DOI:10.2214/AJR.06.1052
AJR 2007; 188:1404-1410
© American Roentgen Ray Society
Hippocampal Volume and the Mini-Mental State Examination in the Diagnosis of Amnestic Mild Cognitive Impairment
Melissa J. Slavin1,
Claire K. Sandstrom2,
Thanh-Thu T. Tran3,
P. Murali Doraiswamy4 and
Jeffrey R. Petrella3
1 School of Psychiatry, University of New South Wales, Sydney, New South Wales,
Australia.
2 School of Medicine, Duke University, Durham, NC.
3 Department of Radiology, Duke University Medical Center, 1527 Hospital Rd.,
Box 3808, Durham, NC, 27710.
4 Department of Psychiatry, Duke University Medical Center, Durham, NC.
Received August 8, 2006;
accepted after revision December 6, 2006.
Address correspondence to J. R. Petrella.
Supported by National Institute on Aging grant R01AG019728.
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Abstract
OBJECTIVE. The purpose of this study was to examine the diagnostic
efficacy of hippocampal volumetry and the Mini-Mental State Examination (MMSE)
in differentiating amnestic mild cognitive impairment from the normal changes
of aging.
SUBJECTS AND METHODS. The conditions of healthy older persons
(n = 17) and persons with amnestic mild cognitive impairment
(n = 18) were classified on the basis of results of comprehensive
neuropsychological assessment. All subjects underwent MRI at 4 T, including
high-resolution coronal T1-weighted images. Hippocampal volume was calculated
by tracing right and left hippocampal formations on coronal slices and
normalizing by single-slice intracranial area. Receiver operating
characteristic analysis and logistic regression analysis were performed to
evaluate the diagnostic efficacy of hippocampal volume and the MMSE in
differentiating subjects with amnestic mild cognitive impairment from subjects
with normal cognitive function.
RESULTS. The mean ± SE area under the receiver operating
characteristics curve (AUC) for left hippocampal volume (0.886 ± 0.056)
was greater than that for right hippocampal volume (0.614 ± 0.097). The
AUC for MMSE score (0.745 ± 0.085) was intermediate and not
statistically different from that of hippocampal volume measurements alone.
The AUC for the combination of left hippocampal volume and MMSE score (0.92)
was significantly greater than that of MMSE score alone (p <
0.05).
CONCLUSION. In the diagnosis of amnestic mild cognitive impairment,
use of left hippocampal volume may be more efficacious than use of right
hippocampal volume and may add to the value of routine screening MMSE.
Automated hippocampal volumetry may become a useful diagnostic adjunct in
settings in which sophisticated neuropsychological testing is not readily
available.
Keywords: Alzheimer's disease • brain • high-resolution • hippocampal volume • Mini-Mental State Examination • MRI • neuroimaging
Introduction
Amnestic mild cognitive impairment is a condition that represents
increased risk of development of Alzheimer's disease. Many experts
[1] consider it a prodromal
stage of Alzheimer's disease. The early pathologic changes of Alzheimer's
disease, especially in the medial temporal lobe (MTL), may begin years before
clinical symptoms, and this region retains the greatest density of
neurofibrillary tangles as the disease progresses
[2]. The role of the MTL,
particularly the hippocampus, in episodic memory
[3] has led a number of
researchers to target MTL structures in the search for in vivo imaging markers
of amnestic mild cognitive impairment. Numerous studies
[4] have shown greater atrophy
of the hippocampus in amnestic mild cognitive impairment and Alzheimer's
disease, and lower baseline hippocampal volumes are known to be predictive of
decline to Alzheimer's disease. Hippocampal asymmetry has been reported to be
present in older adults with subjective memory symptoms
[5], mild cognitive impairment
[6], and Alzheimer's disease
[7]. This finding suggests that
age and degenerative processes do not necessarily affect the brain equally
across hemispheres.
