synergistically to significantly increase the overall risk beyond the sum (or product) of the contributions of each ACE to the outcome. This article reviews the empirical literature on synergistic ACEs including results from a general population adult and a mixed trauma, youth sample both sufficiently powered to examine over 20 different ACE pairings for possible synergy. Synergistic pairs of ACEs vary by gender and age group. About 30-40% of the variance in outcomes is accounted for by additive synergistic interactions between certain pairs of ACEs. Across studies, sexual abuse is the most synergistically reactive ACE. The article concludes with a discussion of the implications of synergistic ACE pairings for psychologists and other allied professionals across clinical practice, prevention, research, and policy. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Synergistic adversities and behavioral problems in traumatized children and adolescents.

OBJECTIVE: This study investigated synergy of commonly co-occurring pairs of childhood traumas/adversities to determine: 1) if synergistic pairings differ by gender and/or age grouping; and 2) if some traumas/adversities were more synergistically reactive. METHODS: A sample of 10,355 clinic-referred youth (1.5-18 years) from the National Child Traumatic Stress Network Core Data Set was divided by gender and categorized into salient age groups (1.5-5 years, 6-12 years, and 13-18 years). Attributable Proportion (AP), a biomedically relevant metric, was calculated to assess additive synergy for behavior problems on the CBCL. RESULTS: Overall, only four pairs of adversities were synergistic. Three involved sexual abuse with physical abuse, parental loss, and domestic violence. When the sample was analyzed by Gender X Age group, however, a more complicated picture emerges. Twelve of the twenty-one possible pairings (57 %) show additive synergy in one or more categories. The mean AP accounted for approximately 40 % of outcome variance. Males had more synergistic pairings (16) than females (7). The average synergistic effect was higher for males (42 % of variance) than females (36 % of variance). The vast majority of synergy occurs in the 6-12 and 13-18 age groups. Sexual abuse was the most synergistically reactive trauma, pairing most frequently (16) followed by physical abuse (10) or neglect (9). CONCLUSION: Sexual abuse was malignantly synergistic, frequently pairing with other adversities, followed by physical abuse, neglect, and domestic violence. The findings underscore that all ACEs are not equal in their contributions to commonly assessed outcomes. The findings also have considerable implications for prevention, intervention, and future research.

The international postpartum depression: action towards causes and treatment (PACT) consortium.

The International Postpartum depression: Action towards Causes and Treatment (PACT) Consortium was founded with the overarching goal of creating an international perinatal psychiatry consortium to conduct novel investigations with large sample sizes to understand the genetic signature of perinatal mood disorders. PACT uses a collaborative and team science approach that includes investigators across 19 institutions and seven continents. The large sample sizes allow for statistically rigorous analyses to investigate perinatal psychiatric disorders, with an initial focus on postpartum depression (PPD). Our current aims are to identify clinical sub-types of PPD that contribute diagnostic heterogeneity, and to elucidate the genetic basis of PPD by conducting the first large genome-wide association study of PPD. To accomplish the latter aim, we are partnering with the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. To date, our consortium members have recruited 17,912 participants and 11,344 participants have been identified using the PPD ACT mobile app, of which 8,432 are PPD cases. Ultimately, we hope this approach will improve detection, diagnosis, and treatment of women who suffer from perinatal psychiatric disorders.

An Online Educational Program for Individuals With Dissociative Disorders and Their Clinicians: 1-Year and 2-Year Follow-Up.

Individuals with dissociative disorders (DDs) are underrecognized, underserved, and often severely psychiatrically ill, characterized by marked dissociative and posttraumatic stress disorder (PTSD) symptoms with significant disability. Patients with DD have high rates of nonsuicidal self-injury (NSSI) and suicide attempts. Despite this, there is a dearth of training about DDs. We report the outcome of a web-based psychoeducational intervention for an international sample of 111 patients diagnosed with dissociative identity disorder (DID) or other complex DDs. The Treatment of Patients with Dissociative Disorders Network (TOP DD Network) program was designed to investigate whether, over the course of a web-based psychoeducational program, DD patients would exhibit improved functioning and decreased symptoms, including among patients typically excluded from treatment studies for safety reasons. Using video, written, and behavioral practice exercises, the TOP DD Network program provided therapists and patients with education about DDs as well as skills for improving emotion regulation, managing safety issues, and decreasing symptoms. Participation was associated with reductions in dissociation and PTSD symptoms, improved emotion regulation, and higher adaptive capacities, with overall sample |d|s = 0.44-0.90, as well as reduced NSSI. The improvements in NSSI among the most self-injurious patients were particularly striking. Although all patient groups showed significant improvements, individuals with higher levels of dissociation demonstrated greater and faster improvement compared to those lower in dissociation |d|s = 0.54-1.04 vs. |d|s  = 0.24-0.75, respectively. These findings support dissemination of DD treatment training and initiation of treatment studies with randomized controlled designs.

Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) Un programa educativo online para personas con trastornos disociativos y sus médicos: Seguimiento de uno y dos años INTERVENCIÓN ONLINE PARA TRASTORNOS DISOCIATIVOS Las personas con trastornos disociativos (TDs) se encuentran sub-reconocidas, con pocos servicios y, a menudo, con enfermedades psiquiátricas graves, caracterizadas por marcados síntomas disociativos y de trastorno de estrés postraumático (TEPT) con discapacidad significativa. Los pacientes con TD tienen altas tasas de autolesión no suicida (ALNS) e intentos de suicidio. A pesar de esto, hay una escasez de entrenamiento sobre los TDs. Reportamos el resultado de una intervención psicoeducativa basado en la web para una muestra internacional de 111 pacientes diagnosticados con trastorno de identidad disociativa (TID) u otros TDs complejos. El programa de la Red de Tratamiento de Pacientes con Trastornos Disociativos (TOP DD Network, en su denominación en inglés) se diseñó para investigar si, en el transcurso de un programa psicoeducativo basado en la web, los pacientes con TD exhibirían un mejor funcionamiento y reducción de síntomas, incluso en los pacientes que generalmente han sido excluidos de los estudios de tratamiento por razones de seguridad. Mediante el uso de videos, ejercicios de escritura y prácticas conductuales, el programa TOP DD Network brindó a los terapeutas y los pacientes educación sobre los TDs y las habilidades para mejorar la regulación de las emociones, manejar los problemas de seguridad, y disminuir los síntomas. La participación se asoció con reducciones en los síntomas de disociación y de TEPT, mejor regulación de las emociones y mayores capacidades de adaptación, muestra total ds = .44-.90, así como reducción de ALNS. Las mejoras en ALNS entre los pacientes más auto-agresivos fueron particularmente sorprendentes. Aunque todos los grupos de pacientes mostraron mejoras significativas, los individuos con niveles más altos de disociación demostraron una mejoría mayor y más rápida en comparación con los más bajos en disociación |d|s = .54-1.04 vs. |d|s = .24-.75, respectivamente. Estos hallazgos apoyan la diseminación de la capacitación en el tratamiento del TD y el inicio de estudios de tratamiento con diseños controlados aleatorios.

Seasonality of cerebrospinal fluid monoamine metabolite concentrations and their associations with meteorological variables in humans.

Seasonal variations in neurotransmitter parameters have been previously reported in humans. However, these studies have involved small sample sizes and have not examined possible relationships with meteorological variables. We compared cerebrospinal fluid (CSF) concentrations of the major monoamine neurotransmitter metabolites (5-HIAA, HVA, and MHPG) in 188 healthy controls (80 men, 108 women) in relationship to age, sex, BMI, and available meteorological variables. All subjects had a lumbar puncture (LP) performed at 9 a.m. after overnight stay. Meteorological data for the day prior to LP were obtained from the National Climatic Association and included the photoperiod, percent sunshine, temperature (max, min, mean), barometric pressure, relative humidity, amount of precipitation and sky cover. Results revealed differences across seasons and cross-seasons for CSF 5-HIAA (p ≤ .05), with post-hoc differences emerging between spring versus summer and fall and between x-spring and x-summer (p ≤ .05). Differences were also found across seasons for CSF HVA (p ≤ .05) with post-hoc differences between spring versus fall. CSF 5-HIAA was significantly inversely correlated with maximum (r = -.28, p ≤ .02), minimum (r = -.24, p ≤ .04), and mean temperature (r = -.28, p ≤ .02) in men. In women, 5-HIAA (r = -.22, p ≤ .02) and HVA (r = -.28, p ≤ .003) were significantly correlated with relative humidity. These data confirm previous findings of variations in serotonin and dopamine metabolites across the year and highlight possible underlying mechanisms involving meteorological changes, which may result in alterations in neurophysiology and behavior.

