Medial temporal atrophy and memory impairment in early stage of Alzheimer’s disease: an MRI volumetric and memory assessment study

Journal of the Neurological Sciences 173 (2000) 18–24 www.elsevier.com / locate / jns

Medial temporal atrophy and memory impairment in early stage of Alzheimer’s disease: an MRI volumetric and memory assessment study Keiko Mizuno, Masakazu Wakai, Akinori Takeda, Gen Sobue* Department of Neurology, Nagoya University School of Medicine, 65 Tsurumai-Cho Showa-ku, Nagoya 466 -8550, Japan Received 15 March 1999; received in revised form 4 October 1999; accepted 21 October 1999

Abstract Memory impairment and medial temporal lobe (MTL) involvement are the earliest and most prominent features of Alzheimer’s disease (AD). A psychological assessment of memory function and an evaluation of the morphological changes in MTL structures, as found in the mild form of AD, are important for early diagnosis as well as for understanding the pathophysiology of the disease. In the present study, we aimed to evaluate correlations in these psychoanatomical changes in terms of the stage of AD. We performed MRI-based volumetric measurements of the MTL structure and neuropsychological tests, using MMSE and the Wechsler memory scale-revised (WMS-R), on 27 elderly normal subjects and 46 probable AD patients, and then checked for possible correlations between the volumetric measurements and memory dysfunction. The severity of the AD patients’ condition was assessed by CDR scale. Each MTL structure decreased in volume with increasing severity of AD. In very early AD, the reduction in the amygdala volume was pronounced, while the hippocampal volumes were relatively unchanged. Neuropsychological scores also declined with increasing severity of AD. Scores on the main WMS-R subsets examined (verbal memory, visual memory, and delayed recall) decreased significantly in the very mild group, as compared with normal controls. The WMS-R test scores correlated significantly with the amygdala volumes in normal control subjects and very mild AD patients. Our findings suggest that MRI-based amygdaloid volumetric measurement provides a sensitive marker, and that the degeneration of the amygdala may begin very early in the course of AD.  2000 Elsevier Science B.V. All rights reserved. Keywords: Alzheimer’s disease (AD); Medial temporal lobe (MTL); Amygdala; Wechsler memory scale-revised (WMS-R)

1. Introduction Memory impairment is usually the earliest and most prominent clinical manifestation of Alzheimer’s disease (AD) [1,2]. The earliest and most severe pathological manifestation of the disease is found in the medial temporal lobe (MTL) [3–9]. In addition to these, a definite diagnosis of AD also depends upon the neuropathological evidence of neurofibrillary tangles, senile plaque, and neuronal cell loss in MTL structures [3–9]. In the very early stage of AD, however, it is difficult to accurately evaluate any change in MTL structure or mild memory *Corresponding author. Tel.: 181-52-744-2385; fax: 181-52-7442384. E-mail address: [email protected] (G. Sobue)

impairment [10–12]. In vivo direct imaging techniques have been proposed for accurate assessment [13–22], and an MR-based volumetric measurement of the hippocampal formation is considered to provide useful diagnostic information [13,16–18]. However, recent reports have suggested that volumetric measurement of the hippocampal formation alone is not enough, and that the assessment of other MTL structures is necessary to differentiate mild AD patients from elderly normal subjects [14,19–21]. It is still unclear which region of the MTL degenerates first in the earliest stages of AD. Since the hippocampus has been thought to play a central role in declarative memory function [23], the investigative focus has been on its degeneration. Recent investigators have found that the anterior segments of the hippocampal formation are responsible for memory function [24,25]. In contrast, the

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role of the amygdala in memory function remains controversial [3,23,26–30]. Although it is considered to be more related to emotional behavior than to memory function [31], there is evidence to support the view that the amygdala also plays a role in memory [26–28]. For example, one patient with bilateral amygdala damage showed a significant deficit in visual memory despite normal intelligence [28]. Thus, the memory impairment in AD could be attributable to the involvement of the amygdala as well as the hippocampus. Given these considerations, it is important to assess the temporal sequence and extent of MTL atrophy, and to determine which MTL structures degenerate and are correlated with memory function in the early stage of AD. The aims of the present study were: (1) to evaluate changes in MTL structures in elderly normal subjects and AD patients, (2) compare the results of neuropsychological tests with the degree of MTL atrophy, and (3) determine any anatomo-functional correlation between them in the early stage of AD.