In primary care, screening for memory deficits and dementia relies largely
on results of brief cognitive tests, such as the Mini-Mental State Examination
(MMSE). The MMSE [8] is used to
test the major domains of cognitive function, including language, visuospatial
ability, and memory. Out of a maximum score of 30, persons with multimodal
functional deficits, such as those of Alzheimer's disease, typically score
less than 24 [9]. However,
among persons in the preclinical stages of Alzheimer's disease, such as those
with amnestic mild cognitive impairment, MMSE scores are less sensitive,
tending to fall within the normal range (3 24)
[10]. As a nonspecific
screening instrument, the MMSE is perhaps more appropriate for directing
clinicians toward more comprehensive diagnostic tests. Such tests, although
currently necessary to assess for amnestic mild cognitive impairment and
probable Alzheimer's disease, often are not performed in routine practice. The
purpose of this study was to assess the diagnostic efficacy of hippocampal
volumetry alone in combination with the MMSE in differentiating amnestic mild
cognitive impairment from the normal changes of aging.
Subjects and Methods
The study received approval from the Duke University Medical Center
institutional review board and was conducted in compliance with the Health
Insurance Portability and Accountability Act. All subjects provided written
informed consent before testing and neuropsychological evaluation.
Subject Selection
Subjects were recruited as part of a large functional MRI study. They
responded to advertisements asking for persons 55-85 years old with memory
problems. Our study group consisted of the first 37 subjects (20 persons with
amnestic mild cognitive impairment and 17 control subjects) who underwent
imaging. One subject with amnestic mild cognitive impairment was excluded
because of imaging acquisition error, and a second was excluded because of
marked base-of-skull artifact. The other 35 subjects were 18 persons with
amnestic mild cognitive impairment and 17 controls.
Subjects were limited to those between the ages of 55 and 85 years and
those free of contraindications to MRI, including claustrophobia and presence
of metallic objects, such as cardiac pacemakers, aneurysm clips, and foreign
bodies in the eyes. The 18 subjects with amnestic mild cognitive impairment
(mean age, 74.4 ± 7.7 years; age range, 55.5-83.0 years) tended to be
slightly older than the 17 controls (mean age, 70.2 ± 3.6 years; age
range, 63.3-78.0 years), but the difference was not statistically significant
(p > 0.05).
Evaluation and Classification
All subjects underwent baseline psychometric evaluation, which included the
MMSE; logical memory and visual reproduction from the Wechsler Memory Scale,
third edition [11]; the
California Verbal Learning Test, second edition
[12]; and the Beck Depression
Inventory [13].
Subjects were classified as having amnestic mild cognitive impairment if
they did not meet the criteria for dementia defined by National Institute of
Neurological and Communicative Diseases and the Stroke/Alzheimer's Disease and
Related Disorders Association
[14] or by the Diagnostic
and Statistical Manual of Mental Disorders, fourth edition
[15]; if they had impairment
(
1 SD below age-adjusted norms) in delayed verbal or visual recall; if
they had an MMSE score of 24 or higher; if they had normal independent
functioning as defined by a clinical dementia rating of 0.5 (questionable
dementia) [16]; and if they
did not have other factors that might better explain memory loss (e.g.,
current major depression). It was required that the study clinicians reach
consensus on each subject's diagnosis. Subjects were classified as controls if
they had an MMSE score of 28 higher, did not meet the aforementioned criteria
for dementia, had normal or near normal independent function, and had a
clinical dementia rating global score of zero and normal memory.
MR Image Acquisition
Imaging was performed with a 4-T MRI system (Signa LX 8.0 NVi, GE
Healthcare) equipped with 41-mT/m gradients, a birdcage radiofrequency
transmitter, and a receiver head coil. Axial T2-weighted spin-echo images
(TR/TE 3,000/80; matrix size, 256 x 256; slice thickness, 3.75 mm;
interslice gap, 0.0 mm; field of view, 240 mm) were obtained for anatomic
screening purposes and were reviewed by a neuroradiologist for significant
intracranial abnormalities. For directed hippocampal volumetric analysis, 128
contiguous T1-weighted images (3D inversion recovery prepare fast spoiled
gradient-recalled acquisition in the steady state; 12.2/5.4; inversion time,
300 milliseconds; flip angle, 20°; field of view, 240 mm; matrix size, 256
x 256; slice thickness, 1.5 mm) through the entire brain were obtained
in the oblique coronal plane perpendicular to the long axis of the
hippocampus.
Hippocampal Tracing
Mouse-driven software (ITK-SnAP 1.0, Cognitica Corporation) was used to
make manual hippocampal tracings on the contiguous oblique coronal T1-weighted
images. This program is included in the open National Library of Medicine
Insight Segmentation and Registration Toolkit. It was designed as a
user-friendly interface for displaying medical images in three planes
simultaneously, for segmenting level threshold anatomic structures, and for
manual editing of the segmentations. Hippocampal tracings were performed by
one investigator, who was blinded to clinical classification.
