P-tau217 as a Reliable Blood-Based Marker of Alzheimer's Disease.

Amyloid plaques and tau tangles are the hallmark pathologic features of Alzheimer's disease (AD). Traditionally, these changes are identified in vivo via cerebrospinal fluid (CSF) analysis or positron emission tomography (PET) scans. However, these methods are invasive, expensive, and resource-intensive. To address these limitations, there has been ongoing research over the past decade to identify blood-based markers for AD. Despite the challenges posed by their extremely low concentrations, recent advances in mass spectrometry and immunoassay techniques have made it feasible to detect these blood markers of amyloid and tau deposition. Phosphorylated tau (p-tau) has shown greater promise in reflecting amyloid pathology as evidenced by CSF and PET positivity. Various isoforms of p-tau, distinguished by their differential phosphorylation sites, have been recognized for their ability to identify amyloid-positive individuals. Notable examples include p-tau181, p-tau217, and p-tau235. Among these, p-tau217 has emerged as a superior and reliable marker of amyloid positivity and, thus, AD in terms of accuracy of diagnosis and ability for early prognosis. In this narrative review, we aim to elucidate the utility of p-tau217 as an AD marker, exploring its underlying basis, clinical diagnostic potential, and relevance in clinical care and trials.

Predicting Neuropsychiatric Symptoms of Parkinson's Disease with Measures of Striatal Dopaminergic Deficiency.

BACKGROUND: The role of nigrostriatal dopaminergic neurons degeneration is well established in the pathophysiology of Parkinson's disease. However, it is unclear if and how the degeneration of the dopamine pathways affects the manifestation of the neuropsychiatric symptoms (NPS) of Parkinson's Disease (PD). Dopamine transporter (DAT) imaging, a technique to measure the reduction in dopamine transporters is increasingly used as a tool in the diagnosis of PD. METHODS: In this study, we examine if the baseline dopamine transporter density in the striatum measured by the Striatal Binding Ratio (SBR) is associated with the longitudinal onset and/or progression of NPS in PD as measured by part 1 of Movement Disorder Society - Unified Parkinson's Disease Rating Scale, over four years. Data of patients with PD and an abnormal screening present on 123I-ioflupane single-proton emission computed tomography were obtained from Parkinson's Progression Markers Initiative (PPMI) database. Latent Growth Modeling (LGM), a statistical technique that can model the change over time while considering the variability in the rate of change at the individual level, was used to examine the progression of NPS over time. RESULTS: The results indicate the SBR did not correlate with the baseline NPS but did correlate with the rate of change of NPS (p<0.001) over the next four years, even after eliminating age-related variance, which can be a significant confounding factor. CONCLUSION: In conclusion, this study showed gradual worsening in NPS in patients with Parkinson's disease, which inversely correlates with the density of the dopamine transporters as measured by SBR at baseline.

Development and optimization of drug-loaded nanoemulsion system by phase inversion temperature (PIT) method using Box-Behnken design.

OBJECTIVE: The objective of the present investigation was to develop a stable and optimized drug-loaded nanoemulsion system using the phase inversion temperature (PIT) method. SIGNIFICANCE: The PIT method has been widely used for the development of food-grade nanoemulsion systems. For the first time, a simple and cost-effective, PIT method was used for the development of a stable drug-loaded nanoemulsion system. METHODS: Box-Behnken experimental design was used for the development of an optimized drug-loaded nanoemulsion system by the PIT method. The independent variables were optimized for responses by using the desirability function. The hydrophobic drug, benidipine was used as a modal drug. Optimized oil phase (blend of long-chain triglycerides oil, medium-chain triglycerides oil and essential oil) was used for the development of oil in water (O/W) nanoemulsion system. RESULTS: Optimum nanoemulsion formulation was stable, transparent and contained 50% of oil to surfactant percentage with a droplet size of 96.57 ± 1.61 nm. The optimum formulation also showed higher in-vitro drug diffusion from dialysis membrane as compared to the marketed formulation. Nanoemulsion droplets were observed as spherical in the transmission electron microscopy (TEM) images. Box-Behnken statistical analysis revealed that all the independent variables had a significant impact on characteristics of nanoemulsion and the predicated value of independent variables was found to be valid. CONCLUSION: It was concluded that the PIT method produces a stable and efficient drug-loaded nanoemulsion system. Further, the optimized oil phase can be used as an alternative to costly, commercial medium-chain triglycerides (MCT) oils, for the development of a stable nanoemulsion system.