Implementing Trauma and Grief Component Therapy for Adolescents and Think Trauma for Traumatized Youth in Secure Juvenile Justice Settings.

We describe a multiyear pilot dissemination of a trauma-focused group treatment, Trauma and Grief Component Therapy for Adolescents, coupled with a trauma-informed staff training, Think Trauma, to six residential juvenile justice (JJ) facilities. All staff members were trained in Think Trauma. Seventy-seven youth from four facilities completed the treatment groups and 69 completed all pre- and postgroup assessment measures. The aims of this study were to determine whether trauma-focused interventions (a) could be implemented in complex JJ systems, (b) would be associated with a decrease in posttraumatic symptoms and reactions in youth, and (c) might contribute to reduced Incident Reports in facilities. A related question was whether we would receive feedback that youth who participated in the trauma and/or grief narrative components of the intervention were adversely affected. Pre- and postgroup assessments indicated significant reductions in symptoms of posttraumatic stress, depression, and anger, but not in anxiety or sexual concerns. There were significantly greater reductions in posttraumatic stress disorder (PTSD) among incarcerated youth who completed all modules of the group treatment intervention relative to incarcerated youth who received an abbreviated version. Two of the facilities tracked their Incident Reports and reported reductions. No Incident Reports or therapist feedback documented that the trauma/grief processing components of the intervention were destabilizing to the youth.

Clinical phenotypes of perinatal depression and time of symptom onset: analysis of data from an international consortium.

BACKGROUND: The perinatal period is a time of high risk for onset of depressive disorders and is associated with substantial morbidity and mortality, including maternal suicide. Perinatal depression comprises a heterogeneous group of clinical subtypes, and further refinement is needed to improve treatment outcomes. We sought to empirically identify and describe clinically relevant phenotypic subtypes of perinatal depression, and further characterise subtypes by time of symptom onset within pregnancy and three post-partum periods. METHODS: Data were assembled from a subset of seven of 19 international sites in the Postpartum Depression: Action Towards Causes and Treatment (PACT) Consortium. In this analysis, the cohort was restricted to women aged 19-40 years with information about onset of depressive symptoms in the perinatal period and complete prospective data for the ten-item Edinburgh postnatal depression scale (EPDS). Principal components and common factor analysis were used to identify symptom dimensions in the EPDS. The National Institute of Mental Health research domain criteria functional constructs of negative valence and arousal were applied to the EPDS dimensions that reflect states of depressed mood, anhedonia, and anxiety. We used k-means clustering to identify subtypes of women sharing symptom patterns. Univariate and bivariate statistics were used to describe the subtypes. FINDINGS: Data for 663 women were included in these analyses. We found evidence for three underlying dimensions measured by the EPDS: depressed mood, anxiety, and anhedonia. On the basis of these dimensions, we identified five distinct subtypes of perinatal depression: severe anxious depression, moderate anxious depression, anxious anhedonia, pure anhedonia, and resolved depression. These subtypes have clear differences in symptom quality and time of onset. Anxiety and anhedonia emerged as prominent symptom dimensions with post-partum onset and were notably severe. INTERPRETATION: Our findings show that there might be different types and severity of perinatal depression with varying time of onset throughout pregnancy and post partum. These findings support the need for tailored treatments that improve outcomes for women with perinatal depression. FUNDING: Janssen Research & Development.

HPA axis reactivity to pharmacologic and psychological stressors in euthymic women with histories of postpartum versus major depression.

