Background: In Alzheimer’s disease, neurodegenerative atrophy progresses from the entorhinal cortex (ERC) to the hippocampus (HP), limbic system and neocortex. The significance of very mild atrophy of the ERC and HP on MRI scans among elderly subjects is unknown. Methods: A validated visual rating system on coronal MRI scans was used to identify no atrophy of the HP or ERC (HP₀; ERC₀), or minimal atrophy of the HP or ERC (HPma; ERCma), among 414 participants. Subjects fell into the following groups: (1) ERC₀/HP₀, (2) ERCma/HP₀, (3) ERC₀/HPma, and (4) ERCma/HPma. HP volume was independently measured using volumetric methods. Results: In comparison to ERC₀/HP₀ subjects, those with ERC₀/HPma had impairment on 1 memory test, ERCma/HP₀ subjects had impairment on 2 memory tests and the Mini Mental State Examination (MMSE), while ERCma/HPma subjects had impairment on 3 memory tests, the MMSE and Clinical Dementia Rating. Progression rates of cognitive and functional impairment were significantly greater among subjects with ERCma. Conclusion: Minimal atrophy of the ERC results in greater impairment than minimal atrophy of the HP, and the combination is additive when measured by cognitive and functional tests. Rates of progression to greater impairment were higher among ERCma subjects.

Very early diagnosis and intervention has been proposed as the most promising approach for the successful treatment of Alzheimer’s disease (AD), which may have two phases prior to the development of a dementia syndrome [1]. These predementia phases of AD include: (1) a presymptomatic stage [1], marked primarily by amyloid deposition, as reflected by elevated levels of cerebrospinal fluid Aβ-42 levels [2,3] and amyloid PET tracer retention [4] but little or no neurodegenerative changes; (2) a prodromal stage characterized not only by amyloid deposition, but also by subtle cognitive deficits associated with synaptic dysfunction, cell death and atrophy [5], especially of the entorhinal cortex and the hippocampus (particularly the anterior aspects of the CA1 sector and the subiculum), and eventually the entire limbic system and neocortex [6]. Measurement of atrophy in the entorhinal cortex (ERC) and subregions of the hippocampus (HP) is therefore likely to be an early biological marker of the neurodegenerative phase of AD.

While moderate-to-severe medial temporal atrophy may support the diagnosis of AD, the significance of isolated minimal or mild atrophy of the ERC and/or the HP, especially among individuals with subjective memory complaints or subtle cognitive deficits, is unknown. Automated methods have been developed to provide quantitative volumetry of the ERC and the subregions of the HP [7,8]; however, these methods are labor intensive, require a high level of technical expertise, are invalidated by common technical deficiencies in image acquisition, and are not easily adaptable for routine clinical or research use.

We have refined a semiquantitative visual rating system for assessing medial temporal atrophy (VRS-MTA), initially developed by Scheltens et al. [9], so as to produce reliable, valid and independent assessments of atrophy in the anterior aspects of the ERC, HP (including the subiculum and CA1 regions) and perirhinal cortex. We have shown that VRS-MTA provides better discrimination between subjects with amnestic MCI (aMCI) and no cognitive impairment, as well as higher correlations with tests of episodic memory among subjects with aMCI, than standard volumetric methods of assessing HP volumes [10]. Furthermore, assessments of ERC and HP atrophy by VRS-MTA or volumetric methods have been shown to predict future cognitive decline and conversion to AD among healthy elderly individuals and those with MCI [10,11,12,13,14].

In the current study, the effect of minimal atrophy of the ERC and the anterior HP on cognitive test performance, functional abilities and progression to more impaired states was assessed. Given that ERC atrophy precedes HP atrophy in AD, and that HP atrophy appears to be a non-specific finding in many conditions, we hypothesized that minimal ERC atrophy (even in the absence of HP atrophy) would be best correlated to subtle cognitive impairment in the elderly, especially among those individuals who are in the early stages of AD.

Subject Recruitment

In this study, we included 414 male and female participants from the Florida Alzheimer’s Disease Research Center Clinical Core in Miami Beach and Tampa. Subjects were between 50 and 88 years of age, with 71% being English- and 29% Spanish-speakers. The study was approved by the Institutional Review Boards at Mount Sinai Medical Center, Miami Beach, University of Miami, Miami, and the University of South Florida, Tampa. All subjects or a legal representative provided informed consent.


