NORMAL AGING A N D DEMENTIA OF ALZHEIMER TYPE
AKADEMISK AVHANDLING
som med vederbörligt tillstånd av Rektorsämbetet vid Umeå Universitet för avläggande av medicine doktorsexamen
kommer att offen tligen försvaras i
hörsal D , Samhällsvetarhuset, fredagen den 19 dec. 1980 kl. 09.00.
av
ROLF ADOLFSSON
ABSTRACT
CLIN IC A L STUDIES A N D CHEM ICAL PA TH O L O G Y IN N O M A L A G IN G A N D D E M E N T IA OF ALZHEIM ER TYPE.
by R. Adolfsson, Department of Psychiatry and Pathology, University of Umeå, S-901 87 Umeå, Sweden.
1. The prevalence of dementia disorders in an institutionalized clientele 65 years and older was 3.7°/o of the total population of the county of Västerbotten. The highest percentage demented (55-65%) of the institutionalized people) was found in somatic long-stay wards, nursing homes and in the mental hospital. A surpris ingly high percentage demented (17.1°/o) was found in the homes for the aged. 2. Brain concentrations of the monoamines, their metabolites and the activity of the
degrading enzyme, monoamine oxidase (MAO) were determined post mortem in normal aging and in dementia of Alzheimer type. Dopamine concentration showed an age dependent decrease in the nucleus caudatus, globus pallidus, mesencephalon and in the cortex gyrus hippocampus.Patients with dementia of Alzheimer type had lower mean concentrations of the monoamines in several parts of the brain compared with age-matched controls.
3. Thirty-six patients with dementia of Alzheimer type were evaluated by means of computerized tomography, cerebrospinal fluid studies and rating for deter mining the degree of dementia. A significant correlation between cortical atrophy and intellectual functioning was found.
Key words: Dementia — senile dementia — Alzheimer’s disease — aging — epidemio- logy — biochemistry — monoamines — monoamine oxidase — com puterized tomopraphy.
From the Department of Psychiatry and Pathology, Umeå University Hospital, Umeå, Sweden.
Clinical Studies and Chemical Pathology
in Normal Aging and Dementia
of Alzheimer Type
4 CONTENTS A b s t r a c t 5 I n t r o d u c t i o n 7 Epidemiology o f dement ia 7 C l i n i c a l a s p e c t s 8 Biochemical f i n d i n g s 10 M a t e r i a l and Methods 13 E p i de m i o l o g i c a l s t u d y 13 Post mortem s t u d i e s 13 C l i n i c a l s t u d i e s 15 R e s u l t s and D i s cu s s i o n 17 P r e v a l e n c e o f dement ia d i s o r d e r s 17 Monoamines, m e t a b o l i t e s , MAO-activity 22 C er ebr al a t r o p h y , c e r e b r o s p i n a l f l u i d m e t a b o l i t e s and mental f u n c t i o n s 33 Acknowledgement 38 Ref e re nc es 39 P r e v a l e n c e o f dement ia d i s o r d e r s in i n s t i t u t i o n a l i z e d
Swedish o l d people and t h e i r workload ( I ) 49
Post mortem d i s t r i b u t i o n o f dopamine and h o m o v a n i l l i c a c i d in human b r a i n , v a r i a t i o n s r e l a t e d t o a g e , and
a review o f t h e l i t e r a t u r e ( I I ) 83
Changes in t h e b r a i n c a t e c h o l a m i n e s in p a t i e n t s with
dement ia o f Alzheimer ty pe ( I I I ) 109
I n c r e a s e d a c t i v i t y o f b r a i n and p l a t e l e t monoamine
o x i d a s e in dement ia o f Alzheimer t y p e (IV) 117 C er e br al a t r o p h y , c e r e b r o s p i n a l f l u i d m e t a b o l i t e s
and i n t e l l e c t u a l impairment in p a t i e n t s w i th dementia
C l i n i c a l s t u d i e s and chemical p a t h o l o g y in normal a g i n g and dementia o f Alzheimer t y p e .
by R. A d o l f s s o n , Department o f P s y c h i a t r y and P a t h o l o g y , U n i v e r s i t y o f Umeå, S - 901 87 Umeå, Sweden.
