Abstract of online articleStructural MRI changes detectable up to ten years before clinical Alzheimer's disease
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] Aβ1–42 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.
Section snippets
Subjects
A group of 148 healthy, cognitively normal, community-dwelling volunteers were recruited from a longitudinal study (De Jager et al., 2002, De Jager et al., 2005). They were recruited through talks and radio advertising for those who thought that their memory and thinking were good as compared with their peers. At baseline, all subjects underwent MRI scan, physical examination, and neuropsychological assessment. Cognitive impairment was excluded at baseline based on Mini Mental State Examination
Demographic and neuropsychological data
At baseline, there were no significant differences between the groups in age, years of education, gender, ApoE status, MMSE, NART-IQ full-scale and verbal IQ (Table 1). CAMCOG scores were significantly higher in the HC group compared with preclinical MCI, but not compared with preclinical AD. This difference was not significant in CAMCOG scores repeated after 2 years of follow-up, where all groups performed the same. In addition, none of the subjects had received a diagnosis of MCI or AD
Discussion
We investigated structural brain differences between groups of healthy subjects stratified by later diagnosis of conversion to MCI or AD, using VBM and subcortical shape analyses. At baseline, all subjects presented homogeneous clinical and cognitive features. In addition, by including only those subjects who remained cognitively normal for at least 4 years from baseline, we can reasonably ensure that all subjects were truly healthy at baseline and did not progress to cognitive impairment
Disclosure statement
The authors declare no conflicts of interest.
Ethical approval was granted from the central Oxford Research Ethics Committee and informed consent was obtained from participants.
Acknowledgements
We thank all study participants and their families, without whose long-term commitment, this study could not have occurred. Similarly, we wish to thank Prof A. David Smith, founder and former director OPTIMA, who organized this longitudinal study and kindly agreed to share the data with the authors, Elizabeth King and Marc Budge for their contribution in establishing the cohort, Kevin Bradley, radiologist, for his input and supervision of the MRI acquisition, and all OPTIMA nurses and staff who
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