Assessing Clinical Status in Prodromal Alzheimer’s Disease
Many assessments are available to evaluate cognition and function in neurodegenerative disease. These assessment tools, however, often lack the sensitivity necessary to detect mild cognitive impairment (MCI) and disease progression in prodromal Alzheimer’s disease (pAD)/MCI due to AD. As a result, assessing the efficacy of therapeutic interventions targeted at slowing disease progression in patients with pAD is challenging. Existing assessment tools may be most sensitive in the dementia stages of AD.
A recent study published in the Journal of Prevention of Alzheimer’s Disease evaluated the psychometrics of several cognitive and functional assessments used in pAD trial populations. The overarching goal of the analyses—conducted by a team of investigators, including Chris Edgar, Ph.D., Cogstate’s Chief Science Officer—was to determine the suitability of the Clinical Dementia Rating–Sum of Boxes (CDR-SB) as a single primary endpoint in clinical trials involving patients with pAD.
Importantly, the data collected supported the CDR-SB as a valid, reliable, and sensitive tool to assess cognitive decline in a population with biomarker-confirmed pAD. Commenting on the findings, Dr. Edgar noted:
“The CDR Sum of Boxes has emerged as an important clinical trial outcome for early Alzheimer’s disease clinical trials along with a number of other commonly used assessments. However, the validity and psychometric properties of the CDR-SB and other commonly used instruments are not fully described in the literature, particularly in biomarker confirmed prodromal AD samples. The data in this recent study provide a useful reference source for trial design and outcome measure selection, with direct comparison of a number of highly relevant clinical outcome assessments.”
Study Design and Results
Investigators assessed the performance score of patients with biomarker-confirmed pAD using several assessments including the CDR-SB, Functional Activities Questionnaire (FAQ), Alzheimer’s Disease Assessment Scale – Cognition Subscale 11 and 13 (ADAS-Cog), Mini Mental State Exam (MMSE), and Free and Cued Selective Reminding Test (FCSRT-IR).
The data were gathered in SCarlet RoAD, a phase 3, multicenter, randomized, double-blind, placebo-controlled clinical trial. Patients between 50 and 58 years of age from 24 countries received gantenerumab or placebo for 100 weeks and completed assessments at baseline, week 52, and week 104. Investigators employed various statistical analyses to determine the reliability, consistency, construct validity, and sensitivity of outcome measures from the study.
The sensitivity of CDR-SB to detect impairment and change in patients with pAD was a key finding. The ability to assess cognition and function in pAD is critical for clinical trials in this area. Data from this study showed that CDR-SB remains an important assessment for clinical trials in this space.
Another unique feature of this study was the biomarker-confirmed clinical population; this was the first clinical trial to fully take this approach. Previous similar studies had only defined AD based on clinical criteria.
CDR-SB is a Valid, Reliable, and Sensitive Outcome Measure
In summary, data from this study reconfirm that CDR-SB has adequate sensitivity to detect cognitive decline in a population with biomarker-confirmed pAD. This further supports continued use as a single primary outcome measure in early AD clinical trials.
Strategies for Ensuring CDR-SB Data Quality
When administering the CDR-SB and similar outcome measures it’s important to have robust data quality programs in place. The nuances of administering complex scales present many challenges that may limit sponsors’ ability to accurately evaluate results. Obstacles such as inter-rater reliability and rater drift can be mitigated by appropriate rater qualification, rater training, and central monitoring. Cogstate has scientific and operational experience in administering complex outcome measures, like the CDR-SB, and can consult with study teams on effective approaches.