The following were completed on all subjects: (1) full clinical history, obtained from a reliable informant; (2) neurological evaluation; (3) psychiatric evaluation, including administration of the Geriatric Depression Scale [15] and the Neuropsychiatric Inventory [16]; (4) Clinical Disease Rating Scale (sum of boxes; CDR-sb) [17]; (5) Mini-Mental State Examination (MMSE) [18]; (6) a neuropsychological test battery, as outlined in the National Alzheimer’s Coordinating Center [19] protocol, as well as additional tests, which included the Three Trial Fuld Object Memory Evaluation [20] and the Hopkins Verbal Learning Test (delayed recall) [21]; (7) Unified Parkinson Disease Rating Scale (motor section) [22].

Diagnostic Procedures

Physician’s Cognitive Diagnosis

The physician assigned a cognitive diagnosis of no cognitive impairment, MCI or dementia, as described previously [23]. Briefly, the physician’s cognitive diagnosis was based on the subject’s entire clinical history and functional status, which was derived from the history itself, CDR rating, functional activity questionnaire, and MMSE score and subscores – taking into account the subject’s educational and cultural background, sensory (especially visual and hearing) and motor deficits, language and speech disorders, medical and psychiatric conditions, and the perceived reliability of the informant. The presence of subtle cognitive and personality deficits – such as repetitiveness, impaired logical reasoning, difficulty understanding or following implicit and even explicit instructions, executive dysfunction, perseverative behaviors and mental rigidity – were also taken into consideration [24].

Neuropsychological Diagnosis

All neuropsychological tests were administered in the subjects’ native language (English or Spanish), and compared to age- and education-adjusted normative data, as described previously [25,26]. Memory measures were: the 3-trial Fuld Object Memory Evaluation [20], Delayed Visual Reproduction of the Wechsler Memory Scale-R [27] and the Hopkins Verbal Learning Test (delayed recall) [21]. Non-memory tests included: category fluency [28], letter fluency (language) [29], block design WAIS-III (visuospatial) [30], trails B (executive) [29] and similarities WAIS-R (executive) [31]. Neuropsychological classifications [25,26] were made as follows: (1) a test score of ≥1.5 SD below expected normative values on any single test for MCI syndromes; (2) ≥2.0 SD below expected normative values in 1 memory and 1 non-memory test for dementia (corresponding to NINCDS-ADRDA criteria) [32]. Nomenclature used for neuropsychological diagnosis was: normal, non-amnestic MCI (naMCI; single or multi-domain), amnestic MCI (aMCI; single or multi-domain) and dementia.

Consensus Cognitive Diagnoses

To ensure that the consensus diagnosis was made systematically across sites and longitudinally in the same individual, an algorithmic approach to combining the physician’s cognitive diagnosis with the neuropsychological diagnosis was used, as described previously [23]. Patients diagnosed with aMCI met all of the formal criteria of Petersen et al. [33] for MCI.

MRI scans were acquired on a 1.5-T machine (Siemen’s Symphony, Iselin, N.J., USA, or General Electric, HDX, Milwaukee, Wisc., USA) using a proprietary 3D-magnetization-prepared rapid-acquisition gradient echo or 3D spoiled gradient echo sequences. MRI scans were acquired in the coronal plane, and contiguous slices with thickness of ≤1.5 mm were reconstructed.

Visual Rating System for Assessing Medial Temporal Atrophy

Using this validated computer-assisted VRS, coronal images on a single coronal MRI slice (at the level of the mamillary bodies) were semiquantitatively assessed so as to grade atrophy of the HP and ERC according to the following scale: 0 = no atrophy; 1 = minimal atrophy; 2 = mild atrophy; 3 = moderate atrophy; 4 = severe atrophy (fig. 1). The VRS-MTA program provides a library of drop-down images, depicting images showing each grade of atrophy for the ERC, HP and perirhinal cortex, as well as the anatomical boundaries of these structures. We have previously reported that excellent inter-rater reliability for individual medial temporal lobe structures has been obtained with ĸ-values among 2 raters ranging between 0.75 and 0.94 for inter-rater reliability 0.87 and 0.93 for intra-rater reliability [34]. Furthermore inter-rater reliabilities for scores 0, 1 or 2 were performed on a new data set of patients by two of the authors on this paper (D.V. and E.P.). The inter-rater reliabilities obtained were: left HP 0.705 (SE = 0.16), right HP 0.835 (SE = 0.11), left ERC 0.744 (SE = 0.13) and right ERC 0.794 (SE = 0.14).