It is unclear whether women with a history of postpartum depression (PPD) have residual, abnormal hypothalamic-pituitary-adrenal (HPA) axis reactivity, as has been reported in major depression (MDD). Further unclear is whether the abnormalities in HPA axis reactivity associated with MDD represent a stable, underlying predisposition or a state-dependent phenomenon. This study sought the following: (1) to determine if euthymic postpartum women with a history of depression have an abnormal HPA axis reactivity to pharmacologic and psychological challenges and (2) to compare HPA reactivity in women with histories of PPD versus MDD. As a secondary objective, we wanted to determine the influence of trauma history on HPA axis function. Forty-five parous (12-24 months postpartum), euthymic women with history of MDD (n = 15), PPD (n = 15), and controls (n = 15) completed pharmacologic (dexamethasone/corticotropin-releasing hormone (CRH) test [DEX/CRH]) and psychological (Trier social stress test [TSST]) challenges during the luteal phase. Outcome measures were cortisol and adrenocorticotropic hormone (ACTH) response after DEX/CRH, and blood pressure, heart rate, epinephrine, norepinephrine, and cortisol response during the TSST. All groups had robust cortisol and ACTH response to DEX/CRH and cortisol response to TSST. Groups did not differ significantly in cortisol or ACTH response to DEX/CRH or in blood pressure, heart rate, epinephrine, norepinephrine, or cortisol response to TSST. Cortisol/ACTH ratio did not differ significantly between groups. Trauma history was associated with decreased cortisol response to DEX/CRH in women with histories of MDD, which was not significant after correction (F 8,125, p = 0.02, Greenhouse-Geisser corrected p = 0.11). Currently euthymic women with histories of MDD or PPD did not demonstrate residual abnormal stress responsivity following administration of either a pharmacologic or psychological stressor.

Maternal Interpersonal Trauma and Child Social-Emotional Development: An Intergenerational Effect.

BACKGROUND: Evidence suggests that maternal interpersonal trauma can adversely affect offspring health, but little is known about potential transmission pathways. We investigated whether interpersonal trauma exposure had direct and indirect associations with offspring social-emotional development at 12-months of age in an at-risk, home visited population. METHODS: A retrospective cohort study was conducted of 1172 mother-child dyads who participated in a multi-site, early childhood home visiting program. Children were born January 2007 to June 2010 and data were collected at enrolment (prenatal/birth) through 12-months of age. Multivariable path analyses were used to examine the relationship between maternal interpersonal trauma, subsequent psychosocial mediators (maternal depressive symptoms, social support, and home environment), and the outcome of child social-emotional development measured with the Ages and Stages Questionnaire: Social-Emotional (ASQ:SE). Maternal interpersonal trauma was characterized as any previous exposure, the level of exposure, and type (e.g. abuse) of exposure. RESULTS: The prevalence of maternal interpersonal trauma exposure was 69.1%, and exposures ranged from 1 type (19.3%) to 7 types (2.3%). Interpersonal trauma was associated with a 3.6 point (95% confidence interval 1.8, 5.4) higher ASQ:SE score among offspring and indicated greater developmental risk. An estimated 23.4% of the total effect was mediated by increased maternal depressive symptoms and lower social support. Differential effects were observed by the level and type of interpersonal trauma exposure. CONCLUSION: Maternal interpersonal trauma exposures can negatively impact child social-emotional development, acting in part through maternal psychosocial factors. Future research is needed to further elucidate the mechanisms of intergenerational risk.

Taking Care of Our Own: A Multispecialty Study of Resident and Program Director Perspectives on Contributors to Burnout and Potential Interventions.

OBJECTIVE: Rates of resident physician burnout range from 60 to 76 % and are rising. Consequently, there is an urgent need for academic medical centers to develop system-wide initiatives to combat burnout in physicians. Academic psychiatrists who advocate for or treat residents should be familiar with the scope of the problem and the contributors to burnout and potential interventions to mitigate it. We aimed to measure burnout in residents across a range of specialties and to describe resident- and program director-identified contributors and interventions. METHODS: Residents across all specialties at a tertiary academic hospital completed surveys to assess symptoms of burnout and depression using the Maslach Burnout Inventory and the Patient Health Questionnaire-9, respectively. Residents and program directors identified contributors to burnout and interventions that might mitigate its risk. Residents were asked to identify barriers to treatment. RESULTS: There were 307 residents (response rate of 61 %) who completed at least one question on the survey; however, all residents did not respond to all questions, resulting in varying denominators across survey questions. In total, 190 of 276 residents (69 %) met criteria for burnout and 45 of 263 (17 %) screened positive for depression. Program directors underestimated rates of burnout, with only one program director estimating a rate of 50 % or higher. Overall residents and program directors agreed that lack of work-life balance and feeling unappreciated were major contributors. Forty-two percent of residents reported that inability to take time off from work was a significant barrier to seeking help, and 25 % incorrectly believed that burnout is a reportable condition to the medical board. CONCLUSIONS: Resident distress is common and most likely due to work-life imbalance and feeling unappreciated. However, residents are reluctant to seek help. Interventions that address work-life balance and increase access to support are urgently needed in academic medical centers.