Monitoring for myocarditis during treatment initiation with clozapine.

OBJECTIVE: Clozapine use is associated with myocarditis. In this study, we investigated what clinical signs and symptoms, and/or laboratory test(s), alert clinicians to presumptive myocarditis (PrMy) most accurately and at the earliest time point. We also investigated the incidence of PrMy during the initial exposure to clozapine versus in patients restarted on clozapine after extended interruption of prior prolonged treatment. METHODS: 100 patients admitted to state psychiatric hospital started on clozapine were recruited into the study. 76 patients were treated with clozapine for the first time and 24 patients were restarts. Creatine kinase (CK), troponin I (TROP), eosinophil count (EOS), and C-reactive protein (CRP) were obtained at baseline and weeks 1, 2, 3, and 4. Descriptive statistics were calculated for demographic and clinical variables. Student's t test and chi-squared test were used to compare means and proportions between initial exposure and restart groups. RESULTS: Clinical features and laboratory tests suggestive of PrMy were seen in 4 patients (5.3%) in initial exposure group and none in restart group. 3.5% of TROP levels were abnormal in initial exposure group and no abnormal levels were found in the restart group. 30% and 46% of CK, 23% and 39% of CRP, and 14% and 23% of EOS were abnormal in initial exposure group and restart groups, respectively. CONCLUSIONS: PrMy was common (5.3%) during clozapine initiation. Prospective management through serial laboratory monitoring with weekly TROP levels was sensitive enough to allow for timely clozapine discontinuation.

A primary care guide to bipolar depression treatment.

Manage uncomplicated cases following guidelines on medical therapy and with adjunctive psychotherapy. Refer complicated and severe cases to Psychiatry.

Techniques for Formulation of Nanoemulsion Drug Delivery System: A Review.

Nanoemulsion drug delivery systems are advanced modes for delivering and improving the bioavailability of hydrophobic drugs and the drug which have high first pass metabolism. The nanoemulsion can be prepared by both high energy and low energy methods. High energy method includes high-pressure homogenization, microfluidization, and ultrasonication whereas low energy methods include the phase inversion emulsification method and the self-nanoemulsification method. Low energy methods should be preferred over high energy methods as these methods require less energy, so are more efficient and do not require any sophisticated instruments. However high energy methods are more favorable for food grade emulsion as they require lower quantities of surfactant than low energy methods. Techniques for formulation of nanoemulsion drug delivery system are overlapping in nature, especially in the case of low energy methods. In this review, we have classified different methods for formulation of nanoemulsion systems based on energy requirements, nature of phase inversion, and self-emulsification.

Blood-based protein predictors of dementia severity as measured by δ: Replication across biofluids and cohorts.

INTRODUCTION: Dementia severity can be empirically described by the latent dementia phenotype "δ" and its various composite "homologs". We have explored δ's blood-based protein biomarkers in the Texas Alzheimer's Research and Care Consortium (TARCC) study. However, it would be convenient to replicate those associations in the Alzheimer's Disease Neuroimaging Initiative (ADNI). To this end, we recently engineered a δ homolog from observed cognitive performance measures common to both projects (i.e., "dT2A"). METHODS: We used nine rationally chosen peripheral blood-based protein biomarkers as indicators of a latent variable "INFLAMMATION". We then associated that construct with dT2A in structural equation models adjusted for age, gender, depressive symptoms, and apolipoprotein E (APOE) ε4 allelic burden. Significant factor loadings and INFLAMMATION's association with dT2A were confirmed in random splits of TARCC's relatively large sample, and across biofluids in the ADNI. RESULTS: Nine proteins measured in serum (TARCC) or plasma (ADNI) explained ≅10% of dT2A's variance in both samples, independently of age, APOE, education, and gender. All loaded significantly on INFLAMMATION, and positively or negatively, depending on their known roles are PRO- or ANTI-inflammatory proteins, respectively. The parameters of interest were confirmed across random 50% splits of the TARCC's sample, and replicated across biofluids in the ADNI. DISCUSSION: These results suggest that SEM can be used to replicate biomarker findings across samples and biofluids, and that a substantial fraction of dementia's variance is attributable to peripheral blood-based protein levels.

Covered CP Stent for Treatment of Right Ventricular Conduit Injury During Melody Transcatheter Pulmonary Valve Replacement.

