Body image, self-compassion, and sexual distress in individuals living with endometriosis.

OBJECTIVE: Extensive psychological burden is associated with the experience of living with endometriosis, including negative changes to body image and sexual functioning. Emerging evidence suggests that potential protective factors such as body appreciation and self-compassion may help mitigate these adverse impacts of endometriosis. This study aimed to investigate the association of body image, both positive (body appreciation) and negative (body image disturbance) dimensions, with sexual distress and the potential buffering effect of self-compassion on the body image-sexual distress link. METHODS: Data were collected via an online cross-sectional survey (N = 471) assessing body image disturbance, body appreciation, self-compassion and sexual distress in individuals with endometriosis. A series of hierarchical linear regression analyses were conducted to explore the relationship between key variables. RESULTS: >80% of the sample reported clinically significant sexual distress and high levels of body image disturbance. Regression analyses indicated a moderate positive effect of body image disturbance with sexual distress, and a weaker inverse effect of self-compassion with sexual distress. Body appreciation was not associated with sexual distress, and no moderating effects of self-compassion were evident. CONCLUSION: The high prevalence of sexual distress identified in this sample, along with the finding that body image disturbance was strongly associated with sexual distress, suggest that psychosocial interventions addressing body image may help ameliorate sexual distress in individuals with endometriosis.

Delineating sociodemographic, medical and quality of life factors associated with psychological distress in individuals with endometriosis.

STUDY QUESTION: What is the relationship between specific quality of life domains and depression, anxiety and stress in the endometriosis population? SUMMARY ANSWER: Psychosocial domains of quality of life, such as a perception of social support and self-image, are more strongly associated with depression, anxiety and stress than pain and medical factors. WHAT IS KNOWN ALREADY: Prior research indicates a high prevalence of anxiety and depression in individuals with endometriosis. Pain is thought to be critical in the development of psychological distress, however prior research has investigated this association without consideration of psychosocial quality of life domains such as social functioning, perceived social support and self-image. STUDY DESIGN, SIZE, DURATION: This study is a cross-sectional analysis of baseline data collected in a longitudinal study exploring psychological distress in endometriosis (n = 584). PARTICIPANTS/MATERIALS, SETTING, METHODS: Individuals living with endometriosis participated in this study and were recruited via online platforms of community organizations and support groups. Demographic and medical information concerning endometriosis treatment and diagnosis was self-reported. Psychological distress and quality of life was measured using the Depression, Anxiety and Stress Scale (DASS-21), Endometriosis Health Profile-30 (EHP-30) and the Short Form Survey (SF-36v2). A series of linear regression analyses explored the relationship between specific quality of life domains and the primary outcomes of depression, anxiety and stress. MAIN RESULTS AND THE ROLE OF CHANCE: Approximately half of the participants in this sample reported moderate to severe anxiety, depression and stress. Quality of life domains, particularly perceived social support, social functioning and self-image, were more strongly associated with psychological distress than medical or demographic factors. Pain was associated with anxiety, but not depression or stress. A greater number of endometriosis symptoms was only associated with depression. LIMITATIONS, REASONS FOR CAUTION: These data are cross-sectional and, therefore, causality cannot be inferred from this analysis. Information about endometriosis diagnosis and treatment was self-reported, and not verified against medical records. WIDER IMPLICATIONS OF THE FINDINGS: This study indicates that psychosocial factors may be more salient factors underlying depression, anxiety and stress in the endometriosis population than pain and medical factors. There is a need for interventions that target psychological distress in this population with a focus on the broader impact of endometriosis beyond pain and physical symptomatology. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Research Training Program (RTP) Scholarship awarded to C.S.M. by Macquarie University. The remaining authors have nothing to declare. TRIAL REGISTRATION NUMBER: ACTRN12619001508167.

Body image distress in head and neck cancer patients: what are we looking at?

