Michael T. Ropacki

Detecting cognitive changes in preclinical Alzheimer's disease: A review of its feasibility

Significant progress has been made in characterizing the biological changes occurring in preclinical Alzheimers disease (AD). Cognitive dysfunction has been viewed, however, as a late‐stage phenomenon, despite increasing evidence that changes may be detected in the decades preceding dementia. In the absence of comprehensive evidence‐based guidelines for preclinical cognitive assessment, longitudinal cohort and neuroimaging studies have been reviewed to determine the temporal order and brain biomarker correlates of specific cognitive functions. Episodic memory decline was observed to be the most salient cognitive function, correlating with high levels of amyloid deposition and hypoconnectivity across large‐scale brain networks. Prospective studies point to early decline in both episodic and semantic memory processing as well as executive functions in the predementia period. The cognitive tests have, however, been principally those used to diagnose dementia. New procedures are required which target more finely the medial temporal lobe subregions first affected by clinically silent AD pathology.

Recommended cognitive outcomes in preclinical Alzheimer's disease: Consensus statement from the European Prevention of Alzheimer's Dementia project

The Horizon 2020/IMI European Prevention of Alzheimers Dementia (EPAD) project will undertake large‐scale proof‐of‐concept trials in predementia Alzheimers disease (AD). Within EPAD, the monitoring of cognitive trajectories in the preclinical period will constitute a central outcome measure; however, there are currently no clear guidelines as to how this should be achieved as most measures have been developed for the period around dementia diagnosis. The EPAD Scientific Advisory Group for Clinical and Cognitive Outcomes identified appropriate cognitive measures based on a literature search covering both cognitive correlates of preclinical brain changes from imaging studies and cognitive changes observed over time in nondementia population cohorts developing incident dementia. These measures were evaluated according to the following criteria: validity, coherence with biomarker changes, psychometric properties, cross‐cultural suitability, availability of alternative forms, and normative data limited practice effects. The resulting consensus statement provides recommendations for both future drug trials and research into preclinical Alzheimers disease.

AlzheimerâÂÂs and ParkinsonâÂÂs Diseases Face Common Challenges inTherapeutic Development: Role of the Precompetitive Consortium,Coalition Against Major Diseases

Alzheimer’s disease (AD) and Parkinson’s disease (PD) pose significant challenges for successful development of new therapies, with anextremely high drug trial failure rate and yet no approved disease modifying drugs available. Given the magnitude of the challenges, it has become clear that larger collaborations and multi-partner joint efforts, pooling resources and expertise,are required for theadvancement of methods and tools that are critically needed to support drug development studies. Critical Path Institute’s Coalition against Major Diseases was formed in 2008, at a time prior to the era of public private partnerships, with the mission of streamlining and de-risking drug development for AD and PD. Since its origin, the consortium has achieved several milestones including development of consensus data standards for AD and PD, a unified clinical trial database comprised of placebo data from AD therapeutic trials and regulatory endorsement of drug development tools. In addition, the consortium is progressing strongly on other initiatives, with ongoing regulatory interactions. The coalition held its annual conference at the U.S. Food and Drug Administration, where diverse stakeholders including industry, academic experts, government agency representatives, patient advocacy organizations and regulators gathered together to share their accomplishments and focus on the needs of the future. The current landscape was emphasized with focus on the need to expand the precompetitive space and enhance data sharing globally.

Novel Statistically-Derived Composite Measures for Assessing the Efficacy of Disease-Modifying Therapies in Prodromal Alzheimer’s Disease Trials: An AIBL Study

BACKGROUND There is a growing consensus that disease-modifying therapies must be given at the prodromal or preclinical stages of Alzheimers disease (AD) to be effective. A major unmet need is to develop and validate sensitive measures to track disease progression in these populations. OBJECTIVE To generate novel statistically-derived composites from standard scores, which have increased sensitivity in the assessment of change from baseline in prodromal AD. METHODS An empirically based method was employed to generate domain specific, global, and cognitive-functional novel composites. The novel composites were compared and contrasted with each other, as well as standard scores for their ability to track change from baseline. The longitudinal characteristics and power to detect decline of the measures were evaluated. Data from participants in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study characterized as mild cognitively impaired with high neocortical amyloid-β burden were utilized for the study. RESULTS The best performing standard scores were CDR Sum-of-Boxes and MMSE. The statistically-derived novel composites performed better than the standard scores from which they were derived. The domain-specific composites generally did not perform as well as the global composites or the cognitive-functional composites. CONCLUSION A systematic method was employed to generate novel statistically-derived composite measures from standard scores. Composites comprised of measures including function and multiple cognitive domains appeared to best capture change from baseline. These composites may be useful to assess progression or lack thereof in prodromal AD. However, the results should be replicated and validated using an independent clinical sample before implementation in a clinical trial.

Frequency of Abnormal Scores on the Neuropsychological Assessment Battery Screening Module (S-NAB) in a Mixed Neurological Sample

The Neuropsychological Assessment Battery (NAB; Stern & White, 2003; White & Stern, 2003) is a comprehensive, modular battery of tests comprised of the following six modules: (a) Screening, (b) Attention, (c) Language, (d) Memory, (e) Spatial, and (f) Executive Functions. The Screening Module is an abbreviated version of the full NAB. The purpose of this descriptive study was to present index and primary test score information for the Screening Module in a mixed sample of patients with known neurological conditions. Participants were 37 outpatients with clear evidence of neurological damage or disease. Performance decrements were found on the Attention Index, most notably on the Numbers and Letters tests. Decrements were also found on the Executive Functions Index, most notably on the Word Generation test. Somewhat surprisingly, patients performed well across most of the individual test scores. This mixed clinical sample showed less neuropsychological compromise than the clinical samples presented in the NAB manual.