ABSTRACT
1. The p r e v a l e n c e o f dement ia d i s o r d e r s in an i n s t i t u t i o n a l i z e d c l i e n t e l e 65 y e a r s and o l d e r was 3.7 % o f t h e t o t a l p o p u l a t i o n o f t h e c ounty o f V ä s t e r b o t t e n . The h i g h e s t p e r c e n t a g e demented (55-65 % o f t h e i n s t i t u t i o n a l i z e d p e o pl e ) was found i n s omat ic l o n g - s t a y w a rd s, n u r s i n g homes and in t h e mental h o s p i t a l . A s u r p r i s i n g l y high p e r c e n t a g e demented
(17.1 %) was found in t h e homes f o r t h e aged.
2. Brain c o n c e n t r a t i o n s o f t h e monoamines, t h e i r m e t a b o l i t e s and t h e a c t i v i t y o f t h e d e g r a d i n g enzyme, monoamine o x i d a s e (MAO) were
d e t er m i ne d p o s t mortem in normal a g in g and in dement ia o f Alzheimer t y p e . Dopamine c o n c e n t r a t i o n showed an age dependent d e c r e a s e in t h e n u c l e u s c a u d a t u s , g lobus pal l i d u s , mesencephalon and in t h e c o r t e x gyrus
hippocampus. P a t i e n t s w i th dement ia o f Alzheimer t y p e had lower mean c o n c e n t r a t i o n s o f t h e monoamines in s e v e r a l p a r t s o f t h e b r a i n compared w i t h a ge- matched c o n t r o l s .
3. T h i r t y - s i x p a t i e n t s w i th dement ia o f Alzheimer t y p e were e v a l u a t e d by means o f c o mp u te r iz ed tomography, c e r e b r o s p i n a l f l u i d s t u d i e s and
r a t i n g f o r d e t e r m i n i n g t h e d e gr ee o f de me nt i a. A s i g n i f i c a n t c o r r e l a t i o n between c o r t i c a l a t r o p h y and i n t e l l e c t u a l f u n c t i o n i n g was found.
Key words: Dementia - s e n i l e dement ia - A l z h e i m e r ' s d i s e a s e - aging - e pi demi ol og y - b i o c h e m i s t r y - monoamines - monoamine o x i d a s e -
The p r e s e n t t h e s i s i s mainly based on t h e f o l l o w i n g r e p o r t s :
I R. A d o l f s s o n , C.-G. G o t t f r i e s , L. Nyström, B. Winblad: P r e v a l e n c e o f dement ia d i s o r d e r s in i n s t i t u t i o n a l i z e d Swedish o l d p e o pl e and t h e i r wo rkl oa d. Acta P s y c h i a t . Scand. Accepted f o r p u b l i c a t i o n .
II R. A do l f s s o n , C.-G. G o t t f r i e s , B.-E. Roos, B. Winblad: Pos t mortem d i s t r i b u t i o n o f dopamine and h o m o v a n i l l i c a c i d in human b r a i n , v a r i a t i o n s r e l a t e d t o a g e , and a review o f t h e l i t e r a t u r e . J . N e u ra l . T r a n s . 45, 8 1-105, 1979.
I I I R. A d o l f s s o n , C.-G. G o t t f r i e s , B.-E. Roos, B. Winblad: Changes in t h e b r a i n c a t e c h o l a m i n e s in p a t i e n t s wi th dement ia o f Alzheimer t y p e . B r i t . J . P s y c h i a t . 135, 21 6-223, 1979.
IV R. A d o l f s s o n , C.-G. G o t t f r i e s , L. O r e l a n d , A. Wiberg, B. Winblad: I n c r e a s e d a c t i v i t y o f b r a i n and p l a t e l e t monoamine o x i d a s e in dement ia o f Alzheimer t y p e . L i f e S c i . 27, 1029-1034, 1980.
V R. A d o l f s s o n , A. F o r s e l l , B. Winblad: Cer eb ral a t r o p h y , c e r e b r o s p i n a l f l u i d m e t a b o l i t e s and i n t e l l e c t u a l impairment in p a t i e n t s wi th dementia o f Alzheimer t y p e . Ann. N eur ol . Su bmi tted f o r p u b i i c a t i o n .