PURPOSE: The aim of the present study is to investigate the prevalence of body image distress among head and neck cancer (HNC) patients after treatment and to examine its association with sociodemographic and clinical factors, health-related quality of life (HRQOL), HNC symptoms, sexuality, self-compassion, and psychological distress. Second, we aim to explore daily life experiences of HNC patients regarding body image. METHODS: A cross-sectional survey among HNC patients investigated the prevalence of body image distress based on the Body Image Scale. Multivariable logistic regression analysis was applied to study associations with sociodemographic and clinical factors, HRQOL (EORTC QLQ-C30), HNC symptoms (QLQ-HN43), sexuality (FSFI-6; IIEF-5), self-compassion (SCS-SF), and psychological distress (HADS). Qualitative data from a body image writing intervention was used to explore experiences in daily life related to body image. RESULTS: Body image distress was prevalent in 13-20% (depending on cut-off scores) of 233 HNC patients. Symptoms of depression (p < 0.001), younger age (p < 0.001), problems with social contact (p = 0.001), problems with wound healing (p = 0.013), and larger extent of surgery (p = 0.014) were associated with having body image distress. This model explained 67% of variance. Writing interventions of 40 HNC patients showed that negative body image experiences were related to appearance and function, with social functioning problems described most often. CONCLUSION: Prevalence of body image distress in HNC patients, using different cut-off scores, is 13-20%. Younger patients, patients after extensive surgery, and patients who had wound healing problems are most at risk. There is a significant association between body image distress and depressive symptoms and social functioning.

Factors associated with romantic relationship formation difficulties in women with breast cancer.

OBJECTIVE: Many un-partnered women report difficulty in forming romantic relationships after breast cancer, characterized by high dating-related anxiety and low perceived interpersonal competence. This study examined the relationship between poor body image (appearance investment and body dissatisfaction) and self-compassion, and women's ability to form romantic relationships post-breast cancer. METHODS: Women (N = 152) diagnosed with breast cancer, who were either un-partnered and expressed interest in romantic dating, or who had commenced a relationship post-diagnosis, completed an online survey. Assessments included the Interpersonal Competence Questionnaire, Dating Anxiety Scale, Self-compassion Scale, Appearance Schemas Inventory-Revised, Body Image Scale, and Experiences in Close Relationships Scale. Multiple regression analyses assessed the relationships between these variables. RESULTS: Partnered and un-partnered women differed in levels of dating anxiety, interpersonal competence, anxious attachment, and the self-evaluative salience facet of appearance investment. Analyses revealed a significant model for dating anxiety, with high self-evaluative salience, body image dissatisfaction, and attachment avoidance independently associated with this outcome. The model for interpersonal competence was also significant, with low attachment avoidance and high self-compassion independently associated with this outcome. CONCLUSIONS: Un-partnered women who place high importance on appearance for their self-worth and who report poor body image and low self-compassion are at risk of experiencing difficulties in forming new romantic relationships after breast cancer. Future interventions should target these variables to facilitate romantic dating during cancer survivorship.

Patient reported outcomes of autologous fat grafting after breast cancer surgery.

INTRODUCTION: Autologous fat grafting (AFG) can be used as an adjunct in breast cancer surgery to improve contour defects. Few previous studies have assessed patient reported outcomes (PROs) for AFG. This study analysed AFG use and assessed PROs in terms of physical and psychosocial well-being. MATERIALS AND METHODS: All patients undergoing AFG were identified from a prospective database and asked to complete the validated BREAST-Q questionnaire and a tool to assess patient-perceived change after AFG (5-point Likert-type scale). Descriptive statistics were computed for all BREAST-Q and perceived change subscales. Independent sample t-tests were conducted to compare scores on each of the BREAST-Q and perceived change subscales by type of breast cancer surgery and radiotherapy status. RESULTS: 156 AFG sessions were performed over 4 years on 119 breasts in 88 patients. Fifty-seven patients received AFG after reconstruction and 19 after breast conserving surgery. Forty-six patients (52%) completed the questionnaire. BREAST-Q scores (out of 100) and patient-perceived change after AFG (out of 5) were respectively: 54 and 4.0 for Breast satisfaction, 69 and 3.3 for Physical well-being and 60 and 3.6 for Psychosocial well-being. Radiotherapy status and type of surgery made little difference. Number of AFG procedures positively correlated with perceived improvement. DISCUSSION: Autologous fat grafting was associated with improved patient satisfaction despite small volumes transferred. BREAST-Q scores were comparable with previously published series on reconstructive breast surgery. Perceived change after AFG was no different in patients receiving radiotherapy.

Body image and psychological distress in nipple-sparing mastectomy: the roles of self-compassion and appearance investment.

