168
Journal of the Neurological Sciences, 108 (1992) 168-177 © 1992 Elsevier Science Publishers B.V. All rights reserved 0022-510X/92/$05.00
JNS 03714
Neuropathological background of twenty-seven centenarian brains Toshio Mizutani i and Hiroyuki Shimada 2 1Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, and 2 Department of Pathology, Tokyo Medical College, Tokyo (Japan) (Received 19 July, 1991) (Revised, received 2 October, 1991) (Accepted 4 October, 1991)
Key words: Centenarian; Brain ageing; Senile change; Senile dementia of Alzheimer type; Idiopathic Parkinson's disease; Head injury Summary The neuropathological features of 27 centenarian brains were investigated. They were found to have no fundamental differences from the brains of younger elderly individuals. It was noted that 3 centenarian brains showed no apparent senile changes or ischemic lesions and this group was designated "supernormal" centenarians, in contrast, there were 6 centenarian brains with numerous senile plaques in the cerebral cortex, a finding resembling that seen in senile dementia of the Alzheimer type (SDAT). However, these brains had only a few neurofibrillary tangles mainly in the hippocampus and the medial temporal lobe, and therefore were not affected by SDAT. These subjects were not truly demented. It was considered that these brains showed the upper limit of normal ageing, while the "supernormar' centenarians showed the lower limit. In addition, idiopathic Parkinson's disease was diagnosed pathologically in 4 subjects who did not show any clinical symptoms of this disease. Finally, 2 out of 5 cases with dementia developed it secondary to subdural haematoma.
Introduction
The proportion of extremely elderly individuals in the general population has increased rapidly, particularly in Japan. In fact, Japanese centenarians numbered over 3000, in September 1990. While there have been several pathological studies on the visceral organs of centenarians (Howell and Piggot 1951; lshii 1978a,b; Klatt and Meyer 1987), only' a few investigations of centenarian brains have been reported (Howell and Piggot 1951; Tomonaga and Yoshimura 1985). A neuropathological study of centenarian brains could provide information on the nature and degree of senile changes in the final stages of brain ageing, and help in our understanding of the morphological features specific to senile dementia of the Alzheimer type (SDAT). It has generally been assumed that SDAT does not represent the terminal stage of normal brain ageing, but is in fact a disease (Katzman and Terry 1983). Correspondence to: T. Mizutani, Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaechou, Itabashi-ku, Tokyo 173, Japan. Tel: (03X3964)3241; Fax: (03)(3579)4776; Telex: 02722468 TIG J.
Previously, we have briefly reported the neuropathological findings of 24 centenarians (Mizutani and Shimada 1990b) and recently added three additional autopsies. In this paper, we describe the detailed neuropathological findings of these 27 cases. Materials and methods
Clinical profile of the centenarians The centenarians included 7 men and 20 women who were autopsied from 1975 to 1991 (see Table 2). All of them remained in good mental condition until almost the end of life and there were no cases of severe dementia comparable with SDAT, even as a terminal event. No subject had a past history of previous neuropsychiatric illness. Unfortunately, long-term detailed neuropsychological studies were not performed for any of the subjects. Many of them temporarily had acute delirium just after admission to hospital. The oldest subject was a 106-year-old man who was a former professor of Japanese history (case 16). He continued to write even from his hospital bed at the end of his life. A 103-year-old man also had a history
169 of high intelligence and read various books even while in hospital (case 6). According to their partners a n d / o r children, another nine subjects had also led an active daily life (cases 5, 7, 8, 9, 12, 15, 17, 21, and 27). A further 9 subjects had slight cognitive dysfunction and disturbance of daily activites before the final admission (cases 1, 2, 3, 4, 13, 18, 20, 22, and 25). Cognitive function was apparently disturbed in cases 11 and 26 for one and five years before death, respectively. In addition, the mental function of another two subjects was altered after they suffered from subdural haematoma (SDH) due to a fall, even though emergency surgery was performed. One had been well until development of the SDH (case 14), while the other had already suffered from cognitive dysfunction for one year and her dementia became worse due to the SDH (case 19). There were 4 subjects with hemiparesis due to cerebral infarction shown by neurological examination at the time of admission (cases 22, 23, 24, and 26). There were also 3 subjects for whom a past history of dementia was not obtained, although slight cognitive dysfunction was observed during the final admission (cases 10, 23, and 24).
TABLE 1 NEUROPATHOLOGICAL FINDINGS OF THE 471 CONTROL BRAINS Disease
Number of cases
No significant changes and dementia 133 Tiny cerebral infarcts without dementia 104 Multi-infarct dementia 13 Large cerebral infarct 46 Large cerebral haemorrhage 25 Large cerebellar haemorrhage 3 Subarachnoid haemorrhagc 5 Progressive subcortical vascular encephalopathy of the Binswanger type 19 Brain tumors 5 Brain metastases of cancers 15 Bacterial meningitis 6 Idiopathic Parkinson's disease (iPD~ 13 Pathologically verified iPD without symptoms 20 Olivopontocerebellar atrophy 2
Sudanophilic leukodystrophy Progressive supranuclear palsy Senile dementia of the Alzheimer type Presenile Alzheimer's disease Dementia with amyloid angiopathy Dementia without significant changes
1 5 9 2 7 38
General pathological findings Except for case 27 whose direct cause of death was in the brain (cerebral haemorrhage), all the subjects died of visceral conditions, with cardiopulmonary diseases being the most common cause of death (16 cases, 59.3%). Pneumonia was found in 11 cases and heart disease in 5. Cancer was the direct cause of death in only 2 cases (lung and colon, respectively). Suffocation due to accidental airway obstruction also occurred in 2 cases.
Among the underlying pathological findings, pulmonary disease was the most frequent occurrence. Of the 9 cases with cardiac disease, organized myocardial infarct was found in 5 cases and valvular disease in 4. Six of these subjects also had a more-than-moderate degree of multiple cerebral infarcts (see Table 2). Cancer was found in 7 cases; it was clinically overt cancers in 4 cases and occult in 3. Another two subjects were cured after the cancer surgery.
Methods The controls were 471 autopsy cases accumulated from November 1988 to March 1991 at our hospital (56 subjects in the 60s age group, 153 in the 70s, 206 in the 80s, and 56 in the 90s). Their major neuropathological findings are shown in Table 1. All the brains were fixed in 10% formalin for 2 weeks. The cerebrum was sliced coronally, the brainstem horizontally, and the cerebellum sagittally. The tissue blocks taken from the sliced brains for histological examination ranged from half of a hemisphere to a whole hemisphere in size. Paraffin-embedded tissues
were cut into 10-/~m sections and were stained with haemtoxylin-eosin (H-E), Kliiver-Barrera (K-B) stain, and modified Bielschowsky method, Bodian's silver impregnation stain, and Hoizer's method. Neurons with neurofibrillary tangles (NFTs) were counted in the 4 anatomical subdivisions of the hippocampus (CA4, 3, 2, 1) at the level of the slice through the left lateral geniculate body (Duvernoy 1988). This was done in 133 normal controls aged from 60 to 94 years at death and in 22 of the 27 centenarians (the remaining 5 brains were not suitable, because of tiny infarcts in the hippocampus). In addition, NFTs were counted in 9 SDAT cases whose age at death ranged from 79 to 97 years (mean: 86.5, S.D.: 6.1) and whose duration of illness ranged from 1 to 16 years (mean: 5.5, S.D.: 4.1). More than 100 neurons were counted in each area of the preparations with the same staining and neurons with NFTs were recorded as a percentage (Mizutani and Shimada 1991). Senile plaques (SP) were counted in 23 of the 27 centenarians (the remaining 4 brains were not suitable, because the stained preparations did not included all the areas designated for counting) and in the 9 SDAT cases. The counting was performed in the following brain regions: the superior and inferior frontal gyri, rectal gyrus, rostral cingulate gyrus, superior, middle, and inferior temporal gyri, medial occipitotemporal gyms, parahippocampal gyrus, supra- and infraparietal lobules, and striate cortex. The number of SPs was determined in I0 different areas of each gyrus examined and the mean number/mm 2 was calculated. Diffuse plaques
170 TABLE THE
2
CEREBROVASCULAR
LESIONS
Mental
State (cognitive disturbance):
middle
cerebral
artery (MCA),
IN THE
PRESENT
+ + +: severe;
the posterior
cerebral
SERIES
OF 27 CENTENARIANS
+ +: moderate; artery (PCA),
+ : slight; -:
absent;
or their main
branches.