The r e p o r t s a r e p r e s e n t e d in a l o g i c a l r a t h e r th a n in a c h r o n o l o g i c a l o r d e r and in t h e f o l l o w i n g t e x t t h e r e p o r t s w i l l be r e f e r r e d t o by t h e i r Roman numeral s.
These s t u d i e s were s u p p o r t e d by r e s e a r c h g r a n t s from t h e Swedish Medical Research C o u n c i l , Medical F a c u l t y U n i v e r s i t y o f Umeå, G r o s c h i n s k y ' s ,
H a n s s o n ' s , M àn gb er g' s, O s t er m an ' s and P f a n n e n s t i l l ' s funds and t h e Svenska L i v f ö r s ä k r i n g s Bolags Nämnd f ö r Medicinsk F o r s k n i n g .
INTRODUCTION Epidemiology o f dement ia
The p r e v a l e n c e r a t e s o f d ement ia in t h e senium as r e p o r t e d from v a r i o u s s u r v e y s ( f o r a r e v i e w , s ee Wang, 1977) a r e r a t h e r c o n s i s t e n t . In t h e s t u d i e s by E s s e n - M ö l l e r ( 1956) , Pa rs ons ( 19 6 5 ) , and Kay e t a l . (1964, 1972) p r e v a l e n c e f i g u r e s r a n g i n g from 4 - 6 % viere found f o r d e f i n i t e c a s e s o f dement ia in t h e e l d e r l y p o p u l a t i o n 65 y e a r s and o l d e r . In o t h e r s u r v e y s , however, one may f i n d s t r i k i n g d i f f e r e n c e s in p r e v a l e n c e r a t e s . D e f i n i t e c a s e s o f dement ia a r e r e p o r t e d as be in g as high as 9 . 0 % by Hagnell ( H a g n e l l , 1970) and 7.1 % by P f e i f f e r ( P f e i f f e r , 1975) o r as low as 3.1 % by N i e l s e n
( N i e l s e n , 1962) and 1 . 6 % by B o l l e r u p ( B o l l e r u p , 1975). The e p i d e m i o l o g i c a l s u r v e y s u n de r t a k e n so f a r have m o s t l y f oc us ed t h e i n t e r e s t on p r e v a l e n c e and i n c i d e n c e r a t e s . A few i n t e r e s t i n g e x c e p t i o n s must be m e nt io ne d . Roth (1955) d e m o n st r a t e d a f a v o u r a b l e outcome in a number o f common p s y c h i a t r i c d i s o r d e r s in t h e e l d e r l y , i . e . a f f e c t i v e d i s o r d e r s , l a t e p a r a p h r e n i a and t o some e x t e n t a c u t e c o n f u s i o n a l s t a t e s . C l i n i c a l l y he c o u l d d i s t i n g u i s h between s e n i l e dement ia and a r t e r i o s c l e r o t i c de ment i a. T hi s has opened t h e way f o r more s p e c i f i c t r e a t m e n t s and improved p r e d i c t i o n s a b o u t outcome and a l s o opened up a f i e l d o f s t u d i e s where comparison between t h e d i f f e r e n t c l i n i c a l syndromes can be made and v a l i d a t e d by f o l l o w - u p s t u d i e s .
The number o f l o n g i t u d i n a l e p i d e m i o l o g i c a l s t u d i e s a r e few, mainly due t o two f a c t o r s . F i r s t l y , t h e small numbers o f any dementing i l l n e s s t h a t would come up t h ro ug h a random sample surve y o r t o t a l p o p u l a t i o n s t u d y and, s e c o n d l y , t h e d i f f i c u l t y t o i n v e s t i g a t e h e a l t h y peo pl e who do n ot c o n s i d e r t h e m s e l v e s t o be i l l . Bergman e t a l . (1971) have p ro vi de d i m p o r t a n t i n fo r ma t i o n on t h e development o f dementia in t h e e l d e r l y . T h e i r f o l l o w - u p s t u d y a f t e r 2 - 4 y e a r s showed t h a t 2 . 8 % o f t h e p r e v i o u s h e a l t h y e l d e r l y had d ev el ope d de ment ia. Of p a r t i c u l a r i n t e r e s t was t h e group d e s i g n a t e d "mild o r e a r l y o r g a n i c s t a t e s " . One t h i r d o f t h e s e had d u ri ng f o l l o w - u p developed
d e m en t ia . Of more i n t e r e s t , however, was t h a t a n o t h e r 33 % were r e g a r d e d as h e a l t h y . On c l o s e r e xa mi n at io n t h e s e s u b j e c t s t u r n e d o u t t o be p s y c h i a t r i - c a l l y normal but o f low I.Q. and s o c i a l c l a s s . P r e l i m i n a r y d a t a from an e x t e n s i v e f o l l o w - u p s t u d y by Gruenberg and Hagnell ( s e e Gruenberg, 1978), have p ro vi de d e v i d e nc e t o s u g g e s t t h a t d u ri ng t h e l a s t t h r e e decades t h e p e r i o d o f s u r v i v a l o f t h o s e w i th dementia has i n c r e a s e d .
