Milawaty Nurjono

Increasing Cu bioavailability inhibits Aβ oligomers and tau phosphorylation

Cognitive decline in Alzheimers disease (AD) involves pathological accumulation of synaptotoxic amyloid-β (Aβ) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3β (GSK3β) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3β. The strategy involves the use of copper-bis(thiosemicarbazonoto) complexes to increase intracellular copper bioavailability and inhibit GSK3β through activation of an Akt signaling pathway. Our lead compound CuII(gtsm) significantly inhibited GSK3β in the brains of APP/PS1 transgenic AD model mice. CuII(gtsm) also decreased the abundance of Aβ trimers and phosphorylated tau, and restored performance of AD mice in the Y-maze test to levels expected for cognitively normal animals. Improvement in the Y-maze correlated directly with decreased Aβ trimer levels. This study demonstrates that increasing intracellular copper bioavailability can restore cognitive function by inhibiting the accumulation of neurotoxic Aβ trimers and phosphorylated tau.

Metal Ionophore Treatment Restores Dendritic Spine Density and Synaptic Protein Levels in a Mouse Model of Alzheimer's Disease

We have previously demonstrated that brief treatment of APP transgenic mice with metal ionophores (PBT2, Prana Biotechnology) rapidly and markedly improves learning and memory. To understand the potential mechanisms of action underlying this phenomenon we examined hippocampal dendritic spine density, and the levels of key proteins involved in learning and memory, in young (4 months) and old (14 months) female Tg2576 mice following brief (11 days) oral treatment with PBT2 (30 mg/kg/d). Transgenic mice exhibited deficits in spine density compared to littermate controls that were significantly rescued by PBT2 treatment in both the young (+17%, p<0.001) and old (+32%, p<0.001) animals. There was no effect of PBT2 on spine density in the control animals. In the transgenic animals, PBT2 treatment also resulted in significant increases in brain levels of CamKII (+57%, p = 0.005), spinophilin (+37%, p = 0.04), NMDAR1A (+126%, p = 0.02), NMDAR2A (+70%, p = 0.05), pro-BDNF (+19%, p = 0.02) and BDNF (+19%, p = 0.04). While PBT2-treatment did not significantly alter neurite-length in vivo, it did increase neurite outgrowth (+200%, p = 0.006) in cultured cells, and this was abolished by co-incubation with the transition metal chelator, diamsar. These data suggest that PBT2 may affect multiple aspects of snaptic health/efficacy. In Alzheimers disease therefore, PBT2 may restore the uptake of physiological metal ions trapped within extracellular β-amyloid aggregates that then induce biochemical and anatomical changes to improve cognitive function.

A Review of Brain-derived Neurotrophic Factor as a Candidate Biomarker in Schizophrenia

Brain-derived neurotrophic factor (BDNF), a neurotrophin known to be responsible for development, regeneration, survival and maintenance of neurons has been implicated in the pathophysiology of schizophrenia. This review seeks to complement previous reviews on biological roles of BDNF and summarizes evidence on the involvement of BDNF in the pathophysiology of schizophrenia with an emphasis on clinical relevance. The expressions of BDNF were altered in patients with schizophrenia and were found to be correlated with psychotic symptomatology. Antipsychotics appeared to have differential effects on expression of BDNF but did not restore BDNF expression of patients with schizophrenia to normal levels. In addition, evidence suggests that BDNF is involved in the major neurotransmitter systems and is associated with disruptions in brain structure, neurodevelopmental process, cognitive function, metabolic and immune systems commonly associated with schizophrenia. Besides that, BDNF has been demonstrated to be tightly regulated with estrogen which has also been previously implicated in schizophrenia. Evidence gathered in this review confirms the relevance of BDNF in the pathophysiology of schizophrenia and the potential utility of BDNF as a suitable biomarker for diagnostic and prognostic purposes for disease outcome and other co-morbidities. However, further investigations are warranted to examine the specificity of BDNF in schizophrenia compared to other neurodegenerative disorders and other neuropsychiatric illness. Longitudinal prospective studies will also be of added advantage for evaluation of prognostic utility of BDNF in schizophrenia.

A Prospective Validation Study of a Rainbow Model of Integrated Care Measurement Tool in Singapore

Introduction: The conceptual ambiguity of the integrated care concept precludes a full understanding of what constitutes a well-integrated health system, posing a significant challenge in measuring the level of integrated care. Most available measures have been developed from a disease-specific perspective and only measure certain aspects of integrated care. Based on the Rainbow Model of Integrated Care, which provides a detailed description of the complex concept of integrated care, a measurement tool has been developed to assess integrated care within a care system as a whole gathered from healthcare providers’ and managerial perspectives. This paper describes the methodology of a study seeking to validate the Rainbow Model of Integrated Care measurement tool within and across the Singapore Regional Health System. The Singapore Regional Health System is a recent national strategy developed to provide a better-integrated health system to deliver seamless and person-focused care to patients through a network of providers within a specified geographical region. Methods: The validation process includes the assessment of the content of the measure and its psychometric properties. Conclusion: If the measure is deemed to be valid, the study will provide the first opportunity to measure integrated care within Singapore Regional Health System with the results allowing insights in making recommendations for improving the Regional Health System and supporting international comparison.

