Neuropathological study of the amygdala in presenile Alzheimer's disease

Journal of the Neurological Sciences, 100 (1990) 165-173

Elsevier

165

JNS 03443

Neuropathological study of the amygdala in presenile Alzheimer's disease K u n i a k i T s u c h i y a 1,2 a n d K e n j i K o s a k a ~ 1Department of Neuropathology, Psychiatric Research Institue of Tokyo (Japan), and 2Department of Neurology, Musashino Red Cross Hospital, Tokyo (Japan)

(Received 20 March, 1990) (Revised, received 7 August, 1990) (Accepted 9 August, 1990) Key words: Presenile Alzheimer's disease; Distribution of amygdaloid changes; Neuronal loss; Senile plaque; Neurofibrillary tangle

Summary We studied neuropathological changes of the amygdala in 10 cases of presenile Alzheimer's disease. According to the anatomical classification of the amygdala, we subdivided the corticomedial group into 3 parts, and the basolateral group into 8 parts. We investigated qualitatively neuronal loss, and quantitatively the numbers of neurofibrillary tangles (NFTs) and senile plaques (SPs) in 11 parts. The degree of atrophy of the amygdala was also checked in relation to the clinical stages of the disease. Neuronal loss was more prominent in the later clinical stages. It was more intense in the corticomedial group than in the basolateral group. The density of NFTs tended also to be greater in the corticomedial group than in the basolateral group, although it did not always increase in parallel with the progress of the dementia. The density of SPs was greater in the basolateral group than in the corticomedial group, and tended to increase in parallel with the progress of the disease. Atrophy of the amygdala was generally more prominent in the more advanced clinical stage. The distribution pattern of neuronal loss was similar to that of NFTs in the amygdala, whereas the distribution pattern of SPs was quite different.

Introduction Alzheimer-type dementia (ATD) is one of the most common dementing illnesses in later life, with the characteristic histologic features including senile plaques (SPs) and neurofibrillary tangles (NFTs). A T D is often divided into a presenile form (Alzheimer's disease, A D ) (Alzheimer 1907, 1911. von Braunmtlhl 1957; Constantinidis et al. 1985) and a senile form (senile dementia of the Alzheimer type, SDAT) (von Braunmtlltl 1957). The validity of the distinction is debated because both forms share essentially the same pathological substrate. However, A D tends to be more severe in both clinical and pathological aspects. In this paper we are concerned with AD. Only a few neuropathological studies of the amygdala in A T D have been reported (Brashear et al. 1988; Brockhaus 1938; Corsellis 1970; Herzog and Kemper 1980; Hooper and Voger 1976; J a m a d a and Mehraein 1968; Tomlinson 1979; Toshima 1961 ; Unger et al. 1988). As far as we know, however, there have been no reports which investigated Correspondence to: K. Tsuchiya, MD, Department of Neurology, Musashino Red Cross Hospital, 1-26-1 Kyonancho, Musashino-City, Tokyo 180, Japan

simukaneously the detailed distribution of neuronal loss, N F T s and SPs in the amygdala and documented all three changes in relation to the severity of the dementia. In this report, we studied neuropathologically the detailed distribution of amygdaloid changes in 10 autopsied cases with various clinical stages of AD.

Materials and methods Among 36 autopsied cases with clinicopathologicaUy verified A D preserved in our institute, we selected 10 cases in which the amygdala could be investigated in detail. The sex, age at onset, age at death, duration illness, clinical stage, atrophy of the amygdala, and brain weight are shown in Table 1. According to the clinical features as described previously, we divided the clinical stages of AD into 3 classes (Arai et al. 1983; Ichimiya et al. 1986). This classification system is basically the same as that of Granthal (1926), SjOgren et al. (1952), Sim (1965). In stage I, patients showed amnesia, disorientation, and character change with the disturbance of affect and aspontaneity. In stage II, which began after an interval of a few years, profound dementia was observed. As this time pronounced focal

0022-510X/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)

166 TABLE 1 CLINICAL AND PATHOLOGICAL DATA OF 10 CASES WITH PRESENILE ALZHEIMER'S DISEASE Case

Sex

Age at onset (yrs)

Age at death (yrs)

Duration of illness (yrs)

Clinicalstage

Atrophy of amygdala

Brain weight (g)