?: unknown. -:
absent;
* Infarcts in areas supplied + : small;
+ +:
moderate;
by the + + +:
e x t e n s i v e , f: f r e s h l e s i o n . * * T i n y i n f a r c t s d e t e c t e d b y t h e n u k e d e y e a n d h i s t o l o g i c a l l y . - : a b s e n t ; + : s l i g h t ; + + : m o d e r a t e ; + + + : m a n y . S u b d u r a l h a e m a t o m a : a : a c u t e ; o : o l d . A I : a o r t i c i n s u f f i c i e n c y ; AS~ a o r t i c s t e n o s i s ; A M I : a c u t e m y o c a r d i a l i n f a r c t ; O M I : o l d m y o c a r d i a l i n f a r c t ; a : acute; o: old. Case
Age/
Mental
Brain
Cerebral
Cerebral Infarct
No.
sex
state
weight (g)
hemorrhage
Large *
Small **
Pontine/
Subdural
Heart
cerebellar infarcts
hematoma
disease
1
100/F
+
1 120
.
.
.
.
/-
-
-
2
IO0/F
+
890
.
.
.
.
/-
+ (o)
-
3 4
101/F 101/F
+ +
1 130 1 170
. .
. .
. .
. .
// -
-
AI
5
102/M
-
1310
-
/
-
-
6
103/M
-
1300
.
.
.
/ -
-
-
7
102/F
-
1030
-
-
-
+ / -
+ (a)
-
8
103/M
-
1080
-
-
-
+ / -
-
-
9
102/F
-
1 100
-
-
-
+ / -
-
-
10 11
103/F 100/F
? + +
1060 1090
. -
-
+
/ + - / -
-
MI
12
lflO/F
-
870
-
-
+
- / -
-
-
13 14
100/F 101/F
+ + +
950 1220
-
-
+ +
- / - / +
+ (o)
OMI
15
105/F
-
1 100
-
-
+
- / -
-
-
16
-
1 140 1020
-
-
+
+ / -
-
-
17
106/M 100/F
-
-
+ +
-/+
-
AI
18 19
100/F 102/F
+
1 llO
-
-
+ +
-/+
+ (o)
+ +
1020
-
-
+ +
- / +
+ (o)
AS AMI, OMI
20
100/F
+
1 120
-
-
+ +
+/-
-
-
21
101/M
-
1 140
-
-
+ + +
+ +/+
+ (o)
-
22
100/F
+
1040
-
+ (MCA)
+ + +
+ +/+
-
OM!
23
100/M
?
1250
-
+ + (MCA)
+ +
- / +
-
-
24
101/F
?
1060
-
+ + + (MCA)
+
+/+
-
OMI
25
104/M
+
1 190
-
+ (f)(PCA)
+ +
+/+
-
-
26
103/F
+ + +
950
-
+ + (f)(PCA)
+
+ + + (f)/ +++
-
OM!
27
100/F
-
+ + + (f)
-
+
-/-
-
-
1260
-
-
.
.
.
that were separated from each other were counted as distinct SPs, while those which were not separated were counted as a single plaque.
Results
General features of the centenarian brains (Table 2) The brain weight ranged from 870 g to 1310 g (mean: 1101 g, S.D.: 113 g). Ten subjects had no apparent ischemic lesions in the cerebrum, while large cerebral infarcts were found in 5 cases and 2 of these showed fresh changes. Multiple infarcts only affecting the striatum were found in 6 cases, infarcts of the thalamus and white matter as well as the striatum were noted in 4 cases, and an infarct extending to the cerebral cortex was noted in one case. Massive cerebral haemorrhage which directly caused death was found
.
only in case 27. Haemorrhage did not affect both the cerebellum and the brainstem in any of the subjects. No apparent infarcts of either the cerebellum or the brainstem were found in 11 cases, while the remaining subjects had old infarcts in one or the other of these structures. Only case 26 had fresh and extensive infarction of the upper pontine base. This subject had lived in a vegetative state for 2 months after developing pontine infarction, and eventually died of severe pneumonia superimposed on idiopathic interstitial pulmonary fibrosis. There were no cases with progressive subcortical vascular encephalopathy of the Binswanger type. Subdural haematoma (SDH) was found in 6 subjects or occupied 22% of the present series of centenarians (cases 2, 7, 14, 18, 19, and 21). This was a much higher percentage than the 5% recorded for patients below 100 years old at our hospital. Only case 7 had acute
171 SDH. No apparent lesions were found in the brains of these centenarians, except that cases 14 and 19 had uncal herniation with bilateral laminar necrosis. Macroscopically, even small brains with a weight of under 1000 g showed no remarkable lobar atrophy a n d / o r ventricular dilatation. Only two brains (cases 3 and 10) showed temporal lobe atrophy, which was far less marked than that seen in the SDAT group.
Senile changes of the centenarian brains No SPs were found in 7 cases (Table 3). In the frontal and temporal lobes, SPs were absent in about
50% of cases. In the parieto-occipital region, there were no SPs in about 70% of cases (Fig. 1, Table 4). SPs were numerous in 6 subjects (cases 2, 3, 7, 10, 13, and 26) where they were significantly more common, and not different from the number found in SDAT cases (Figs. 3 and 4, Table 5). Therefore, the pathological findings of these centenarians resembled SDAT to some degree (SDAT-like changes). Furthermore, cases 2 and 26 had SPs in the hippocampus (Fig. 4A), and case 2 had them in the medial mamillary nucleus, whereas all the other brains had no SPs in these areas or in the other subcortical nuclei.
TABLE 3 S E N I L E C H A N G E S IN T H E C E N T E N A R I A N S Mental state (cognitive dysfunction): see Table 2. SP: senile plaques; NFT: neurofibrillary tangles. Senile changes: + + + : marked; + + : moderate; + : mild; - : absent, na: not available for examination, because of tiny infarcts. Cases 13, 24 and 26 appear in two different groups, because they had two major pathological findings. Case
Age/sex
No.
1. "Supernormal" centenarians 6 103/M 8 103/M 16 106/M 2. SDAT-like change 2 100/F 3 101/F 7 102/F 10 103/F 13 100/F 26 103/F
Mental
Brain
state
weight (g)
Senile changes SP Cerebral
NFT
cortex
Hippocampus
-
1300 1080 1 140 Mean: 1 173 g, S.D.: 93 g
+ + -
890 1 130 1030 1060 950 950 Mean: 1001 g, S.D.: 80 g
+ + + + + +
1 120 1 100 950 1060 Mean: 1058 g, S.D.: 66 g
+ + + + + +
? + +
3. Pathologically verified idiopathic Parkinson's disease 1 100/F + 9 102/F 13 100/F + 24 101/F ?
+ + + +
+ + + + + +
+ + + + + +
+ + + + + + + + + + +
+ + + + na
4. Cerebrovascular changes 17 18 19 20 21 22 23 24 25 26 27
100/F 100/F 102/F 100/F 101/M 100/F 100/M 101/F 104/M 103/F 100/F
5. Miscellaneous 4 5 11 12 14 15
101/F 102/M IO0/F 100/F 101/F 105/F
+ + + + + ?