Clioquinol Improves Cognitive, Motor Function, and Microanatomy of the Alpha-Synuclein hA53T Transgenic Mice.

The abnormal accumulation of alpha-synuclein (α-syn) has been linked to a number of neurodegenerative disorders, the most noteworthy of which is Parkinsons disease. Alpha-synuclein itself is not toxic and fulfills various physiological roles in the central nervous system. However, specific types of aggregates have been shown to be toxic, and metals have been linked to the assembly of these toxic aggregates. In this paper, we have characterized a transgenic mouse that overexpresses the A53T mutation of human α-syn, specifically assessing cognition, motor performance, and subtle anatomical markers that have all been observed in synucleinopathies in humans. We hypothesized that treatment with the moderate-affinity metal chelator, clioquinol (CQ), would reduce the interaction between metals and α-syn to subsequently improve the phenotype of the A53T animal model. We showed that CQ prevents an iron-synuclein interaction, the formation of urea-soluble α-syn aggregates, α-syn-related substantia nigra pars compacta cell loss, reduction in dendritic spine density of hippocampal and caudate putamen medium spiny neurons, and the decline in motor and cognitive function. In conclusion, our data suggests that CQ is capable of mitigating the pathological metal/α-syn interactions, suggesting that the modulation of metal ions warrants further study as a therapeutic approach for the synucleinopathies.

Increased Framingham 10-year CVD risk in Chinese patients with schizophrenia.

UNLABELLED BACKGROUND & HYPOTHESIS: Schizophrenia is associated with increased mortality rates, which has been attributed to the greater incidence of cardiovascular disease (CVD) events. The Framingham risk score (FRS) is a widely-used age- and gender-specific algorithm to estimate 10-year CVD risk and vascular age. The main aim of this study was to determine the cardiovascular risk profile in schizophrenia and examine the effect of metabolic syndrome (MetS) as a predictor of CVD risk. We hypothesized that patients with schizophrenia have an increased 10-year CVD risk. METHODS 83 Chinese patients with schizophrenia and 243 Chinese community controls were recruited. Their medical and smoking histories were obtained, and anthropometric parameters measured. All subjects provided fasted venous blood samples for lipid and glucose measurements. 10-year CVD risk and the difference between vascular and actual age (VAdiff) for each participant were computed using the FRS and compared between patients and controls. RESULTS Schizophrenia patients had a higher mean 10-year CVD risk of 4.6%, as compared with 3.1% in controls, and a greater VAdiff of 4.6 years vs. 0.6 years. Both smoking and MetS contributed significantly to the 10-year CVD risk in patients with schizophrenia, with smoking having a greater effect than MetS on this risk. CONCLUSION This study found a significantly elevated mean 10-year CVD risk and VAdiff in patients with schizophrenia compared with controls. Findings point towards the importance of smoking cessation and screening for MetS to decrease the excess CVD risk in patients with schizophrenia.

Effects of Neonatal Iron Feeding and Chronic Clioquinol Administration on the Parkinsonian Human A53T Transgenic Mouse

Increased nigral iron (Fe) is a cardinal feature of Parkinsons disease, as is the accumulation of aggregates comprising α-synuclein. We used wild-type mice and transgenic mice overexpressing the human A53T mutation to α-synuclein to examine the influence of increased Fe (days 10-17 postpartum) on the parkinsonian development phenotype of these animals (including abnormal nigral Fe levels and deficits in both cell numbers and locomotor activity), and to explore the impact of the Fe chelator clioquinol in the model. Both untreated and Fe-loaded A53T mice showed similar levels of nigral cell loss, though 5 months of clioquinol treatment was only able to prevent the loss in the non-Fe-loaded A53T group. Iron levels in the Fe-loaded A53T mice returned to normal at 8 months, though effects of dopamine denervation remained, demonstrated by limited locomotor activity and sustained neuron loss. These data suggest that Fe exposure during a critical developmental window, combined with the overexpression mutant α-synuclein, presents a disease phenotype resistant to intervention using clioquinol later in life.