2. Materials and methods

2.1. Subjects We studied 46 patients with probable Alzheimer’s diseases (14 men and 32 women, mean age 68.267.9 years), who were referred to the Department of Neurology, Nagoya University Hospital during 1996 to 1998. Neurologists evaluated all patients, and a complete history was obtained from the patients and his or her relatives. Some patients had ongoing medical problems such as ischemic heart diseases or hypertension, but they were not excluded from this study since such illness did not interfere with the cognitive function. All patients had normal results from routine laboratory studies, including blood and urine chemistry, blood cell counts, a serological test for inflammatory markers, and plasma hormone levels for thyroid, pituitary and adrenals. The diagnosis of probable AD was made according to the NINCDS-ADRDA criteria [1], and disease severity was assessed by the Clinical Dementia Rating (CDR) scale [32]; very mild CDR 0.5 (n515); mild CDR 1 (n518); moderate and severe CDR 2?3 (n513). Mean duration of the disease was 2.561.6 years, and mean educational attainment was 10.062.9 years. The mean scores of mini mental status examination (MMSE) [33] were, CDR 0.5: 23.263.7; CDR 1: 20.262.7; and CDR 2?3, 12.263.4, respectively. Twenty-seven cognitively normal control subjects (14 men and 13 women, mean age 71.167.3 years) were volunteers. Control subjects had no history of neurologic or psychological illness, and were examined in the same way as the AD patients. Their mean educational attainment was 10.362.5 years, and their MMSE score 27.762.0.

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Age distribution and educational attainment were not significantly different between control subjects and AD patients. Before the clinical / cognitive assessment as well as MRI studies, informed consent was obtained.

2.2. MR volumetry An MRI examination was performed within 1 month of the neuropsychological evaluation. All subjects were imaged at 1.5 T (Signa, General Electric). T1-weighted sagittal images were used to measure total intracranial volume (TIV) and for landmarking subsequent sequences. Coronal T1-weighted (three-dimensional) spoiled gradient echo (SPGR) images (field of view 22 cm, 2563256 matrix, 1.5-mm contiguous sections, a 20-degree flip angle) were scanned [21] and reconstructed parallel to the long axis of the brainstem [34]. These reconstructed images were used for the volumetric study. Axial T1- and T2-weighted images were also obtained for diagnosis. All image processing steps were performed by the same trained operator who was blinded to clinical / cognitive information. MRI images were directly input to a personal computer and analyzed using the NIH image version 1.60 program. All volume measurements were performed by a segmentation technique combining tracing and thresholding. The borders of the hippocampal formation, the amygdala, and the parahippocampal cortex were manually traced with a mouse-driven cursor. Images were sequential from posterior to anterior. After the boundaries of the MTL anatomic structures had been identified, the number of pixels in each were automatically counted and multiplied by voxel size to give a numeric value in cubic millimetres. The values of individual MTL structure were normalized for individual head size by dividing each value of TIV. The interrater and intrarater test–retest coefficient of variations in TIV and MTL volumetric measurements were under 4.8% using this method. Boundaries of the hippocampal formations, the amygdala, and the parahippocampal cortex on oblique coronal MR images were drawn in comparison with histologic sections obtained in the same plane, referring to neuroanatomy atlases [35,36]. The neuroanatomic hippocampal and amygdaloid boundary criteria were those employed by Jack et al. [16], ´ epilepsy research groups [37,38] and Lehericy et al. [19]. Boundaries were defined as follows (Fig. 1). Hippocampal anatomic boundaries were defined to include the CA1 to CA4 sectors of the hippocampal proper, the dentate gyrus, the subiculum, and the white matter tracts of the alveus and fimbria. The posterior boundary of the hippocampus was determined by the oblique coronal anatomic section on which the crus fornix was visible in full profile. Amygdala measurements were considered to include the corticomedial, central, basolateral subgroups, the gyrus

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K. Mizuno et al. / Journal of the Neurological Sciences 173 (2000) 18 – 24

2.4. Statistical methods A stepwise analysis including TIV-normalized MTL volumes as dependent variables, and age, sex, and education as predictor variables was performed for both controls and AD patients. An analysis of variance (ANOVA) was performed to compare normalized MTL volumes among controls and AD patients with the varying severity of the disease. The differences between the two groups were ´ F test. Neuropsychological tested by post hoc Scheffe’s scores were analyzed by the same method. The relation between scores on the MMSE or WMS-R tests and each TIV-normalized MTL volume was evaluated by regression analysis. A linear regression analysis with the former as the dependent variables and the latter as the independent variables were performed. The significant level was determined as a P-value less than 0.05. Fig. 1. Boundaries of medial temporal structure on MRI. H indicates hippocampal formation; A, amygdala; PHC, parahippocampal cortex.

semilunaris, and the gyrus ambiens, while excluding the entorhinal cortex inferior to the uncal notch. The posterior, superior, medial, and lateral boundaries of the amygdala were formed by gray–white matter borders or CSF in the uncal cistern. The inferior borders of the amygdala were either the uncal recess of the lateral ventricle or the alveus delineating from the hippocampal head. The anterior boundary of the amygdala is ill defined in nature. The most anterior section measured was determined to be the section at the level of the closure of the lateral sulcus. The parahippocampal cortex (PHC) was defined as including gray matter in the parahippocampal gyrus (PHG). The posterior boundary of the PHC was similar to that for the hippocampal formation. The inferior and lateral boundary of the PHC were the collateral sulcus, and its internal border was the gray–white matter interface. The anterior boundary was the plane including the most anterior part of the temporal stem. We measured the volumes of the hippocampus and the PHC subdivided into the anterior and the posterior portions by the plane where the amygdala first appeared.

