Development of a General Composite Scale (GENCOMS) for Progressive Neurodegenerative Diseases and Implications for the Assessment of Disease-Modifying Therapies.

Introduction: The reliable assessment of treatment outcomes for disease-modifying therapies (DMT) in neurodegenerative disease is challenging. The objective of this paper is to describe a generalized framework for developing composite scales that can be applied in diverse, degenerative conditions, termed "GENCOMS." Composite scales optimize the sensitivity for detecting clinically meaningful effects that slow disease progression.

Safety, tolerability, immunogenicity, and efficacy of UB-311 in participants with mild Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 2a study.

Background: Anti-amyloid vaccines may offer a convenient, affordable, and accessible means of preventing and treating Alzheimer's disease. UB-311 is an anti-amyloid-β active immunotherapeutic vaccine shown to be well-tolerated and to have a durable antibody response in a phase 1 trial. This phase 2a study assessed the safety, immunogenicity, and preliminary efficacy of UB-311 in participants with mild Alzheimer's disease.

Avoiding future controversies in the Alzheimer's disease space through understanding the aducanumab data and FDA review.

Key points of disagreement between the aducanumab FDA statistical review, which had primarily negative conclusions, and the clinical review, which had primarily positive conclusions, were investigated. Results from secondary endpoints in positive Study 302 were significant and these endpoints provided meaningful additional information. Findings indicate the statistical review of the aducanumab data was incorrect in a number of key areas.

GenoRisk: A polygenic risk score for Alzheimer's disease.

Introduction: Recent clinical trials are considering inclusion of more than just apolipoprotein E () ε4 genotype as a way of reducing variability in analysis of outcomes.

Methods: Case-control data were used to compare the capacity of age, sex, and 58 Alzheimer's disease (AD)-associated single nucleotide polymorphisms (SNPs) to predict AD status using several statistical models. Model performance was assessed with Brier scores and tenfold cross-validation.

Perspectives on statistical strategies for the regulatory biomarker qualification process.

Qualification of a biomarker for use in a medical product development program requires a statistical strategy that aligns available evidence with the proposed context of use (COU), identifies any data gaps to be filled and plans any additional research required to support the qualification. Accumulating, interpreting and analyzing available data is outlined, step-by-step, illustrated by a qualified enrichment biomarker example and a safety biomarker in the process of qualification. The detailed steps aid requestors seeking qualification of biomarkers, allowing them to organize the available evidence and identify potential gaps.

36-month LipiDiDiet multinutrient clinical trial in prodromal Alzheimer's disease.

Introduction: The LipiDiDiet trial investigates the effects of the specific multinutrient combination Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease (AD). Based on previous results we hypothesized that benefits increase with long-term intervention.

Methods: In this randomized, double-blind, placebo-controlled trial, 311 people with prodromal AD were recruited using the International Working Group-1 criteria and assigned to active product (125 mL once-a-day drink) or an isocaloric, same tasting, placebo control drink.

The Alzheimer's Prevention Initiative Composite Cognitive Test: a practical measure for tracking cognitive decline in preclinical Alzheimer's disease.

Background: There is growing interest in identifying sensitive composite cognitive tests to serve as primary endpoints in preclinical Alzheimer's disease (AD) treatment trials. We reported previously a composite cognitive test score sensitive to tracking preclinical AD decline up to 5 years prior to clinical diagnosis. Here we expand upon and refine this work, empirically deriving a composite cognitive test score sensitive to tracking preclinical AD decline up to 11 years prior to diagnosis and suitable for use as a primary endpoint in a preclinical AD trial.

24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial.

Background: Nutrition is an important modifiable risk factor in Alzheimer's disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimer's disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease.

Cognitive Composites Domain Scores Related to Neuroimaging Biomarkers within Probable-Amnestic Mild Cognitive Impairment-Storage Subtype.

The probable-amnestic (Pr-a) mild cognitive impairment (MCI)-storage subtype is a phenotype with 8.5 times more risk of conversion to dementia, mainly Alzheimer's disease (AD), than the possible non-amnestic (Pss-na) MCI. The aim of this study was to find the optimized cognitive composites (CCs) domain scores most related to neuroimaging biomarkers within Pr-aMCI-storage subtype patients.

ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials.

Background: Development of new therapies for Alzheimer's disease (AD) is increasingly focused on more mildly affected populations, and requires new assessment and outcome strategies. Patients in early stages of AD have mild cognitive decline and no, or limited, functional impairment. To respond to these assessment challenges, we developed a measurement approach based on established scale items that exhibited change in previous amnestic Mild Cognitive Impairment (aMCI) trials.

Cumulative, additive benefits of memantine-donepezil combination over component monotherapies in moderate to severe Alzheimer's dementia: a pooled area under the curve analysis.

