Using voxel-based morphometry to map the structural changes associated with rapid conversion in MCI: A longitudinal MRI study
Introduction
Capturing the dynamics of gray matter (GM) atrophy in relation to the conversion from mild cognitive impairment (MCI) to clinically probable AD is a crucial goal. As non-invasive surrogate markers of progression to AD are not available, tracking those brain areas that show greatest structural changes over time would be of interest to develop strategies for disease-modifying therapies and to monitor their effects.
Because of its documented high rate of rapid conversion, progressive episodic memory deficit without dementia, termed “amnestic MCI” (Petersen et al., 2001), is well suited to assess the earliest features of AD. Among patients with amnestic MCI, some rapidly convert to AD (to be referred to as “converters” in what follows) whereas others do not, though might do so later (“non-converters”). The most appropriate approach to identify the changes specifically associated with rapid conversion is therefore to compare the changes observed in converters to those observed in non-converters, according to a longitudinal design.
Structural imaging techniques are well suited to assess progression of GM loss. Using longitudinal MRI and each individual's first scan as the reference, changes can be assessed over time against progression to probable AD. However, studies comparing converters to non-converters have reported discrepant results regarding the rate of temporal lobe atrophy measured with manually traced regions of interest (ROIs), i.e., higher for the hippocampus (Jack et al., 2000, Jack et al., 2004) or for the temporal neocortex (Kaye et al., 1997, Yamada et al., 1996). The ROI method is time consuming, observer dependent, and implies a priori hypotheses regarding the structures to assess, which might explain some of these discrepancies (for a review, see Chételat and Baron, 2003). Furthermore, the ROI method does not allow a comprehensive and objective assessment of the entire cortex and may not be sensitive enough to detect small and more diffuse changes that may arise over a short period of time. Novel automatic methods for computer-assisted image processing offer an attractive alternative (for a review, see Ashburner et al., 2003). These methods have been successfully applied to patients progressing from the moderate to the severe stages of AD (Thompson et al., 2003), and to symptom-free individuals with known autosomal dominant AD mutations (Fox et al., 2001, Scahill et al., 2002). In the present work, we have used voxel-based morphometry (VBM) in sporadic MCI patients to prospectively map the progression of atrophy specifically associated with rapid conversion to AD. From a clinical standpoint, this category of patients clearly represents the main target for therapeutic trials since sporadic AD represents at least 95% of AD cases.
Our purpose in this study was therefore to longitudinally assess the structural changes in amnestic MCI patients using a voxel-based approach. Our primary aim was to compare the progression of GM atrophy over an 18-month period between converters and non-converters so as to identify changes specifically associated with rapid conversion to AD. We made the following hypotheses. Firstly, based on the abovementioned ROI studies, we anticipate a higher rate of atrophy in the hippocampus and the temporal neocortex in converters relative to non-converters. Secondly, based on two voxel-based studies reporting greater atrophy in posterior cingulate, precuneus, and posterior—mainly temporoparietal—association areas in AD relative to MCI (Chételat et al., 2002, Karas et al., 2004), we also predict higher atrophy rates in these posterior areas in relation to the passage from MCI to AD.
Section snippets
Patients
Eighteen patients with amnestic MCI (Petersen et al., 2001) were prospectively studied. All were exclusively right-handed according to the Edinburgh inventory (Oldfield, 1971), except one patient who scored 67%. They were all recruited through a memory clinic, and all complained of memory impairment. They underwent medical, neurological, neuropsychological, and neuroradiological examinations and were selected according to the following stringent criteria: (i) lack of present or historical
Clinical data
At completion of the 18-month follow-up period, seven patients were declared as converters, while the remaining 11 patients still had isolated memory deficits (non-converters). The characteristics of both groups are listed in Table 1. They differed neither in mean age nor in mean years of education, but converters scored significantly less at the MMSE than non-converters at entry into the study.
Standard VBM study
The comparison between baseline data of converters and non-converters revealed no significant cluster
Methodological considerations
The novel longitudinal voxel-based method implemented here is based on Jacobian determinants estimation from intrasubject high-dimensional warping. This allows one to estimate both baseline and follow-up data from a same mean image of the first scan and the warped second scan. The former corresponds to the mean image itself, and the latter to the mean image multiplied by the Jacobian determinants. This method has the distinct advantage to protect against non-specific subtle differences
Acknowledgments
We are indebted to Ms. C. Lalevée, Ms. A. Pélerin, D. Hannequin, and B. Dupuy for their help in this study. This work was supported by INSERM U.320, Ministère de la Santé (PHRC, Principal Investigator: J-C Baron), Ministère de l’éducation nationale, Fondation France-Alzheimer and Institut de Recherches Internationales Servier.
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