BACKGROUND: High-pressure balloon and stent angioplasty are frequently necessary to prepare the dysfunctional right ventricular outflow tract conduit before transcatheter pulmonary valve replacement (TPVR). Conduit injury can result, which may be catastrophic to the patient or prevent successful TPVR. METHODS AND RESULTS: The PARCS trial (Pulmonary Artery Repair With Covered Stent) was a pivotal, prospective multicenter trial to evaluate the safety and efficacy of the NuMED Covered CP Stent (CCPS) for treatment of conduit injury occurring during TPVR. The study also evaluated immediate and short-term TPVR function in patients receiving covered stents. A total of 616 patients were consented; 120 (19.5%) had a wall injury identified and were treated with CCPS. Severe conduit injuries were uncommon (5%), but predictors for severe injury were not identified. Stenotic homografts had the highest incidence of injury (29%), compared with other conduit substrates. Among patients receiving CCPS implant, 96% required no further therapy for conduit injury, and 94% underwent TPVR at that procedure. Only 2 patients (1.6%) required urgent surgery for conduit injury, despite CCPS implant. There were few CCPS-related complications. TPVR function was similar between CCPS and non-CCPS groups at follow-up. CONCLUSIONS: Conduit injury during TPVR is common, although severe injury is rare. The CCPS was a safe and effective treatment for right ventricular outflow tract conduit injury during preparation for TPVR, allowing nearly all patients to complete the procedure without identifiable impact on valve performance. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01824160.

Neurobiological Mediators of Squalor-dwelling Behavior.

Squalor-dwelling behavior has been characterized as living in conditions so unsanitary that feelings of revulsion are elicited among visitors. This behavior is commonly associated with an insensitivity to distress/disgust and a failure to understand the direness of one's living situation, which leads to social isolation and impairment in quality of life. Etiologically, several associations have been described in the literature, including age-related decline, lower socioeconomic status, and rural dwelling status. Primary neuropsychiatric disorders, such as psychosis, alcoholism, dementia, personality disorders, developmental delays, and learning or physical disabilities are frequently seen in squalor-dwelling individuals. However, none of these disorders seems to be necessary or sufficient to explain the behavior. Neurobiologically, squalor-dwelling behavior has been associated with frontal lobe dysfunction as evidenced by executive dysfunction; however, cognitive impairments also fail to completely explain this behavior. The purpose of this report is to describe a typical case of squalor-dwelling behavior and use it as an example to illustrate the complexity of uncovering the neurobiological basis for this maladaptive personal and public health threat. Neuroimaging findings from our case and a review of the literature point toward decreased activity in the insular cortex and the amygdala as a unifying biological explanation for squalor-dwelling behaviors.

Serum proteins mediate depression's association with dementia.

The latent variable "δ" (for "dementia") uniquely explains dementia severity. Depressive symptoms are independent predictors of δ. We explored 115 serum proteins as potential causal mediators of the effect of depressive symptoms on δ in a large, ethnically diverse, longitudinal cohort. All models were adjusted for age, apolipoprotein E, education, ethnicity, gender, hemoglobin A1c, and homocysteine, and replicated in randomly selected 50% subsets. Alpha1-antitrypsin (A1AT), FAS, Heparin-binding EGF-like Growth Factor (HB-EGF), Insulin-like Growth Factor-1 (IGF-1), Luteinizing Hormone (LH), Macrophage Inflammatory Protein type 1 alpha (MIP-1α), Resitin, S100b, Tissue Inhibitor of Metalloproteinase type 1 (TIMP-1), and Vascular Cell Adhesion Molecule type 1 (VCAM-1) each were partial mediators of depression's association with δ. These proteins may offer targets for the treatment of depression's specific effect on dementia severity and Alzheimer's Disease (AD) conversion risk.

Few serum proteins mediate APOE's association with dementia.

The latent variable "δ" (for "dementia") appears to be uniquely responsible for the dementing aspects of cognitive impairment. Age, depression, gender and the apolipoprotein E (APOE) e4 allele are independently associated with δ. In this analysis, we explore serum proteins as potential mediators of APOE's specific association with δ in a large, ethnically diverse longitudinal cohort, the Texas Alzheimer's Research and Care Consortium (TARCC). APOE was associated only with C-Reactive Protein (CRP), Adiponectin (APN) and Amphiregulin (AREG), although the latter two's associations did not survive Bonferroni correction for multiple comparisons. All three proteins were associated with δ and had weak potential mediation effects on APOE's association with that construct. Our findings suggest that APOE's association with cognitive performance is specific to δ and partially mediated by serum inflammatory proteins. The majority of APOE's significant unadjusted effect on δ is unexplained. It may instead arise from direct central nervous system effects, possibly on native intelligence. If so, then APOE may exert a life-long influence over δ and therefore all-cause dementia risk.