Each hippocampus was traced independently with reference to previous
hippocampal MR volumetric studies
[4,
17] and the hippocampal atlas
by Duvernoy [18]. The
hippocampus was first identified at the most posterior portion where the
hippocampal tail became visible under the fornix and proceeded on contiguous
slices to the most anterior slice on which the hippocampus could be delineated
from the amygdala. The selected area was reviewed for consistency on the axial
and sagittal representations. The traced region encompassed the subiculum,
regions CA1-4, and the internal and external digitations. The fimbria lining
the dorsal aspect of the hippocampus and the vertical digitations and
semilunar gyrus extending superiorly toward the amygdala were omitted. Each
hippocampus spanned approximately 20-25 slices in each subject (Fig.
1A,
1B,
1C,
1D,
1E,
1F,
1G,
1H,
1I,
1J,
1K,
1L).
After manual tracing was completed, the number of voxels included was
calculated. For simplicity, we did not convert voxel counts to volume (1 voxel
= 1.318 mm3), and volume was reported as voxel count. Intrarater
reliability in six cases (three subjects with amnestic mild cognitive
impairment and three controls) was calculated for the single experimenter. The
kappa values were 0.91 and 0.88 for the right and left raw hippocampal voxel
counts. For calculation of interrater reliability, images of another six
randomly selected subjects (three with amnestic mild cognitive impairment and
three controls) were traced by a second observer. The kappa values were 0.90
and 0.85 for the right and left raw hippocampal voxel counts.
Volume Normalization
Normalization of right and left hippocampal voxel counts was accomplished
by division of raw counts by intracranial area, also measured in voxels. This
value was calculated for each subject from a manually traced single-slice
intracranial area as measured on the oblique coronal T1-weighted image at the
level of the anterior commissure. This method has been described by Laakso et
al. [19] as an appropriate
index for intracranial volume correction. Intrarater reliability for this
measurement of intracranial area voxel count was greater than 0.99. Interrater
reliability for intracranial area voxel count was considerably lower at 0.79,
possibly because the template used was a single slice, making it more
challenging to reproduce across different brains. Dividing the right and left
hippocampal voxel counts by intracranial area resulted in the normalized
values.
Age Correction
Hippocampal volume and cognitive test scores decrease with age regardless
of associated cognitive decline
[20]. Results of linear
regression indicated that left and right hippocampal volumes varied
significantly with age (p < 0.05). Age correction, therefore, was
conducted for the right and left normalized hippocampal voxel counts and for
the raw MMSE scores according to the following equation:
where valuen is the right or left normalized hippocampal voxel
count or raw MMSE score; agesubj is the age of the subject;
agemean is the mean age of all subjects in the study; and
Bage is the slope calculated by linear regression for each volume
or test score with age as the independent variable. The result was three
measures corrected for age for each subject: right hippocampal volume, left
hippocampal volume, and MMSE score.
Data Analysis
Repeated-measures analysis of covariance was calculated with side (right
and left normalized hippocampal voxel counts) as the within-subject factor and
group (amnestic mild cognitive impairment or control) as the between-subject
factor. Age was the covariate. A post hoc paired-samples Student's t
test of right and left normalized hippocampal voxel counts was performed
separately for subjects with amnestic mild cognitive impairment and control
subjects.
Receiver operating characteristic (ROC) curves were generated for
comparison of age-adjusted normalized hippocampal volumes with MMSE score.
Area under the ROC curve (AUC) and SE were calculated for each ROC curve. ROC
curves depict the sensitivity (ability to indicate presence of disease when
disease is truly present) and 1 - specificity (ability to exclude disease when
truly absent) of a test at each possible cutoff point
[21]. AUC reflects overall
test accuracy, but unlike measures of accuracy (sum of true-positive results
and true-negative results divided by study population), which depend on
disease prevalence, AUC is independent of prevalence.
Binary logistic regression analysis was performed to investigate the
independence of contributions of left hippocampal volume and MMSE score to the
diagnosis of amnestic mild cognitive impairment. The regression equation was
reconstructed and applied to determine the probability that a given subject
would have amnestic mild cognitive impairment on the basis of that subject's
MMSE and left hippocampal volume with optimal weighting of the two test
results. The ROC curve (left hippocampal volume plus MMSE score) was based on
these predicted probabilities.