1 2 3 4 5 6 7 8 9 10

M F M F F M M F F F

62 59 60 61 54 38 56 59 51 45

72 67 68 65 57 45 66 74 64 57

10 8 8 4 3 7 10 15 13 12

II II II II II III III III III III

slight slight moderate slight slight moderate moderate severe slight severe

1170 1140 1120 1020 1016 1300 1070 940 900 800

symptoms appeared, in the form of aphasia, apraxia and agnosia. In addition, Klaver-Bucy syndrome occurred in some patients. Extrapyramidal symptoms including muscular rigidity and myoclonus were commonly observed in this stage. The activity of daily living was greatly disturbed. By stage III (terminal stage) of the disease, patients were bedridden, and soon fell into a decerebrated vegetative state. 5 of our cases [cases 1-5] were in stage II, and the other 5 (cases 6-10) in stage III. Case 6, 3 of whose 8 siblings had been affected with AD, had familial type of A D (Heston et al. 1966). In consideration of his age at onset, patient 6 could be classified into the juvenile type of A D (Jervis and Soltz 1936). Neuropathological examination was performed as follows. 10~o formalin-fixed brains were coronally cut, and hemispherical tissue blocks were obtained. The blocks were paraffin-embedded and sectioned for staining by conventional methods, including hematoxylin and eosin, Kltiver-Barrera, Nissl, and Holzer techniques. For the visualization of N F T s and SPs, Bodian, Merks-modified Bodian ( H a g a et al. 1987), methenamine-Bodian (Kondo et al. 1987) stainings were used. Bodian, Merks-modified Bodian, and methenamine-Bodian staining had the same ability to stain N F T s as described previously (Haga et al. 1987; K o n d o et al. 1987). For the detection of SPs, Merksmodified Bodian and methenamine-Bodian stainings were more sensitive than Bodian staining ( H a g a etal. 1987; K o n d o et al. 1987). Merks-modified Bodian staining is almost similar to methenamine-Bodian staining for the visualization of SPs ( H a g a et al. 1989; K o n d o et al. 1987). For the ability to stain SPs, Merks-modified Bodian and methenamine Bodian stainings are similiar to periodic acidmethenamine silver (PAM), modified Bielschowsky, and anti-/~-protein stainings (Haga et al. 1989). In all 10 A D cases, SPs and N F T s were present in the neocortex, hippocampus, and amygdala in sufficient number and distribution for the confident diagnosis of A D (Khachaturian 1985).

Neuropathological examination of the amygdala in each case was carried out in the coronal hemispherical section at a thickness of 10/~m through the level of the optic tract, anterior commissure, and column of fornix (Figs. 1 and 2a). The left side of the amygdala was examined in cases 2, 4, 5, 7, 8 and 9, and the right side in cases 1, 3, 6, and 10. The

Fig. 1. Amygdala (arrow) in the level used for our study. Normal brain K.B. stain, x 1.8.

167

olumn of fornix

anterior commissure

commissure

Ant op~tic tract

b Fig. 2. (a) Scheme of the amygdala in Fig. 1. (b) Classification of the amygdala in our study. Corticomedial group: cortical amygdaloid nucleus (Cor) 1; medial amygdaloid nucleus (Med) 2; anterior amygdaloid area (Ant) 3. Basolateral group: accessory basal amygdaloid nucleus (Ace) 4, 5; basal amygdaloid nucleus (Bas) 6, 7, 8; lateral amygdaloid nucleus (Lat) 9, 10, 11.

amygdala is usually divided into two main nuclear groups; the corticomedial group and the basolateral group (Carpenter and Sutin 1983; Crosby and Humphrey 1941; Humphrey 1968). The corticomedial group includes the anterior area, nucleus of the lateral olfactory tract, medial nucleus, cortical nucleus, and central nucleus. The basolateral group is also subdivided into the lateral nucleus, basal nucleus, and accessory basal nucleus. The section of the amygdala used here contains the anterior area, medial nucleus, and cortical nucleus of the corticomedial group, and the accessory basal nucleus, basal nucleus, and lateral nucleus of the basolateral group (Fig. 2a). Nuclear subdivisions of the amygdala were usually performed according to the morphology of the neurons and the construction of myelin. The identification of nuclear subdivisions of the amygdala is easy for normal cases, but more difficult for Alzheimer's case. Therefore, we took photographs of the Kltiver-Barrera stained section of each case, and divided microscopically the amygdala into 11 parts taking into consideration the size of neurons and the fiber bundles with the aid of the various stainings, according to the classification of Crosby and Hamphrey (1941). The corticomedial group was subdivided into the cortical nucleus (Cor, 1) medial nucleus (Med, 2), and anterior area (Ant, 3) (Fig. 2a,b). As far as the basolateral group is concerned, the accessory basal nucleus (Acc) was subdivided into the lateral part (4) (the lateral portion of the accessory basal nucleus, magnocellular part of the accessory basal nucleus) and the medial