? + + + + -
+ + + + + -
1020 1 110 + 1020 + 1120 1 140 + 1040 + ! 250 + 1060 + 1 190 + 950 + 1260 Mean: 1106 g, S.D.: 95 g 1 170 1310 1090 870 1220 1 100 Mean: 1127 g, S.D.: 137
+
+ + + +
+ + + + + + + + + g
+ + + + + + + + + + na + + na + + na
+ + na na + + + +
172 changes was not significantly different from that in the other centenarians, and differed from SDAT only in CA4 (Table 7). No apparent correlation was found between the frequency of SPs and NFTs in the neocortex, and that of NFTs in the hippocampus (Table 3). The distribution and the number of NFTs in the subcortical and brainstem nuclei of the centenarians with SDAT-like changes seemed to be essentially similar to those in the other centenarians, although a quantitative analysis was not performed. NFTs were found in the nucleus basalis of Meynert (Fig. 4E), the diagonal band of Broca, the intermediate and lateral mamillary nuclei, and the lateral and posterior nuclei of the hypothalamus. In the brainstem, the locus coeruleus always had NFTs. Lewy bodies were found in 8 centenarian brains (Fig. 6). Four of them also showed the typical pathological features of idiopathic Parkinson's disease (iPD), none of these subjects had any symptoms of this disease (cases 1, 9, 13, and 24). They showed loss of neurons accompanied by astrocytosis in the suhstantia nigra, the locus coeruleus, and the dorsal motor nucleus of the vagal nerve (Fig. 5). Neuronal loss was more severe in the locus coeruleus than in the substantia nigra. Lewy bodies were also found in the EdingerWestphal nucleus, the interstitial nucleus of Cajal, the subcuneiform nucleus, the superior central nucleus, the posterior nucleus of the hypothalamus, the lateral and intermediate mamillary nuclei, and the nucleus basalis of Meynert. However, no "cortical" Lewy bodies were found in the cerebral cortex. Another 4 centenarian brains had occasional Lewy bodies only in the locus coeruleus a n d / o r dorsal motor nucleus of the vagal nerve, with no neuronal loss being found in any of these nuclei (cases 10, 14, 15, and 16).
1312-
~]F! []Fa ~lac t~cc
1066420
i
I
i
I
I
I
I
13-
12I~1T1 ~ T = []T3 L~:':':'~T4LmPH
10O 0 e g
8=
u
6,O
E
II Z
42.
I
I
I
0, o I
I
16--
142 i
I~P~ r~p= msc
12108~,-
420
I
0
f5 Number
I
li:lO
i
li:15
I
I;20
I
li:25
!
>25
of Senile Plaques/ram 2
Fig. I. Histogram of the number of senile plaques/mm 2 in each region of the cerebral cortex in the present series of centenarians. FI: superior frontal cortex; F3: inferior frontal cortex; RC: rectal cortex; CC: cingulate cortex; TI: superior temporal cortex; T2: middle temporal cortex; T3: inferior temporal cortex; T4: medial occipito-temporal cortex; PH: parahippocampal cortex; PI: supraparietal cortex; P2: infraparietal cortex; SC: striate cortex.
1210m
:e l; U
Jm
In contrast, NFTs were very rare in the cerebral cortex in all the centenarians. Even the subjects with SDAT-like changes showed only a few NFTs in the temporal lobe and in the orbital region of the frontal lobe (Fig. 4B). In the hippocampus, all the brains had NFTs in all subdivisions from CA4 to CA1 (Table 6). In CA4, CA3, and CA2, a frequency of NFTs below 10% was found in 95% of all the subjects. In the CA1, however, they occupied only 10% (Fig. 2). The frequency of NFTs in the centenarians with SDAT-like
6=l 4
Z
2 !
0
~10 Number of NFTs (%)
[] CA4 []CA: [] e,: [] CA, Fig. 2. Histogram of the frequency of neurofibrillary tangles (percentages) in each region of the hippocampus in the centenarians.
i
i gi) N~
~--, ~_,~
~n
1,7'
,-
'.~.
t"
-~e~
Fig. 3. Distribution of senile changes in the "supernormal" centenarians, the centenarians with SDAT-like features and the SDAT patients. Brains of the "supemormal" centenarians are shown in A (case 6), B (case 8) and C (case 16). Centenarians with SDAT-Iike changes are shown in D (case 3), E (case 13) and F (case 2), while SDAT brains are shown in G (96 years old at death), H (83 years old) and I (89 years). Numerals in the cerebral cortex indicate the number of senile plaques/ram 2, and dots indicate neurofibrillary tangles.
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Fig. 4. Centenarian brains with SDAT-like features. A: CA] of the hippocampus in case 26 (modified Bielschowsl~ method, x 100). B: the parahippocampal cortex in case 2 (modified Bielschowsky method, x 100). C: the visual cortex in case 2 (modified Bielschowsky method, x 100). D: the inferior frontal cortex in case 3 (modified Bielschowsky method, x40). E: nucleus basalis of Meynert in case 2. Well-preserved neurons and slight astrocytosis (K-B, x 100).
Miscellaneous findings Among the 6 cases of SDH, 2 cases showed marked bilateral neuronal loss with astrocytosis in the uncus
and the oral portion of the hippocampus (cases 14 and 19). However, the caudal portion of the hippocampus showed no changes secondary to herniation. In addi-
175 TABLE 4 NUMBER OF CORTICAL SENILE PLAQUES/mm 2 IN THE PRESENT CENTENARIANS Twenty.three centenarian brains were available for assessment of the entire cortex. Fl: superior frontal cortex; F3: inferior frontal cortex; RC: rectal cortex; CC: cingulate cortex; Tl: superior temporal cortex; T2: middle temporal cortex; T3: inferior temporal cortex; T4: medial occipitotemporai cortex; PH: parahippocampus; Pl: supraparietai cortex; P2: infraparietal cortex; SC: striate cortex. Cortex
Mean
S.D.
Median
95th percentile
Maximum
Minimum
FI F3 RC CC T1 T2 T3 T4 PH Pl P2 SC
4.2 2.9 3.9 4.4 2.1 4.0 4.5 4.4 3.7 1.8 4.7 1.6
6.9 4.5 5A 6.8 3.3 6.0 6.2 6.0 5.6 3.0 12.2 2.8
0.0 0.5 0.3 0.1 0.0 0.5 0.6 0.0 0.0 0.0 0.0 0.0
14.5 6.9 11.7 14.5 4.8 13.0 11.4 13.2 11.8 6.3 9.0 5.8
27.3 18.7 18.4 22.3 13.6 21.5 20.9 20.9 18.9 10.1 59.0 10.3
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
TABLE 5 CORTICAL SENILE PLAQUES IN THE CENTENARIANS WITH AND WITHOUT SDAT-LIKE CHANGES AND IN THE SDAT PATIENTS Data are expressed as the number of senile plaques/mm 2. The values with the different letters were significantly different ( P < 0.01 ). Data are shown as the mean with S.D. in parentheses. The average age at death for SDAT patients was 86.5 years. The abbreviations are the same as those in Table 4. Cortex
Number of cases FI F3 RC CC T1 T2 I"3 T4 PH Pl P2 SC
Centenarians without SDATlike change
Centenarians with SDATlike change
SDAT
17 1.4 (2.9)a 0.9 (2.0)a 1.5 (3.1)a 1.9 (3.7)a 0.7 (1.5)a 1.6 (3.2)a 1.5 (2.9)a i.7 (3.7)a 1.6 (3.5)a 0.5 (l,4)a 0A (1.3)a 0.7 (1.6)a
6 12.0 (8.7)b 8.7 (4.8)b 10.6 (4.7)b 11.3 (8.3)b 6.1 (3.9)b 10.7 (7.0)b 12.9 (5.3)b 12.2 (4.5)b 9.5 (6.4)b 5.6 (3.1)b 16.0 ( 17.4)b 4.5 (3.6)b
9 11.9 (6.4)b 9.1 (5.3)b 12.9 (5.2)b 17.2 (7.4)b 8.7 (4.4)b 17.5 (7.0)b 18.1 (4.2)b 18.4 (6.8)b 16.1 (9.2)b 7.5 (5.3)b 11.4 (6.7)b 5.0 (2.8)b
TABLE 6 FREQUENCY OF HIPPOCAMPAL NEUROFIBRILLARY TANGLES IN THE CENTENARIANS The number of brains examined was 22. Data are shown as percentages.
Mean S.D. Median 95th Percentile Maximum Minimum
CA4
CA3
CA2
CAI
2.7 4.4 IA 4.3 21.1 0.0
2.6 5.4 1.1 4.5 26.0 0.0
3.3 7.0 1.0 10.4 30.8 0.0
22.6 23.2 12.1 43.1 91.7 0.0
tion, cortical contusions were found in the orbital region and in the temporal pole. In these areas, extensive degeneration of the subcortical white matter had occurred, but no astrocytosis was noted. Diffuse axonai injury (DAD was not found at any site (Adams et al. 1982; Mizutani et al. 1990a).