The AUC for MMSE score was compared with those of right hippocampal volume,
left hippocampal volume, and left hippocampal volume plus MMSE score. The
method described by Hanley and McNeil
[22] was used to examine the
significance of differences in AUC. This calculation was performed for each of
the following comparisons: right hippocampal volume versus MMSE score, left
hippocampal volume versus MMSE score, combination of left hippocampal volume
and MMSE versus MMSE score.
Results
Subject Demographics
The amnestic mild cognitive impairment and control groups did not differ in
sex, age, or education (Table
1). As expected, the score on the delayed-recall measure of the
California Verbal Learning Test among subjects with amnestic mild cognitive
impairment (5.2 ± 2.4) differed significantly from that of controls
(10.8 ± 2.5) (p < 0.001). Group differences in MMSE score
(amnestic mild cognitive impairment group, 26.8 ± 1.3; controls, 28.2
± 1.3) also reached significance (p <0.05).
Hippocampal Volume
Analysis of covariance showed a significant interaction between brain side
and group. Results of post hoc Student's t tests revealed that mean
left hippocampal volume was significantly smaller in the subjects with
amnestic mild cognitive impairment than in controls (p < 0.01)
(Table 2). In subjects with
amnestic mild cognitive impairment, the left hippocampus (mean, 0.131) was
significantly more atrophied than the right (mean, 0.142) (p <
0.01). By contrast, controls had comparable right (mean, 0.151) and left
(mean, 0.154) volumes (p > 0.05).
View larger version (10K):
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Fig. 2 —Graph shows receiver operating characteristic (ROC) curves of
predicted probability of amnestic mild cognitive impairment based on
hippocampal volumes compared with Mini-Mental State Examination (MMSE) score.
Solid line indicates area under ROC curve (AUC) of 0.886 for left hippocampal
volume; dashed line, AUC of 0.745 for MMSE; dotted line, AUC of 0.614 for
right hippocampal volume.
|
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View larger version (9K):
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Fig. 3 —Graph shows receiver operating characteristic (ROC) curve of
predicted probability of amnestic mild cognitive impairment calculated from
combined left hippocampal volume and Mini-Mental State Examination (MMSE)
score compared with predicted probability based on MMSE score alone. Solid
line indicates area under ROC curve (AUC) of 0.918 for combination of left
hippocampal volume and MMSE; dotted line, AUC of 0.745 for MMSE.
|
|
ROC Curves
Hippocampal volume versus MMSE score—ROC curves for
comparison of sensitivity and 1 - specificity of hippocampal measurements and
psychometric scores are shown in Figures
2 and
3. Corresponding AUC data are
shown in Table 3. Of the
hippocampal measurements, left hippocampal volume (AUC, 0.886) was the most
accurate for classification of amnestic mild cognitive impairment. This value,
however, was not statistically more accurate than MMSE score (AUC, 0.745)
(p = 0.147). Right hippocampal volume (AUC, 0.614) was a poor
indicator of clinical classification, lower even than MMSE score, although the
difference was not statistically significant
(Fig. 2).
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TABLE 3: Area Under the Receiver Operating Characteristic Curve (AUC) Values for
Age-Adjusted and Normalized Hippocampal Volume and Age-Adjusted Mini-Mental
State Examination (MMSE) Score
|
|
Combinination of left hippocampal volume with MMSE score—The
ROC curve generated from the combination of left hippocampal volume and MMSE
score in logistic regression (AUC, 0.918)
(Fig. 3) showed a
statistically significant difference in AUC from the ROC curve of MMSE alone
(p < 0.05). The optimal value for differentiating subjects with
amnestic mild cognitive impairment from controls was 0.53.
Classification
The logistic regression equation was used to calculate probability of
classification for each subject. The threshold for a group was set at 0.50.
Subjects with a calculated probability of 0.50 or greater were classified as
controls and those with a calculated probability less than 0.50 as having
amnestic mild cognitive impairment. Use of the MMSE led to correct
classification of 11 of 18 subjects with amnestic mild cognitive impairment
and 11 of 17 controls (sensitivity, 0.61; specificity, 0.65)
(Table 4). After the addition
of left hippocampal volume to MMSE score in the logistic regression equation,
classification improved to 15 of 18 subjects with amnestic mild cognitive
impairment and 14 of 17 controls (sensitivity, 0.83; specificity, 0.82)
(Table 4).