part (5) (the medial portion of the accessory basal nucleus, the parvocellular part of the accessory basal nucleus) (Fig. 2b). We divided the basal nucleus [Bas] into the medial part (6) (the medial part of the basal nucleus, the superficial and deep portion of the basal nucleus), the intermediate part (7) (the lateral large-celled portion of the basal nucleus), and the lateral part (8) (the lateral large-celled portion of the basal nucleus) (Fig. 2b). The lateral nucleus was also subdivided into the lateral part (9) (the lateral part of the lateral nucleus), the intermediate part (10) (intermediate part of the lateral nucleus), and the medial part (11) (the ventromedial part of the lateral nucleus (Fig. 2b). The degree of neuronal loss was placed into 3 categories: slight, slight neuronal loss with gliosis; moderate, moderate neuronal loss with gliosis and spongy change of the tissue; and severe, severe neuronal loss with marked gliosis and devastation of the tissue. It was plotted on the schema of the amygdala in each case (Fig. 3). The number of NFTs was counted with Bodian staining, and the number of SPs was counted with methenamine-Bodian staining. For the measurements of the numbers of NFTs and SPs, we microscopically divided each of the above-mentioned 11 parts into 10 subparts. Each subpart corresponded to a ,microscopic field encompassing 0.25 mm2 (magnification × 200). NFTs and SPs were quantitatively counted in a microscopic field encompassing 0.25 mm 2 (magnification × 200) by the use of an eyepiece micrometer. The numbers of NFTs and SPs were counted in each of the

168 dorsal

dorsal

,t

me,~dial

medial

case 1

case 2

dorsal

dorsal

L_

mea'l

medial

3

case

case 4

dorsal

dorsal

medial

medial

case 6 case

5 dorsal

_J medial

case

7

case

8

dorsal medial

:tl

~dial case

9

case

Fig. 3. Distribution of neuronal loss in the amygdala, slight, ~ ;

10 subparts. The average numbers were then calculated for all 11 parts of the amygdala (Table 2). With regard to the numbers and distribution of NFTs and SPs, statistical analysis was also performed, t-Tests were used to compare the data between the corticomedial and the basolateral groups, and between clinical stage lI [cases 1-5] and stage III groups [cases 6-10] (Tables 3 and 4). The degree of the amygdaloid atrophy was also checked (Table 1, Fig. 4). Results

(I) Neuronal loss in the amygdala was, in general, more prominent in stage III cases than in stage II cases, although there were exceptions (Fig. 3). In case 9, which was in

l0

moderate, r/T777~; severe, ~ .

stage III and whose brain weighed 900 g, neuronal loss in the amygdala was slight, whereas case 3 belonging to the stage II group had an exceptionally prominent degree of neuronal loss in the amygdala. The corticomedial group was more intensely affected by neuronal loss than the basolateral group, regardless of the clinical stages. Within the corticomedial group, the cortical nucleus was most conspicuously affected by neuronal loss in cases 1, 4 and 6. Within the basolateral group, there were, however, different degrees of neuronal loss in the subgroups. Neuronal loss was more conspicuous in the lateral nucleus (cases 3, 8, and 10) and/or in the accessory basal nucleus (cases 2, 7, 8, and 10). It was noteworthy that neuronal loss in the dorsal part of the basal nucleus was relatively slight.

169 TABLE 2 A V E R A G E N U M B E R OF N E U R O F I B R I L L A R Y T A N G L E S A N D SENILE P L A Q U E S IN T H E A M Y G D A L A PER F I E L D (0.25 m m 2) Case