The relationship between serum brain-derived neurotrophic factor (BDNF) and cardiometabolic indices in schizophrenia

Brain derived neurotrophic factor (BDNF), which has been implicated in the pathogenesis of schizophrenia, has been recently shown to be involved in the regulation of metabolism and energy homeostasis. This study seeks to examine the relationship between BDNF, metabolic indices and cardiovascular (CVD) risk in patients with schizophrenia. Medical histories, demographic information and anthropometric measurements were collected and analyzed from 61 participants with schizophrenia. Fasting glucose and lipids were measured in a central laboratory, and serum BDNF was analyzed using commercially available enzyme-linked immunosorbent assay (ELISA). The 10-year CVD risk for each participant was computed using the Framingham risk score (FRS). Linear regressions were performed to examine the relationships between serum BDNF with body mass index (BMI), blood pressure (BP), triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-C) and glucose. To examine the relationship between serum BDNF and FRS, serum BDNF was categorized into quartiles, and a multiple regression was performed. After adjusting for age, gender and current smoking status, diastolic BP (dBP) (p=0.045) and TG (p=0.015) were found to be significantly associated with serum BDNF. Participants in the highest quartile of serum BDNF had a 3.3 times increase in FRS over those in the lowest quartile. Our findings support the possible regulatory role of BDNF in metabolism and cardiovascular homeostasis among patients with schizophrenia similar to that observed among the non-mentally ill. Serum BDNF not only present itself as a candidate biomarker of schizophrenia but also might be a viable marker of metabolic co-morbidities associated with schizophrenia.

Regulation of Interleukin-6 and Leptin in Schizophrenia Patients: A Preliminary Analysis

Objective Immune-inflammatory mediators play a pivotal role in brain signaling and have been increasingly associated with the pathophysiology of schizophrenia. Many studies have indicated an increased level of immune-inflammatory interleukin-6 (IL-6) in schizophrenia. IL-6 is a well-known chief stimulator of inflammation. Of late leptin has also been implicated in the inflammatory pathway of schizophrenia. In this study we measured and compared serum levels of IL-6 and leptin in patients with schizophrenia to healthy controls, and investigated the relationship between IL-6 and leptin. Methods Serum IL-6 and leptin were determined in 20 patients diagnosed with schizophrenia and in 19 healthy controls matched by gender, age and body mass index (BMI) using commercial Bioplex assays. Results Using Mann-Whitney U-test, significantly increased IL-6 levels were found in the patients but there was no significant difference in leptin levels though a trend towards higher leptin was observed in the patients. Spearman correlations did not show any correlation between IL-6 and clinical variables except antipsychotic dosage. Leptin significantly correlated with gender and BMI. A large effect size correlation was observed between IL-6 and leptin in the patients but not in the controls. Multiple regression analysis performed on patients, after adjusting for gender and BMI, revealed there was no significant association between IL-6 and leptin. Conclusion IL-6 and leptin levels may reflect the chronic inflammatory state associated with schizophrenia but further evaluation is required. Also, it is important to consider the confounding effects of obesity in any examination of relationships between groups with regard to cytokines and adipokines.

Instruments Measuring Integrated Care: A Systematic Review of Measurement Properties.

Policy Points: Investigations on systematic methodologies for measuring integrated care should coincide with the growing interest in this field of research. A systematic review of instruments provides insights into integrated care measurement, including setting the research agenda for validating available instruments and informing the decision to develop new ones. This study is the first systematic review of instruments measuring integrated care with an evidence synthesis of the measurement properties. We found 209 index instruments measuring different constructs related to integrated care; the strength of evidence on the adequacy of the majority of their measurement properties remained largely unassessed. CONTEXT Integrated care is an important strategy for increasing health system performance. Despite its growing significance, detailed evidence on the measurement properties of integrated care instruments remains vague and limited. Our systematic review aims to provide evidence on the state of the art in measuring integrated care. METHODS Our comprehensive systematic review framework builds on the Rainbow Model for Integrated Care (RMIC). We searched MEDLINE/PubMed for published articles on the measurement properties of instruments measuring integrated care and identified eligible articles using a standard set of selection criteria. We assessed the methodological quality of every validation study reported using the COSMIN checklist and extracted data on study and instrument characteristics. We also evaluated the measurement properties of each examined instrument per validation study and provided a best evidence synthesis on the adequacy of measurement properties of the index instruments. FINDINGS From the 300 eligible articles, we assessed the methodological quality of 379 validation studies from which we identified 209 index instruments measuring integrated care constructs. The majority of studies reported on instruments measuring constructs related to care integration (33%) and patient-centered care (49%); fewer studies measured care continuity/comprehensive care (15%) and care coordination/case management (3%). We mapped 84% of the measured constructs to the clinical integration domain of the RMIC, with fewer constructs related to the domains of professional (3.7%), organizational (3.4%), and functional (0.5%) integration. Only 8% of the instruments were mapped to a combination of domains; none were mapped exclusively to the system or normative integration domains. The majority of instruments were administered to either patients (60%) or health care providers (20%). Of the measurement properties, responsiveness (4%), measurement error (7%), and criterion (12%) and cross-cultural validity (14%) were less commonly reported. We found <50% of the validation studies to be of good or excellent quality for any of the measurement properties. Only a minority of index instruments showed strong evidence of positive findings for internal consistency (15%), content validity (19%), and structural validity (7%); with moderate evidence of positive findings for internal consistency (14%) and construct validity (14%). CONCLUSIONS Our results suggest that the quality of measurement properties of instruments measuring integrated care is in need of improvement with the less-studied constructs and domains to become part of newly developed instruments.