CMP3: A CSF Multiple Pathophysiology Panel for Clinical Trials in Alzheimer's Disease PROJECT SUMMARY / ABSTRACT Alzheimer's disease (AD) is a complex disease driven by cycles of protein misfolding, inflammation, neurovascular injury, and metabolic stress. The core AD biomarkers (the levels of Tau and Ab protein in cerebrospinal fluid (CSF)) are strong indicators of the presence of AD pathology, but are inadequate for measuring progression of the disease or response to drug treatments. In order to diagnose the disease earlier and maximize the potential for treatment, it is critical that more useful biomarkers of AD are characterized. Measurement of related proteins (a.k.a. pathways) that drive the disease might provide more accurate biomarkers of disease susceptibility, progression, and therapeutic effects, which would benefit both basic science and clinical trials. In preliminary studies, over 70 commercially available tests (analytes) were analysed for their ability to detect AD associated proteins, using CSF collected 8-weeks apart in placebo subjects of a drug trial for mild cognitive impairment (MCI)/AD). Markers of neurovascular injury, immune response, neurodegeneration, and metabolism were evaluated, along with Ab and Tau. The technical variability of these tests, as well as the stability of the measurements within individuals over 8 weeks was assessed. Based on this preliminary work, a core set of 30 reliable analytes were identified that represent diverse AD related pathways. In this proposal, these analytes will be used to derive a CSF multiple pathophysiology panel (CMP3) for the diagnosis, staging, and pathophysiological profiling of AD in well-characterized cases from the MassGeneral Institute for Neurodegenerative Disease (MIND) Tissue Bank and a novel clinical trial.
In Aim 1 all 30 analytes in CSF will be tested in a well-characterized cohort of AD related early dementia cases versus matched cognitively unimpaired aged controls (n = 60/group). Using statistical modeling of individual and combinations of analytes, the panel will be refined to the most informative analytes in each AD-related pathway.
In Aim 2, the refined CMP3 panel will be validated in an independent set of AD cases verses controls, and the approach extended to test the utility of the panel for measuring AD severity across the spectrum of pre-clinical AD, MCI due to AD, and early and moderate-severe dementia due to AD.
In Aim 3 the CMP3 panel will be used to test CSF samples for treatment efficacy in a clinical trial of a novel combinatorial AD treatment targeting inflammation, metabolism and neurodegeneration. It is anticipated that the CMP3 will prove an accurate, sensitive, and flexible tool for characterization of AD in both basic research and clinical trial settings.
Alzheimer's disease is a complex disease with no cure, and no accurate, sensitive biomarkers for predicting progression, disease stage or treatment response. Progress in designing novel treatments is currently held back by the lack of informative biomarkers, and a narrow tau and amyloid-b centric view of the disease. We propose to develop a multivariate panel (?CMP3?) of informative and sensitive biomarkers that represent the multiple pathophysiological pathways active in AD, in order to accelerate progress in both clinical trials and basic research.