C l i n i c a l a s p e c t s on dementia o f Alzheimer t y p e
Dementia r e f e r s t o a g loba l d e t e r i o r a t i o n in a l l a s p e c t s o f mental f u n c t i o n i n g , i n c l u d i n g memory, ge ner al i n t e l l e c t , emotional a t t r i b u t e s and d i s t i n c t i v e f e a t u r e s o f p e r s o n a l i t y . At t h e p r e s e n t time t h e d i a g n o s i s o f dement ia i s made l a r g e l y on t h e b a s i s o f c l i n i c a l e x a mi n at io n a i d e d by p s y c h o l o g i c a l t e s t i n g , co mput eri zed tomography (CT-scan) and c e r t a i n l a b o r a t o r y p r o c e d u r e s .
The phenomenology o f dementia and i t s d i f f e r e n t i a l d i a g n o s i s has been f u l l y d e s c r i b e d in s t a n d a r d t e x t s and a number o f r e c e n t paper s ( S j ö g r e n , 1950, 1951; S l a t e r and Roth, 1969; Roth and Myers, 1969; P o s t , 1975; L i s t o n 1979 a , b ) . The term dement ia o f Alzheimer t y p e r e f e r s t o a
dementing c o n d i t i o n w i t h Alzheimer changes o c c u r r i n g h i s t o p a t h o l o g i c a l l y . Thus, i t c o ve r s both A l z h e i m e r ' s d i s e a s e - t h e p r e s e n i l e v a r i e t y (S oura nder
and S j ö g r e n , 1970) and s e n i l e dement ia - t h e s e n i l e form (Roth, 1955). Recent i n v e s t i g a t i o n s ( L a u t e r and Meyer, 1968; McDonald, 1969; Pearce and P e a r c e , 1979) have d e s c r i b e d t h e c l i n i c a l s i m i l a r i t i e s between e a r l y and l a t e o n s e t c a s e s . F u r t h e r m o r e , no q u a l i t a t i v e h i s t o p a t h o l o g i c a l
d i f f e r e n c e s have been found between A l z h e i m e r ' s d i s e a s e and s e n i l e dementia (Tomlinson e t a l . , 1970). Thus, i t seems j u s t i f i e d t o i n c l u d e both d i s e a s e s under t h e same t e r m , dementia o f Alzheimer t y p e .
Of p a r t i c u l a r i mpor tance in t h e d i a g n o s t i c s e t t i n g i s t h e a namn es is. Dementia o f Alzheimer t y p e s t a r t s wi th an i n s i d i o u s o n s e t and d e s c r i b e s
i n v e s t i g a t i o n r e v e a l s a prof ound memory l o s s and g l ob a l i n t e l l e c t u a l and p e r s o n a l i t y d e t e r i o r a t i o n . I n v e s t i g a t i o n s s h o u l d be made t o r u l e o u t p a t i e n t s w i th a h i s t o r y o f h y p e r t e n s i o n , s t r o k e , h e a r t f a i l u r e , d i s t u r b a n c e s o f
l i v e r o r re na l f u n c t i o n s , anemia o r e n d o c r i n o l o g i c a l d i s o r d e r , o r o t h e r d i s e a s e s c a u s i n g o r mimicking dementia (Hachi nski e t a l . , 1976; Haase, 1976; I s a a c s , 1979; Roth, 1980).
