Elsevier

NeuroImage

Volume 18, Issue 2, February 2003, Pages 525-541
NeuroImage

Review article
Early diagnosis of alzheimer’s disease: contribution of structural neuroimaging

https://doi.org/10.1016/S1053-8119(02)00026-5Get rights and content

Abstract

To accurately predict the development of Alzheimer’s disease (AD) at its predementia stage would be a major breakthrough from both therapeutic and research standpoints. In this review, our focus is on markers obtained with structural imaging—especially magnetic resonance imaging (MRI)—and on studies of subjects at risk of developing AD. Among the latter, amnestic mild cognitive impairment (MCI) is currently the most commonly accepted reference, and therefore is specially targeted in this review. MCI refers to patients with significant but isolated memory impairment relative to subjects of identical age. Consistent with established histopathological data, structural imaging studies comparing patients with early probable AD to healthy aged subjects have shown that the most specific and sensitive features of AD at this stage are hippocampal and entorhinal cortex atrophy, especially when combined with a reduced volume of the temporal neocortex. MCI patients have significant hippocampal atrophy when compared to aged normal controls. When comparing patients with probable AD to MCI subjects, hippocampal region atrophy significantly extends to the neighboring temporal association neocortex. However, only longitudinal studies of MCI subjects are suited to assess (in a retrospective way) the predictive value of initial atrophy measurements for progression to AD. Few such studies have been published so far and for the most they were based on small samples. Furthermore, the comparison among studies is clouded by differences in both populations studied and MRI methodology used. Nevertheless, comparing the initial MRI data of at-risk subjects who convert to AD at follow-up to those of nonconverters suggests that a reduced association temporal neocortex volume combined with hippocampal or anterior cingulate cortex atrophy may be the best predictor of progression to AD. These data, although still preliminary, are consistent with postmortem studies describing the hierarchical progression of tau lesions in normal aging and early stages of AD, such that damage to the medial temporal lobe and association cortex would account for the memory and nonmemory cognitive impairments, respectively, the combination of which is required to operationally define probable AD. Future research in this field should capitalize on thorough methodology for brain structure delineation, and combine atrophy measurements to cognitive and/or functional imaging data.

Section snippets

Definition of terms

Dementia: deficits in two or more areas of cognition, sufficient to interefere significantly in social and occupational functioning (DSMIV; American Psychiatric Association, 1994).

AD: patients with clinically probable AD according NINCDS-ADRDA (McKhann et al., 1984) or DSMIV (American Psychiatric Association, 1994) criteria.

Mild AD: Patients with probable AD at a mild stage of global cognitive impairment as assessed by MMSE >20 and/or a CDR score <1.

Accuracy: Although when referring to

Methodological considerations

Three different types of studies involving structural imaging in early AD can be distinguished. First, if there exist structural magnetic resonance imaging (MRI) indices able to predict the development of AD in at-risk subjects, then in a first approximation such indices would be expected to remain prominently abnormal at later stages of the disease. Therefore, studies that compare healthy aged subjects (HAS) and AD patients should be considered a first but necessary step in the quest for early

Studies comparing mild AD to has

The first volumetric MRI study of AD was published in 1988 (Seab et al., 1988). It disclosed a decrease in Hcp volume averaging 40% in AD patients when compared to healthy aged subjects (HAS), which probably preceded overall brain atrophy. There was no overlap of individual values. Since then, studies have repeatedly found significant atrophy of the hippocampal and parahippocampal formation in AD, ranging from 20 to 52% (Mega et al., 2000, for review), and already present at the first stages of

Cross-sectional studies on at-risk subjects

Table 2 lists the percentage change in cerebral structure size in different categories of at risk subjects as compared to HAS and probable AD. The accuracy of atrophy measurements is not listed in this table for it was only assessed in Convit et al 1997, Xu et al 2000, Du et al 2001, and De Santi et al. (2001) (see below) and has but little interest, because of the heterogeneity of the at-risk population. Furthermore, in most of these studies, the AD patients were not exclusively at an early

Longitudinal studies on at-risk subjects

De Leon et al. (1989) were the first to publish a small-scale MRI study on MCI subjects with longitudinal follow-up. The results of this preliminary study were confirmed in 1993 on a larger sample and with longer follow-up; therefore, only the results from this second study are presented here. These authors visually assessed the dilatation of the perihippocampal fissure according to a 4-point scale and found that significant dilatation was much more frequent in those MCI subjects who eventually

Conclusions

Quite logically guided by histopathological data on the distribution of neurodegenerative changes at early stages of AD, structural imaging studies have targeted the hippocampal region. However, these histopathological studies have also shown that what differentiates AD from “normal” aging is the involvement of the association neocortex, and this corresponds to the operational criteria for AD which require impairment in memory and at least one other cognitive function. Quite appropriately, this

Suggestions for future research

Based on the above review, it is clear that further prospective studies on larger samples, with sufficient but also same follow-up for all subjects, a detailed analysis of both medial temporal and association neocortex substructures, and incorporating sensitive cognitive tests, are needed to complement these preliminary findings. It will also be of interest to consider in future studies the fraction of MCI patients that convert in a reasonably short interval (“rapid converters”), as being able

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