Fig. 1

VRS-MTA. Images depicting 4 degrees of atrophy in HP and ERC. 0 = No atrophy; 1 = minimal atrophy; 2 = mild atrophy; 3 = moderate atrophy; 4 = severe atrophy.

Fig. 1

VRS-MTA. Images depicting 4 degrees of atrophy in HP and ERC. 0 = No atrophy; 1 = minimal atrophy; 2 = mild atrophy; 3 = moderate atrophy; 4 = severe atrophy.

Close modal

Specifically for this study, we included only those subjects who had no atrophy of the HP (HP₀) or ERC (ERC₀) on both right and left sides or minimal atrophy of the HP (HPma) or the ERC (ERCma), on either the left, right or both sides – thus providing subjects with 4 possible combinations of HP and ERC atrophy: (1) ERC₀/HP₀; (2) ERCma/HP₀; (3) ERC₀/HPma; (4) ERCma/HPma.

Volumetric Measures

Volumetric analysis of brain MRIs utilized the modified International Brain Atlases using Statistical Parametric Mapping (IBASPM) [35].

ApoE Genotype

ApoE genotype was determined using standard methods [34], and ApoE-ε4 frequencies were subsequently calculated for each diagnostic group. ApoE genotypes were available for 296 subjects.

Longitudinal Evaluation Procedures

A total of 305 subjects had a 1-year follow-up evaluation, including neurological, psychiatric and neuropsychological evaluations, all clinical scales and re-diagnosis by the diagnostic algorithm.

Statistical Analysis

Group comparisons of demographic variables across the 4 atrophy groups were analyzed using ANOVA or χ2 tests, as appropriate. Comparisons of clinical variables (e.g. MMSE score) across 4 four atrophy groups were analyzed using a general linear model from SAS for Windows version 9.1 (SAS Institute, Inc, Cary, N.C., USA), with age as a covariate, or with a χ2 test. The Scheffe post hoc procedure was used to examine differences between means of demographic variables. The GT2 post-hoc option in the general linear model of SAS, which is more conservative than the Tukey-Kramer option, was used to examine differences between age-adjusted means of clinical variables. Differences in progression rates between groups were assessed using χ2 procedures.

Demographics and ApoE

The subjects differed with respect to age [F(3, 410) = 14.7; p < 0.0001]. Post hoc tests indicated that the ERC₀/HPma group was older than the ERC₀/HP₀ group by nearly 3 years, and the ERCma/HPma group was significantly older than the other 3 groups by as much as 6 years. There were no significant differences among the groups in terms of years of education, race or ApoE-ε4 allele frequency (table 1). Among subjects diagnosed with no cognitive impairment, the largest percentage belonged to the ERC₀/HP₀ group, and the lowest percentage belonged to the ERCma/HPma group (χ2 = 26.5; p = <0.03). Among subjects diagnosed with naMCI, aMCI or dementia, the largest percentage belonged to the ERCma/HPma group, whereas the lowest percentage belonged to the ERC₀/HP₀ group of subjects (χ2 = 26.5; p = <0.003) (table 1).

Table 1

Demographics, diagnosis and ApoE allele

Demographics, diagnosis and ApoE allele
Demographics, diagnosis and ApoE allele

Clinical Data and Volumetric Hippocampal Measures

Analyses of ordinal measures were adjusted for age, since there were significant age differences between atrophy groups. Subjects in the ERC₀/HP₀ group had the highest scores on the cognitive tests – MMSE, Logical Memory (delayed recall), Fuld Object Memory Evaluation and the Hopkins Verbal Learning Test (delayed recall) – and the lowest (least impaired) scores on the functional tests – CDR-sb. Those in the ERCma/HPma group had the lowest scores on the cognitive tests and the highest scores on the CDR-sb group, with the ERC₀/HPma and ERCma/HP₀ groups being intermediate on all test scores (table 2). The percentage of subjects with global CDR scores of ≥0.5 was lowest among ERC₀/HP₀ (38%) and greatest among the ERCma/HPma group (80%), with the other 2 groups being intermediate [χ2(3) = 32.4, p < 0.0001].

Table 2

Cognitive/functional scores and HP volumes among subjects with and without ERCma or HPma

Cognitive/functional scores and HP volumes among subjects with and without ERCma or HPma
Cognitive/functional scores and HP volumes among subjects with and without ERCma or HPma

The right HP volume was higher for the ERC₀/HP₀ than for the ERC₀/HPma, ERCma/HP₀ and ERCma/HPma groups, while the left HP volume was significantly higher in the ERC₀/HP₀ group than for the ERCma/HP₀ and the ERCma/HPma groups, but not higher than for the ERC₀/HPma group. There were no differences between the ERCma/HP₀, ERC₀/HPma and ERCma/HPma groups with regards to HP volumes on either side (table 2).