Discussion If the final stage of brain ageing is considered to be a state where the largest possible amount of senile changes have accumulated, then the centenarian brains we studied clearly did not fit this pattern. Instead, the neuropathological features of the 27 centenarian brains were not fundamentally different from those already detected in less elderly populations (Tomlinson et al. 1968, 1970). Our study also disclosed that 3 of the centenarian brains had only slight senile changes and
TABLE 7 HIPPOCAMPAL NEUROFIBRILLARY TANGLES IN THE C E N T E N A R I A N S WITH A N D W I T H O U T SDAT-LIKE CHANGES, AND IN THE SDAT PATIENTS Data are expressed as percentages. The values with the different letters are significantly different from each other ( P < 0.05). Data are shown as mean with S.D. in parentheses. The average age at death for SDAT patients was 86.5 years.
Number of cases CA4 CA3 CA2 CA1
Centenarians without SDATlike changes
Centenarians with SDATlike changes
SDAT
16 3.2 (5.0)a 1.3 (1.7)a 1.8 (3.5)a 25.2 (26.3)a
6 1.3 (1.6)a 6.0 (9.1)a 7.5(11.0)a 15.6 (7.5)a
9 7.5 (5.6)b 4.2 (3.1)a 4.9 (6.9)a 18.5 (13.8)a
176
~'~ ,,~
posed by Karasawa (1979, 1985), and by Keevil-Rogers and Schnore (1969). T h e r e was a contrasting group of brains with numerous SPs in the cerebral cortex that resembled S D A T brains in some respects, although there were also obvious differences. The most remarkable finding was that NFTs in the SDAT cerebral cortex far exceeded those in the SDAT-Iike centenarian brains with regard to both distribution and number. In addition, there was no neuronal loss with fibrillary gliosis in the cerebral cortex, the hippocampus, and the subcorticai nuclei in these centenarians. Both the number and the distribution of NFTs in the SDAT-like centenarians were not essentially different from those in the other centenarians and the younger elderly subjects. These results suggest that SDAT is not the final stage of brain ageing but a disease (Katzman and Terry 1983). In this regard, Karasawa performed evaluations using various dementia scales and found that although centenarians with moderate dementia were similar to SDAT cases, they still preserved adequate attention to their environment and the ability to join in conversation. He concluded that centenarians, even those with cognitive dysfunction, were different from truly demented elderly patients (1979, 1985). Quantitative studies on NFTs in the hippocampus have indicated that individual variations became larger with advancing age (Mizutani and Shimada 1991). While absence of NFTs in all subdivisions was found in any age group, the maximum frequency of NFTs became higher. The range from the minimum (total absence) to the maximum number of NFTs rapidly widened from the 70s to the 80s age group, and reached its broadest in the 90s age group. Therefore, it seems % 15"
/
Fig. 5, A centenarian brain with pathological changes suggesting idiopathic Parkinson's disease (ease 13). A: moderate loss of pigmented neurons with loss of myelin in the substantia nigra (K-B, × 10). B: moderate loss of neurons with Lewybodies (arrows) in the locus coeruleus(K-B, × 100). C: marked lossof neurons in the dorsal motor nucleusof the vagal nerve (K-B. ×40).
""
S o'
'° ': : :....:....:o..:...o:o..i........... o,..i.o..i,
0 no lesions of a vascular origin. The frequency of hippocampal NFTs in these 3 cases was comparable with that in the 80s age group (Mizutani and Shimada 1991), and we have proposed the term "supernormal" centenarians for such individuals (Mizutani and Shimada 1990). The present series was not examined by a long-term neuropsychological survey, but these subjects might correspond to the "excellent centenarians" pro-
.. ~,~ y
60s
7h
80a AGE
90a
100e
Fig. 6. Relationship of Lewybodies to idiopathic Parkinson's disease. A: subjects with incidental Lew¥ bodies; B: subjects with pathologically verified idiopathic Parkinson's disease; C: subjects with a clinicopathologicaldiagnosisof idiopathic Parkinson's disease. The curves A, B and C indicate the percentage of cases belonging to each category in relation to the total number of autopsycases in the same age group (the total number of autopsy cases for each age group is given in the text).
177 likely that the "supernormal" centenarians represented the lower limit of brain ageing in the 100s age group, with the SDAT-Iike centenarians showing the upper limit. It appears that they were naturally selected individuals with the ability to live longer. Furthermore, we would like to stress such "supernormai" people coutd be found at any age (Mizutani and Shimada 1991). If they avoid systemic diseases, particularly those of the cardiovascular organs, such individuals may be able to live for over one hundred years. It is usually assumed that Lewy bodies are one of the senile changes seen in brain ageing (Lipkin 1959; Woodard 1962; Forno 1969). Our study showed that the brains with neuronal loss and astrocytosis in the substantia nigra, locus coeruleus and dorsal motor nucleus of the vagal nerve had the same distribution of Lewy bodies as iPD patients; those without any neuronal loss also had scattered Lewy bodies mainly in the locus coeruleus and dorsal motor nucleus of the vagal nerve. Both types of brains increase in number with advancing age. After 60 years of age, the subjects with neuronal loss and Lewy bodies could be divided into clinical iPD and pathologically verified iPD without clinical symptoms. While the former group decreased in number (5.4% of all autopsy cases in the 60s age group and 0% in the 100s age group), the latter increased (0% in the 60s age group and 12.5% in the 100s age group) (Fig. 6). The multiple appearance of many Lewy bodies thus seems to be more than just a feature of brain ageing (Gibb and Lees 1987; Gibb 1988). Aclmewledlments We are grateful to all the staff of the Tokyo Metropolitan Geriatric Medical Centre and the staff of the New ropathology Department of the Tokyo Metropolitan Institute of Gerontology for their collaboration. We also thank Dr. Hiroynki Sato, of the Department of Statistics, Gakushuin University, for statistical analysis of the data and useful advice. This study was supported by funds for Research Projects of Senile Dementia from the Tokyo Metropolitan Government.