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TABLE 4: Predicted Classification of Amnestic Mild Cognitive Impairment Based on
Logistic Regression with Mini-Mental State Examination (MMSE) Alone and MMSE
Combined with Left Hippocampal Volume
|
|
Discussion
We tested the diagnostic utility of hippocampal volumetry in the assessment
of amnestic mild cognitive impairment. In accordance with results of previous
studies
[4-7,
17], our finding was that
subjects with amnestic mild cognitive impairment had more hippocampal atrophy
than healthy subjects and that hippocampal volume decreased significantly with
increasing age. We also found that left hippocampal volume had more
discriminatory value than right hippocampal volume. The addition of left
hippocampal volume increased both the sensitivity and specificity of the MMSE
to more than 0.80, a level that would be clinically acceptable if replicated
in a broader sample.
Although measures of left hippocampal atrophy in this study helped
differentiate subjects with amnestic mild cognitive impairment from healthy
older adults, group distributions of left hippocampal volume nevertheless
overlap. As a result, six subjects would still be misclassified after MMSE
score and left hippocampal volume were combined. There may be several
explanations for these normal variations, including the presence of silent
preclinical disease and measurement error. This finding suggests the continued
need for additional measures such as neuropsychological testing and other
imaging markers. The MMSE is a simple screening tool and is not intended for
use as a diagnostic test, although it often is used as such in primary care.
This practice reinforces the need to find simple markers that can supplement
the MMSE in the detection of disease in its early stages.
We found more left than right hippocampal atrophy in subjects with amnestic
mild cognitive impairment. Hippocampal asymmetry has been reported frequently,
not only among persons with pathologic conditions but also in the healthy
population [7,
23] and among older adults
with subjective memory symptoms
[5]. Studies have shown a
change in persons with asymmetry in amnestic mild cognitive impairment and
Alzheimer's disease. This change suggests a preferentially unilateral change
responsible for cognitive impairment. The laterality of this asymmetry,
however, has varied between greater atrophy on the right side
[7] and greater atrophy on the
left side [6]. Our subjects
with amnestic mild cognitive impairment were identified largely because of
verbal delayed recall deficits, which in previous studies
[24] have been found to
correlate with left hippocampal volume. Petersen et al.
[25] reported that the volume
of the left hippocampus in persons with Alzheimer's disease was predictive of
performance on a verbal learning task. Right hippocampal volume, however, was
more closely associated with performance on a nonverbal task of visual
representation.
There were limitations to this study, such as small sample size,
cross-sectional design, lower interrater reliability regarding intracranial
area, and lack of disease controls (e.g., depression, other forms of
dementia). Furthermore, although 4-T magnets may not be common in clinical
practice, we used an ultra-high-field imaging unit to acquire high-resolution
images so that we could examine which measure was most sensitive to disease
state in a group without having to acquire onerously large numbers of
subjects. Our findings can now be confirmed with lower-resolution images.
Although hippocampal volumetric studies have been conducted with variable
sample sizes, in few studies has the relation between hippocampal volume and
MMSE score been examined from a practical diagnostic point of view. Our
findings must be interpreted in this context.
Manual tracing of the hippocampi is labor intensive and operator dependent.
Thus an automated protocol for hippocampal volumetry would be more practical
in a clinical setting. Warping and segmentation algorithms for automated
volumetry of the hippocampus have been evaluated in subjects with Alzheimer's
disease and amnestic mild cognitive impairment
[26]. Such algorithms,
however, usually require manual input, thus observer bias is not completely
removed. Moreover, the accuracy of automated methods may suffer when a
substantial amount of image noise or poor contrast enhancement is present.
The findings of our study suggest that the combination of left hippocampal
volume and MMSE score may have reasonably high diagnostic accuracy for
separating amnestic mild cognitive impairment from the normal changes of
aging. Larger studies with automated volumetry in representative samples are
needed to replicate the findings. Future studies also should examine the value
of adding hippocampal volumetry to more sensitive neuropsychological
measures.
Acknowledgments
We thank the subjects who participated in this study.
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Abstract
Introduction
