Biomarker-based prediction of progression in MCI: Comparison of AD signature and hippocampal volume with spinal fluid amyloid-β and tau

Abstract

Objective: New diagnostic criteria for mild cognitive impairment (MCI) due to Alzheimer's disease (AD) have been developed using biomarkers aiming to establish whether the clinical syndrome is likely due to underlying AD. We investigated the utility of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers in predicting progression from amnesic MCI to dementia, testing the hypotheses that (1) markers of amyloid and neurodegeneration provide distinct and complementary prognostic information over different time intervals, and that (2) evidence of neurodegeneration in amyloid-negative MCI individuals would be useful prognostically.

Methods: Data were obtained from the ADNI-1 (Alzheimer's Disease Neuroimaging Initiative Phase 1) database on all individuals with a baseline diagnosis of MCI, baseline MRI and CSF data, and at least one follow-up visit. MRI data were processed using a published set of a priori regions of interest to derive a measure known as the ``AD signature,'' as well as hippocampal volume. The CSF biomarkers amyloid-β, total tau, and phospho tau were also examined. We performed logistic regression analyses to identify the best baseline biomarker predictors of progression to dementia over 1 or 3 years, and Cox regression models to test the utility of these markers for predicting time-to-dementia.

Results: For prediction of dementia in MCI, the AD signature cortical thickness biomarker performed better than hippocampal volume. Although CSF tau measures were better than CSF amyloid-β at predicting dementia within 1 year, the AD signature was better than all CSF measures at prediction over this relatively short-term interval. CSF amyloid-β was superior to tau and AD signature at predicting dementia over 3 years. When CSF amyloid-β was dichotomized using previously published cutoff values and treated as a categorical variable, a multivariate stepwise Cox regression model indicated that both the AD signature MRI marker and the categorical CSF amyloid-β marker were useful in predicting time-to-event diagnosis of AD dementia.

Conclusion: In amnesic MCI, short-term (1 year) prognosis of progression to dementia relates strongly to baseline markers of neurodegeneration, with the AD signature MRI biomarker of cortical thickness performing the best among MRI and CSF markers studied here. Longer-term (3 year) prognosis in these individuals was better predicted by a marker indicative of brain amyloid. Prediction of time-to-event in a survival model was predicted by the combination of these biomarkers. These results provide further support for emerging models of the temporal relationship of pathophysiologic events in AD and demonstrate the utility of these biomarkers at the prodromal stage of the illness.

Keywords: Alzheimer's disease; CSF biomarkers; MRI; biomarkers; mild cognitive impairment.

FIGURE 1

(A) The cortical signature of AD is composed of a priori regions of interest in which consistent atrophy has been previously observed in multiple samples of patients with mild AD dementia. (B) The cortical signature of normal aging is composed of a priori regions of interest in which consistent atrophy has been previously described in healthy cognitively intact older adults compared with younger adults. We calculated the “AD signature index” measure by performing a linear regression with the Aging signature (excluding regions overlapping with AD signature regions; see Figures 1 and 2 of Bakkour et al., 2013) as the independent variable and the AD signature as the dependent variable. The residuals of this regression analysis were then saved as the “AD signature index.” Key: A: medial temporal, B: inferior temporal, C: temporal pole, D: Angular, E: superior frontal, F: superior parietal, G: supramarginal, H: precuneus, I: middle frontal, J: calcarine, K: caudal insula, L: cuneus, M: caudal fusiform, N: dorsomedial frontal, O: lateral occipital, P: precentral, Q: inferior frontal.

FIGURE 2

Values for the AD signature cortical thickness and CSF amyloid-β for each of the three MCI subgroups based on outcome (stable over 3 years, 3-year converters, and 1-year converters). The mean values for CSF amyloid-β are lower in both groups of converters than in stable MCI (left), while the values for AD signature index of cortical thickness are lower in the 1-year converters than in the other two groups (right; all values shown are Z scores derived from the normative values of controls and bars represent statistically significant comparisons).

FIGURE 3

Survival curves in MCI participants who were “amyloid-negative” at baseline (left) vs. those who were “amyloid positive” (right) as a function of baseline AD signature index using dichotomous cutoff.