Timing of changes in Alzheimer's disease plasma biomarkers as assessed by amyloid and tau PET clocks.

Plasma biomarkers for Alzheimer's disease (AD) are increasingly being used to assist in making an etiological diagnosis for cognitively impaired (CI) individuals or to identify cognitively unimpaired (CU) individuals with AD pathology who may be eligible for prevention trials. However, a better understanding of the timing of plasma biomarker changes is needed to optimize their use in clinical and research settings. The aim of this study was to evaluate the timing of change of key AD plasma biomarkers (Aβ42/Aβ40, p-tau217, p-tau181, GFAP and NfL) from six different companies, along with established AD biomarkers, using AD progression timelines based on amyloid and tau PET.

Public-Private Partnerships for Neuropsychiatric Drug Development: A Perspective.

There is a long-standing interest in developing biomarkers for neuropsychiatric disorders that might assist in drug development or clinical management. To date, however, progress has been limited in part because of the limited nature of the studies and the absence of the types of large-scale networks that would be required for clinical validation. The first public-private partnership (PPP) for biomarker validation-the Alzheimer's Disease Neuroimaging Initiative (ADNI)-was formed in 2004 to focus on the development of amyloid deposition in the brain as a potential biomarker of Alzheimer's disease pathology.

Rationale and Challenges for a New Instrument for Remote Measurement of Negative Symptoms.

There is a broad consensus that the commonly used clinician-administered rating scales for assessment of negative symptoms share significant limitations, including (1) reliance upon accurate self-report and recall from the patient and caregiver; (2) potential for sampling bias and thus being unrepresentative of daily-life experiences; (3) subjectivity of the symptom scoring process and limited sensitivity to change. These limitations led a work group from the International Society of CNS Clinical Trials and Methodology (ISCTM) to initiate the development of a multimodal negative symptom instrument. Experts from academia and industry reviewed the current methods of assessing the domains of negative symptoms including diminished (1) affect; (2) sociality; (3) verbal communication; (4) goal-directed behavior; and (5) Hedonic drives.

The origins of ADNI.

A brief history of events surrounding the conceptualization and original implementation of the Alzheimer's Disease Neuroimaging Initiative (ADNI) as a public-private partnership (PPP) is provided from the perspective of three individuals directly involved from the outset. Potential barriers and how they were addressed are summarized, especially the decision to make all data freely accessible in real-time. Decisions made at the beginning of ADNI are revisited in light of what has been learned over the past 20 years, especially the importance of the investment in cerebrospinal fluid (CSF) and blood measures and the commitment to data sharing.

Clinical breakage, slippage and acceptability of two commercial ultra-thin polyurethane male condoms compared to a commercial thin latex condom: a randomised, masked, 3 way crossover, multi centre controlled study (SAGCS 2).

Background: Although natural rubber latex remains dominant as the primary manufacturing material for male condoms synthetic materials first introduced in the early 1990s address many of the limitations of latex including the risk of allergies. Polyurethane elastomers allow condoms to be made significantly thinner to provide greater sensitivity and encourage greater use of condoms for contraception and STI prophylaxis. The primary objective of this Study was to evaluate the breakage, slippage and acceptability of two ultra-thin polyurethane condoms against a thin control latex male condom, designated latex C, in a randomized, cross over, masked, non-inferiority study.

Head-to-head comparison of leading blood tests for Alzheimer's disease pathology.

Introduction: Blood tests have the potential to improve the accuracy of Alzheimer disease (AD) clinical diagnosis, which will enable greater access to AD-specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD-related outcomes.

Methods: Plasma samples from the Alzheimers Disease Neuroimaging Initiative were assayed with AD blood tests from C2N Diagnostics, Fujirebio Diagnostics, ALZPath, Janssen, Roche Diagnostics, and Quanterix.

Shifting the trajectory of therapeutic development for neurological and psychiatric disorders.

Clinical trials for central nervous system disorders often enroll patients with unrecognized heterogeneous diseases, leading to costly trials that have high failure rates. Here, we discuss the potential of emerging technologies and datasets to elucidate disease mechanisms and identify biomarkers to improve patient stratification and monitoring of disease progression in clinical trials for neuropsychiatric disorders. Greater efforts must be centered on rigorously standardizing data collection and sharing of methods, datasets, and analytical tools across sectors.

Finding new and better treatments for psychiatric disorders.

In contrast to most fields of medicine, progress to discover and develop new and improved psychiatric drugs has been slow and disappointing. The vast majority of currently prescribed drugs to treat schizophrenia, mood and anxiety disorders are arguably no more effective than the first generation of psychiatric drugs introduced well over 50 years ago. With only a few exceptions current psychiatric drugs work via the same fundamental mechanisms of action as first-generation agents.

Using latent profile analyses to classify subjects with anhedonia based on reward-related measures obtained in the FAST-MAS study.

Background: Growing evidence indicates that anhedonia is a multifaceted construct. This study examined the possibility of identifying subgroups of people with anhedonia using multiple reward-related measures to provide greater understanding the Research Domain Criteria's Positive Valence Systems Domain and pathways for developing treatments.

Methods: Latent profile analysis of baseline data from a study that examined the effects of a novel kappa opioid receptor (KOR) antagonist drug on measures and biomarkers associated with anhedonia was used to identify subgroups.

A primary microcephaly-associated sas-6 mutation perturbs centrosome duplication, dendrite morphogenesis, and ciliogenesis in Caenorhabditis elegans.