2.3. Neuropsychological assessment Memory function was evaluated using the Wechsler memory scale-revised (WMS-R) [39], with subsets of (1) verbal memory (logical memory and verbal paired associates), (2) visual memory (figure memory, visual paired associates and visual reproduction), and (3) delayed recall (delayed recall trials of verbal memory and visual memory). The scores of subjects over 75 years old were assessed by the normalized value from 70 to 74 years. Those of patients scaled out were calculated as 0.

3. Results

3.1. Normalized MTL volumes Both in normal control subjects and AD patients, each MTL volume did not correlate with educational attainment and sex. Each MTL volume declined with increasing CDR severity in AD patients (all, P,0.01). That remained significant after partialling out variance due to age. The volumetric measurements of the anterior hippocampus and PHC decreased significantly in the CDR 1 group and CDR 2?3 group, as compared with the control group (all, P, 0.01). The volume of the amygdala was significantly smaller even in the CDR 0.5 group, as well as the CDR 1 group and CDR 2?3 group, compared with the control group (all, P,0.01). The volumetric measurements of the posterior hippocampus and PHC declined significantly in the CDR 2?3 group compared with the control group (P,0.05, P,0.01) (see Fig. 2).

3.2. Neuropsychological assessment The MMSE scores declined with increasing CDR severity in AD patients (P,0.01). The decease was significant as early as in the CDR 0.5 group, and in the CDR 1 group and CDR 2?3 group, compared with the control group (all, P,0.01) (see Fig. 3). The scores on the three WMS-R subsets declined with increasing CDR severity in AD patients (all, P,0.01). This decrease was significant in the CDR 0.5 group compared with the control group (all, P,0.01), but not in the CDR 1 group compared with the CDR 0.5 group (see Fig. 4). A systemic WMS-R assessment was not possible in the CDR 2?3 group.

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Fig. 2. Plots of normalized volumes of control subjects (n527) and patients (n546) with very mild AD (CDR 0.5, n515), mild AD (CDR 1, n518), moderate and severe (CDR 2?3, n513). Top left, volumes of anterior hippocampus. Top right, volumes of posterior hippocampus. Middle, volumes of amygdala. Bottom left, volumes of anterior parahippocampal cortex. Bottom right, volumes of posterior parahippocampal cortex. TIV indicates total intracranial volume. *P,0.05, **P,0.01; NS, not significant.

3.3. Correlation between normalized MTL volumes and neuropsychological scores Table 1 summarizes the regression analyses in normal controls and patients with very mild AD (CDR 0.5) and mild AD (CDR 1). In the control group and the CDR 0.5 group, the MMSE scores did not correlate with the volume of any MTL structure. The volumetric measurements of the amygdala were correlated with scores on each of the WMS-R subsets

examined (P,0.01), whereas those of the anterior hippocampus, the posterior hippocampus, and the posterior PHC were not. The volumetric measurements of the anterior PHC were correlated with only scores on the visual memory. In the control and CDR 1 groups, the volumetric measurements of the amygdala, the anterior hippocampus, and the anterior PHC were correlated with scores on all the neuropsychological tests given (P,0.05 or P,0.01), whereas those of the posterior hippocampus were not. The

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K. Mizuno et al. / Journal of the Neurological Sciences 173 (2000) 18 – 24 Table 1 Correlation between MTL volumes and MMSE or WMS-R scores in control subjects and patients with very mild AD and mild AD a Neuropsychological tests

AH b

Control subjects and very mild AD MMSE 0.091 NS c WMS-R Verbal memory 0.149 NS Visual memory 0.390 NS Delayed recall 0.315 NS

Fig. 3. Plots of MMSE scores of control subjects (n527) and patients (n546) with very mild AD (CDR 0.5, n515), mild AD (CDR 1, n518), moderate and severe (CDR 2?3, n513). **P,0.01.

posterior PHC volumes were correlated with scores on the MMSE, and the delayed recall.