Corticomedial group 1

Basolateral group

2

3

4

5

6

7

8

9

10

11

1.7 4.2 10.1 4.9 1.5 7.0 10.2 2.1 6.1 2.4

0.7 1.9 11.0 3.6 1.0 4.0 10.4 1.2 4.4 2.0

2.5 8.9 19.2 10.6 5.2 5.2 11.2 1.8 8.1 1.0

2.5 6.3 11.2 14.3 2.1 5.8 2.7 2.1 5.8 3.6

0.6 11.7 12.2 5.5 2.8 1.9 5.1 2.3 3.9 1.6

2.2 7.7 10.0 4.3 6.1 2.7 10.3 1.3 4.6 1.4

1.0 3.1 6.1 1.8 3.4 3.4 7.1 0.8 2.2 1.0

4.4 9.2 10.0 0.9 3.2 2.4 14.4 0 2.0 0.6

4.9 12.0 13.0 2.2 6.0 2.2 11.8 0.3 4.0 1.0

1.2 12.0 8.8 5.8 5.0 0.6 5.5 1.5 6.8 2.0

0.5 0.5 0.6 0.4 0 0.9 1.3 0 1.1 1.5

0.4 0.4 3.0 0.4 0 0.9 2.6 0.9 0.5 1.0

1.9 0.4 5.0 1.1 1.0 6.6 4.9 0.6 0.8 20.0

3.3 5.2 3.0 6.1 2.7 6.5 5.0 5.4 3.0 9.8

2.5 0.3 5.0 0.1 1.0 6.0 2.6 5.1 1.7 7.0

1.6 0.2 3.0 0.1 1.0 5.9 2.2 0.5 0 6.8

0.5 0.6 1.0 0 0.1 0.5 2.3 0.4 0 0.9

1.3 1.6 0 0.5 0 1.0 0.9 0.5 0 1.2

1.6 0.4 3.0 0.4 0 8.4 2.2 1.2 0 I0.0

2.8 3.0 5.0 0.9 1.0 5.0 1.8 3.1 0 3.0

(a) Neurofibrilla~ mngles (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)

6.9 7.4 25.4 7.6 8.7 6.2 12.0 6.1 10.8 2.0

Sen~p~ques (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)

2.8 0.7 2.0 1.6 1.0 2.8 1.1 1.7 3.1 9.5

(2) The density of NFTs in the amygdala was not always greater in the later clinical stages (Table2a, Table 4). In this regard, it was noteworthy that two stage III cases (cases 8 and 10) had a density of NFTs less than that found in most stage II cases. The comparison of the corticomedial group with the basolateral group demonstrated that the former had a higher density of NFTs than the latter in stage III cases (P = 0.006). However, in cases 2 and 4 NFTs were more prominent in the basolateral group rather than in the corticomedial group. Within the corticomedial group, NFTs TABLE 3 R E S U L T S O F S T A T I S T I C A L ANALYSIS O F N E U R O F I B RILLARY T A N G L E S A N D SENILE P L A Q U E S B E T W E E N T H E CORTICOMEDIAL GROUP AND BASOLATERAL GROUP OF THE AMYGDALA

CM

N F T (mean + SD)

SP (mean +_ SD)

6.1 + 4.1

1.4 + 1.0

a paired t-test; NS: not significant; *P < 0.05. Abbreviations: N F T = neurofibrillary tangles; SP = senile plaques; CM = corticomedial group; BL = basolateral group.

were most conspicuous in the cortical nucleus (cases 1, 2, 4, 5, 8 and 9), whereas they were relatively inconspicuous in the anterior area (cases 2, 4, 6, 8 and 9). (3) When we compared stage II cases with stage III cases, the density of SPs in the amygdala (Table 2b) tended to be greater in stage III cases, but the difference was not statistically significant (P --- 0.1565) (Table 4). Contrary to the distribution of neuronal loss and NFTs, the density of SPs was greater in the basolateral group than in the corticomedial group, and the difference was statistically significant ( P = 0.018) (Table3). In stage II, a statistically significant difference (P---0.0092) was found between the corticomedial group and the basolateral group, but in stage III no statistically significant difference (P = 0.1112) was found (Table 4). Concerning the distribution pattern of SPs in the corticomedial group, the density of SPs tended to be greater in the cortical nucleus. Within the basolateral group, the density of SPs was more prominent in the ventral parts than in the dorsal parts in all cases. (4) Atrophy of the amygdala (Table 1, Fig. 4). The atrophy of the amygdala generally advanced according to the progress of the clinical stages. In case 1 belonging to the second clinical stage, whose brain weighed l170g, the atrophy of the amygdala was slight in degree, and the

170

!

d Fig. 4. Atrophy of the amygdala (arrow) in different stages of Alzheimer's disease. (a) Case 1 K.B. stain x 1.8. (b) Case 3 K.B. stain × 1.8. (c) Case 8 K.B. stainl.8. (d) Case 10 K.B. stain x 1.8.

171 TABLE 4 RESULTS OF STATISTICAL ANALYSIS OF NEUROFIBRILLARY TANGLES AND SENILE PLAQUES IN THE AMYGDALA BETWEEN THE CLINICAL STAGE II AND III GROUPS NFT (mean + SD)

SP (mean + SD)

Stage II

CM 6.4 _ 5.1 ~ NS a BL 6.5 + 3.6 --J (P = 0.9685) CM + BL 6.5 + 3.8

1.0 _+ 0.6 - ~ **a 1.7 + 0.9 --/ (P = 0.0092) 1.5 + 0.8

Stage III

CM 5.8 _+ 3.5 ~ BL 3.8 _+ 3.0 / CM + BL 4.3 + 3.1

**a (p = 0.0058)

NS b (P = 0.9685)