The Effects of Trauma History and Prenatal Affective Symptoms on Obstetric Outcomes.

Prenatal maternal mood may inform the adverse obstetric outcomes seen in disadvantaged populations. The contribution of having a trauma history is not well studied. We examined the impact of trauma exposure and mood symptoms on obstetric outcomes in 358 women. Women with antecedent trauma were more likely to have a history of depression, odds ratio = 2.83, 95% confidence interval [1.81, 4.42], were younger at their first pregnancy, 18.86 years versus 20.10 years, and had a higher number of previous pregnancies, 2.01 versus 1.54, compared to those with no trauma exposure. Women with prenatal anxiety had significantly smaller babies than nonanxious women, 3,313.17 g, (SD = 441.58) versus 3,429.27 g, (SD = 437.82) Trauma history magnified the effects of maternal prenatal mood on birthweight; the moderating effect was limited to those who first experienced a trauma under 18 years of age. Childhood trauma exposure increased vulnerability for low birthweight delivery associated with prenatal mood disturbance. Screening pregnant women for trauma history and current mood symptoms is indicated.

Antecedent trauma exposure and risk of depression in the perinatal period.

OBJECTIVE: To assess the impact of antecedent trauma on the risk of antenatal and postpartum depression in a prospective, longitudinal cohort of pregnant women. METHOD: 374 participants (pregnant women aged 20-34 years) were recruited from a hospital-based obstetrics practice serving a predominantly low-income, inner-city population between May 2007 and May 2012. Clinical diagnostic interviews and psychosocial questionnaires were administered at 18 and 32 weeks of gestation and at 6 weeks and 6 months postpartum. Lifetime exposure to and details of traumatic events were recorded. Depression during pregnancy or the postpartum period was diagnosed according to DSM-IV-TR. RESULTS: 39% of the sample reported at least 1 traumatic event; trauma history (odds ratio [OR] = 2.16; 95% CI, 1.31-3.54) and, particularly, experiencing childhood sexual abuse (OR = 2.47; 95% CI, 1.27-4.78), someone close experiencing violence (OR = 2.19; 95% CI, 1.11-4.32), and the unexpected death or illness of someone close (OR = 2.15; 95% CI, 1.14-4.05) predicted antenatal but not postpartum depression. A clear dose-response effect of trauma on antenatal depression was observed; women who experienced 3 or more traumas had a 4-fold risk (OR = 4.34; 95% CI, 2.16-8.70) of antenatal depression compared to women with no trauma history. CONCLUSIONS: Antecedent trauma significantly increases the risk of antenatal depression, but antenatal depression alone does not appear to predict postpartum depression. Routine screening for trauma exposure and depression is warranted during pregnancy to aid in the early detection and treatment of depression. Future studies need to examine mechanisms that may trigger affective episodes in trauma-exposed women, who may be especially vulnerable to depressive episodes during pregnancy.

Synergistic childhood adversities and complex adult psychopathology.

Numerous studies find a cumulative effect of different types of childhood adversities on increasing risk for serious adult mental and medical outcomes. This study uses the National Comorbidity Survey-Replication sample to investigate the cumulative impact of 8 childhood adversities on complex adult psychopathology as indexed by (a) number of lifetime diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed., DSM-IV; American Psychiatric Association, 1994); (b) number of 4 DSM-IV disorder categories (mood, anxiety, impulse control, and substance abuse disorders); and (c) coexistence of internalizing and externalizing disorders. Seven of the 8 childhood adversities were significantly associated with complex adult psychopathology. Individuals with 4 or more childhood adversities had an odds ratio of 7.3, 95% confidence interval [4.7, 11.7] for 4 disorder categories. Additive and multiplicative synergistic effects increasing adult psychopathology were found for specific pairwise combinations of childhood adversities. Synergistic patterns differed by gender suggesting that women are more impacted by sexual abuse and men by economic hardship. The absence of childhood adversities was protective, in that it significantly decreased an individual's risk for subsequent adult mental illness. The results support the clinical impression that increased childhood adversity is associated with more complex adult psychopathology.

Childhood sexual abuse and adolescent pregnancy: a meta-analytic update.