References Adams, J.H., T.A Gennarelli and D.I. Graham (1982) Brain damage in non-missile head injury: observations in man and subhuman primates. In: Smith, W.T. and Cavanagh, J.B. (Eds.), Recent Advances in Neuropathology, Vol. 2, Churchill Livingstone, London, pp. 165-190. Ball, M.J. (1978) Topographical distribution of neurnfibrillary tangles and granulovacuolar degeneration in the hippocampal cortex of
aging and demented patients. A quantitative study. Acta Neuropathoi. (Bed.), 42: 73-80. Duvernoy, H.M. (1988) The human hippocampus. An atlas of applied anatomy. Bergmann, Munich. Forno, L.S. (1969) Concentric hyaline intraneuronal inclusions of Lewy type in the brains of elderly persons (50 incidental cases). Relationship to parkinsonism. J. Am. Geriatr. Snc., 17: 557-575. Gibb, W.R.G. and AA. Lees (1987) The progression of idiopathic Parkinson's disease is not explained by age-related changes. Clinical and pathological comparisons with post-encephalitic parkinsonian syndrome. Acta Neuropathol. (Bed.), 73: 195-201. Gibb, W.R.G. (1988) The neuropathology of Pal"kj.nsoniandisorders. In: Jankovic, J. and Tolosa, E. (Eds.), Parkinson's disease and movement disorders. Urban and Schwarzenberg, Baltimore, pp. 2O5-223. Howell, T.H. and A.P. Piggot (1951) Morbid anatomy of old age. Geriatrics, 6: 85-95. lshii, T. (1978a) Pathology of centenarians. I. Cardiovascular system and lungs. J. Am. Geriatr. Soc, 26: 108-115. lshii, T. (1978b) Pathology of centenarians. II. Urogenital and digestive systems. J. Am. Geriatr. Soc., 26: 391-396. Karasawa, A. (1985) Changes in intellectual ability in normal human aging. Shinkei Kenkyu no Shinpo, 29:536-546 (in Japanese). Karasawa, A., K. Kawashima and H. Kasahara (1979) Mental aging and its medico-psycho-socialbackground in the very old Japanese. J. Gerontol., 14: 680-686. Katzman, R. and R.D. Terry (1983) Normal aging of the nervous system. In: Katzman, R. and Terry, R.D. (Eds.), The neurology of aging. Davis, Philadelphia, pp. 15-50. Keevil-Rogers, P. and M.M. Schnore (1969) Short-term memory as a function of age in persons of above average intelligence. J. Gerontol., 24: 184-188. Klatt, E.C. and P.R. Meyer (1987) Geriatric autopsy pathology in centenarians. Arch. Pathol. Lab. Med., 111: 367-369. Lipkin, L.E. (1959) Cytoplasmic inclusions in ganglion cells associated with parkinsonian states. Am. J. Pathol., 35: 1117-1133. Mizutani, T. and H. Shimada (1990) Neuropathological aspects of centenarian brains: study of 24 autopsy cases. In: Hasegawa, K. and Homma, A. (Eds.), Psychogeriatrics - Biomedical and Social Advances, Exce~ta Medica, Tokyo, pp. 128-133. Mizutani, T. and H. Shimada (1991) Quantitative study of neurofibrillary tangles in subdivisions of the hippocampus: CA?. as a special area in normal aging and senile dementia of Alzheimer type. Acta Pathnl. Jpn, 41:597-603. Mizutani, T., K. Hayakawa, T. Takizawa, M. Matsumoto and Y. Morimatsu (1990) Non-missile head injury: report of a patient surviving for six years. Neuropathol. Appl. Neurobioi., 16: 431435. Tomlinson, B.E., G. Blessed and M. Roth (1968) Observations on the brains of non-demented old people. J. Neurol. Sci., 7: 331-356. Tomlinson, B.E., G. Blessed and M. Roth (1970) Observations on the brains of demented people. J. Neurol. Sci., 11: 205-242. Tomonaga, M. and M. Yoshimura (1985) Neuropathology of the centenarian brains. Jpn. J. Geriat., 22:530-535 (Japanese). Woodard, J.S. (1962) Concentric hyaline inclusion body formation in mental disease. Analysis of twenty-seven cases. J. Neuropathol. Exp. Neurol., 21: 442-449.
Journal of the Neurological Sciences, 108 (1992) 168-177 © 1992 Elsevier Science Publishers B.V. All rights reserved 0022-510X/92/$05.00
JNS 03714
Neuropathological background of twenty-seven centenarian brains Toshio Mizutani i and Hiroyuki Shimada 2 1Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, and 2 Department of Pathology, Tokyo Medical College, Tokyo (Japan) (Received 19 July, 1991) (Revised, received 2 October, 1991) (Accepted 4 October, 1991)
Key words: Centenarian; Brain ageing; Senile change; Senile dementia of Alzheimer type; Idiopathic Parkinson's disease; Head injury Summary The neuropathological features of 27 centenarian brains were investigated. They were found to have no fundamental differences from the brains of younger elderly individuals. It was noted that 3 centenarian brains showed no apparent senile changes or ischemic lesions and this group was designated "supernormal" centenarians, in contrast, there were 6 centenarian brains with numerous senile plaques in the cerebral cortex, a finding resembling that seen in senile dementia of the Alzheimer type (SDAT). However, these brains had only a few neurofibrillary tangles mainly in the hippocampus and the medial temporal lobe, and therefore were not affected by SDAT. These subjects were not truly demented. It was considered that these brains showed the upper limit of normal ageing, while the "supernormar' centenarians showed the lower limit. In addition, idiopathic Parkinson's disease was diagnosed pathologically in 4 subjects who did not show any clinical symptoms of this disease. Finally, 2 out of 5 cases with dementia developed it secondary to subdural haematoma.
Introduction
The proportion of extremely elderly individuals in the general population has increased rapidly, particularly in Japan. In fact, Japanese centenarians numbered over 3000, in September 1990. While there have been several pathological studies on the visceral organs of centenarians (Howell and Piggot 1951; lshii 1978a,b; Klatt and Meyer 1987), only' a few investigations of centenarian brains have been reported (Howell and Piggot 1951; Tomonaga and Yoshimura 1985). A neuropathological study of centenarian brains could provide information on the nature and degree of senile changes in the final stages of brain ageing, and help in our understanding of the morphological features specific to senile dementia of the Alzheimer type (SDAT). It has generally been assumed that SDAT does not represent the terminal stage of normal brain ageing, but is in fact a disease (Katzman and Terry 1983). Correspondence to: T. Mizutani, Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaechou, Itabashi-ku, Tokyo 173, Japan. Tel: (03X3964)3241; Fax: (03)(3579)4776; Telex: 02722468 TIG J.
Previously, we have briefly reported the neuropathological findings of 24 centenarians (Mizutani and Shimada 1990b) and recently added three additional autopsies. In this paper, we describe the detailed neuropathological findings of these 27 cases. Materials and methods
Clinical profile of the centenarians The centenarians included 7 men and 20 women who were autopsied from 1975 to 1991 (see Table 2). All of them remained in good mental condition until almost the end of life and there were no cases of severe dementia comparable with SDAT, even as a terminal event. No subject had a past history of previous neuropsychiatric illness. Unfortunately, long-term detailed neuropsychological studies were not performed for any of the subjects. Many of them temporarily had acute delirium just after admission to hospital. The oldest subject was a 106-year-old man who was a former professor of Japanese history (case 16). He continued to write even from his hospital bed at the end of his life. A 103-year-old man also had a history
169 of high intelligence and read various books even while in hospital (case 6). According to their partners a n d / o r children, another nine subjects had also led an active daily life (cases 5, 7, 8, 9, 12, 15, 17, 21, and 27). A further 9 subjects had slight cognitive dysfunction and disturbance of daily activites before the final admission (cases 1, 2, 3, 4, 13, 18, 20, 22, and 25). Cognitive function was apparently disturbed in cases 11 and 26 for one and five years before death, respectively. In addition, the mental function of another two subjects was altered after they suffered from subdural haematoma (SDH) due to a fall, even though emergency surgery was performed. One had been well until development of the SDH (case 14), while the other had already suffered from cognitive dysfunction for one year and her dementia became worse due to the SDH (case 19). There were 4 subjects with hemiparesis due to cerebral infarction shown by neurological examination at the time of admission (cases 22, 23, 24, and 26). There were also 3 subjects for whom a past history of dementia was not obtained, although slight cognitive dysfunction was observed during the final admission (cases 10, 23, and 24).
TABLE 1 NEUROPATHOLOGICAL FINDINGS OF THE 471 CONTROL BRAINS Disease
Number of cases
No significant changes and dementia 133 Tiny cerebral infarcts without dementia 104 Multi-infarct dementia 13 Large cerebral infarct 46 Large cerebral haemorrhage 25 Large cerebellar haemorrhage 3 Subarachnoid haemorrhagc 5 Progressive subcortical vascular encephalopathy of the Binswanger type 19 Brain tumors 5 Brain metastases of cancers 15 Bacterial meningitis 6 Idiopathic Parkinson's disease (iPD~ 13 Pathologically verified iPD without symptoms 20 Olivopontocerebellar atrophy 2
Sudanophilic leukodystrophy Progressive supranuclear palsy Senile dementia of the Alzheimer type Presenile Alzheimer's disease Dementia with amyloid angiopathy Dementia without significant changes
1 5 9 2 7 38
General pathological findings Except for case 27 whose direct cause of death was in the brain (cerebral haemorrhage), all the subjects died of visceral conditions, with cardiopulmonary diseases being the most common cause of death (16 cases, 59.3%). Pneumonia was found in 11 cases and heart disease in 5. Cancer was the direct cause of death in only 2 cases (lung and colon, respectively). Suffocation due to accidental airway obstruction also occurred in 2 cases.
Among the underlying pathological findings, pulmonary disease was the most frequent occurrence. Of the 9 cases with cardiac disease, organized myocardial infarct was found in 5 cases and valvular disease in 4. Six of these subjects also had a more-than-moderate degree of multiple cerebral infarcts (see Table 2). Cancer was found in 7 cases; it was clinically overt cancers in 4 cases and occult in 3. Another two subjects were cured after the cancer surgery.