1.9 _+ 1.2 - 7 NS a 3.6 _+ 2.6 --J (P = 0.1112) 3.1 +2.2

NS b (P = 0.1565)

a Paired t-test; b t-test (two sample); NS.: not significant; *P < 0.05; **P < 0,01. Abbreviations: stage II = clinical stage II (case 1-5): stage III = clinical stage III (case 6-10). Other abbreviations as for Table 3.

contour of the amygdala was almost normal (Fig. 4a). In case 3 (stage II group) the weight of the brain was 1120 g, and the atrophy of the amygdala was moderate in degree. The contour of the amygdala was slightly deformed, and the inferior horn of the lateral ventricle was moderately dilated (Fig. 4b). Case 8 with a brain weight of 940 g in the third clinical stage, had a severe atrophy of the amygdala, and showed a prominent dilatation in the inferior horn of the lateral ventricle (Fig. 4c). In case 10 (stage III) the weight of the brain was 800 g. The atrophy of the amygdala in this case was severe, and the inferior horn of the lateral ventricle was severely dilated (Fig. 4d).

Discussion

The results of our neuropathological study on the amygdala in AD are summarized as follows. (1) Neuronal loss was more prominent in stage III than in stage II, and more intense in the corticomedial group than in the basolateral group regardless of the clinical progression of the disease. (2) The density of NFTs was not always greater in later clinical stages. Concerning the distribution of NFTs in the subgroups of the amygdala, they were more densely distributed in the corticomedial group than in the basolateral group of stage III cases. (3) SPs tended to increase in number according to the progression of the clinical stages. As far as the distribution of SPs in the subgroups of the amygdala was concerned, they were more densely distributed in the basolateral group than in the corticomedial group. (4) The atrophy of the amygdala generally advanced in parallel with the progression of the disease. (5) The distribution pattern of neuronal loss was similar to that of NFTs in the subgroup of the amygdala, while the distribution pattern of SPs was different. The amygdala is one of the components of the limbic

system, and it is usually divided into two main nuclear groups; the corticomedial group and the basolateral group (Carpenter and Sutin 1983; Crosby and Humphrey 1941; Humphrey 1968). Phylogeneticallyit is known that the corticomedial group is older than the basolateral group. The amygdala is thought to play a major role not only in behavioral functions that are prominently disturbed in AD, such as emotion, motivation, and memory, but also in autonomic and endocrine functions (Carpenter and Sutin 1983). Bilateral lesions of the amygdala in animals have been reported to cause striking disturbances of emotional behavior (Carpenter and Sutin 1983). The observations in man indicated that the lesions in bilateral anteromedial temporal lobe including the amygdala occasionally cause not only the decrease of aggressive and assaultive behavior (Pool 1954), but also partial (Sourander and Sjtigren 1970; Terzian and Ore 1955) and complete KRlver-Bucy syndrome (Marlowe et al. 1975). The investigations of selectively damaged amygdala in man showed marked changes in emotional behavior (Narabayashi etal. 1963; Sawa etal. 1954). KRlver-Bucy syndrome also occurs in some AD patients (Lilly etal. 1983; Pilleri 1966; Sourander and SjOgren 1970). The case reported by Pilleri (1966) showed all elements of Kltlver-Bucy syndrome except for abnormal sexual behavior. Neuropathologically, this case had a severe atrophy of the hippocampus and amygdala in addition to neocortical changes. There have been only a few neuropathological studies on the amygdala in ATD. In an anatomical and pathological study on the amygdala, Brockhaus (1938) studied a case with SDAT. In this case, neuronal loss and SPs were prominent in the cortical nucleus of the corticomedial group and in the medial and ventral parts of the basolateral group. Toshima (1961) studied histopathological changes of the amygdala in various diseases including SDAT. He reported that in SDAT, NFTs were conspicuous in the cortical nucleus of the corticomedial group, and that SPs were prominent in the accessory basal nucleus of the basolateral