The d i a g n o s t i c i n s t r u m e n t s t h a t a r e commonly used in c l i n i c a l p r a c t i c e t o h e l p t o e v a l u a t e t h e r o l e o f an e v e n t u a l o r g a n i c d y s f u n c t i o n a r e EEG, CT-scan, c e r e b r o s p i n a l f l u i d i n v e s t i g a t i o n s , p s y c h o l o g i c a l t e s t i n g and n e u r o l o g i c e x a m i n a t i o n . None o f t h e s e i n s t r u m e n t s used a l o n e i s o f any p a r t i c u l a r h e l p , n e i t h e r in t h e d i a g n o s i s o f dement ia n o r in t h e d i a g n o s i s o f a s p e c i f i c dementia d i s o r d e r such as dementia o f Alzheimer t y p e ( W e l l s , 1980). The d i a g n o s t i c s e t t i n g must be based on a combination o f t h e s e i n s t r u m e n t s .
The p s y c h i a t r i c i n t e r v i e w i s p r o b a bl y t h e most s e n s i t i v e i n s t r u m e n t f o r a p o s i t i v e d i a g n o s i s o f d e me nt i a , having in mind t h e c l i n i c a l f e a t u r e s d i f f e r e n t i a t i n g dementia from o t h e r c o n d i t i o n s i . e . pseudodementia ( We l l s , 1979). In t r u e de ment ia t h e symptoms have u s u a l l y been p r e s e n t f o r many y e a r s b e f o r e medical h e l p i s s o u g h t . The o n s e t o f t h e symptoms can seldom be s p e c i f i e d , n e i t h e r by t h e p a t i e n t no r by h i s r e l a t i v e s . I t i s unusual t o f i n d a h i s t o r y o f p r e v i o u s p s y c h i a t r i c d i s o r d e r . The p a t i e n t s with dementia u s u a l l y complain l i t t l e o f c o g n i t i v e l o s s and a r e t h e r e f o r e o f t e n unconcerned a b o u t t h i s . T h e i r a t t e n t i o n and c o n c e n t r a t i o n i s d i s t u r b e d and t h e y u s u a l l y a r e s h al l o w in t h e i r a f f e c t . Having in mind t h e s e b a s i c f e a t u r e s o f a t r u e dement ia s t a t e , i t i s o f t e n p o s s i b l e a l r e a d y a t t h e c l i n i c a l i n t e r v i e w t o make a f a i r l y a c c u r a t e d i a g n o s i s .
10
Biochemical f i n d i n g s in dement ia o f Alzheimer t y p e
Dementia o f Alzheimer t y p e i s t h e f a r most common d i s e a s e p r oduc ing dementia in high age (Tomlinson e t a l . , 1970). The e t i o l o g y remains o b s c u r e and
g e n e t i c f a c t o r s a r e p r o b a bl y i n v o l v e d . The g r e a t m a j o r i t y o f c a s e s a r e s p o r a d i c , b ut even he r e t h e r e a pp ea r s t o be an i n c r e a s e d r i s k among f i r s t o r d e r r e l a t i v e s o f p a t i e n t s ( S l a t e r and Cowie, 1971). An i n c r e a s e d f r e q u e n c y o f a n e u p l o i d y and chromosomal a b n o r m a l i t i e s in p e r i p h e r a l lymphocytes has been found (Nordenson e t a l . , 1979).
The h i s t o p a t h o l o g i c a l l e s i o n s s e n i l e p l a q u e s and t h e n e u r o f i b r i l l a r y t a n g l e s a r e c h a r a c t e r i s t i c f o r t h e d i s e a s e and o f d i a g n o s t i c s i g n i f i c a n c e . There seems t o be a r e l a t i o n s h i p between c o g n i t i v e d e c l i n e on t h e one hand and number o f s e n i l e p la q ue s ( B l e ss e d e t a l . , 1968), EE G- abn or ma li ti es ( O b r i s t e t a l . , 1963) and d e g r ee o f a t r o p h y on t h e o t h e r hand ( W i l l a n g e r e t a l . , 1968; Tomlinson e t a l . , 1970; Huckman e t a l . , 1975). In a d d i t i o n , c o r r e l a t i o n s have been found between c o r t i c a l d e g e n e r a t i v e changes and r e g i o n a l c e r e b r a l blood flow ( G u s t a f s s o n e t a l . , 1977) and a l s o between EEG a b n o r m a l i t i e s and r e g i o n a l c e r e b r a l blood flow (J oh annes so n e t a l . , 1977).