OBJECTIVE: Recent increases in adolescent pregnancies have sparked a renewed impetus to identify risk factors, such as childhood sexual abuse (CSA), associated with adolescent pregnancy. Given mixed evidence regarding the strength of the relationship between CSA and adolescent pregnancy (Blinn-Pike, Berger, Dixon, Kuschel, & Kaplan, 2002), our objective was to provide an estimate of the effect size of this relationship using updated literature and meta-analytic techniques. METHODS: Meta-analyses of 21 studies were conducted using a random effects model of binary outcomes to determine aggregate effect-size estimates controlling for study heterogeneity. RESULTS: CSA significantly increased the odds of experiencing an adolescent pregnancy by 2.21-fold (95% CI: 1.94-2.51). A supplemental analysis suggested that 4.5 out of 10 pregnant adolescents may have a prior history of CSA. CONCLUSIONS: CSA places females at increased risk for subsequent adolescent pregnancy. Addressing conditions associated with CSA might impact the overall adolescent pregnancy rate.

Biomarkers in the diagnosis of Alzheimer's disease: are we ready?

Although clinical manifestations of cognitive dysfunction and impairments of activities of daily living are the current standard measures for the diagnosis of Alzheimer's disease, biomarkers are receiving increasing attention in research centers as possible early diagnostic measures or as surrogate measures of the ongoing pathology. In preparation for the upcoming development of the Diagnostic and Statistical Manual of Mental Disorders (5th ed; DSM-V) nosology, the American Psychiatric Association has sponsored an effort to reassess the current approaches to diagnosis in dementia in general and Alzheimer's disease in particular. This article focuses on the potential use of biomarkers in the diagnosis of Alzheimer's disease, in the monitoring of mild cognitive impairment, and as possible prognostic markers in normal controls at risk for dementia. Most advanced information is available with the biomarkers found in the cerebrospinal fluid, but there are many other potential biomarkers using blood, brain imaging, or a combination. The current biomarker approaches to diagnosis are reviewed along with a special emphasis on near-term recommendations and further research directions.

Stability of CSF beta-amyloid(1-42) and tau levels by APOE genotype in Alzheimer patients.

BACKGROUND: Cerebrospinal fluid (CSF) measures of beta-amyloid(1-42 )and tau differ between patients with Alzheimer's Disease (AD) and elderly normal controls. The effect of time and APOE genotype on these biomarkers continues to be elucidated. METHODS: We assessed CSF beta-amyloid(1-42) and tau in 20 mild-to-moderate AD patients, 11 APOE epsilon4+ and 9 APOE epsilon4-, over a mean time of 3.8 years (range 1-11.1 years). RESULTS: Over the period measured, CSF beta-amyloid(1-42) levels were lower in APOE epsilon4+ compared to APOE epsilon4- patients, and the levels decreased over time. Tau levels were stable over time and did not show an effect of APOE allele. CONCLUSIONS: While this is a limited clinical sample, the further decrease in CSF beta-amyloid(1-42 )(i.e., more abnormal) combined with the CSF tau stability over a mean period of almost 4 years suggests that beta-amyloid(1-42 )and tau maintain their potential usefulness as diagnostic biomarkers over time. These findings should be taken into account if CSF beta-amyloid(1-42) and tau are used as measures of treatment response.

A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia.

OBJECTIVE: To evaluate neurotransmitter deficiencies and neurotransmitter-based treatments for frontotemporal dementia (FTD). METHODS: The authors conducted a systematic review of the literature on the mechanism and treatment of FTD and a meta-analysis of treatment studies of antidepressants for the behavioral symptoms of FTD. RESULTS: Patients with FTD show deficiencies in the serotonin and dopamine neurotransmitter systems, while the acetylcholine system appears relatively intact. Antidepressant treatment significantly improves behavioral symptoms in FTD, but most studies are small and uncontrolled. Serotonergic treatments appear to improve the behavioral but not cognitive symptoms of FTD. CONCLUSIONS: Studies of neurotransmitter deficiencies in frontotemporal dementia (FTD) can be helpful in developing treatments. Treatment studies on FTD are scarce, given the prevalence and severity of this illness. Larger, well-controlled treatment studies are required to reach more definitive conclusions about treatment efficacy. Multicenter studies are likely the best way to complete treatment studies in a timely manner.

Cerebrospinal fluid beta-amyloid1-42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE epsilon4 allele.