OBJECTIVE: Women with breast cancer face threats to body image following surgery. Nipple-sparing mastectomy with immediate breast reconstruction (NSM + IBR) may minimise body image disturbance as this preserves the woman's skin and areola complex. We assessed levels of body image disturbance and psychological distress in women undergoing NSM + IBR. To further understand the body image-distress relationship, we investigated the potential moderating effect of self-compassion and appearance investment on this relationship. METHODS: Women diagnosed with breast cancer (N = 75) who had undergone NSM + IBR completed online questionnaires including the Body Image Scale, general (Depression, Anxiety and Stress Scales) and cancer-specific (Impact of Event Scale) psychological distress and Self-Compassion Scale and Appearance Schemas Inventory - Revised. RESULTS: Mean general and cancer-specific psychological distress scores were within normal ranges, and body image disturbance was moderately low. Body image was positively correlated with depression, stress, Impact of Event Scale scores and appearance investment and negatively correlated with self-compassion. MANCOVA analyses indicated a significant moderating effect of self-compassion and appearance investment on the body image disturbance-distress relationship (for depression, stress and intrusion), such that participants with high self-compassion and low appearance investment experienced lower distress than individuals with low self-compassion and high appearance investment. CONCLUSIONS: Moderately low levels of psychological distress and body image disturbance suggest NSM + IBR may minimise adverse psychological impacts of mastectomy. Increased body image disturbance was associated with psychological distress and moderated by self-compassion and appearance investment, suggesting a potential role for these characteristics as the focus of psychological interventions to minimise the negative impacts of mastectomy. Copyright © 2016 John Wiley & Sons, Ltd.

Prevalence and predictors of distress in women taking part in surgical continuity of care for breast cancer: A cohort study.

PURPOSE: Women with breast cancer often experience distress. This cohort study investigated the prevalence of distress, predictors of distress, and changes in distress during surgical continuity of care for breast cancer (from diagnosis to commencement of adjuvant treatment). METHODS: The participants were 1079 women with breast cancer who were recruited between April 2013 and May 2014 from 11 breast surgery departments in Denmark. Distress was evaluated using the Distress Thermometer (DT) and predictors of distress were assessed with a self-administered questionnaire at the time of diagnosis (T1), at discharge (T2), and by the start of adjuvant treatment or follow-up (T3). Repeated measures ANOVA, simple and multiple linear regression, and mixed effects regression models were used to identify predictors and estimate changes in distress. RESULTS: At T1, 249 (24.3%) women reported no or minimal distress, 298 (29.1%) moderate distress, and 407 (39.8%) severe distress. The mean distress was 5.5 points on the DT, which decreased by 0.70 (95% confidence interval (CI) -0.80, -0.54) points from T1 to T3. Predictors of distress were time since diagnosis, age, prior or concurrent intake of antidepressants or sedative medicine, prior emotional status, children living at home, feelings regarding femininity and attractiveness, and hospital. CONCLUSIONS: More than two-thirds of women with breast cancer experienced moderate or severe distress. Mean distress decreased slightly during surgical continuity of care. However, for some women, distress remained unchanged or even worsened. These findings highlight the need to identify the individual women with distress and offer them adequate support and care.

The effect of monitoring 'processing style' on post-surgical neuropathic pain in women with breast cancer.

BACKGROUND: Pain is a commonly reported symptom following surgery that is more likely to occur in individuals psychologically distressed prior to surgery. Monitoring processing style, a cognitive tendency to focus on health-related threats, has been associated with increased reporting of somatic symptoms, but no studies have specifically addressed the link between this cognitive style and pain. This prospective clinical study aimed to investigate whether monitoring processing style predicted post-surgical pain in women undergoing breast surgery, controlling for pre-surgical psychological distress. METHODS: Women scheduled to undergo breast cancer surgery (N = 106) completed pre-surgical assessments of monitoring processing style (Miller Behavioral Style Scale) and psychological distress (Depression Anxiety Stress Scales-21). Demographic and medical characteristics were documented. Self-reported neuropathic pain (Neuropathic Pain Scale) was assessed at 3 months post surgery. RESULTS: Post-surgical neuropathic pain levels were low to moderate (M = 19.3, SD = 21.1). Higher pre-surgical monitoring processing style scores significantly predicted higher post-surgical neuropathic pain (ß = 0.23, p = 0.023), over and above psychological stress (ß = 0.22, p = 0.020) and age (ß = -0.25, p = 0.011). CONCLUSIONS: Pre-surgical monitoring processing style was an independent predictor of post-surgical neuropathic pain, even when accounting for pre-surgical psychological distress. Since the reduction of post-surgical pain is a key goal of healthcare, efforts should be made prior to breast cancer surgery to counsel and support individuals with high monitoring processing styles irrespective of their level of distress.