Serum protein mediators of dementia and aging proper.

The latent variable "δ" (for "dementia") appears to be uniquely responsible for the dementing aspects of cognitive impairment. Age, depressive symptoms, gender and the apolipoprotein E (APOE) ε4 allele are independently associated with δ. In this analysis, we explore serum proteins as potential mediators of age's specific association with δ in a large, ethnically diverse longitudinal cohort, the Texas Alzheimer's Research and Care Consortium (TARCC). 22 serum proteins were recognized as partial mediators of age's association with δ. These include Insulin-like Growth Factor-Binding Protein 2 (IGF-BP2), which we had previously associated with age-specific cognitive change, and both Pancreatic Polypeptide (PP) and von Willebrand Factor (vWF), previously associated with δ. Nine other δ-related proteins were not confirmed by this ethnicity adjusted analysis. Our findings suggest that age's association with the disabling fraction of cognitive performance is partially mediated by serum proteins, somatomedins and hormones. Those proteins may offer targets for the specific treatment of age-related effects on dementia severity and conversion risk.

Methodological issues associated with preclinical drug development and increased placebo effects in schizophrenia clinical trials.

Recent failures to detect efficacy in clinical trials investigating pharmacological treatments for schizophrenia raise concerns regarding the potential contribution of methodological shortcomings to this research. This review provides an examination of two key methodological issues currently suspected of playing a role in hampering schizophrenia drug development; 1) limitations on the translational utility of preclinical development models, and 2) methodological challenges posed by increased placebo effects. Recommendations for strategies to address these methodological issues are addressed.

Serum IGF-BP2 strongly moderates age's effect on cognition: a MIMIC analysis.

We have used structural equation models to explicitly distinguish functional status and therefore "dementia-relevant" variance in cognitive task performance (i.e., "δ" for dementia). Our approach is modular and can be directed to other targets. In this analysis, we construct a δ ortholog representing the "cognitive correlates of age" (cAGE). cAGE largely mediates age's effects on dementia severity, as rated by the Clinical Dementia Rating Scale Sum of boxes and has an area under the receiver operating curve = 0.96 for the diagnosis of Alzheimer's Disease versus controls. We then test cAGE's association with serum insulin-like growth factor binding protein 2 (IGF-BP2), which has previously been associated with age-related cognitive changes in animals, and with cortical atrophy in older humans. IGF-BP2's adverse effects on cognition are largely mediated through cAGE, independent of education, ethnicity, gender, depression ratings, serum homocysteine levels, hemoglobin A1c, and apolipoprotein e4 status. This suggests that age-specific cognitive decline may be moderated by IGF-BP2 and that modulation of that protein's function(s) might ameliorate age-specific cognitive impairments.

A case of nicotine withdrawal delirium.

Nicotine withdrawal is not a well recognized cause of delirium. A few published cases are on post-operative, terminally ill cancer or neuro-intensive care unit patients. Because of the high incidence of morbidity and mortality of delirium it is important to identify and treat delirium promptly and effectively. We report a case of delirium after sudden cessation of smoking in a heavy smoker, with schizophrenia, hospitalized for stabilization of psychiatric illness.

Serum interleukin (IL)-15 as a biomarker of Alzheimer's disease.

Interleukin (IL-15), a pro-inflammatory cytokine has been studied as a possible marker of Alzheimer's disease (AD); however its exact role in neuro-inflammation or the pathogenesis AD is not well understood yet. A Multiple Indicators Multiple Causes (MIMIC) approach was used to examine the relationship between serum IL-15 levels and AD in a well characterized AD cohort, the Texas Alzheimer's Research and Care Consortium (TARCC). Instead of categorical diagnoses, we used two latent construct d (for dementia) and g' (for cognitive impairments not contributing to functional impairments) in our analysis. The results showed that the serum IL-15 level has significant effects on cognition, exclusively mediated by latent construct d and g'. Contrasting directions of association lead us to speculate that IL-15's effects in AD are mediated through functional networks as d scores have been previously found to be specifically related to default mode network (DMN). Our finding warrants the need for further research to determine the changes in structural and functional networks corresponding to serum based biomarkers levels.