BACKGROUND: Cerebrospinal fluid (CSF) measures of beta-amyloid(1-42) and tau are linked with the known neuropathology of Alzheimer's disease (AD). Numerous lines of evidence have also suggested that individuals with at least one APOE epsilon4 allele on chromosome 19 are at increased risk of developing AD. We tested these CSF markers in groups of subjects with AD and healthy older control subjects, using the absence or presence of the APOE epsilon4 allele as a predictive variable in the search for possible prognostic biomarkers of AD. METHODS: We assessed the levels of beta-amyloid(1-42) and total tau in the CSF of 292 subjects (142 control subjects and 150 subjects with mild-to-moderate AD), who were research participants at the National Institute of Mental Health. The group of control subjects was enriched with a high percentage of subjects with a positive family history of AD. All subjects underwent extensive global cognitive testing. RESULTS: When divided according to the absence or presence of the APOE epsilon4 allele, the control subjects with at least one epsilon4 allele had significantly lower CSF beta-amyloid(1-42) but not tau levels than control subjects without an APOE epsilon4 allele (p < .01). As expected, the AD patients had lower levels of CSF beta-amyloid(1-42) and higher CSF tau levels than the normal control group (p < .01). CONCLUSIONS: The association of APOE epsilon4 allele and lower, more AD-like levels of CSF beta-amyloid(1-42) in older control subjects is consistent with previous studies showing possible neuroimaging and cognitive abnormalities with epsilon4 carriers and suggests that CSF beta-amyloid(1-42) decreases might represent an early biomarker of AD. Longitudinal follow-up is of course required to verify whether this biomarker is indeed predictive of clinical conversion to AD.

Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease.

CONTEXT: Alzheimer disease (AD) is characterized by pathological results at autopsy of amyloid plaques and tau-associated neurofibrillary tangles, but the clinical diagnosis of AD is determined on the basis of medical history, cognitive symptoms, and exclusionary criteria. The search for antemortem biomarkers is intense and has focused on cerebrospinal fluid (CSF) beta-amyloid1-42 and tau proteins. OBJECTIVES: To compare CSF beta-amyloid and tau levels in a new population of AD patients and controls. To perform a meta-analysis of studies of CSF beta-amyloid and tau levels in AD patients and controls. DESIGN: Cross-sectional study of the comparison of baseline CSF beta-amyloid1-42 and tau levels in AD patients and controls. Meta-analysis involved 17 studies of CSF beta-amyloid and 34 studies of CSF tau. SETTING: Clinical research unit of the National Institute of Mental Health, Bethesda, Md. PATIENTS: The Geriatric Psychiatry Branch evaluated AD patients as inpatients at the National Institutes of Health Clinical Center between May 1985 and January 2001. A total of 203 patients participated in this study (131 with AD and 72 controls). None had other serious illnesses, and 31 of 131 AD cases had AD confirmed at autopsy. Meta-analysis provided an additional 3133 AD patients and 1481 controls. MAIN OUTCOME MEASURES: Levels of CSF beta-amyloid1-42 were measured by a sandwich enzyme-linked immunoabsorbent assay with a polyclonal capture antibody and a monoclonal detection antibody. Levels of CSF tau were measured with a standard commercial immunoassay. RESULTS: Levels of CSF beta-amyloid1-42 were significantly lower in the AD patients vs controls (mean [SD], 183 [121] pg/mL vs 491 [245] pg/mL; P<.001). Levels of CSF tau were significantly higher in AD patients (mean [SD], 587 [365] pg/mL vs 244 [156] pg/mL; P<.001). The cutpoints of 444 pg/mL for CSF beta-amyloid1-42 and 195 pg/mL for CSF tau gave a sensitivity and specificity of 92% and 89%, respectively, to distinguish AD patients from controls, which is comparable with rates with clinical diagnosis. Meta-analyses of studies comparing CSF beta-amyloid and tau levels in AD participants and controls confirmed an overall difference between levels in these 2 groups. CONCLUSIONS: Alzheimer disease is associated with a significant decrease in CSF beta-amyloid1-42 levels along with an increase in CSF tau levels. These findings suggest that the 2 measures are biological markers of AD pathophysiology. While these CSF measures may have a potential clinical utility as biomarkers of disease, the preliminary and retrospective nature of the findings, the absence of assay standardization, and the lack of comparison patient populations must be addressed in future studies testing the usefulness of these CSF measures for predictive, diagnostic, or treatment evaluation purposes.