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. 2016 Oct 4;54(3):983-993.
doi: 10.3233/JAD-160537.

Staging Alzheimer's Disease Risk by Sequencing Brain Function and Structure, Cerebrospinal Fluid, and Cognition Biomarkers

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Free PMC article

Staging Alzheimer's Disease Risk by Sequencing Brain Function and Structure, Cerebrospinal Fluid, and Cognition Biomarkers

Guangyu Chen et al. J Alzheimers Dis. .
Free PMC article

Abstract

This study aims to develop a composite biomarker that can accurately measure the sequential biological stages of Alzheimer's disease (AD) on an individual level. We selected 144 subjects from the Alzheimer's Disease Neuroimaging Initiative 2 datasets. Ten biomarkers, from brain function and structure, cerebrospinal fluid, and cognitive performance, were integrated using the event-based probabilistic model to estimate their optimal temporal sequence (Soptimal). We identified the numerical order of the Soptimal as the characterizing Alzheimer's disease risk events (CARE) index to measure disease stage. The results show that, in the Soptimal, hippocampal and posterior cingulate cortex network biomarkers occur first, followed by aberrant cerebrospinal fluid amyloid-β and p-tau levels, then cognitive deficit, and finally regional gray matter loss and fusiform network abnormality. The CARE index significantly correlates with disease severity and exhibits high reliability. Our findings demonstrate that use of the CARE index would advance AD stage measurement across the whole AD continuum and facilitate personalized treatment of AD.

Keywords: Alzheimer’s disease; CARE index; biomarkers sequence; functional connectivity; stage.

Figures

Fig.1
Fig.1
Probability distributions of normal (cyan) and abnormal (black) events measured by biomarkers from the AD and CN populations. The y-axis denotes the proportion of subjects, while the x-axis indicates the detected value of each biomarker measurement. The (–1) is employed to reverse the signs of the biomarker, indicating the left distribution is an event that occurred and the right distribution is an event that did not occur.
Fig.2
Fig.2
Optimal temporal order, Soptimal, of the 10 AD biomarkers estimated by the EBP model. A) The y-axis shows the Soptimal and the x-axis shows the CARE index score at which the corresponding event occurred. B) Bootstrap cross-validation of the Soptimal. Each entry in the matrix represents the proportion of the Soptimal during 500 bootstrap samples. The proportion values range from 0 to 1 and correspond to color, from white to black. The CARE index scores with their corresponding biomarkers follow: 1, increased HIPFCI; 2, decreased PCCFCI; 3, decreased Aβ concentration; 4, increased p-tau concentration; 5, decreased MMSE score; 6, increased ADAS score; 7, decreased HIPGMI; 8, decreased AVLT score; 9, decreased FUSGMI; 10, increased FUSFCI.
Fig.3
Fig.3
CARE index associated with AD clinical stages. A) Normalized likelihoods across the CARE index. The cyan, yellow, red, and black lines represent the likelihoods at each score on the CARE index for a CN subject, an EMCI subject, an LMCI subject, and an AD subject, respectively. B) CARE index distribution in CN and AD groups calculated from the EBP model. The CARE index is ordered by the maximum likelihood event sequence. Each score on the CARE index corresponds to the occurrence of a biomarker event. CARE index score 0 corresponds to no events having occurred and CARE index score 10 corresponds to all events having occurred. Both CN and AD groups showed heterogeneous index distributions. C) CARE index distributions in EMCI and LMCI groups. The proportion of EMCI (yellow) and LMCI (red) subjects at each CARE index score was plotted. D) A box plot of the CARE index score differences between groups. The median CARE index scores for CN, EMCI, LMCI, and AD groups are 2, 4, 6, and 9, respectively. The two-sample t-tests between CN and EMCI, CN and LMCI, EMCI and LMCI, and AD and LMCI showed significant differences. The red “+” denotes an outlier in the CN group.
Fig.4
Fig.4
Correlations between CARE index score and episodic memory performance. Both the within-group linear regression model and across-groups nonlinear curve-fitting analysis demonstrated significantly negative correlations between the CARE index scores and AVLT30 min scores. The higher the CARE index score, the worse the episodic memory function. Note that, since the data are discrete, many individual data points overlap; for clarity, we perturbed each of the individual plot points by adding a small random displacement in the horizontal and vertical directions. The linear regression analysis used only the original (nonperturbed) data as an input.
Fig.5
Fig.5
Intrasubject consistency of the CARE index score between repeated measures. The x-axis is individual’s baseline CARE index score, and the y-axis is the individual’s CARE index score from a measurement repeated within six months. Circle size and the number next to the circle represent the number of subjects falling on the same data point. The correlation value between two CARE index scores from repeated measurements is 89% with a slope of 1.04 (p < 1.69e-016).

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References

    1. Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ (2013) Tracking pathophysiological processes in Alzheimer’s disease: An updated hypothetical model of dynamic biomarkers. Lancet Neurol 12, 207–216. - PMC - PubMed
    1. Sperling R, Mormino E, Johnson K (2014) The evolution of preclinical Alzheimer’s disease: Implications for prevention trials. Neuron 84, 608–622. - PMC - PubMed
    1. Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9, 119–128. - PMC - PubMed
    1. Musiek ES, Holtzman DM (2015) Three dimensions of the amyloid hypothesis: Time, space and wingmen. Nat Neurosci 18, 800–806. - PMC - PubMed
    1. Herrup K (2015) The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 18, 794–799. - PubMed

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