The human SASS6(I62T) missense mutation has been linked with the incidence of primary microcephaly in a Pakistani family, although the mechanisms by which this mutation causes disease remain unclear. The SASS6(I62T) mutation corresponds to SAS-6(L69T) in Caenorhabditis elegans. Given that SAS-6 is highly conserved, we modeled this mutation in C.

Remote Assessment of Negative Symptoms of Schizophrenia.

In contrast to the validated scales for face-to-face assessment of negative symptoms, no widely accepted tools currently exist for remote monitoring of negative symptoms. Remote assessment of negative symptoms can be broadly divided into 3 categories: (1) remote administration of an existing negative-symptom scale by a clinician, in real time, using videoconference technology to communicate with the patient; (2) direct inference of negative symptoms through detection and analysis of the patient's voice, appearance, or activity by way of the patient's smartphone or other device; and (3) ecological momentary assessment, in which the patient self-reports their condition upon receipt of periodic prompts from a smartphone or other device during their daily routine. These modalities vary in cost, technological complexity, and applicability to the different negative-symptom domains.

Better Approaches to Derisking Psychiatric Drug Development are Needed, Not New Funding Mechanisms.

Background: The pulling back of large pharma from psychiatric drug development over the last 15 years has been a cause of concern. The uncertainty of success with any novel mechanism raises questions concerning whether current funding mechanisms for the various components of drug development need to be revisited. Alternatively, advances in neuroscience and translational methods may provide a sufficient incentive for continued private sector investment.

Comparative analytical performance of multiple plasma Aβ42 and Aβ40 assays and their ability to predict positron emission tomography amyloid positivity.

Introduction: This report details the approach taken to providing a dataset allowing for analyses on the performance of recently developed assays of amyloid beta (Aβ) peptides in plasma and the extent to which they improve the prediction of amyloid positivity.

Methods: Alzheimer's Disease Neuroimaging Initiative plasma samples with corresponding amyloid positron emission tomography (PET) data were run on six plasma Aβ assays. Statistical tests were performed to determine whether the plasma Aβ measures significantly improved the area under the receiver operating characteristic curve for predicting amyloid PET status compared to age and apolipoprotein E (APOE) genotype.

Central Nervous System Trial Failures: Using the Fragile X Syndrome-mGluR5 Drug Target to Highlight the Complexities of Translating Preclinical Discoveries Into Human Trials.

Purpose/background: Drug trials of the central nervous system(CNS) have been plagued with uninformative failures, often because of the difficulties of knowing definitively whether dosing achieved was sufficient to modulate the intended CNS target at adequate concentrations to produce pharmacodynamic or dose-related changes in readouts of brain function. Key design elements can be introduced into early-stage trials to get at this issue.

Methods/procedures: This commentary builds on a review of earlier clinical studies in Fragile X syndrome to explore the extent to which the chain of evidence is in place to allow for interpretation of the results as ruling in or out the utility of modulating one or another molecular target to treat this disorder.

BIOMARKERS AND NEUROBEHAVIORAL DIAGNOSIS.

Our current diagnostic methods for treatment planning in Psychiatry and Neurodevelopmental Disabilities leave room for improvement, and null results in clinical trials in these fields may be a result of insufficient tools for patient stratification. Great hope has been placed in novel technologies to improve clinical and trial outcomes, but we have yet to see a substantial change in clinical practice. As we examine attempts at biomarker validation within these fields, we find that it may be the diagnoses themselves that fall short.

Longitudinal CSF proteomics identifies NPTX2 as a prognostic biomarker of Alzheimer's disease.

Introduction: Biomarkers that reflect pathologic processes affecting neuronal function during preclinical and early stages of Alzheimer's disease (AD) are needed to aid drug development.

Methods: A targeted, stable isotope, quantitative mass spectrometry-based investigation of longitudinal changes in concentrations of previously identified candidate biomarkers was performed in cerebrospinal fluid (CSF) of Alzheimer's Disease Neuroimaging Initiative participants who were classified as cognitively normal (CN; n = 76) or with mild cognitive impairment (MCI; n = 111) at baseline.

Results: Of the candidate biomarkers, the CSF concentration of neuronal pentraxin 2 (NPTX2), a protein involved in synaptic function, exhibited rates of change that were significantly different between three comparison groups (i.

The NIMH 'Fast-Fail Trials' (FAST) Initiative: Rationale, Promise, and Progress.

In 2012, the US National Institute of Mental Health launched three clinical trial contracts under a new FAST initiative. The overall goal for these contracts (Fast-Fail Trials) was to focus early-stage trials, testing novel pharmacologic agents that target the central nervous system, on pharmacologic-based designs to objectively identify doses that produce central nervous system effects. The three contracts targeted different psychiatric populations: psychotic (FAST-PS), mood and anxiety (FAST-MAS), and autism spectrum disorders (FAST-AS).

Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers.

Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio).

Effects of Music Therapy During Total Knee Arthroplasty Under Spinal Anesthesia: A Prospective Randomized Controlled Study.

Purpose Music therapy is an effective non-pharmacologic intervention that is cost-effective, easy to implement, and customize. It has been shown to significantly alleviate anxiety and improve patient satisfaction. In this study, we aimed to compare music therapy to a control (no music) group with respect to sedation requirements, anxiety levels, and patient satisfaction for patients undergoing total knee arthroplasty under spinal anesthesia.

A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating κ-opioid antagonism as a treatment for anhedonia.

The National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)).