Clinical Diagnoses (table 3)

Subjects with ERCma (isolated or co-occurring with HPma) were more likely to be cognitively impaired (naMCI, aMCI and dementia) (56 vs. 27%), and were more likely to have global CDR scores of ≥0.5 (69%) than subjects with no ERC atrophy, with or without minimal HP atrophy (45%) (fig. 2). The frequency of progression from a global CDR score of 0 to 0.5 was significantly greater among those with ERCma/HP₀ or ERCma/HPma as compared to those who with ERC₀/HP₀ or ERC₀/HPma (27 vs. 11%). There was no difference in the distribution of atrophy among those who progressed from a CDR of 0.5 to 1.

Table 3

Clinical diagnosis, CDR global score and progression (or improvement) in subjects with and without ERCma

Clinical diagnosis, CDR global score and progression (or improvement) in subjects with and without ERCma
Clinical diagnosis, CDR global score and progression (or improvement) in subjects with and without ERCma
Fig. 2

Frequency of cognitive impairment, defined by clinical diagnosis and CDR scores, for minimal ERC versus HPC atrophy. * p < 0.05, ERC = 1 vs. ERC = 0 for both definitions of cognitive impairment (χ2 test).

Fig. 2

Frequency of cognitive impairment, defined by clinical diagnosis and CDR scores, for minimal ERC versus HPC atrophy. * p < 0.05, ERC = 1 vs. ERC = 0 for both definitions of cognitive impairment (χ2 test).

Close modal

This study demonstrates that among mildly impaired subjects (mean MMSE score = 27.8), isolated minimal atrophy of the HP was associated with deficits in 1 of 3 episodic memory tests (i.e. the Hopkins Verbal Learning Test delayed recall), while isolated minimal atrophy of the ERC was associated with more widespread cognitive deficits on memory tests and the MMSE. The combination of HPma and ERCma was associated with even more accentuated cognitive deficits, along with functional deficits (i.e. elevated scores on the CDR-sb). The presence of minimal atrophy of the ERC was also more likely to be associated with a cognitively impaired diagnosis than if there was no atrophy of the ERC. Regardless of the presence of HPma, subjects with ERCma more frequently than not (56 vs. 27%) were diagnosed with naMCI, aMCI or dementia or a CDR score of 0.5 or 1 (69 vs. 45%) (table 3), suggesting that minimal atrophy of the ERC is a clinically significant finding.

In this study, ApoE-ε4 carriers were no more likely to have minimal atrophy of the ERC or HP than non-carriers. ApoE-ε4 frequencies were not different across patient groups categorized by the presence or absence of minimal atrophy in the HP, ERC or HP+ERC. This lack of influence of the ApoE-ε4 genotype on the likelihood of having ERC or HP atrophy is consistent with the already known mechanism of action of the ApoE-ε4 genotype, which mediates its risk for AD solely via increasing amyloid deposition, but not by enhancing risk of neurodegeneration and resulting selective atrophy of medial temporal structures [5]. As shown by data obtained from the Alzheimer’s Disease Neuroimaging Initiative patients [1], atrophy of the hippocampus (and presumably of the ERC) becomes detectable only after a substantial delay following detectable deposition of Aβ protein in the brain, suggesting that degenerative changes – presumably mediated by amyloid deposition and measured by HP and ERC atrophy – will be relatively insensitive to the rate or amount of amyloid deposition in the brain mediated by the ApoE genotype.

The rate of progression from a CDR score of 0 to 0.5 was significantly greater among those with minimal ERC atrophy, as compared to those without ERC atrophy. There was also a trend towards improvement (p = 0.07) in CDR scores from 0.5 to 0 among those without ERC atrophy compared to those with minimal ERC atrophy. These findings point to the importance of even minimal atrophy of the ERC as a marker of neurodegenerative disease in very early stages.

While minimal atrophy of the HP is also indicative of neurodegenerative disease – as suggested by the cognitive impairment associated with isolated minimal HP atrophy – it appears clear from the results of this study that minimal atrophy of the ERC has a greater impact than minimal atrophy of the HP on cognition, as well as on functional abilities, as reflected in elevated CDR-sb scores. An apparent ‘dose effect’ is also suggested in tables 2 and 3, such that the combination of minimal atrophy of the ERC with minimal atrophy of the HP has greater cognitive and functional consequences than isolated minimal ERC atrophy.