Validation of the Croatian and Lebanese Revised Illness Perception Questionnaires for Healthy People (IPQ-RH).

The absence of Croatian- and Arabic-language measures to assess illness representations has contributed to lack of research among Croatian and Lebanese populations. Utilising the robust confirmatory factor analysis (CFA) approach, this study aimed to validate Croatian and Arabic versions of the Revised Illness Perception Questionnaire for Healthy People (IPQ-RH) in the breast and cervical cancer contexts, and compared these illness perceptions among Croatian and Lebanese women living in Australia. Forward and back-translated versions of the IPQ-RH were administered in Croatian to Croatian-born (n = 238), and Arabic to Lebanese-born (n = 240) women. The IPQ-RH illness perceptions were assessed for each cancer type, and the Negative Affect (NA) subscale of the Positive and Negative Affect Schedule (PANAS) assessed discriminant validity. The CFA method demonstrated acceptable models across the Croatian and Lebanese IPQ-RH measures. The internal reliabilities for the IPQ-RH subscales were adequate and the subscales had low correlations with the NA subscale of the PANAS, indicating that the IPQ-RH measures are largely distinguishable from negative affective dispositions. These findings demonstrate that the Croatian and Lebanese IPQ-RH breast and cervical cancer measures have a factor structure similar to the originally developed IPQ-RH scale and provide further support for the theoretically developed illness representations.

Rumination, psychological distress and post-traumatic growth in women diagnosed with breast cancer.

OBJECTIVE: Rumination, the repetitive and recursive rehearsal of cognitive content, has been linked to depression and anxiety in physically well populations, and to post-traumatic growth (PTG) in physical illness populations. Women diagnosed with breast cancer may experience both psychological distress and PTG. As rumination may influence outcomes through distinct pathways, this study investigated the association of intrusion, brooding and instrumental subcomponents of rumination with psychological distress and PTG in the breast cancer context. METHODS: Women diagnosed with primary breast cancer (n = 185), mean age 55.98 years (SD = 9.26), completed an online survey including the Multi-dimensional Rumination in Illness Scale, Depression Anxiety and Stress Scales, Post-traumatic Growth Inventory, Medical Outcomes Social Support Survey, demographic and health-related questions. RESULTS: As predicted, regression analyses indicated that brooding was positively related to depression, anxiety and stress, but was also negatively related to the PTG dimensions of new possibilities and spiritual growth. Partially supporting the study hypotheses, intrusion was positively associated with stress and the PTG of relating to others and new possibilities. As hypothesised, instrumental rumination was positively associated with all five dimensions of PTG. CONCLUSIONS: Rumination is a key consideration in both positive and negative psychological responses of women diagnosed with breast cancer. Associations of specific components of rumination with varying psychological outcomes suggest differential paths by which the specific subcomponents of rumination exert this influence.

Assessing rumination in response to illness: the development and validation of the Multidimensional Rumination in Illness Scale (MRIS).

The cognitive style of rumination extends existing cognitive models of emotional response to illness. In the absence of a specific measure, we developed the Multidimensional Rumination in Illness Scale (MRIS). In Study 1, an initial 60-item pool was tested, followed by confirmation of the factor structure in Study 2. In Study 1 participants (n = 185) completed the pilot version of the MRIS, then in Study 2 (n = 163) a reduced 41-item model was tested. Study 1: Exploratory factor analysis of a reduced 32-item scale indicated an initial four-factor solution for the MRIS (Intrusion, Brooding, Instrumental, Preventability), with satisfactory internal consistency and stable factor structure across gender. Study 2: Following scale revision, confirmatory factor analysis substantiated the adequacy of a three-factor MRIS structure, and good internal consistency, test-rest reliability, and concurrent and discriminant validity was demonstrated for the MRIS. The MRIS exhibited good psychometric properties in the current sample, providing a comprehensive assessment of the cognitive style of rumination in the context of physical illness.

