Integration and relative value of biomarkers for prediction of MCI to AD progression: Spatial patterns of brain atrophy, cognitive scores, APOE genotype and CSF biomarkers

Sharon X. Xie,Jarcy Zee,Jon B. Toledo,Paraskevi Parmpi,John Q. Trojanowski,Christos Davatzikos,David A. Wolk,Xiao Da,Yangming Ou,Leslie Shaw,Amanda Shacklett

doi:10.1016/j.nicl.2013.11.010

Sharon X. Xie, Jarcy Zee + Show 9 more

Open Access

https://doi.org/10.1016/j.nicl.2013.11.010

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Abstract

This study evaluates the individual, as well as relative and joint value of indices obtained from magnetic resonance imaging (MRI) patterns of brain atrophy (quantified by the SPARE-AD index), cerebrospinal fluid (CSF) biomarkers, APOE genotype, and cognitive performance (ADAS-Cog) in progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) within a variable follow-up period up to 6 years, using data from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI-1). SPARE-AD was first established as a highly sensitive and specific MRI-marker of AD vs. cognitively normal (CN) subjects (AUC = 0.98). Baseline predictive values of all aforementioned indices were then compared using survival analysis on 381 MCI subjects. SPARE-AD and ADAS-Cog were found to have similar predictive value, and their combination was significantly better than their individual performance. APOE genotype did not significantly improve prediction, although the combination of SPARE-AD, ADAS-Cog and APOE ε4 provided the highest hazard ratio estimates of 17.8 (last vs. first quartile). In a subset of 192 MCI patients who also had CSF biomarkers, the addition of Aβ1–42, t-tau, and p-tau181p to the previous model did not improve predictive value significantly over SPARE-AD and ADAS-Cog combined. Importantly, in amyloid-negative patients with MCI, SPARE-AD had high predictive power of clinical progression. Our findings suggest that SPARE-AD and ADAS-Cog in combination offer the highest predictive power of conversion from MCI to AD, which is improved, albeit not significantly, by APOE genotype. The finding that SPARE-AD in amyloid-negative MCI patients was predictive of clinical progression is not expected under the amyloid hypothesis and merits further investigation.

Highlights

Alzheimer's Disease (AD) is the most common form of dementia and a major health and socioeconomic concern (Hurd et al, 2013); early detection and disease modifying drug development are critically important
We investigate the value of the SPARE-AD index in predicting 3-year stability from baseline scans, as well as its combination with APOE genotype, cerebrospinal fluid (CSF) biomarkers, and ADAS-Cog data
The best magnetic resonance imaging (MRI)-based diagnostic accuracy was achieved by jointly considering the RAVENS maps of gray matter (GM), white matter (WM) and CSF, thereby forming a SPARE-AD score by evaluating regional patterns of atrophy and ventricular enlargement. 3D visualizations (Fig. 1) help appreciate brain regions participating in the diagnostic model

Summary

Introduction

Alzheimer's Disease (AD) is the most common form of dementia and a major health and socioeconomic concern (Hurd et al, 2013); early detection and disease modifying drug development are critically important. Aβ deposition can be measured using PET tracers (Clark et al, 2012a; Ikonomovic et al, 2008) which correlate with decrease in Aβ1–42 in CSF (Fagan et al, 2009; Toledo et al, 2011). Both measures show a high accuracy for predicting AD neuropathology (Clark et al, 2012a; Shaw et al, 2009; Silverman et al, 2001; Toledo et al, 2012).

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