The Preclinical Alzheimer Cognitive Composite (PACC): From Theory to Practical Application in Global Clinical Trials

Drug development strategies for early Alzheimer’s disease (AD) require clinical endpoints that are sensitive to the subtlest cognitive changes that may be occurring at even preclinical stages. Commonly used measures of cognition in clinical trials of treatments for Alzheimer’s disease, such as the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Clinical Dementia Rating (CDR), have inadequate measurement properties (e.g., ceiling effects, practice effects, restricted range, and/or skewed distributions), which render them insensitive to subtle change.

The most common approach to defining novel endpoints has been to assemble composite measures by combining tests, or specific items of tests, which assess domains of cognitive function that have historically been shown to be most sensitive to change in studies of early clinical populations (i.e., mild cognitive impairment or prodromal AD) or in observational studies of preclinical, “at-risk” samples.

One such composite measure, the Alzheimer’s Disease Cooperative Study- Preclinical Alzheimer Cognitive Composite (ADCS-PACC), was based on retrospective analyses of datasets from 3 longitudinal, observational studies of cognitively normal elderly individuals. These studies were the Australian Imaging, Biomarkers, and Lifestyle (AIBL) Flagship Study of Aging, the Alzheimer’s Disease Neuroimaging Study (ADNI), and the ADCS Prevention Instrument (ADCS-PI) study. Those members of the study samples with risk factors for Alzheimer’s disease, such as positive brain amyloid (AIBL, ADNI) or ApoE4 allele ( ADCS-PI), showed the greatest decline relative to members without risk factors on measures of episodic memory (delayed word recall and delayed story recall), executive functioning, and orientation. Although the specific tests were not completely aligned across the three studies, the following tests and outcome scores were proposed as the PACC:

• Free and Cued Selective Reminding Test (FCSRT) – Total Free and Cued Recall Score
• Logical Memory from the Wechsler Memory Scale – Delayed Recall Score (from a single story)
• Digit Symbol-Coding from the Wechsler Intelligence Scale – Number of Correct Symbols
• Mini-Mental Status Examination (MMSE) – Total MMSE score

The ADCS-PACC is currently being prospectively validated in a number of ongoing studies, including the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study.

By attending this webinar, you will learn about:

• The PACC component tests – how they were selected, paradigms measured, and applications of the composite as a primary endpoint in clinical trials
• Challenges to implementation and possible solutions, including
  • Translating and culturally adapting the tests for global deployment
  • Training raters for reliable and accurate administration
  • Monitoring data quality during studies
• Possible alternative component measures — potential pros and cons

Speakers

Paul Maruff, Chief Science Officer, Cogstate

Professor Paul Maruff is a founder of Cogstate. Paul is a neuropsychologist with expertise in the measurement of subtle behavioral and cognitive dysfunction in neuropsychiatric and neurological disease and disorders and in brain injury. Paul’s research integrates conventional and computerized neuropsychological testing with cognitive neuroscientific methods, neuroimaging, genetics and clinical assessment in to guide decision making in about brain function in both clinical medicine in drug development.

Paul has worked extensively to develop methods for identification of the nature and magnitude of cognitive impairment, and to assess the efficacy of licensed and experimental drugs and procedures, in Alzheimer’s disease, mild cognitive impairment and the HIV dementia complex. He has extended these methods to the identification of cognitive dysfunction and the effects of treatment in psychiatric diseases such as schizophrenia, attention deficit disorder and obsessive-compulsive disorder, major depressive disorder and substance abuse in adults and children.

In addition to being responsible for the scientific progress at Cogstate, Paul is also appointed Professor at the Florey Institute for Neuroscience and Mental Health where is an active member of the Alzheimer’s disease research group. He is currently clinical co-chair of the clinical committee in the Australian Imaging Biomarkers and Lifestyle (AIBL) study and also sits on the executive committee for that group. Paul has published over 300 research articles in international peer-reviewed scientific journals and has co-authored 10 book chapters.

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Edward Bartolic, Senior Science Director, Cogstate

Edward I. Bartolic, PhD, is Senior Science Director at Cogstate and a clinical neuropsychologist with 20 years of postdoctoral clinical research experience. Nearly 15 of those years have been in various scientific positions within global contract research organizations, including the Director of CNS Research and Scientific Director for the Rater Training Services department at i3 Research and Director of Clinical Assessment Technologies at Worldwide Clinical Trials.

For the past 9 years, in his roles with rater training groups, Dr. Bartolic functioned as clinical/therapeutic lead, providing oversight of the development and management of global rater training and data monitoring/rater surveillance programs for studies in psychiatry and neurology. He has served as lead rater trainer at numerous investigators meetings for studies in indications that include Alzheimer’s disease (AD), mild cognitive impairment (MCI)/prodromal AD, multiple sclerosis, major depressive disorder, bipolar disorder-mania, bipolar depression, schizophrenia, and generalized anxiety disorder. He has designed customized methodologies for remote monitoring of clinical trial assessments, including review of source documentation and assessment results for verification of study eligibility criteria during the screening period and confirmation of proper administration and scoring of cognitive and other neurobehavioral assessments. He also has the unique experience of having coordinated and managed two different committees consisting of independent clinical neurologists and geriatric psychiatrists responsible for adjudicating investigator-determined progression to AD endpoints in prodromal AD/MCI trials.

Dr. Bartolic graduated from the University of Cincinnati with a Ph.D. in Clinical Psychology and specialization in Neuropsychology. Prior to working in the Pharmaceutical industry, Dr. Bartolic served for five years as Assistant Professor of Psychiatry at the Medical College of Pennsylvania and Hahnemann University in Philadelphia (currently known as Drexel University College of Medicine). During that time, he was also the Director of Neuropsychology at the Medical College of Pennsylvania Hospital and the Eastern Pennsylvania Psychiatric Institute, leading an active inpatient and outpatient clinical service and supervising neuropsychology students, interns and post-doctoral fellows. He has numerous publications and invited presentations in the area of neuropsychological assessment and cognitive disorders.

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