Biometric monitoring devices for assessing end points in clinical trials: developing an ecosystem.

Biometric monitoring devices for assessing end points in clinical trials: developing an ecosystem

Clinically Meaningful Outcomes in Early Alzheimer Disease: A Consortia-Driven Approach to Identifying What Matters to Patients

Background: Numerous statistically derived composite measures have recently been proposed as clinical outcome assessments (COAs) for clinical trials in the early stages of Alzheimer disease. Critical Path Institute’s Coalition Against Major Diseases (CAMD) advanced a proposed statistically derived composite measure to regulatory agencies with the goal of qualifying it as a COA for pre-dementia trials. In response to FDA’s requirement to demonstrate that proposed COAs are meaningful to patients, this project aimed to identify the most important cognition-related concerns patients and informants report early in the disease and determine how this information maps to what is assessed by several statistically derived composite measures. Methods: Leveraging qualitative research completed by Critical Path Institute’s Patient-Reported Outcome Consortium, CAMD utilized a summary report that included frequency grids of reported concerns of amnestic mild cognitive impairment patients and their informants, as well as the narrative transcripts from focus groups. Transcripts were reviewed and analyzed to identify which cognitive domains the patient- and informant-reported concerns mapped onto. The results were then compared to see how well these cognitive domains were represented in various statistically derived composite measures. Results: The patient- and informant-reported concerns primarily mapped to the cognitive domains of episodic memory and, secondarily, orientation and language. Depending on the specified composite, there were varying levels of alignment between their subcomponents and these cognitive domains. Conclusion: Through secondary analyses of existing qualitative data, this study examined several statistically derived composite measures and found that they generally capture cognitive domains that reflect aspects of day-to-day functioning that patients and informants consider meaningful.

Measuring cognition and function in the preclinical stage of Alzheimer's disease

The Alzheimers Associations Research Roundtable met in November 2016 to explore how best to measure changes in cognition and function in the preclinical stage of Alzheimers disease. This review will cover the tools and instruments currently available to identify populations for prevention trials, and measure subtle disease progression in the earliest stages of Alzheimers disease, and will include discussions of suitable cognitive, behavioral, functional, composite, and biological endpoints for prevention trials. Current prevention trials are reviewed including TOMMOROW, Alzheimers Prevention Initiative Autosomal Dominant Alzheimers Disease Trial, the Alzheimers Prevention Initiative Generation Study, and the Anti‐Amyloid Treatment in Asymptomatic Alzheimers to compare current approaches and tools that are being developed.

THE REPEATABLE BATTERY FOR THE ASSESSMENT OF NEUROPSYCHOLOGICAL STATUS (RBANS) AS A USEFUL OUTCOME MEASURE IN PRODROMAL AD TRIALS

Until now, no curative treatment is accessible. During the last years, our group designed all D-enantiomeric peptides, with the effort to capture toxic amyloid-beta (Ab) species. Here, we investigated the therapeutic in vivo efficacy of a newly developed D-enantiomeric peptide in old APP/PS1 animals at an age, when they have developed already a full blown amyloid pathology and in pyroglutamate-Ab expressing TBA2.1 mice, which are characterized by a motoric phenotype.Methods:Aged male APP/PS1 mice were orally treated with placebo or 200mg/kg peptide for 3 months. Homozygous TBA2.1 mice and non-transgenic littermates were treated with placebo, 20 mg/kg or 100 mg/kg peptide orally for 3 months. After treatment, mice were tested in different general, cognitive (APP/PS1) and motoric (TBA2.1) behavioural tests (Morris Water Maze, Open field test, SHIRPA test battery). Brains were analysed for changes in amyloid pathology, inflammation and neurodegeneration (histological and biochemical). Results:Analysis of general behavioural tests resulted in no difference in behaviour of treated mice in comparison to non-transgenic littermates. After peptide treatment, APP/PS1 mice showed a significant improved cognitive performance in the Morris Water Maze compared to placebo controls (p 1⁄4 0,05). Treated TBA2.1 mice revealed a significant lower SHIRPA-Score than non-treated littermates, indicating an improvedmotoric phenotype. APP/PS1mice exhibited a significant decrease in plaque burden in the cortex. Treated non-transgenic littermates showed no abnormalities due to treatment with the peptide. Conclusions:We were able to show that the D-enantiomeric peptide has a truly curative effect on cognitive performance, motoric phenotype and plaque load in both mouse models without side effects on behaviour. These results qualify the peptide as promising candidate for the treatment of AD.

LANDSCAPE ANALYSIS OF BIOMETRIC MONITORING DEVICES (BMDS) UTILIZED IN ASSESSING COGNITION, SLEEP AND MOBILITY IN ALZHEIMER’S DISEASE AND OTHER AGE-RELATED NEUROLOGICAL DISEASES

Acknowledgments: This work was supported by a grant from the Arizona Alzheimer’s Consortium and, in part, by grant number 1U18FD005320 from the U.S. Food and Drug Administration’s Critical Path Public Private Partnerships Grant, and members including: AbbVie Inc., Alzheimer’s Association, Alzheimer’s Disease Discovery Foundation, Alzheimer’s Research UK, Biogen, Boehringer Ingelheim, CHDI Foundation, Eisai, Eli Lilly, F. Hoffmann La Roche, Merck Sharp & Dohme, Novartis Pharmaceuticals Corporation, Pfizer Inc., Takeda Pharmaceuticals, and UsAgainstAlzheimer’s. Acronyms in Table 1: (GCP) – good clinical practice; (RCT) randomized clinical trial; (PSG) – polysomnography; (PMLS) – periodic leg movement during sleep; (MVPA) – moderate-to-vigorous physical activity Background