In this study, we used existing knowledge about regional cortical thinning in a sample of patients with mild AD dementia to investigate, using an a priori ROI-based approach, regional cortical thinning in a sample of patients with questionable AD dementia, many characteristics of which are similar to those of patients with MCI. The magnitude of thinning of certain regions correlates with the relative severity of very mild symptoms in daily life (as measured by CDR-SB) and signs on performance testing (MMSE). Furthermore, the thickness of particular regions of the cerebral cortex known to undergo thinning in mild AD provides a useful measure for the prediction of progression from questionable AD dementia (CDR 0.5) to mild AD dementia (CDR 1).
While extensive investigation has been performed in MCI of certain morphometric measures, such as the volumes of the whole brain, ventricular system, hippocampal formation, and entorhinal cortex,1–3,24
there is scant evidence regarding anatomic abnormalities in other cortical brain regions. Most of the literature on cortical atrophy in MCI has focused on exploratory mapping of atrophy in MCI compared to controls or patients with AD,6,25,26
or in MCI converters to mild AD dementia compared to nonconverters.8,9,27
In the former studies of atrophy in MCI in which the diagnostic outcome is unknown, atrophy patterns are largely similar to, although of lesser magnitude, than those of mild AD dementia. Of the previous investigations that have followed patients clinically after scanning, two demonstrated distributed atrophy patterns in the MCI progressors that are typical of those of patients with AD when comparing MCI progressors to controls,7
but surprisingly one study showed more widespread atrophy when comparing MCI progressors to nonprogressors,7
while the other showed much less widespread differences involving only supramarginal, inferior frontal, and hippocampal regions.9
A third investigation identified focal ventromedial temporal atrophy.8
There are no previous comparable data regarding the magnitude of atrophy (% difference) between progressors vs nonprogressors. The present data are consistent with previous data indicating that, when AD symptoms are still incipient or very mild, atrophy is already present in a set of heteromodal and limbic cortical regions. These data build on previous results by showing that although a lesser magnitude of atrophy is present in these very mildly affected patients, the spatial pattern is predictable based on what is known about the cortical regions affected in mild AD dementia (when defined using an independent sample).
Besides comparisons between diagnostic patient groups, we also investigated the relationships between regional cortical thickness and relative severity of mild symptoms in daily life (as measured by CDR-SB) and signs of cognitive impairment (as measured by MMSE) within this group of participants. To our knowledge, only one study has investigated the relationship of MMSE to cortical atrophy within a sample restricted to MCI or prodromal AD, and no regions of correlation were found.9
We observed robust relationships between the average thickness of the nine AD-signature regions and MMSE performance as well as CDR-SB. Such similar relationships, while intuitive, are not inevitable given the frequent dissociation between symptoms in daily life and signs on cognitive testing, particularly in the mildest prodromal stages of the illness.28
The correlations were anatomically distinct, however, in that CDR-SB correlates most prominently with ventromedial temporal and superior parietal thickness whereas MMSE correlates with superior frontal and lateral parietal thickness. Overall, the strength of the correlations was relatively subtle, as has been the case in previous reports focusing on medial temporal lobe regions. Further investigation will be necessary to determine whether consistent localized brain–behavior relationships can be illuminated through the investigation of regional cortical thinning in neurodegenerative diseases.
Most importantly, measures of the thickness of specific cortical regions known to be affected by AD are useful in predicting progression from questionable dementia to mild AD dementia within a few years. These findings build on a large body of work focused on morphometric measures of the medial temporal lobe in predicting progression from incipient dementia/MCI to AD dementia, expanding now to include regions of the temporoparietal and frontal cortices. The use of ROC analysis illuminates the utility of these measures across a broad spectrum of sensitivity-specificity tradeoffs, allowing the clinician to choose cutpoints depending on the question at hand. Also, by comparing the novel cortical thickness methods to more widely used volumetric measures (the results of which are similar to those of previous studies2,29
), these analyses further demonstrate the potential utility of thickness measures.
Of the global measures, the average thickness of the cerebral cortex outperforms whole brain volume substantially with respect to predicting progression. This is not surprising given that whole brain volume likely reflects large classes of tissue that are relatively unaffected by AD. Of the regional volume measures, entorhinal volume performed better than hippocampal volume, as has been seen previously.30
MTL thickness performed better yet in comparison to entorhinal volume, which may relate in part to past observations that thickness appears to be a purer reflection of the effects of AD on cortical morphology while surface area, and therefore volume, are altered substantially by aging.31
Finally, ROC analysis demonstrated that the average thickness of all nine AD-signature ROIs was the most powerful measure for predicting progression to mild dementia. Compared to MTL ROI measures, such a disease composite measure probably increases sensitivity by including individuals with thinning in additional brain regions involved in the disease and increases specificity by excluding individuals with relative preservation of thickness in those regions (whose relatively isolated MTL thinning may be due to other pathologies).
Several limitations of this study deserve mention. The diagnosis of AD was not confirmed by autopsy or any other imaging markers. Longitudinal MRI measures were not performed. Finally, to translate these measures into biomarkers for use in individual patient diagnostic classification, as has been done with other approaches to cortical morphometric analysis in AD,32,33
further work is necessary. Yet the robust effects observed provide optimism that this approach to cortical anatomic measurement may be able to achieve such goals.