Methods The controls were 471 autopsy cases accumulated from November 1988 to March 1991 at our hospital (56 subjects in the 60s age group, 153 in the 70s, 206 in the 80s, and 56 in the 90s). Their major neuropathological findings are shown in Table 1. All the brains were fixed in 10% formalin for 2 weeks. The cerebrum was sliced coronally, the brainstem horizontally, and the cerebellum sagittally. The tissue blocks taken from the sliced brains for histological examination ranged from half of a hemisphere to a whole hemisphere in size. Paraffin-embedded tissues
were cut into 10-/~m sections and were stained with haemtoxylin-eosin (H-E), Kliiver-Barrera (K-B) stain, and modified Bielschowsky method, Bodian's silver impregnation stain, and Hoizer's method. Neurons with neurofibrillary tangles (NFTs) were counted in the 4 anatomical subdivisions of the hippocampus (CA4, 3, 2, 1) at the level of the slice through the left lateral geniculate body (Duvernoy 1988). This was done in 133 normal controls aged from 60 to 94 years at death and in 22 of the 27 centenarians (the remaining 5 brains were not suitable, because of tiny infarcts in the hippocampus). In addition, NFTs were counted in 9 SDAT cases whose age at death ranged from 79 to 97 years (mean: 86.5, S.D.: 6.1) and whose duration of illness ranged from 1 to 16 years (mean: 5.5, S.D.: 4.1). More than 100 neurons were counted in each area of the preparations with the same staining and neurons with NFTs were recorded as a percentage (Mizutani and Shimada 1991). Senile plaques (SP) were counted in 23 of the 27 centenarians (the remaining 4 brains were not suitable, because the stained preparations did not included all the areas designated for counting) and in the 9 SDAT cases. The counting was performed in the following brain regions: the superior and inferior frontal gyri, rectal gyrus, rostral cingulate gyrus, superior, middle, and inferior temporal gyri, medial occipitotemporal gyms, parahippocampal gyrus, supra- and infraparietal lobules, and striate cortex. The number of SPs was determined in I0 different areas of each gyrus examined and the mean number/mm 2 was calculated. Diffuse plaques
170 TABLE THE
2
CEREBROVASCULAR
LESIONS
Mental
State (cognitive disturbance):
middle
cerebral
artery (MCA),
IN THE
PRESENT
+ + +: severe;
the posterior
cerebral
SERIES
OF 27 CENTENARIANS
+ +: moderate; artery (PCA),
+ : slight; -:
absent;
or their main
branches.
?: unknown. -:
absent;
* Infarcts in areas supplied + : small;
+ +:
moderate;
by the + + +:
e x t e n s i v e , f: f r e s h l e s i o n . * * T i n y i n f a r c t s d e t e c t e d b y t h e n u k e d e y e a n d h i s t o l o g i c a l l y . - : a b s e n t ; + : s l i g h t ; + + : m o d e r a t e ; + + + : m a n y . S u b d u r a l h a e m a t o m a : a : a c u t e ; o : o l d . A I : a o r t i c i n s u f f i c i e n c y ; AS~ a o r t i c s t e n o s i s ; A M I : a c u t e m y o c a r d i a l i n f a r c t ; O M I : o l d m y o c a r d i a l i n f a r c t ; a : acute; o: old. Case
Age/
Mental
Brain
Cerebral
Cerebral Infarct
No.
sex
state
weight (g)
hemorrhage
Large *
Small **
Pontine/
Subdural
Heart
cerebellar infarcts
hematoma
disease
1
100/F
+
1 120
.
.
.
.
/-
-
-
2
IO0/F
+
890
.
.
.
.
/-
+ (o)
-
3 4
101/F 101/F
+ +
1 130 1 170
. .
. .
. .
. .
// -
-
AI
5
102/M
-
1310
-
/
-
-
6
103/M
-
1300
.
.
.
/ -
-
-
7
102/F
-
1030
-
-
-
+ / -
+ (a)
-
8
103/M
-
1080
-
-
-
+ / -
-
-
9
102/F
-
1 100
-
-
-
+ / -
-
-
10 11
103/F 100/F
? + +
1060 1090
. -
-
+
/ + - / -
-
MI
12
lflO/F
-
870
-
-
+
- / -
-
-
13 14
100/F 101/F
+ + +
950 1220
-
-
+ +
- / - / +
+ (o)
OMI
15
105/F
-
1 100
-
-
+
- / -
-
-
16
-
1 140 1020
-
-
+
+ / -
-
-
17
106/M 100/F
-
-
+ +
-/+
-
AI
18 19
100/F 102/F
+
1 llO
-
-
+ +
-/+
+ (o)
+ +
1020
-
-
+ +
- / +
+ (o)
AS AMI, OMI
20
100/F
+
1 120
-
-
+ +
+/-
-
-
21
101/M
-
1 140
-
-
+ + +
+ +/+
+ (o)
-
22
100/F
+
1040
-
+ (MCA)
+ + +
+ +/+
-
OM!
23
100/M
?
1250
-
+ + (MCA)
+ +
- / +
-
-
24
101/F
?
1060
-
+ + + (MCA)
+
+/+
-
OMI
25
104/M
+
1 190
-
+ (f)(PCA)
+ +
+/+
-
-
26
103/F
+ + +
950
-
+ + (f)(PCA)
+
+ + + (f)/ +++
-
OM!
27
100/F
-
+ + + (f)
-
+
-/-
-
-
1260
-
-
.
.
.
that were separated from each other were counted as distinct SPs, while those which were not separated were counted as a single plaque.
Results
General features of the centenarian brains (Table 2) The brain weight ranged from 870 g to 1310 g (mean: 1101 g, S.D.: 113 g). Ten subjects had no apparent ischemic lesions in the cerebrum, while large cerebral infarcts were found in 5 cases and 2 of these showed fresh changes. Multiple infarcts only affecting the striatum were found in 6 cases, infarcts of the thalamus and white matter as well as the striatum were noted in 4 cases, and an infarct extending to the cerebral cortex was noted in one case. Massive cerebral haemorrhage which directly caused death was found
.
only in case 27. Haemorrhage did not affect both the cerebellum and the brainstem in any of the subjects. No apparent infarcts of either the cerebellum or the brainstem were found in 11 cases, while the remaining subjects had old infarcts in one or the other of these structures. Only case 26 had fresh and extensive infarction of the upper pontine base. This subject had lived in a vegetative state for 2 months after developing pontine infarction, and eventually died of severe pneumonia superimposed on idiopathic interstitial pulmonary fibrosis. There were no cases with progressive subcortical vascular encephalopathy of the Binswanger type. Subdural haematoma (SDH) was found in 6 subjects or occupied 22% of the present series of centenarians (cases 2, 7, 14, 18, 19, and 21). This was a much higher percentage than the 5% recorded for patients below 100 years old at our hospital. Only case 7 had acute
171 SDH. No apparent lesions were found in the brains of these centenarians, except that cases 14 and 19 had uncal herniation with bilateral laminar necrosis. Macroscopically, even small brains with a weight of under 1000 g showed no remarkable lobar atrophy a n d / o r ventricular dilatation. Only two brains (cases 3 and 10) showed temporal lobe atrophy, which was far less marked than that seen in the SDAT group.
Senile changes of the centenarian brains No SPs were found in 7 cases (Table 3). In the frontal and temporal lobes, SPs were absent in about
50% of cases. In the parieto-occipital region, there were no SPs in about 70% of cases (Fig. 1, Table 4). SPs were numerous in 6 subjects (cases 2, 3, 7, 10, 13, and 26) where they were significantly more common, and not different from the number found in SDAT cases (Figs. 3 and 4, Table 5). Therefore, the pathological findings of these centenarians resembled SDAT to some degree (SDAT-like changes). Furthermore, cases 2 and 26 had SPs in the hippocampus (Fig. 4A), and case 2 had them in the medial mamillary nucleus, whereas all the other brains had no SPs in these areas or in the other subcortical nuclei.