Oral versus transdermal selegiline: antidepressant-like activity in rats.

These studies compared the dose-response effects of oral vs. transdermal selegiline on antidepressant-like activity and brain monoamine oxidase (MAO) activities in rats. Rats received selegiline by gavage (0-100 mg/kg) or via transdermal patches (0-4.8 cm2, 0-8.7 mg/kg) daily for 7 days; antidepressant-like activity was determined using the forced-swim test. Following behavioral testing, cerebral cortices were assayed for MAO-A and MAO-B activities. Doses of selegiline that selectively inhibited MAO-B (3 and 10 mg/kg/day by gavage and 0.4 mg/kg/day via patch) did not alter either immobility or latency time. However, the oral administration of 30 or 100 mg/kg/day or the transdermal administration of 8.7 mg/kg/day, doses that led to greater than 70% inhibition of MAO-A, decreased immobility time significantly. The IC50s for inhibition of MAO-A following oral and transdermal administration for 7 days were 19.8 and 1.1 mg/kg, respectively. Results indicate that both oral and transdermal selegiline have antidepressant-like activity as assessed by the forced-swim test, and that transdermal administration, which bypasses first-pass metabolism, allows for using lower doses than oral administration.

The effect of the selective reversible acetylcholinesterase inhibitor E2020 on extracellular acetylcholine and biogenic amine levels in rat cortex.

E2020 is a piperidine cholinesterase inhibitor (ChEI) which is structurally distinct from other compounds presently under study for treatment of Alzheimer's disease. We studied the effect of this compound on acetylcholine (ACh), norepinephrine (NE), dopamine (DA) and serotonin (5-HT; 5-hydroxytryptamine) by means of transcortical microdialysis in the cortex of awake rats with no ChEI in the probe. We also compared the inhibition of brain cholinesterase (ChE) by two different approaches. Following 0.5 and 2.0 mg/kg s.c. administration, the increase in ACh was 200% (30 min) and 2100% (1 hr), respectively. The maximal ChE inhibition at 30 min was 35.5% (2.0 mg/kg) and 15.6% (0.5 mg/kg) when measured as ACh hydrolysis in the diluted homogenate. After the 2.0 mg/kg dose, phosphorylation by DFP was completely blocked at 30 min. After 0.5 mg/kg, ChE phosphorylation was maximally inhibited at 30 min (56%) and declined thereafter to negligible levels by 3 hr. In addition, E2020 increased extracellular levels of catecholamines in cortex in agreement with our previous findings with carbamate ChEI. Following 2.0 mg/kg, both NE (100%) and DA (80%) were elevated, whereas after 0.5 mg/kg only NE (50%) was affected. Neither dose affected extracellular 5-HT. Thus, E2020, which inhibits brain ChE by a novel, reversible mechanism, elevates extracellular ACh in a comparable manner to other centrally-active ChEI, and this elevation of ACh is associated with stimulation of catecholamine release.

Cyclosporine-A increases spontaneous and dopamine agonist-induced locomotor behavior in normal rats.

Cyclosporine-A (CsA) has been increasingly used as an immunosuppressant concomitant with neural transplantation treatment for different degenerative disorders. However, the possible role that CsA itself may have in the recovery of transplant patients is not known. Some investigators have argued that clinical improvement following transplantation (e.g., myoblast) may be confounded by CsA administration. The present study was conducted to delineate CsA-induced behavioral alterations. Four groups of normal 5-wk old Sprague-Dawley rats (n = 8 per group) were utilized in two separate experiments. In both experiments, two groups of animals were used; each group either received daily injections of 15 mg/kg of CsA or olive oil for 32 days (experiment 1) and 21 days (experiment 2). Animals in both experiments were subsequently tested for nocturnal locomotor behavior. Animals in experiment 2 were further tested in passive avoidance task, motor coordination, and amphetamine-induced locomotor activity. Results demonstrated that CsA-treated animals were significantly hyperactive compared to controls across the 12-h nocturnal activity periods and in amphetamine-induced locomotor activity. No significant differences between the CsA- and vehicle-treated animals were observed in passive avoidance or in motor coordination. Postmortem analyses of dopamine and its metabolites in the striatum and olfactory tubercle did not show any significant differences between the CsA- and the vehicle-treated groups. In summary, CsA significantly increased nocturnal spontaneous and amphetamine-induced locomotor behavior, but the neurochemical correlates for these effects need to be investigated. In addition, while the present study demonstrated that CsA induced motor alterations, any possible effects CsA may have on neurological or dystrophic patients with motor dysfunctions remain to be determined.