PH b

Ab

APHC b

PPHC b

patients (CDR 0.5) 0.284 0.281 0.317 NS NS NS

0.188 NS

0.034 NS 0.134 NS 0.187 NS

0.372 NS 0.423 * 0.305 NS

0.170 NS 0.193 NS 0.083 NS

0.624 **

0.357 *

0.505 ** 0.550 ** 0.624 **

0.263 NS 0.280 NS 0.360 *

0.522 ** 0.618 ** 0.601 **

Control subjects and mild AD patients (CDR 1) MMSE 0.495 0.104 0.598 ** NS ** WMS-R Verbal memory 0.513 0.221 0.605 ** NS ** Visual memory 0.451 0.192 0.537 ** NS ** Delayed recall 0.620 0.250 0.612 ** NS ** a

4. Discussion Our volumetric measurements showed that the volumes of the MTL structures declined with advancing severity of AD. This finding is consistent with previous MRI-based volumetric studies of AD patients [16,19,20]. In particular, our study demonstrated a significant decrease in the volume of the amygdala in very mild AD, but not in the anterior or posterior hippocampus. There is ongoing controversy over which MTL structures are most impaired in the initial stage of AD [13,14,16–21,24]. The hippocampus is believed to degenerate predominantly in the early stage. However, some recent reports have provided evidence that the amygdala begins to atrophy in AD much earlier than previously believed [14,19–21]. The present study unequivocally demonstrates that all structures in the MTL do not atrophy simultaneously, and supports the view that the

Control subjects (n515) and patients with very mild AD (CDR 0.5, n515), mild AD (CDR 1, n518). b AH, anterior hippocampus; PH, posterior hippocampus; A, amygdala; APHC, anterior parahippocampal cortex; PPHC, posterior parahippocampal cortex. c *P,0.05; **P,0.01; NS, not significant.

amygdala is more likely than the hippocampus to degenerate in the very early stage of AD. The neuropsychological measurements revealed that the scores on the MMSE and memory tests declined with increasing CDR severity in AD patients. The scores decreased markedly in very mild AD (CDR 0.5), indicating that these batteries are sensitive and reliable markers of the very early stage of AD. This observation is in agreement with previous reports [40–42]. The most striking finding in this study was the significant anatomo-functional correlation between the volumes of each MTL structure and the MMSE / WMS-R scores. Cognitive and memory function declined with the ad-

Fig. 4. Plots of WMS-R subsets scores of control subjects (n515) and patients (n533) with very mild AD (CDR 0.5, n515), mild AD (CDR 1, n518). Left, verbal memory. Middle, visual memory. Right, delayed recall. *P,0.05, **P,0.01; NS, not significant.

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vancing atrophy of the MTL structure. In the very early stage of AD, the major memory function assessed by the WMS-R subsets declined significantly in association with the atrophy of the amygdala. It is widely accepted that the amygdala is involved in emotional behavior and also cognition during emotional changes in humans [43,44]. Adolphs et al. [45] reported that it appeared to be important for social judgment with regard to visual stimuli. Their report and recent studies [46–48] using PET scans and functional MRI provide evidence that the human amygdala may have a role in memory function related to individual experience based on social and emotional behavior. Therefore, our observation of atrophy of the amygdala indicates that memory impairment in the early stage of AD may be attributable to involvement of the amygdala. However, the amygdala by itself may not be responsible for memory. It receives direct projections from the temporoparietal association area, which connects the hippocampus via the entorhinal cortex [49], degeneration of the amygdala may influence the function of the surrounding cortices and the hippocampus. Since measurements of the amygdala in the present study included its surrounding cortices, this is something which needs to be assessed by further investigation. Recently, Jack et al. [24] demonstrated that the atrophy of the hippocampal head rather than that of the whole formation is a more sensitive marker of the earliest stage of AD. They also speculated that since the neural connections to cortical input are different among the hippocampal head and the more posterior segments of the hippocampus [50–52], the head may be most susceptible to atrophy. We also found that the anterior PHC as well as the anterior hippocampus were atrophied in the mild stage of AD, whereas the posterior hippocampus and the posterior PHC were not. These results indicate that the anterior portions are more susceptible to atrophy than the posterior portions. Furthermore, the present study suggests that the degeneration of the amygdala may affect the anterior portions of the hippocampus and the PHC. In summary, we demonstrated that MR-based volumetric measurement of the amygdala is a sensitive marker for distinguishing very mild AD patients from elderly normal subjects, and that the amygdala may play an important role in the memory impairment of very mild AD patients.

Acknowledgements This work was supported by grants from the Ministry of Welfare and Health of Japan and by a COE grant from the Ministry of Education, Science, Sports and Culture of Japan. The authors would like to thank Kenji Wakai, MD, Department of Preventive Medicine, Nagoya University School of Medicine, for statistical assistance, and Professor Sugishita, Department of Neuroscience, Faculty of Medi-

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cine, University of Tokyo, for assistance with the neuropsychological assessment.

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