Disease progression model using the integrated Alzheimer's Disease Rating Scale.

Introduction: An Alzheimer's disease (AD) dementia disease progression model was developed based on the integrated Alzheimer's Disease Rating Scale (iADRS).

Methods: Data from 3483 placebo participants in six AD trials were used to develop the disease progression model with NONMEM (version 7.4.

Demonstration of Clinical Meaningfulness of the Integrated Alzheimer's Disease Rating Scale (iADRS): Association Between Change in iADRS Scores and Patient and Caregiver Health Outcomes.

Background: The integrated Alzheimer's Disease Rating Scale (iADRS) is a validated cognitive/functional composite that effectively captures cognitive and functional decline over a broad spectrum of disease. The clinical meaningfulness of change on iADRS can be supported by establishing an association with changes on important health outcome measures.

Objective: To evaluate the relationship between change on the iADRS and changes in health outcomes in individuals with mild cognitive impairment (MCI) due to Alzheimer's disease (AD), or mild or moderate AD dementia using placebo data from four AD clinical trials and data from one AD observational study.

Integrated Alzheimer's Disease Rating Scale: Clinically meaningful change estimates.

Introduction: The Integrated Alzheimer's Disease Rating Scale (iADRS) has been used to detect differences in disease progression in early Alzheimer's disease (AD). The objectives of this study were to enhance understanding of iADRS point changes within the context of clinical trials, and to establish a minimal clinically important difference (MCID) on the iADRS.

Methods: Data from AMARANTH and EXPEDITION3 were analyzed using various approaches, including anchor-based, distribution-based, regression analyses, and cumulative distribution function (CDF) plots.

Building clinically relevant outcomes across the Alzheimer's disease spectrum.

Demonstrating that treatments are clinically meaningful across the Alzheimer's disease (AD) continuum is critical for meeting our goals of accelerating a cure by 2025. While this topic has been a focus of several Alzheimer's Association Research Roundtable (AARR) meetings, there remains no consensus as to what constitutes a "clinically meaningful outcome" in the eyes of patients, clinicians, care partners, policymakers, payers, and regulatory bodies. Furthermore, the field has not come to agreement as to what constitutes a clinically meaningful treatment effect at each stage of disease severity.

Lanabecestat: Neuroimaging results in early symptomatic Alzheimer's disease.

Introduction: Lanabecestat, a beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitor, was investigated as a potential Alzheimer's disease (AD)-modifying treatment. As previously reported, amyloid beta (Aβ) neuritic plaque burden reduction did not result in clinical benefit. Lanabecestat's effects on neuroimaging biomarkers and correlations between neuroimaging biomarkers and efficacy measures are reported.

Cognitive Go/No-Go decision-making criteria in Alzheimer's disease drug development.

Go/No-Go decision making in early phase clinical trials is challenging for drug developers working in Alzheimer's disease. Recent negative trial results have been attributed to a lack of efficacy and important safety concerns. Furthermore, demonstrated target engagement has rarely translated into demonstrable clinical efficacy.

Cognitive outcomes in trials of two BACE inhibitors in Alzheimer's disease.

Introduction: The APECS and AMARANTH trials showed that beta-secretase (BACE) inhibitors verubecestat and lanabecestat failed to slow cognitive and functional decline in individuals with prodromal or early Alzheimer's disease. Here, the performance on secondary and exploratory cognitive measures in both studies is reported.

Methods: APECS (verubecestat) and AMARANTH (lanabecestat) were randomized, double-blind, placebo-controlled, parallel-group, 104-week clinical trials conducted by different sponsors.

Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials.

Importance: Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive deterioration and impaired activities of daily living. Current treatments provide only minor symptomatic improvements with limited benefit duration. Lanabecestat, a brain-permeable inhibitor of human beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1/β-secretase), was developed to modify the clinical course of AD by slowing disease progression.

Statistical properties of continuous composite scales and implications for drug development.

