James Schmeidler

Neurochemical correlates of dementia severity in Alzheimer's disease: relative importance of the cholinergic deficits.

Abstract: Cholinergic markers, neuropeptides, and amines and their metabolites were sampled from identical specimens across 10 neocortical regions in a large sample of Alzheimers disease (AD) cases and controls. Levels of choline acetyltransferase, acetylcholinesterase, somatostatin, corticotropin‐releasing factor, serotonin, and 5‐hydroxyindoleacetic acid were significantly reduced in AD versus controls. After data reduction, the most descriptive neurochemical indices were used to examine the relationship of neurochemical measures and dementia severity within the AD sample, controlling for age effects. Dementia severity ratings were based on antemortem assessments (46.9% of AD sample) and postmortem chart review (53.1% of the AD sample). Choline acetyltransferase activity was highly correlated with clinical dementia ratings across the neocortex of the AD cases. Somatostatin and corticotropin‐releasing factor levels were correlated with dementia severity only when control cases were included in the analyses. None of the amines, their metabolites, or the neuropeptides quantified related significantly to dementia severity in the AD cohort. These data (a) confirm the strong association of cholinergic deficits with functional impairment in AD and show that this association is independent of age and (b) suggest that of all the neurochemical species quantified, the cholinergic indices may be unique in their association with dementia severity.

Gene Expression Patterns Associated with Posttraumatic Stress Disorder Following Exposure to the World Trade Center Attacks

BACKGROUND Although genetic risk factors for posttraumatic stress disorder (PTSD) in similarly traumatized cohorts can be confounded with risk for type of exposure, the primary risk for exposure to the 9/11 attack on New York City was proximity, allowing study of PTSD risk in a sample that is not confounded by exposure-related risk. METHODS Thirty-five Caucasians (15 with PTSD, stratified for exposure, age, and gender) were selected from a population-representative sample of persons exposed to the attack from which longitudinal data had been collected in four previous waves. Whole blood gene expression and cortisol levels were obtained. RESULTS Seventeen probe sets were differentially expressed in PTSD. Identified genes were generally involved in hypothalamic-pituitary-adrenal (HPA) axis, signal transduction, or brain and immune cell function. FKBP5, a modulator of glucocorticoid receptor (GR) sensitivity, showed reduced expression in PTSD, consistent with enhanced GR responsiveness. FKBP5 expression was predicted by cortisol when entered with PTSD severity in regression analysis. Quantitative polymerase chain reaction confirmed significant reductions in FKBP5. Also less expressed in PTSD were STAT5B, a direct inhibitor of GR, and major histocompatibility complex (MHC) Class II. CONCLUSIONS Consistent with observations of HPA axis dysfunction in PTSD, several genes involved in glucocorticoid signaling are differentially expressed among those with current PTSD.

Diabetes mellitus in midlife and the risk of dementia three decades later

Objective: To examine the association between diabetes in midlife (1963–1968) and dementia more than three decades later (1999–2001). Methods: The authors characterized dementia using standard methods for 1,892 participants among 2,606 survivors of 10,059 participants in the Israeli Ischemic Heart Disease study, a longitudinal investigation of the incidence of and risk factors for cardiovascular disease among Jewish male civil servants in Israel. Face to face interviews were conducted with the 652 subjects identified as possibly demented by the Modified Telephone Interview for Cognitive Status. Logistic regression analysis was performed to assess the association of diabetes with dementia controlling for sociodemographic and cardiovascular variables compared to those with no cognitive impairment. Results: Of 1,892 assessed subjects (mean age 82 at assessment), 309 (16.3%) had dementia. Diabetic subjects had significantly more dementia than non-diabetic subjects (χ2 = 7.54, df = 1, p = 0.006, OR 2.83 [95% CI = 1.40 to 5.71]). Those who survived to the time of this study were younger and healthier than those who died. Conclusions: Evidence for diabetes as a risk factor for dementia was found, similar to other epidemiologic studies. In contrast to the earlier studies, however, the authors linked diabetes in midlife to dementia more than three decades later in the very old survivors of a large male cohort.

