Correspondence:
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Correspondence to: Eric Yang, Tel.: 215-628-7114; E-mail: Eyang3@its.jnj.com.
Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Authorship_List.pdf.
Abstract: Hypothetical models of AD progression typically relate clinical stages of AD to sequential changes in CSF biomarkers, imaging, and cognition. However, quantifying the continuous trajectories proposed by these models over time is difficult because of the difficulty in relating the dynamics of different biomarkers during a clinical trial that is significantly shorter than the duration of the disease. We seek to show that through proper synchronization, it is possible to de-convolve these trends and quantify the periods of time associated with different pathophysiological changes associated with Alzheimer's disease (AD). We developed a model that replicated the observed progression of ADAS-Cog 13 scores and used this as a more precise estimate of disease-duration and thus pathologic stage. We then synchronized cerebrospinal fluid (CSF) and imaging biomarkers according to our new disease timeline. By de-convolving disease progression via ADAS-Cog 13, we were able to confirm the predictions of previous hypothetical models of disease progression as well as establish concrete timelines for different pathobiological events. Specifically, our work supports a sequential pattern of biomarker changes in AD in which reduction in CSF Aβ42 and brain atrophy precede the increases in CSF tau and phospho-tau.