Little research has been conducted on the statistical properties of composite measures comprising linear combinations of continuous component scales. We assessed the quantitative relationship between the composites and their individual components regarding their abilities to detect treatment effects. In particular, we developed the mathematical derivation of the treatment effect size of a continuous composite in relation to the treatment effect sizes of its components and proved multiple properties of the composite.

Differential impact of subclinical carotid artery disease on cerebral structure and functioning in type 1 diabetes patients with versus those without proliferative retinopathy.

Background: Type 1 diabetes mellitus (T1DM) is associated with cerebral compromise, typically found in patients with microangiopathy. Associations between subclinical macroangiopathy and the brain, whether or not in the presence of microangiopathy, have not been fully explored in T1DM. We hypothesized that subclinical macroangiopathy in adult T1DM may affect the brain and interacts with microangiopathy.

Adherence to escitalopram treatment in depression: a study of electronically compiled dosing histories in the 'Depression: the search for phenotypes' study.

Poor adherence to depression treatment is common. Understanding determinants of poor adherence to therapy is crucial to ensure optimal clinical outcomes. The aim of this study was to describe characteristics of dosing history in participants with depression receiving once daily escitalopram.

Diabetes and cognitive decline in elderly African Americans: a 15-year follow-up study.

Background: Diabetes mellitus is associated with an increased risk for cognitive impairment and vascular factors seem to play a role in this relationship. In a sample involving elderly African Americans, we tested the hypothesis that diabetes accelerates cognitive decline and explored possible mediating mechanisms within a follow-up period of 15 years.

Methods: A total of 1,702 subjects, of whom 441 had diabetes, were given the community screening interview for dementia to measure cognitive functioning at six different time points spread over a 15-year follow-up period.

Age and sex impact clozapine plasma concentrations in inpatients and outpatients with schizophrenia.

Background: Although clozapine is primarily used in a younger to mid-life population of patients with psychosis, there are limited data on the clinical pharmacology of clozapine later in life. The objective of this study was to assess the magnitude and variability of plasma concentrations of clozapine and norclozapine across the lifespan in a real-world clinical setting.

Design: A population pharmacokinetic study using nonlinear mixed effect modeling (NONMEM).

Association of 9-hydroxy risperidone concentrations with risk of switching or discontinuation in the clinical antipsychotic trial of intervention effectiveness-Alzheimer's disease trial.

Risperidone has been used to treat behavioral symptoms, such as delusions and agitation, in people with Alzheimer's disease. The relationship between magnitude and variability of risperidone and 9-hydroxy risperidone exposure and the relationship with time to discontinuation of the medication were explored. Sixty-five subjects from the Clinical Antipsychotic Trial of Intervention Effectiveness-Alzheimer's Disease Trial that received risperidone were included in this study.

Hyperglycaemia as a determinant of cognitive decline in patients with type 1 diabetes.

Individuals with type 1 diabetes show mild performance deficits in a range of neuropsychological tests compared to healthy controls, but the mechanisms underlying this cognitive deterioration are still poorly understood. Basically, two diabetes-related mechanisms can be postulated: recurrent severe hypoglycaemia and/or chronic hyperglycaemia. Intensive insulin therapy in type 1 diabetes, resulting in a durable improvement of glycaemic control, has been shown to lower the risk of long-term microvascular and macrovascular complications.

Microvascular disease in type 1 diabetes alters brain activation: a functional magnetic resonance imaging study.

Individuals with type 1 diabetes have mild performance deficits on a range of neuropsychological tests compared with nondiabetic control subjects. The mechanisms underlying this cognitive deterioration are still poorly understood, but chronic hyperglycemia is now emerging as a potential determinant, possibly through microvascular changes in the brain. In 24 type 1 diabetic patients, we tested at euglycemia and at acute hypoglycemia whether the presence of proliferative diabetic retinopathy, as a marker of microvascular disease, adversely affects the ability of the brain to respond to standardized hypoglycemia, using functional magnetic resonance imaging with a cognitive task.