Abuse and Neglect in Childhood: Relationship to Personality Disorder Diagnoses

BACKGROUND Childhood history of abuse and neglect has been associated with personality disorders and has been observed in subjects with lifetime histories of suicidality and self-injury. Most of these findings have been generated from inpatient clinical samples. METHODS This study evaluated self-rated indices of sustained childhood abuse and neglect in an outpatient sample of well-characterized personality disorder subjects (n=182) to determine the relative associations of childhood trauma indices to specific personality disorder diagnoses or clusters and to lifetime history of suicide attempts or gestures. Subjects met criteria for ~2.5 Axis II diagnoses and 24% reported past suicide attempts. The Childhood Trauma Questionnaire was administered to assess five dimensions of childhood trauma exposure (emotional, physical, and sexual abuse, and emotional and physical neglect). Logistic regression was employed to evaluate salient predictors among the trauma measures for each cluster, personality disorder, and history of attempted suicide and self-harm. All analyses controlled for gender distribution. RESULTS Seventy-eight percent of subjects met dichotomous criteria for some form of childhood trauma; a majority reported emotional abuse and neglect. The dichotomized criterion for global trauma severity was predictive of cluster B, borderline, and antisocial personality disorder diagnoses. Trauma scores were positively associated with cluster A, negatively with cluster C, but were not significantly associated with cluster B diagnoses. Among the specific diagnoses comprising cluster A, paranoid disorder alone was predicted by sexual, physical, and emotional abuse. Within cluster B, only antisocial personality disorder showed significant associations with trauma scores, with specific prediction by sexual and physical abuse. For borderline personality disorder, there were gender interactions for individual predictors, with emotional abuse being the only significant trauma predictor, and only in men. History of suicide gestures was associated with emotional abuse in the entire sample and in women only; self-mutilatory behavior was associated with emotional abuse in men. CONCLUSION These results suggest that childhood emotional abuse and neglect are broadly represented among personality disorders, and associated with indices of clinical severity among patients with borderline personality disorder. Childhood sexual and physical abuse are highlighted as predictors of both paranoid and antisocial personality disorders. These results help qualify prior observations of the association of childhood sexual abuse with borderline personality disorder.

Diffusion Tensor Imaging Findings in First-Episode and Chronic Schizophrenia Patients

OBJECTIVE Comparisons of diffusion tensor imaging (DTI) data between first-episode and chronic schizophrenia patients assessed in different studies have led to the suggestion that the decreased fractional anisotropy observed in chronic schizophrenia patients is less pronounced in first-episode patients. However, such comparisons of imaging data generated across studies are susceptible to numerous confounders, which may limit the interpretation of any differences. In order to address these issues and determine whether the DTI abnormalities of chronic schizophrenia are present at illness onset, the authors conducted a DTI investigation of the largest cohort of first-episode schizophrenia patients yet reported in conjunction with a group of chronic schizophrenia patients and healthy subjects for comparison. METHOD Fractional anisotropy data generated by diffusion tensor imaging with a 3-T Siemens Allegra head-dedicated MRI system were compared between 40 first-episode schizophrenia patients and 39 age- and gender-matched healthy comparison subjects and between 40 chronic schizophrenia patients and 40 age- and gender-matched healthy comparison subjects. The following regions of interest were assessed: forceps minor (bilaterally), forceps major (bilaterally), inferior longitudinal fasciculus (bilaterally), and the genu and splenium of the corpus callosum. RESULTS In most regions, chronic schizophrenia patients showed significant or trend-level lower fractional anisotropy than healthy comparison subjects, whereas the first-episode schizophrenia patients showed only trend-level lower fractional anisotropy in the inferior longitudinal fasciculus. CONCLUSIONS The cross-sectional data reported here suggest less widespread changes in white matter at illness onset in schizophrenia which progress in more chronic states. More definitive conclusions will require follow-up imaging of first-episode schizophrenia patients.

Maternal, not paternal, PTSD is related to increased risk for PTSD in offspring of Holocaust survivors.

BACKGROUND A significant association between parental PTSD and the occurrence of PTSD in offspring has been noted, consistent with the idea that risk for the development of PTSD is transmitted from parent to child. Two recent reports linking maternal PTSD and low offspring cortisol prompted us to examine the relative contributions of maternal vs. paternal PTSD in the prediction of PTSD and other psychiatric diagnoses in offspring. METHODS One hundred seventeen men and 167 women, recruited from the community, were evaluated using a comprehensive psychiatric battery designed to identify traumatic life experiences and lifetime psychiatric diagnoses. 211 of these subjects were the adult offspring of Holocaust survivors and 73 were demographically comparable Jewish controls. Participants were further subdivided based on whether their mother, father, neither, or both parents met diagnostic criteria for lifetime PTSD. RESULTS A higher prevalence of lifetime PTSD, mood, anxiety disorders, and to a lesser extent, substance abuse disorders, was observed in offspring of Holocaust survivors than controls. The presence of maternal PTSD was specifically associated with PTSD in adult offspring of Holocaust survivors. However, other psychiatric diagnoses did not show specific effects associated with maternal PTSD. CONCLUSION The tendency for maternal PTSD to make a greater contribution than paternal PTSD to PTSD risk suggests that classic genetic mechanisms are not the sole model of transmission, and paves way for the speculation that epigenetic factors may be involved. In contrast, PTSD in any parent contributes to risk for depression, and parental traumatization is associated with increased anxiety disorders in offspring.