Acetylcholine formation from glucose following acute choline supplementation.

The effects of choline administration on acetylcholine metabolism in the central nervous system are controversial. Although choline supplementation may elevate acetylcholine (ACh) content in brain, turnover studies with labelled choline precursors suggest that systemic choline administration either has no effect or actually diminishes brain ACh synthesis. Since choline supplementation elevates brain choline levels, the apparent decreases in previous turnover studies may reflect dilution of the labelled choline precursor pool rather than altered ACh formation. Therefore, brain ACh formation from [U-14C]glucose was determined after choline supplementation. A two to three fold elevation of brain choline did not alter ACh levels or [U-14C]glucose incorporation into ACh in the cortex, hippocampus or striatum. Although atropine stimulated ACh formation from [U-14C]glucose in hippocampus, two to three fold increases in brain choline did not augment ACh synthesis or content in atropine pretreated animals. Atropine depressed brain regional glucose utilization and this effect was not reversed by choline treatment. These results suggest that short-term elevation of brain choline does not enhance ACh formation from [U-14C]glucose, and argue against enhanced presynaptic cholinergic function after acute, systemic choline administration.

Pre- and post-synaptic cholinergic dysfunction in aged rodent brain regions: new findings and an interpretative review.

Age-related impairment of dynamic aspects of central cholinergic neurotransmission has been indicated by many studies of aged rodents, but the regional distribution of cholinergic deficits and the relative contribution of presynaptic hypofunction and reduced acetylcholine release, loss of synaptic integrity or loss of muscarinic receptors remains unclear. This study therefore compared choline acetyltransferase activity (as a structural marker) and sodium-dependent high affinity choline uptake (which reflects both ongoing cholinergic neuronal activity and structural integrity) in the hippocampus, cortex and straitum of male C57BL mice at 3-4, 10-12 or 28-32 months of age. To evaluate the relationship of changes in muscarinic receptors to presynaptic alterations, binding of the antagonist 3H-quinuclidinyl benzilate was compared in membranes prepared from each of these brain regions. High affinity choline uptake was significantly reduced in all three brain regions by 28-32 months of age. This trend was already evident by 10-12 months of age, especially in hippocampus and cortex. By contrast, choline acetyltransferase activity was unchanged in striatum and actually increased in hippocampus and cortex of aged mice. Muscarinic binding was reduced significantly only in striatum and this effect was significant by 10-12 months of age. This decrease in antagonist binding was accompanied by a small but significant reduction in the relative proportion of high affinity agonist sites as defined by carbachol displacement. The impairment of high affinity choline uptake in the absence of a parallel reduction of choline acetyltransferase activity suggests a decline of ongoing cholinergic activity rather than loss of terminal integrity as the basis of presynaptic deficits in aging. This functional decline may be exacerbated by reduction of muscarinic receptors in striatum. Despite considerable literature support for the hypothesis that cholinergic mechanisms are impaired with age, several controversies leave important issues unresolved. Therefore, the present results are discussed in the context of a critical review with emphasis on dynamic properties of presynaptic function which require analysis in experimental animal models. The impact of normal aging on brain cholinergic systems is distinguished from the neurodegenerative changes in Alzheimer disease in that presynaptic function is compromised with a relative preservation of the integrity of innervation.(ABSTRACT TRUNCATED AT 400 WORDS)

Advances in Alzheimer therapy: cholinesterase inhibitors.