TABLE 3 S E N I L E C H A N G E S IN T H E C E N T E N A R I A N S Mental state (cognitive dysfunction): see Table 2. SP: senile plaques; NFT: neurofibrillary tangles. Senile changes: + + + : marked; + + : moderate; + : mild; - : absent, na: not available for examination, because of tiny infarcts. Cases 13, 24 and 26 appear in two different groups, because they had two major pathological findings. Case
Age/sex
No.
1. "Supernormal" centenarians 6 103/M 8 103/M 16 106/M 2. SDAT-like change 2 100/F 3 101/F 7 102/F 10 103/F 13 100/F 26 103/F
Mental
Brain
state
weight (g)
Senile changes SP Cerebral
NFT
cortex
Hippocampus
-
1300 1080 1 140 Mean: 1 173 g, S.D.: 93 g
+ + -
890 1 130 1030 1060 950 950 Mean: 1001 g, S.D.: 80 g
+ + + + + +
1 120 1 100 950 1060 Mean: 1058 g, S.D.: 66 g
+ + + + + +
? + +
3. Pathologically verified idiopathic Parkinson's disease 1 100/F + 9 102/F 13 100/F + 24 101/F ?
+ + + +
+ + + + + +
+ + + + + +
+ + + + + + + + + + +
+ + + + na
4. Cerebrovascular changes 17 18 19 20 21 22 23 24 25 26 27
100/F 100/F 102/F 100/F 101/M 100/F 100/M 101/F 104/M 103/F 100/F
5. Miscellaneous 4 5 11 12 14 15
101/F 102/M IO0/F 100/F 101/F 105/F
+ + + + + ?
? + + + + -
+ + + + + -
1020 1 110 + 1020 + 1120 1 140 + 1040 + ! 250 + 1060 + 1 190 + 950 + 1260 Mean: 1106 g, S.D.: 95 g 1 170 1310 1090 870 1220 1 100 Mean: 1127 g, S.D.: 137
+
+ + + +
+ + + + + + + + + g
+ + + + + + + + + + na + + na + + na
+ + na na + + + +
172 changes was not significantly different from that in the other centenarians, and differed from SDAT only in CA4 (Table 7). No apparent correlation was found between the frequency of SPs and NFTs in the neocortex, and that of NFTs in the hippocampus (Table 3). The distribution and the number of NFTs in the subcortical and brainstem nuclei of the centenarians with SDAT-like changes seemed to be essentially similar to those in the other centenarians, although a quantitative analysis was not performed. NFTs were found in the nucleus basalis of Meynert (Fig. 4E), the diagonal band of Broca, the intermediate and lateral mamillary nuclei, and the lateral and posterior nuclei of the hypothalamus. In the brainstem, the locus coeruleus always had NFTs. Lewy bodies were found in 8 centenarian brains (Fig. 6). Four of them also showed the typical pathological features of idiopathic Parkinson's disease (iPD), none of these subjects had any symptoms of this disease (cases 1, 9, 13, and 24). They showed loss of neurons accompanied by astrocytosis in the suhstantia nigra, the locus coeruleus, and the dorsal motor nucleus of the vagal nerve (Fig. 5). Neuronal loss was more severe in the locus coeruleus than in the substantia nigra. Lewy bodies were also found in the EdingerWestphal nucleus, the interstitial nucleus of Cajal, the subcuneiform nucleus, the superior central nucleus, the posterior nucleus of the hypothalamus, the lateral and intermediate mamillary nuclei, and the nucleus basalis of Meynert. However, no "cortical" Lewy bodies were found in the cerebral cortex. Another 4 centenarian brains had occasional Lewy bodies only in the locus coeruleus a n d / o r dorsal motor nucleus of the vagal nerve, with no neuronal loss being found in any of these nuclei (cases 10, 14, 15, and 16).
1312-
~]F! []Fa ~lac t~cc
1066420
i
I
i
I
I
I
I
13-
12I~1T1 ~ T = []T3 L~:':':'~T4LmPH
10O 0 e g
8=
u
6,O
E
II Z
42.
I
I
I
0, o I
I
16--
142 i
I~P~ r~p= msc
12108~,-
420
I
0
f5 Number
I
li:lO
i
li:15
I
I;20
I
li:25
!
>25
of Senile Plaques/ram 2
Fig. I. Histogram of the number of senile plaques/mm 2 in each region of the cerebral cortex in the present series of centenarians. FI: superior frontal cortex; F3: inferior frontal cortex; RC: rectal cortex; CC: cingulate cortex; TI: superior temporal cortex; T2: middle temporal cortex; T3: inferior temporal cortex; T4: medial occipito-temporal cortex; PH: parahippocampal cortex; PI: supraparietal cortex; P2: infraparietal cortex; SC: striate cortex.
1210m
:e l; U
Jm
In contrast, NFTs were very rare in the cerebral cortex in all the centenarians. Even the subjects with SDAT-like changes showed only a few NFTs in the temporal lobe and in the orbital region of the frontal lobe (Fig. 4B). In the hippocampus, all the brains had NFTs in all subdivisions from CA4 to CA1 (Table 6). In CA4, CA3, and CA2, a frequency of NFTs below 10% was found in 95% of all the subjects. In the CA1, however, they occupied only 10% (Fig. 2). The frequency of NFTs in the centenarians with SDAT-like
6=l 4
Z
2 !
0
~10 Number of NFTs (%)
[] CA4 []CA: [] e,: [] CA, Fig. 2. Histogram of the frequency of neurofibrillary tangles (percentages) in each region of the hippocampus in the centenarians.
i
i gi) N~
~--, ~_,~
~n
1,7'
,-
'.~.
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Fig. 3. Distribution of senile changes in the "supernormal" centenarians, the centenarians with SDAT-like features and the SDAT patients. Brains of the "supemormal" centenarians are shown in A (case 6), B (case 8) and C (case 16). Centenarians with SDAT-Iike changes are shown in D (case 3), E (case 13) and F (case 2), while SDAT brains are shown in G (96 years old at death), H (83 years old) and I (89 years). Numerals in the cerebral cortex indicate the number of senile plaques/ram 2, and dots indicate neurofibrillary tangles.
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Fig. 4. Centenarian brains with SDAT-like features. A: CA] of the hippocampus in case 26 (modified Bielschowsl~ method, x 100). B: the parahippocampal cortex in case 2 (modified Bielschowsky method, x 100). C: the visual cortex in case 2 (modified Bielschowsky method, x 100). D: the inferior frontal cortex in case 3 (modified Bielschowsky method, x40). E: nucleus basalis of Meynert in case 2. Well-preserved neurons and slight astrocytosis (K-B, x 100).
Miscellaneous findings Among the 6 cases of SDH, 2 cases showed marked bilateral neuronal loss with astrocytosis in the uncus
and the oral portion of the hippocampus (cases 14 and 19). However, the caudal portion of the hippocampus showed no changes secondary to herniation. In addi-
175 TABLE 4 NUMBER OF CORTICAL SENILE PLAQUES/mm 2 IN THE PRESENT CENTENARIANS Twenty.three centenarian brains were available for assessment of the entire cortex. Fl: superior frontal cortex; F3: inferior frontal cortex; RC: rectal cortex; CC: cingulate cortex; Tl: superior temporal cortex; T2: middle temporal cortex; T3: inferior temporal cortex; T4: medial occipitotemporai cortex; PH: parahippocampus; Pl: supraparietai cortex; P2: infraparietal cortex; SC: striate cortex. Cortex
Mean
S.D.