Introduction: Treatment in moderate or severe Alzheimer's disease (AD) often involves adding memantine to a cholinesterase-inhibitor (ChEI: donepezil, galantamine, rivastigmine). Evidence from six-month randomized trials and long-term observational studies supports superiority of memantine-ChEI combination to ChEI monotherapy. We utilized area-under-the-curve (AUC) analysis to assess six-month cumulative treatment efficacy of memantine-donepezil combination versus component monotherapies on individual clinical domains and on a composite index.

The Alzheimer's prevention initiative composite cognitive test score: sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers.

Objective: To identify a cognitive composite that is sensitive to tracking preclinical Alzheimer's disease decline to be used as a primary end point in treatment trials.

Method: We capitalized on longitudinal data collected from 1995 to 2010 from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the world's largest known early-onset autosomal dominant Alzheimer's disease kindred to identify a composite cognitive test with the greatest statistical power to track preclinical Alzheimer's disease decline and estimate the number of carriers age 30 years and older needed to detect a treatment effect in the Alzheimer's Prevention Initiative's (API) preclinical Alzheimer's disease treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of 1 to 7 cognitive tests/subtests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a 2- and 5-year follow-up period (n = 78 and 57), using data from noncarriers (n = 31 and 56) during the same time period to correct for aging and practice effects.

An empirically derived composite cognitive test score with improved power to track and evaluate treatments for preclinical Alzheimer's disease.

Background: There is growing interest in the evaluation of preclinical Alzheimer's disease (AD) treatments. As a result, there is a need to identify a cognitive composite that is sensitive to track preclinical AD decline to be used as a primary endpoint in treatment trials.

Methods: Longitudinal data from initially cognitively normal, 70- to 85-year-old participants in three cohort studies of aging and dementia from the Rush Alzheimer's Disease Center were examined to empirically define a composite cognitive endpoint that is sensitive to detect and track cognitive decline before the onset of cognitive impairment.

Separation of cognitive domains to improve prediction of progression from mild cognitive impairment to Alzheimer's disease.

Addressing causes of heterogeneity in cognitive outcomes is becoming more critical as Alzheimer's disease (AD) research focuses on earlier disease. One of the causes of this heterogeneity may be that individuals with deficiencies in different cognitive domains may perform similarly on a neuropsychological (NP) test for very different reasons. Tatsuoka and colleagues have applied a Bayesian model in order to integrate knowledge about cognitive domains relevant to each NP test with the observed outcomes from the Alzheimer's Disease Neuroimaging Initiative (ADNI) mild cognitive impairment data.

Measuring clinical progression in MCI and pre-MCI populations: enrichment and optimizing clinical outcomes over time.

Recent biomarker research has improved the identification of individuals with very early stages of Alzheimer's disease (AD) and has demonstrated that biomarkers are sensitive for measuring progression in the pre-dementia or mild cognitive impairment (MCI) stage and even pre-symptomatic or pre-MCI stage of AD. Because there are no validated biomarkers in AD, it is important to seek out clinical outcomes that are also sensitive for measuring progression in these very early stages of disease. Clinical outcomes are more subjective and more affected by measurement error than biomarkers but represent the core aspects of the disease and are critical for validation of biomarkers and for evaluation of clinical relevance.

Requiring an amyloid-β1-42 biomarker may improve the efficiency of a study, and simulations may help in planning studies.

A recent article by Schneider and colleagues has generated a lot of interest in simulation studies as a way to improve study design. The study also illustrates the foremost principal in simulation studies, which is that the results of a simulation are an embodiment of the assumptions that went into it. This simulation study assumes that the effect size is proportional to the mean to standard deviation ratio of the Alzheimer Disease Assessment Scale - cognitive subscale in the population being studied.

Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial.

Background: The amyloid-beta peptide Abeta(42) has been implicated in the pathogenesis of Alzheimer's disease (AD). We aimed to test the effects of tarenflurbil, a selective Abeta(42)-lowering agent (SALA), on cognition and function in patients with mild to moderate AD.

Methods: 210 patients living in the community who had a mini-mental state examination (MMSE) score of 15-26 were randomly assigned to receive tarenflurbil twice per day (400 mg [n=69] or 800 mg [n=70]) or placebo (n=71) for 12 months in a phase II, multicentre, double-blind study.

Witness and nonwitness children's violent and peaceful behavior in different types of simulated conflict with peers.

The violent and peaceful behaviors of 115 children who had or had not witnessed domestic violence were measured in five types of simulated conflict. Witnesses did not differ from nonwitnesses in conflicts involving limited resources, jealousy over possessions, or intimidation; witnesses were significantly more violent in conflicts involving aggression and exclusion. The most violent responses were found among abusers' sons who had been excluded by peers.

Gender, types of conflict, and individual differences in the use of violent and peaceful strategies among children who have and have not witnessed interparental violence.

Child witnesses' use of violent or peaceful strategies to resolve conflicts with peers were compared with strategies used by nonwitnesses. Stories depicting 5 types of peer conflicts were presented to each child, and the strategies used by the child to reach peaceful resolutions were scored. Findings include differences between witnesses and nonwitnesses, differences between genders, differences according to types of conflicts, and individual differences.