172 group. In a quantitative neuropathological study in ATD, Jamada and Mehraein (1968) reported that SPs and NFTs were most numerous in the amygdala. They counted SPs and NFTs in the cortical nucleus, accessory basal nucleus, basal nucleus, and lateral nucleus of the amygdala. In AD cases both SPs and NFTs were most numerous in the cortical nucleus and basal nucleus, and least in the lateral nucleus. They also emphasized that in the amygdala the distribution pattern of SPs was similiar to that of NFTs. Corsellis (1970) reported that plaque formation was usually more noticeable in the medial half of the amygdala. Hooper and Vogel (1976) investigated the limbic system in 9 cases with ATD, and reported that the corticomedial group of the amygdala was severely affected by ATD lesions. They also speculated that the phylogenetically older corticomedial group was more susceptible to the lesions. According to Tomlinson (1979), the amygdala is probably the most severely involved structure by both SPs and NFTs in the entire brain of normal and demented old subjects. Herzog and Kemper (1980)investigated the divisional distribution of volumetric and cell-packing density changes in the amygdala in cases with advanced aging and SDAT. According to them, the amygdala underwent marked degeneration in SDAT cases, which preferentially affected the corticomedial group. Unger et al. (1988) studied neuropeptides and neuropathology in the amygdala in ATD cases. According to their study, the corticomedial group exhibited the most marked neuropathological change. Brashear et al. (1988) reported the distribution of SPs and acetylcholinesterase staining in the amygdala in ATD cases, and found that SP counts were high in most amygdaloid nuclei but were significantly lower in the most acetylcholinesterase-positive region, namely the lateral portion of the basal nucleus of the amygdala. As mentioned above, more researchers have reported that in ATD the neuropathological changes were more prominent in the corticomedial group than in the basolateral group of the amygdala. Regarding the distribution of neuronal loss and NFTs in the amygdala, our results roughly coincide with the literature. On the other hand, the distribution of SPs in our investigation is not in accord with past studies. There have been few reports on the detailed distribution of SPs in the amygdala. Jamada and Mehraein (1968) described that the number of SPs was greatest in the cortical and basal nuclei, and least in the lateral nucleus. Our study disclosed a difference in the density of SPs between the parts of the basolateral group. Brashear et al. (1988) also demonstrated that the distribution of SPs was not uniform within the basal nucleus of the basolateral group, and that SPs occurred more frequently in the medial portion of the basal nucleus than in the lateral portion. Regarding the distribution of SPs in the basal nucleus of the basolateral group, our study almost agrees with their study in spite of the different level of the amygdala used by these

authors. In our 10 AD cases, SPs were more prominent in the ventral parts than in the dorsal parts of the basolateral group. In our study, neuronal loss and SPs in the amygdala were more prominent in the later clinical stage of AD, and the degree of amygdaloid atrophy advanced according to the progress of the clinical stages. The density of NFTs was, however, not always associated with the progress of the clinical stages. This might suggest that in the amygdala of the late clinical stage of AD, neuronal loss is not always closely associated with NFTs. In our study, the distribution of neuronal loss and NFTs was not in keeping with that of SPs. The mechanism for this difference in the distribution patterns remains unclear. It could be hypothesized that the difference depends on the phylogenesis of the amygdala. Phylogenetically, the amygdala consists of the relatively old corticomedial group and the relatively new basolateral group. It is well known that in normal aged brains, and in some cases with SDAT, NFTs are found only in the phylogenetically old hippocampus and parahippocampal gyrus, while relatively few SPs are found in these regions. We speculate that NFTs are prone to occur in phylogenically older regions while SPs tend to appear in the phylogenically newer regions. The above speculation seems to be in accord with the distribution of neuronal loss, NFTs, and SPs in the amygdala of AD. Another explanation for these distribution patterns might be neurochemical differences in the subdivisions of the amygdala. Recently, new biochemical findings in the amygdala have been reported in animals and man (Shiosaka et al. 1983; Svendsen and Bird 1985; Unger et al. 1988; Zech et al. 1986). According to the study by Shiosaka et al. (1983), various peptides, such as somatostatin, substance P, and enkephalin, are rich in the corticomedial group of the amygdala in rat, while acetylcholine esterase activity is conspicuous in the basolateral group. Svendsen and Bird (1985) reported that acetylcholinesterase staining was strong in the basolateral group, and particularly prominent in the basal nucleus of the human amygdala. Recently several studies (Armstrong et al. 1986; Struble et al. 1982) have suggested that changes in cortical cholinergic innervation are an important component in the pathogenesis and evolution of SPs. Struble et al. (1982) reported that immature and mature SPs contain acetylcholinesterase-rich dystrophic axons. Armstrong etal. (1986) observed dystrophic choline acetyltransferase-positive neurites surrounding the amyloid cores of SPs in the neocortex, amygdala, and hippocampus. In this study we did not investigate the relationship between clinical signs such as Kltlver-Bucy syndrome and the amygdaloid lesions. Further investigations on this clinicopathological relationship will be published elsewhere. Acknowledgements Wewouldliketo thankProf.H. Tsukagoshi(Tokyo

Medical and Dental University, Japan) and Prof. M. Matsushita

173 (Yokohama City University School of Medicine, Japan) for their supervision of this study, and to Prof. K. Harada (University of Tokyo, Japan) for his kind advice. We are also grateful to Mr. A. Kagiwada, Mr. K. Kato, Mrs. T. Haga, Mrs. K. Kondo, and Mrs, T. Yamashita for their skilful photographic and technical assistance, and to Mr. K. Matsui for help with the statistics.

