CSF and Brain Structural Imaging Markers of the Alzheimer's Pathological Cascade

Xianfeng Yang,Anqi Qiu,Ming Zhen Tan,Yong Fan

doi:10.1371/journal.pone.0047406

Abstract

Cerebral spinal fluid (CSF) and structural imaging markers are suggested as biomarkers amended to existing diagnostic criteria of mild cognitive impairment (MCI) and Alzheimer's disease (AD). But there is no clear instruction on which markers should be used at which stage of dementia. This study aimed to first investigate associations of the CSF markers as well as volumes and shapes of the hippocampus and lateral ventricles with MCI and AD at the baseline and secondly apply these baseline markers to predict MCI conversion in a two-year time using the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Our results suggested that the CSF markers, including Aβ42, t-tau, and p-tau, distinguished MCI or AD from NC, while the Aβ42 CSF marker contributed to the differentiation between MCI and AD. The hippocampal shapes performed better than the hippocampal volumes in classifying NC and MCI, NC and AD, as well as MCI and AD. Interestingly, the ventricular volumes were better than the ventricular shapes to distinguish MCI or AD from NC, while the ventricular shapes showed better accuracy than the ventricular volumes in classifying MCI and AD. As the CSF markers and the structural markers are complementary, the combination of them showed great improvements in the classification accuracies of MCI and AD. Moreover, the combination of these markers showed high sensitivity but low specificity for predicting conversion from MCI to AD in two years. Hence, it is feasible to employ a cross-sectional sample to investigate dynamic associations of the CSF and imaging markers with MCI and AD and to predict future MCI conversion. In particular, the volumetric information may be good for the early stage of AD, while morphological shapes should be considered as markers in the prediction of MCI conversion to AD together with the CSF markers.

Highlights

Cerebral spinal fluid (CSF) and imaging markers have been suggested as biomarkers to augment existing diagnostic criteria of both mild cognitive impairment (MCI) and Alzheimer’s disease (AD) [1,2,3,4,5,6]
No significant differences in age were found among the normal controls (NC), MCI, and AD groups (ANOVA, p = 0.454). 25 out of 111 MCI subjects were diagnosed as AD at the two-year follow up and were denoted as the MCI-c group
Bilateral hippocampal volumes distinguished MCI and AD subjects from normal controls at an accuracy of 61.9% and 65.5% respectively, with relatively high specificity (MCI: 66.1%; AD: 73.3%) but low sensitivity (MCI: 57.7%; AD: 57.8%) (Table 2)

Summary

Introduction

Cerebral spinal fluid (CSF) and imaging markers have been suggested as biomarkers to augment existing diagnostic criteria of both mild cognitive impairment (MCI) and Alzheimer’s disease (AD) [1,2,3,4,5,6]. Jack et al [7] proposed a possible hypothetical model in which biomarkers were temporally arranged in order of abnormality along the pathological cascade of AD In this model, abnormal CSF Ab42 could occur two decades before the first dementia-related symptoms, reaching a plateau prior any manifestation of cognitive impairment. In comparison to trajectories of CSF tau, magnetic resonance imaging (MRI) markers surfaced much later and were well correlated with the severity of AD symptoms. This hypothetical model was directly derived from longitudinal studies, where statistical inferences were founded primarily on the rate of change of AD-related biomarkers over time. Increased rates of ventricular expansion and brain atrophy in the medial temporal lobe were found to be significantly correlated with cognitive decline, with good predictions for MCI to AD conversion [8] [9] [10]

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