Median
95th percentile
Maximum
Minimum
FI F3 RC CC T1 T2 T3 T4 PH Pl P2 SC
4.2 2.9 3.9 4.4 2.1 4.0 4.5 4.4 3.7 1.8 4.7 1.6
6.9 4.5 5A 6.8 3.3 6.0 6.2 6.0 5.6 3.0 12.2 2.8
0.0 0.5 0.3 0.1 0.0 0.5 0.6 0.0 0.0 0.0 0.0 0.0
14.5 6.9 11.7 14.5 4.8 13.0 11.4 13.2 11.8 6.3 9.0 5.8
27.3 18.7 18.4 22.3 13.6 21.5 20.9 20.9 18.9 10.1 59.0 10.3
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
TABLE 5 CORTICAL SENILE PLAQUES IN THE CENTENARIANS WITH AND WITHOUT SDAT-LIKE CHANGES AND IN THE SDAT PATIENTS Data are expressed as the number of senile plaques/mm 2. The values with the different letters were significantly different ( P < 0.01 ). Data are shown as the mean with S.D. in parentheses. The average age at death for SDAT patients was 86.5 years. The abbreviations are the same as those in Table 4. Cortex
Number of cases FI F3 RC CC T1 T2 I"3 T4 PH Pl P2 SC
Centenarians without SDATlike change
Centenarians with SDATlike change
SDAT
17 1.4 (2.9)a 0.9 (2.0)a 1.5 (3.1)a 1.9 (3.7)a 0.7 (1.5)a 1.6 (3.2)a 1.5 (2.9)a i.7 (3.7)a 1.6 (3.5)a 0.5 (l,4)a 0A (1.3)a 0.7 (1.6)a
6 12.0 (8.7)b 8.7 (4.8)b 10.6 (4.7)b 11.3 (8.3)b 6.1 (3.9)b 10.7 (7.0)b 12.9 (5.3)b 12.2 (4.5)b 9.5 (6.4)b 5.6 (3.1)b 16.0 ( 17.4)b 4.5 (3.6)b
9 11.9 (6.4)b 9.1 (5.3)b 12.9 (5.2)b 17.2 (7.4)b 8.7 (4.4)b 17.5 (7.0)b 18.1 (4.2)b 18.4 (6.8)b 16.1 (9.2)b 7.5 (5.3)b 11.4 (6.7)b 5.0 (2.8)b
TABLE 6 FREQUENCY OF HIPPOCAMPAL NEUROFIBRILLARY TANGLES IN THE CENTENARIANS The number of brains examined was 22. Data are shown as percentages.
Mean S.D. Median 95th Percentile Maximum Minimum
CA4
CA3
CA2
CAI
2.7 4.4 IA 4.3 21.1 0.0
2.6 5.4 1.1 4.5 26.0 0.0
3.3 7.0 1.0 10.4 30.8 0.0
22.6 23.2 12.1 43.1 91.7 0.0
tion, cortical contusions were found in the orbital region and in the temporal pole. In these areas, extensive degeneration of the subcortical white matter had occurred, but no astrocytosis was noted. Diffuse axonai injury (DAD was not found at any site (Adams et al. 1982; Mizutani et al. 1990a).
Discussion If the final stage of brain ageing is considered to be a state where the largest possible amount of senile changes have accumulated, then the centenarian brains we studied clearly did not fit this pattern. Instead, the neuropathological features of the 27 centenarian brains were not fundamentally different from those already detected in less elderly populations (Tomlinson et al. 1968, 1970). Our study also disclosed that 3 of the centenarian brains had only slight senile changes and
TABLE 7 HIPPOCAMPAL NEUROFIBRILLARY TANGLES IN THE C E N T E N A R I A N S WITH A N D W I T H O U T SDAT-LIKE CHANGES, AND IN THE SDAT PATIENTS Data are expressed as percentages. The values with the different letters are significantly different from each other ( P < 0.05). Data are shown as mean with S.D. in parentheses. The average age at death for SDAT patients was 86.5 years.
Number of cases CA4 CA3 CA2 CA1
Centenarians without SDATlike changes
Centenarians with SDATlike changes
SDAT
16 3.2 (5.0)a 1.3 (1.7)a 1.8 (3.5)a 25.2 (26.3)a
6 1.3 (1.6)a 6.0 (9.1)a 7.5(11.0)a 15.6 (7.5)a
9 7.5 (5.6)b 4.2 (3.1)a 4.9 (6.9)a 18.5 (13.8)a
176
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posed by Karasawa (1979, 1985), and by Keevil-Rogers and Schnore (1969). T h e r e was a contrasting group of brains with numerous SPs in the cerebral cortex that resembled S D A T brains in some respects, although there were also obvious differences. The most remarkable finding was that NFTs in the SDAT cerebral cortex far exceeded those in the SDAT-Iike centenarian brains with regard to both distribution and number. In addition, there was no neuronal loss with fibrillary gliosis in the cerebral cortex, the hippocampus, and the subcorticai nuclei in these centenarians. Both the number and the distribution of NFTs in the SDAT-like centenarians were not essentially different from those in the other centenarians and the younger elderly subjects. These results suggest that SDAT is not the final stage of brain ageing but a disease (Katzman and Terry 1983). In this regard, Karasawa performed evaluations using various dementia scales and found that although centenarians with moderate dementia were similar to SDAT cases, they still preserved adequate attention to their environment and the ability to join in conversation. He concluded that centenarians, even those with cognitive dysfunction, were different from truly demented elderly patients (1979, 1985). Quantitative studies on NFTs in the hippocampus have indicated that individual variations became larger with advancing age (Mizutani and Shimada 1991). While absence of NFTs in all subdivisions was found in any age group, the maximum frequency of NFTs became higher. The range from the minimum (total absence) to the maximum number of NFTs rapidly widened from the 70s to the 80s age group, and reached its broadest in the 90s age group. Therefore, it seems % 15"
/
Fig. 5, A centenarian brain with pathological changes suggesting idiopathic Parkinson's disease (ease 13). A: moderate loss of pigmented neurons with loss of myelin in the substantia nigra (K-B, × 10). B: moderate loss of neurons with Lewybodies (arrows) in the locus coeruleus(K-B, × 100). C: marked lossof neurons in the dorsal motor nucleusof the vagal nerve (K-B. ×40).
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0 no lesions of a vascular origin. The frequency of hippocampal NFTs in these 3 cases was comparable with that in the 80s age group (Mizutani and Shimada 1991), and we have proposed the term "supernormal" centenarians for such individuals (Mizutani and Shimada 1990). The present series was not examined by a long-term neuropsychological survey, but these subjects might correspond to the "excellent centenarians" pro-
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60s
7h
80a AGE
90a
100e
Fig. 6. Relationship of Lewybodies to idiopathic Parkinson's disease. A: subjects with incidental Lew¥ bodies; B: subjects with pathologically verified idiopathic Parkinson's disease; C: subjects with a clinicopathologicaldiagnosisof idiopathic Parkinson's disease. The curves A, B and C indicate the percentage of cases belonging to each category in relation to the total number of autopsycases in the same age group (the total number of autopsy cases for each age group is given in the text).
177 likely that the "supernormal" centenarians represented the lower limit of brain ageing in the 100s age group, with the SDAT-Iike centenarians showing the upper limit. It appears that they were naturally selected individuals with the ability to live longer. Furthermore, we would like to stress such "supernormai" people coutd be found at any age (Mizutani and Shimada 1991). If they avoid systemic diseases, particularly those of the cardiovascular organs, such individuals may be able to live for over one hundred years. It is usually assumed that Lewy bodies are one of the senile changes seen in brain ageing (Lipkin 1959; Woodard 1962; Forno 1969). Our study showed that the brains with neuronal loss and astrocytosis in the substantia nigra, locus coeruleus and dorsal motor nucleus of the vagal nerve had the same distribution of Lewy bodies as iPD patients; those without any neuronal loss also had scattered Lewy bodies mainly in the locus coeruleus and dorsal motor nucleus of the vagal nerve. Both types of brains increase in number with advancing age. After 60 years of age, the subjects with neuronal loss and Lewy bodies could be divided into clinical iPD and pathologically verified iPD without clinical symptoms. While the former group decreased in number (5.4% of all autopsy cases in the 60s age group and 0% in the 100s age group), the latter increased (0% in the 60s age group and 12.5% in the 100s age group) (Fig. 6). The multiple appearance of many Lewy bodies thus seems to be more than just a feature of brain ageing (Gibb and Lees 1987; Gibb 1988). Aclmewledlments We are grateful to all the staff of the Tokyo Metropolitan Geriatric Medical Centre and the staff of the New ropathology Department of the Tokyo Metropolitan Institute of Gerontology for their collaboration. We also thank Dr. Hiroynki Sato, of the Department of Statistics, Gakushuin University, for statistical analysis of the data and useful advice. This study was supported by funds for Research Projects of Senile Dementia from the Tokyo Metropolitan Government.
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