References Alzheimer, A. (1907) ~ber eine eigenartige Erkrankung der Hirnrinde. Allg. Z. Psychiat., 64: 146-148. Alzheimer, A. (1911) Ober eigenartige Krankheitsf~ille des sp~iteren Alters. Z. Ges. Neurol. Psychiat., 4: 356-385. Arai, H.; K. Kobayashi, K. Ikeda, Y. Nagao, R. Ogihara and K. Kosaka (1983) A computed tomography study of Alzheimer's disease. J. Neurol., 229, 69-77. Armstrong, D.M., G. Bruce, L.B. Hersh and R.D. Terry (1986) Choline acetyltransferase immunoreactivity in neuritic plaques of Alzheimer brain. Neurosci. Lett., 71: 229-234. Brashear, H.R., M.S. Godec and J. Carlsen (1988) The distribution of neuritic plaques and acetylcholinesterase staining in the amygdala in Alzheimer's disease. Neurology, 38: 1694-1699. Brockhaus, H. (1938) Zur normalen und pathologischen Anatomic des Mandelkerngebiets (Subzona semicorticalis amygdalea und Subzona claustralis praeamygdalea). J. Psychol. Neurol., 49: 1-136. Carpenter, M.B. and J. Sutin (1983) Amygdaloid nuclear complex. In: Human Neuroanatomy, 8th edn., Williams & Wilkins, Baltimore, London, pp. 634-639. Constantinidis, J. and J. Richard (1985) Alzheimer's disease; In: Vinken, P.J., Bruyn, G.W., Klawans, H.L. and Frenderiks, J.A.M. (Eds.), Handbook of Clinical Neurology, Vol. 46, Elsevier Science Publishers, Amsterdam, pp. 247-282. Corsellis, J.A.N. (1970) The limbic areas in Alzheimer's disease and in other conditions associated with dementia. In: Wolstenholme, G.E.W., O'connor, M. (Eds.), Alzheimer's disease, J. & A. Churchill, London, pp. 37-50. Crosby, E.C. and T. Humphrey (1941) Studies of the vertebrate telencephalon. II. The nuclear pattern of the anterior olfactory nucleus, tuberculum olfactorium and the amygdaloid complex in adult man. J. Comp. Neurol., 74: 309-352. Griinthal, E. (1926) Ober die Alzheimersche Krankheit. Eine histopathologisch-klinische Studie. Z. Ges. Neurol. Psychiat., 101: 128-157. Haga, C., H. Kondo, T. Kitou and M. Matsushita (1987) A modified Bodian stain for senile plaques. J. Med. Technol., 31:897-901 (Japanese). Haga, C., K. Ikeda, K. Kosaka, Y. Izumiyama and S. Oyanagi (1989) Light and electron microscopic study of "plaque-like structures" in Alzheimer-type dementia. Dementia, 3:85-90 (in Japanese). Heston, L.L., D.L.W. Lowther, P. Ore and C.M. Leventhal (1966) Alzheimer's disease. A family study. Arch. Neurol., 15: 225-233. Herzog, A.G. and T.L. Kemper (1980) Amygdaloid changes in aging and dementia. Arch. Neurol., 37: 625-629. Hooper, M.W. and F.S. Vogel (1976) The limbic system in Alzheimer's disease. A neuropathological investigation. Am. J. Pathol. 85: 1-20. Humphrey, T. (1968) The development of the human amygdala during early embryonic life. J. Comp. Neurol., 132: 135-165. Ichimiya, Y., K. Kobayashi, H. Arai, K. Ikeda and K. Kosaka (1986) A computed tomography study of Alzheimer's disease by regional volumetric and parenchymal density measurements. J. Neurol. 233: 164-167. Jamada, M. and P. Mehraein (1968) Verteilungsmuster der senilen Ver~inderungen im Gehirn. Die Beteiligung des limbischen Systems bei hirnatrophischen Prozessen des Seniums und bei Morbus Alzheimer. Arch. Psychiat. Z. Ges. Neurol., 211: 308-324.