Increased pituitary activation following metyrapone administration in post-traumatic stress disorder.

Our previous findings have demonstrated that individuals with post-traumatic stress disorder (PTSD) show lower basal cortisol levels, a larger number of lymphocyte glucocorticoid receptors, and an enhanced suppression of cortisol following the administration of dexamethasone compared to normals and patients with major depression. We have previously suggested that these alterations reflect an enhanced negative feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis in PTSD. However, in the absence of direct knowledge of pituitary capability in this disorder, it has been equally likely that the alterations observed reflected either pituitary or adrenal insufficiency. In the present study, we examined ACTH release from the pituitary gland in PTSD following the administration of metyrapone. Metyrapone resulted in a significantly greater increase of ACTH and 11-deoxycortisol in combat veterans with PTSD (n = 11) compared with normal male volunteers (n = 8). When seen in the context of other abnormalities observed in PTSD, the present demonstration of increased pituitary activity in the absence of negative feedback provides unequivocal support for the hypothesis of enhanced negative feedback.

Randomized pilot study of nimesulide treatment in Alzheimer's disease.

BackgroundNonsteroidal anti-inflammatory drugs (NSAID) may be useful in the treatment of AD. Clinical and laboratory experience with nimesulide, an NSAID with preferential cyclooxygenase-2 inhibition, suggests that it may be a good candidate for AD therapy. MethodsThis pilot study investigated the clinical feasibility of nimesulide treatment in AD. Forty persons with probable AD, most of whom were taking cholinesterase inhibitors, were enrolled in a randomized, controlled, parallel-group trial designed to assess tolerability and short-term cognitive/behavioral effects of nimesulide. In the initial 12-week double-blind phase, participants were treated with nimesulide 100 mg by mouth twice daily or matching placebo; during the second 12-week phase all participants received active drug. Participants who tolerated the drug well and perceived benefit were invited to continue open-label nimesulide treatment. ResultsShort-term therapy with nimesulide, compared with placebo, had no significant effect on total assessment scores of measures of cognition, clinical status, activities of daily living, affect, and behavior. Long-term therapy was well tolerated for periods exceeding 2 years. ConclusionThese findings support the feasibility of nimesulide therapy in AD; assessment of efficacy will require a larger, long-term treatment study.

Functional Decline in Alzheimer's Disease: A Longitudinal Study

Objective: To assess the reliability of activities of daily living (ADL) measures and determine the rate and pattern of longitudinal ADL change in patients with Alzheimers disease (AD).

Plasma norepinephrine and 3-methoxy-4-hydroxyphenylglycol concentrations and severity of depression in combat posttraumatic stress disorder and major depressive disorder.

BACKGROUND Catecholamines are thought to play a significant role in the pathophysiology of posttraumatic stress disorder (PTSD), but findings in PTSD have been discrepant. METHODS To obtain more information about catecholamine activity in PTSD, we sampled plasma norepinephrine (NE) and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations over a 24-hour period in men with PTSD (n = 15) and major depressive disorder (MDD) (n = 12), and nonpsychiatric comparison subjects (n = 13), under unstimulated conditions. Chronobiological analyses were performed to determine possible changes in the circadian and ultradian release of these hormones. RESULTS Significant group differences were present for mean plasma NE levels (p = .03), but not MHPG. NE levels were significantly associated with severity of depression in the PTSD group (p = .002). Therefore, PTSD subjects were further subdivided into those with and without a comorbid secondary depression. Increased NE levels were only present in PTSD subjects who did not have a secondary depression. This study also found no significant group differences on any of the chronobiological parameters. CONCLUSIONS The results clarify that increased NE levels in PTSD may be confined to the subgroup of subjects who do not have comorbid depression, and as such, may help resolve some of the discrepancies in the literature regarding basal catecholamine activity.