After a decade of intense study of cholinergic therapies for Alzheimer's disease, three conditions in this field are apparent: 1) The potential that cholinergic agents will ameliorate the memory dysfunction of Alzheimer patients (as 1-dopa benefits Parkinson patients) is still a stimulus for research. 2) Cholinergic neuropharmacology and its impact on the therapy of memory disorders associated with cholinergic dysfunction needs to be further characterized and understood. 3) While there is still a search for a symptomatic treatment for AD, the path to find a treatment for the Alzheimer disease process must first pass through a phase of basic research to find the cause of Alzheimer's disease. At the meeting, there was an undercurrent of concern that the cholinergic deficit is too severe to be treated, that the cholinergic systems are too complex to respond to a pharmacologic therapy and that too many other systems are involved in Alzheimer's disease for a cholinergic treatment to be successful. However, this concern was balanced by the evidence of basic scientific experiments which indicate that the central cholinergic system mediating memory can be positively manipulated in animal lesion preparations and Alzheimer tissue. Also there were reports that improved pharmacological approaches and psychological measures are being developed. It appears that Alzheimer therapy is at the stage that cancer chemotherapy was 20 years ago: the promising agents cause nausea without producing clear effects but the basic laboratory studies strongly suggest that substantial benefits are possible and several agents have shown encouraging results. Meanwhile, patients and scientists are becoming increasingly interested in the field.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholinesterase inhibitor therapy for Alzheimer dementia: what do animal models tell us?

Despite a strong rationale for the use of cholinesterase (ChE) inhibitors and related drugs to augment cholinergic function as palliative treatment for Alzheimer dementia, this approach met with limited and variable success until the striking results recently reported with tacrine (THA). Our previous studies have shown the potential utility of blood ChE inhibition to define the optimum dose of such drugs. In the present studies, THA was reinvestigated in rats because several literature reports of weak inhibition of blood and brain acetylcholinesterase (AChE) after systemic treatment leave unresolved the mechanism of action for THA. Consistent with previous reports, we find an in vitro IC50 of 1 microM THA or less for brain or red blood cell AChE, dependent on the substrate concentration. Results were independent of tissue dilution in vitro. However, after in vivo THA, the inhibition of plasma ChE or brain AChE declined as a log function of tissue dilution. These results indicate that the degree of inhibition is underestimated as a result of dilution of tissue for enzyme assay. We therefore used minimal tissue dilution to establish the dose-response and time course functions after s.c. administration of THA and to compare the effect of THA in various brain regions with that on blood enzymes. Pons-medulla AChE was much less sensitive to the effects of THA than hippocampus, cortex, cerebellum or plasma ChE, particularly at doses of 2.5 mg/kg or less. In these other brain regions, AChE was inhibited 22-44% after doses of 1.25 to 2.5 mg/kg THA, the dose range which maximally improved retention performance in mice. Peak inhibition occurred rapidly in plasma, but was delayed in brain (30-60 min after THA). Inhibition was long-lasting in both plasma and cortex (greater than or equal to 5 hr). It is concluded that long-lasting inhibition of the metabolism of acetylcholine is the most heuristic explanation of THA's pharmacological activity.

Cortisol responses to cholinergic drugs in Alzheimer's disease.

Patients with Alzheimer's disease participated in a trial of two sessions in which they received physostigmine and neostigmine in a double-blind crossover design. Most of these patients subsequently participated in a scopolamine vs saline double-blind crossover trial using a similar design. Physostigmine increased plasma cortisol relative to neostigmine, with the greatest difference at time points greater than 90 min post drug oral administration. Physostigmine also significantly decreased plasma cholinesterase (ChE). There was a significant positive correlation between the effects of physostigmine on increasing cortisol and decreasing ChE; there was no correlation between the increase in cortisol of cholinesterase inhibitor following neostigmine administration, but neither of these chemical parameters is related to the drug's effects on cognitive functioning.

Diminished mitogen-induced calcium uptake by lymphocytes from Alzheimer patients.

Recent studies demonstrate diminished calcium uptake by cultured skin fibroblasts from Alzheimer patients. To determine if altered calcium homeostasis is also present in tissue taken from Alzheimer patients, calcium homeostasis was assessed in mitogen-stimulated lymphocytes. Calcium uptake by lymphocytes from Alzheimer patients was 10%-15% lower (p less than 0.002) than that of lymphocytes from age-matched controls. However, neither superficially bound nor total calcium was altered by Alzheimer's disease. These small differences in uptake may reflect larger differences in cytosolic calcium, in later calcium-mediated events, or in the response of particular subsets of lymphocytes. Their biological significance remains to be determined.