Jervis, G.A. and S.E. Soltz (1936) Alzheimer's disease - the so-called juvenile type. (With report of a case). Am. J. Psychiatry, 93: 39-56. Khachaturian, Z.S. (1985) Diagnosis of Alzheimer's disease. Arch. Neurol. 42: 1097-1105. Kliiver, H. and P.C. Bucy (1938) An analysis of certain effects of bilateral temporal lobectomy in the rhesus monkey, with special reference to "psychic blindness". J. Psychol., 5: 33-54. Kliiver, H. and P.C. Bucy (1939) Preliminary analysis of functions of the temporal lobes in monkeys. Arch. Neurol. Psychiat., 42: 979-1000. Kondo, H., C. Haga, T. Kitou, K. Kosaka and M. Matsushita (1987) Methenamine-Bodian stain for senile plaques. Pathol. Clini. Med., 5: 1365-1369 (in Japanese). Lilly, R., J.L. Cummings, D.F. Benson and M. Frankel (1983) The human Klfiver-Bucy syndrome. Neurology, 33:1141-1145. Marlowe, W.B., E.L. Mancall and J.J. Thomas (1975) Complete Kliiver-Bucy syndrome in man. Cortex, 11: 53-59. Narabayashi, M., T. Nagao, Y., Saito, M. Yoshida and M. Nagahata (1963) Stereotaxic amygdalotomy for behavior disorders. Arch. Neurol., 9: 1-16. Pool, J.L. (1954) The visceral brain of man. J. Neurosurg., 11: 45-63. Pilleri, G. (1966) The Klilver-Bucy syndrome in man. Psychiat. Neurol. (Basel), 152: 65-103. Sawa, M., Y. Ueki, M. Arita and T. Harada, (1954) Preliminary report on the amygdaloidectomy on the psychotic patients, with interpretation of oral-emotional manifestation in schizophrenics. Fol. Psychiat. Neurol. Jap., 7: 309-329. Shiosaka, K., M. Sakanaka, S. Inagaki, E. Senba, Y. Hara, K. Takatsuki, H. Takagi, Y. Kawai and M. Tohyama (1983) Putative neurotransmitters in the amygdaloid complex with special reference to peptidergic pathways. In: Emson, P.C. (Ed.), Chemical Neuroanatomy, Raven Press, New York, pp. 359-389. Sim, M. (1965) Alzheimer's disease: a forgotten entity. Geriatrics, 20: 668-674. SjOgren, T., H. Sj0gren and A.G.H. Lindgren (1952) Morbus Alzheimer and Morbus Pick. A genetic, clinical and pathoanatomical study. Acta Psychiat. Neurol. Scan& Suppl., 82, 1-151. Sourander, P. and H. Sjrgren (1970) The concept of Alzheimer's disease and its clinical implications. In: Wolstenholme, G,E.W. and O'Connor, M. (Eds.), Alzheimer's Disease, J. & A. Churchill, London, pp. 11-36. Struble, R.G., L.C. Cork, P.J. Whitehouse and D.L. Price (1982) Cholinergic innervation in neuritic plaques. Science, 216: 413-415. Svendsen, C.N. and E.D. Bird (1985) Acetylcholinesterase staining of the human amygdala. Neurosci. Lett., 54: 313-318. Terzian, H. and G.D. Ore (1955) Syndrome of Kltlver and Bucy. Reproduced in man by bilateral removal of the temporal lobes. Neurology, 5: 373-380. Tomlinson, B.E. (1979)The ageing brain. In: Smith, W.T. and Cavanagh, J.B. (Eds.), Recent advances in neuropathology, Churchill Livingstone, London, pp. 129-159. Toshima, Y. (1961) Histopathology of the amygdaloid nucleus. Seishin skinkeigaku Zasshi, 63:1178-1198 (in Japanese). Unger, J.W., T.H. McNeill, L.L. Lapham and R.W. Hamill (1988) Neuropeptides and neuropathology in the amygdala in Alzheimer's disease: relationship between somatostatin, neuropeptide Y and subregional distribution of neuritic plaques. Brain Res., 452: 293-302. von Braunm~hl, A. (1957) Alterserkrankungen des Zentralnervensystems. Senile Involution. Senile Demenz. Alzheimersche Krankheit. In: Lubarsch, O., Henke, F., ROssle, R. (Eds.), Handbuch der Speziellen Pathologischen Anatomie und Histologie, Vol. 13, Springer-Verlag, Berlin, GSttingen, Heidelberg, pp. 337-539. Zech, M., G.W. Roberts, G. Bogerts, T.J. Crow and J.M. Polak (1986) Neuropeptides in the amygdala of controls, schizophrenics and patients suffering from Huntington's chorea: an immunohistochemical study. Acta Neuropathol. (Berl.), 71: 259-266.