Structural MRI changes detectable up to ten years before clinical Alzheimer's disease

Abstract

Structural brain changes have been described in both mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, less is known about whether structural changes are detectable earlier, in the asymptomatic phase. Using voxel-based morphometry (VBM) and shape analyses of magnetic resonance imaging (MRI) data, we investigated structural brain differences between groups of healthy subjects, stratified by subsequent diagnoses of MCI or AD during a 10-year follow-up. Images taken at baseline, at least 4 years before any cognitive symptoms, showed that subjects with future cognitive impairment (preclinical AD and MCI) had reduced brain volume in medial temporal lobes, posterior cingulate/precuneus, and orbitofrontal cortex, compared with matched subjects who remained cognitively healthy for 10 years (HC). For only those subjects later diagnosed as AD, significantly greater atrophy at baseline was detected in the right medial temporal lobe, which was also confirmed by shape analysis of the right hippocampus in these subjects. Our results demonstrate that structural brain changes occur years before clinical cognitive decline in AD and are localized to regions affected by AD neuropathology.

Introduction

Converging evidence from neuroimaging (Fennema-Notestine et al., 2009, Jack et al., 2009, Morris et al., 2009, Ries et al., 2008, Yuan et al., 2009) and biochemical (Hampel et al., 2008, Mattsson et al., 2009) research indicates that the pathologic process of Alzheimer's disease (AD) begins years, if not decades, prior to the diagnosis of clinical dementia. Thus, there is a long preclinical phase of AD in which there are no symptoms of cognitive dysfunction but in which AD pathology is already ongoing (Jack et al., 2010).

Neurofibrillary tangles and amyloid plaques are the principal pathologic features of AD and it has been suggested that abnormal processing of amyloid precursor protein leads to a cascade of events characterized by abnormal tau aggregations, synaptic dysfunction, cell death, and changes in brain structure, i.e., atrophy (Hardy and Selkoe, 2002). Several studies have shown that markers of amyloid deposition (i.e., CSF [cerebrospinal fluid] Aβ_1–42 and amyloid PET [positron emission tomography] imaging) are altered early, i.e., in both cognitively normal and mild cognitive impairment (MCI) subjects before they develop AD (Mattsson et al., 2009, Morris et al., 2009, Storandt et al., 2009).

Instead, changes in brain structure as detected by structural magnetic resonance imaging (MRI), which are an expression of decreased synaptic density, neuronal loss, and cell shrinkage (Bobinski et al., 2000), are thought to become evident later during the disease progression (Jack et al., 2010) and to match more closely the cognitive symptoms (Vemuri et al., 2009). In the AD phase, when clinical symptoms of AD are evident and clinical diagnostic criteria for dementia are fulfilled, structural MRI estimates of changes in brain structure show diffuse cortical atrophy in the medial temporal lobe, in the posterior association cortex, and in other neocortical association areas (Busatto et al., 2008, Karas et al., 2004). There is also strong evidence that changes in brain structure can be detected with structural MRI in elderly subjects in the MCI phase. In fact, several studies have shown that subjects with MCI destined to convert to AD have greater atrophy in medial temporal lobes, posterior cingulate, lateral temporal, and parietal cortex compared with healthy controls or stable MCI, although with heterogeneous results in terms of laterality and atrophy extent (Bozzali et al., 2006, Chételat et al., 2005, Hänninen et al., 2007, Karas et al., 2008, Risacher et al., 2009, Whitwell et al., 2008). More precisely, detection of atrophy in the medial temporal lobe and the hippocampus in particular, has been proposed as a possible marker of incipient AD at the MCI stage (Dubois et al., 2007, Frisoni et al., 2010). However, less is known about how early and where in the brain the first structural changes occur in the asymptomatic stage preceding cognitive impairment. To investigate this issue, several MRI studies focused their attention on normal subjects at genetic risk of developing AD in order to show the earliest brain changes associated with this risk (Berti et al., 2011, Chen et al., 2007, Honea et al., 2011, Reiman et al., 1998). As the apolipoprotein E (ApoE) ε4 allelic variant is the best established risk factor for sporadic AD, several studies have looked at its effect on brain structure, showing hippocampal volume reduction in ε4 carriers compared with noncarriers in cognitively normal people (Reiman et al., 1998) and association of ApoE ε4 gene dose (single or double allele) with accelerated brain atrophy rates before the onset of cognitive impairment (Chen et al., 2007). Other studies demonstrated that cognitively normal subjects with maternal history of AD have reduced volume in several brain regions, including medial temporal lobe and precuneus (Berti et al., 2011, Honea et al., 2011).

To our knowledge, only a few studies have used structural MRI to study the localization of brain atrophy in healthy subjects who later converted to MCI or AD (den Heijer et al., 2006, Hall et al., 2008, Rusinek et al., 2003, Smith et al., 2007). Two studies that used whole-brain, voxel-based and not hypothesis-driven approaches, showed heterogeneous results (Hall et al., 2008, Smith et al., 2007), highlighting the role of atrophy in the medial temporal lobes in combination with that in lateral temporal regions (Smith et al., 2007) or in the basal forebrain (Hall et al., 2008).

The purpose of our study was to identify structural MRI changes of preclinical AD occurring early in the asymptomatic stage, years before any symptoms are measurable. We analyzed MRI data in elderly healthy subjects who were followed-up for 10 years and remained cognitively healthy for at least 4 years. Using a whole-brain voxel-based approach, we examined the distribution of brain atrophy suggestive of later progression to cognitive impairment. We hypothesized that early brain atrophy would be detectable several years before the clinical onset of MCI and AD, with a greater relevance in the medial-temporal lobes.