In each group in which minimal atrophy of either the HP, ERC or HP+ERC was present (as measured by the VRS), HP volumes were also reduced (table 2). Even though the reduction in HP volumes appeared to be severest among those with combined ERC and HP minimal atrophy, there was no significant difference found in HP volumes between the 3 groups with minimal atrophy measured by VRS. Reduction of HP volumes appears to be a relatively non-specific event that occurs in response to various degenerative and non- degenerative insults to the brain. Mild degrees of HP atrophy have been associated with neocortical amyloid deposition [37]. Conditions, such as Lewy body disease, depression, stress-related disorders, steroid treatment, seizures, multiple sclerosis, stroke and brain trauma have all been associated with mild HP atrophy [38]. Many of these conditions are often not associated with cognitive or functional deficits, which by itself results in very subtle, if any, cognitive deficits. Atrophy of the ERC may be more specific to early degenerative diseases, such as AD and frontotemporal lobar dementias.

The anterior aspects of the ERC and the HP, especially the subiculum and CA1 sector of the HP – which is the focus of atrophy measurement by VRS-MTA at the coronal slice intersecting the mamillary bodies – may be especially vulnerable to the pathological changes in early AD [6,39]. A close correlation between whole HP volume measures and VRS-MTA measures of minimal atrophy of HP on a single slice intersecting the anterior aspect of the HP was not expected. Reduction in HP volumes (5.8–7.7%) was found among those with HPma, but there was no significant further reduction in HP volume among those with isolated ERCma or the combination of ERCma and HPma (10.6–13.3%). Even though subjects with ERCma/HPma clearly had more cognitive and functional impairment than subjects with isolated HPma, or isolated ERCma, HP volumes did not distinguish between these subject groups.

Quantitative assessment of the volume of the ERC can be achieved by a technique involving manual outlining of the boundaries of the ERC in contiguous MRI slices. This method – which is labor-intensive and requires rigorous attention to detail to ensure reliability – has shown that among patients with MCI and early AD, ERC volume is reduced well before HP volume [40], and may be superior to HP volume reduction in predicting conversion from MCI to AD [14,41,42,43]. These findings suggest that in a typical clinical setting, visual rating of ERC atrophy – in addition to rating of HP atrophy – can be a practical and reliable biomarker of early AD pathology [32] for confirming the diagnosis of early predementia stages of AD.

A limitation of this study is that we measured atrophy of the ERC and HP on a single coronal slice, which may not always be representative of the anatomy and severity of atrophy of the entire medial temporal lobe. The advantage gained by using a single standard slice is that it considerably increases inter-rater and intra-rater reliability of measurement. However, VRS-MTA measurements can be limited by the ability of the raters, the quality of the images and the slice thickness (slice thickness of <2 mm is required to avoid partial volume artifacts from neighboring structures).

Currently used criteria for the diagnosis of AD have been found to have high sensitivity (range 0.81–0.98), but relatively low specificity (range 0.41–0.84), when assessed against a histopathological diagnosis of AD [44]. The results of this study demonstrate that the presence of a degenerative disease, such as AD, is implied by even minimal atrophy of the ERC, because it is associated with progressive cognitive and functional impairment. This suggests that the accuracy of a diagnosis of early AD (in the MCI or pre-MCI stage) could be improved by using even minimal atrophy of the ERC and HP as biomarkers to support the diagnosis. These findings may be of particular importance among subjects with MCI, very mild dementia, or those with confounding factors such as ongoing psychiatric illness, low education and cultural deprivation. Structural MRI is ordered routinely for the assessment of patients with cognitive impairment and dementia so as to exclude the presence of structural abnormalities, such as stroke, brain tumors and hydrocephalus as causative factors. The results of this study suggest that the use of visual rating of the ERC on appropriately ordered sequences and slice thicknesses of structural MRI scans could be a highly cost effective method of confirming the diagnosis of early forms of AD, thereby often avoiding the expense of additional methods.

Research was supported by the National Institute of Aging (NIH 5R01AG020094-03 and NIH 1P50AG025711-03) and Byrd Alzheimer Center and Research Institute grants.

The authors report no conflicts of interest.

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Statistical analysis was performed by W.B. and D.A.L.

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