Although t h e e s t a b l i s h e d h i s t o p a t h o l o g i c a l f e a t u r e s o f dement ia o f Alzheimer t y p e have been known f o r a long t i m e , neurochemical r e s e a r c h has mai nl y been u nd e r t a k e n in t h e l a s t 15 y e a r s . In view o f t h e w id e s p r e a d d e g e n e r a t i o n i t has been c o n s i d e r e d u n l i k e l y t h a t a s i n g l e n e u r o t r a n s m i t t e r would be a f f e c t e d s e l e c t i v e l y (Dayan, 1974). G o t t f r i e s e t a l . (1969 a , b , 1970, 1973) found t h a t p a t i e n t s w i th A l z h e i m e r ' s d i s e a s e and t o a l e s s e r d eg re e t h e s e n i l e demented had lower c o n c e n t r a t i o n s o f h o m o v a n i l l i c a c i d
(HVA) in t h e c e r e b r o s p i n a l f l u i d (CSF) as well as in t h e basal g a n g l i a . A f t e r l o a d i n g w i th p ro b e n e ci d t h e r i s e o f HVA and 5 - h y d r o x y i n d o l e a c e t i c a c i d (5-HIAA) was s i g n i f i c a n t l y lower in t h e demented p a t i e n t s . In a d d i t i o n
i t was found t h a t t h e i n t e l l e c t u a l l y most s e v e r e l y i mp ai re d p a t i e n t s had t h e l o w e s t l e v e l s o f HVA in CSF. Parkes e t a l . ( 19 7 4 ) , however, found no
s i g n i f i c a n t d i f f e r e n c e s in HVA-concentration in demented compared t o c o n t r o l s . F i s c h e r (1975) r e p o r t e d a l o w e r , a l t h o u g h n ot s i g n i f i c a n t , 2 4 - h o u r u r i n a r y e x c r e t i o n o f HVA in 16 demented p a t i e n t s . In t h i s s t u d y , however, t h e d i a g n o s e s i n c l u d e d o t h e r demented p a t i e n t s t h a n o f t h e Alzheimer t y p e . The a c t i v i t y o f a r o m a t i c a m i n o- ac i d d e c a r b o x y l a s e (Bowen e t a l . , 1974), g l u t a m i c a c i d d e c a r b o x y l a s e and t h e c o n c e n t r a t i o n o f ne u ro n in S-6 (Bowen e t a l . ,
1973) were r e p o r t e d t o be reduced in dement ia o f Alzheimer t y p e , but t h e f i n d i n g s were l a t e r r e f u t e d as i t was found t h a t t h e mode o f d e a t h , e s p e c i a l l y when p ro lo ng e d and a s s o c i a t e d w i t h bronchopneumonia, had a
marked i n f l u e n c e on t h e s e enzyme a c t i v i t i e s and on t h e p r o t e i n c o n c e n t r a t i o n (Bowen e t a l . , 1976). P r e l i m i n a r y r e s u l t s by Davies and Maloney (1976)
i n d i c a t e d t h a t t h e a c t i v i t i e s o f t y r o s i n e h y d r ox y la s e and monoamine o x i d a s e in b r a i n a r e unchanged in dementia o f Alzheimer t y p e . Thus, t h e r e a r e
f i n d i n g s f o r and a g a i n s t a d i s t u r b a n c e o f monoaminergic systems in dement ia o f Alzheimer t y p e .
An e s s e n t i a l and d i a g n o s t i c a i l y o b l i g a t o r y symptom in dement ia i s t h e p r e s e n c e o f amnes ia . Drachman and L e v i t t (1974) and Drachman (1977) showed t h a t c e n t r a l l y a c t i n g a n t i c h o l i n e r g i c drugs mimic t h e impairment o b s e r v e d in memory f u n c t i o n s in o l d a ge. T h e r e a f t e r , s e v e r a l s t u d i e s have shown t h a t t h e c h o l i n e r g i c system, measured as a r e d u c t i o n o f c h o l i n e a c e t y l - t r a n s f e r a s e a c t i v i t y , i s d i s t u r b e d in dement ia o f Alzheimer t y p e (Davies and Maloney, 1976; White e t a l . , 1977; P e rr y e t a l . , 1977).
