Posterior cingulate atrophy and metabolic decline in early stage Alzheimer's disease

Abstract

To test the hypothesis that Alzheimer's disease (AD) patients with posterior cingulate/precuneus (PCP) atrophy would be a distinct disease form in view of metabolic decline. Eighty-one AD patients underwent ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and structural magnetic resonance imaging (MRI). Positron emission tomography and voxel-based morphometry (VBM) Z-score maps were generated for the individual patients using age-specific normal databases. The patients were classified into 3 groups based on atrophic patterns (no-Hipp-PCP, atrophy in neither hippocampus nor PCP; Hipp, hippocampal atrophy; PCP, PCP atrophy). There were 16 patients classified as no-Hipp-PCP, 55 as Hipp, and 10 as PCP. The Mini Mental State Examination (MMSE) score was similar among the groups. The greater FDG decline than atrophy was observed in all groups, including the no-Hipp-PCP. The PCP group was younger, and was associated with a greater degree of FDG decline in PCP than the others. There are diverse atrophic patterns in a spectrum of AD. In particular, a subset of patients show PCP atrophy, which is associated with greater metabolic burden.

Introduction

Alzheimer's disease (AD) is the leading form of age-related dementia in many countries and therefore, efforts have been made to characterize its pathophysiology using noninvasive or invasive biomarkers such as neuroimaging (Petrella et al., 2003) or tau-protein in cerebrospinal fluid (CSF) (Marksteiner et al., 2007). Of these, structural magnetic resonance imaging (MRI) has attracted great attention because it is noninvasive and relatively widely available in clinical settings. Prior studies have demonstrated that atrophy of the medial temporal lobe, including the hippocampal area, is a common structural feature of AD (Petrella et al., 2003). However, recent studies using structural MRI combined with the voxel-based morphometric (VBM) approach have demonstrated that diverse atrophic patterns may exist in a spectrum of AD (Frisoni et al., 2007). Some structural MRI studies have demonstrated that AD-associated brain atrophy may involve not only the medial temporal lobe but also the posterior cingulate gyri/precuneus (PCP), and parietotemporal area particularly in early onset AD (Ishii et al., 2005a, Shiino et al., 2006). These brain structures are known to be the area where AD-associated metabolic reduction occurs even at early stage as assessed by positron emission tomography (PET) with ¹⁸F-fluorodeoxyglucose (FDG) (Herholz et al., 2002, Minoshima et al., 1997, Petrella et al., 2003). It is also noteworthy that AD patients with posterior cortical atrophy reportedly reveal greater neurofibrillary tangle (NFT) densities in the neocortical areas than in the hippocampal areas (Tang-Wai et al., 2004), suggesting the presence of a distinct form of AD mainly involving the neocortex. To date, however, the relationship between such atrophic patterns and metabolic disease extent/severity assessed by FDG PET is unknown.

The CSF biomarkers, on the other hand, are considered to reflect ongoing histopathological changes in the brain. It is known that AD is associated with elevated phosphorylated tau (p-tau) or reduced amyloid-beta (Aβ) 42 protein (Marksteiner et al., 2007). In particular, high tau levels have often been associated with a more rapid decline of cognitive function (Snider et al., 2009), and higher NFT densities (Tapiola et al., 1997), suggesting that CSF biomarkers may reflect disease aggressiveness. The levels of CSF biomarkers have also been linked to cognitive profiles (Koric et al., 2010, van der Vlies et al., 2009). Thus, CSF biomarkers may be of important value not only for diagnosis but for disease characterization. However, data on the relationship among CSF biomarkers, brain atrophic patterns, and cognitive profiles are missing.

The aim of this study was to test the hypothesis that AD patients with PCP atrophy would represent a distinct disease form associated with a greater metabolic decline, and more increased CSF p-tau levels, which may be linked to disease aggressiveness. In this study, we computed the VBM and PET Z-score maps (Chételat et al., 2008) using age-specific normal database sets strictly matched to each individual AD patient in order to avoid confounding aging effects on the resulting Z-score maps. Furthermore, we applied correction for partial-volume effects (PVE) on PET to compensate for atrophy in small brain structures.