A g a i n s t t h i s background, t h e aims o f t h e p r e s e n t work can be summarized as f o l l o w s :
1. To d e t er m i n e t h e p e r c e n t a g e o f dementia d i s o r d e r s in t h e 65 y e a r s and o l d e r p o p u l a t i o n .
2. To i n v e s t i g a t e t h e r e g i o n a l d i s t r i b u t i o n o f b r a i n monoamines, m e t a b o l i t e s and monoamine o x i d a s e a c t i v i t y in normal a gi ng and in dementia o f
To s t u d y t h e r e l a t i o n s h i p between degree o f c e r e b r a l a t r o p h y , c e r e b r o s p i n a l f l u i d m e t a b o l i t e s and i n t e l l e c t u a l and motor impairment in dement ia o f Alzheimer t y p e .
MATERIAL AMD METHODS
E p i d em i ol o g i ca l s t u d y ( I )
P r e v a l e n c e o f dementia d i s o r d e r s in t h e o v e r p o p u l a t i o n
The i n v e s t i g a t i o n c over ed t h e c ou nt y o f V ä s t e r b o t t e n ( t o t a l p o p u l a t i o n 1975, 237 0 0 0 ) , where 33 838 p eople were aged 65 y e a r s o r more ( 4 7 . 9 % men, 52.1 % women). P er so na l c o n t a c t s were made wi th a l l i n s t i t u t i o n s and h o s p i t a l , 4 s o mat i c l o n g - s t a y wa rds, 21 n u r s i n g homes and 3 a c u t e medical c l i n i c s were i n v e n t o r i e d . The t o t a l number o f people 65 y r s o r more who were i n v e s t i g a t e d was 3 523 (1 374 men, 2 149 women). T h e i r de gr ee o f
dementia was measured by a s p e c i a l g e r i a t r i c r a t i n g s c a l e ( G o t t f r i e s and G o t t f r i e s , 1968) ( s e e Appendix 1 in p a pe r I ) . P a t i e n t s w i t h more th a n 3 p o i n t s on t h e I 1 - s u b s c a l e were c o n s i d e r e d s e v e r e l y demented. The workload was d e t er m i n e d by use o f two r a t i n g s c a l e s . One was d e t a i l e d and measured
d i f f e r e n t ADL-functions ( s e e Appendix 2 in pa per I ) . The o t h e r s c a l e was a gl oba l r a t i n g s c a l e measuring workload from "no workload" t o "maximal workload" ( s i x - s t e p s c a l e ) . There was no a t t e m p t t o i n v e s t i g a t e t h e a c t u a l c au s e o f a p a t i e n t ' s c o n d i t i o n o f d e me n t i a .
Post mortem s t u d i e s
C o n c e n tr at io n s_ of _m on o am in e s, jponoamine j n e t a b o l i t e s _ a n d _ t h e _ a c t i vi t y _ o f monoamine„ o x i d a s e _ { M A 0 I I , _ I I I , _ IV)
Three d i f f e r e n t s e r i e s o f b r a i n m a t e r i a l were c o l l e c t e d from c o n t r o l s and p a t i e n t s w i th a d i a g n o s i s o f d ement ia o f Alzheimer t y p e . In t h e s e r i e s w i t h demented p a t i e n t s ( I I I , IV) o n l y p a t i e n t s w i th an u n m i s t a k e a b l e p i c t u r e o f dement ia h i g h l y s u g g e s t i v e o f dement ia o f Alzheimer t y p e (an i n s i d i o u s o n s e t , profound memory l o s s , i n t e l l e c t u a l and p e r s o n a l i t y d e t e r i o r a t i o n and a t y p i c a l n o n - f l u c t u a t i n g c o u r s e ) were i n c l u d e d . P a t i e n t s s u f f e r i n g from d i s e a s e s known t o l e a d t o dement ia were e x c lu d ed (Hachi nski e t a l . , 1976;
14
Haase, 1976; I s a a c s , 1979; Roth, 1980). F u r t h e r m o r e , a t a u t o p s y no s i g n s o f s e v e r e a r t e r i o s c l e r o s i s o r e n c e p h a l o m a l a c i a s were found.
The f i r s t s e r i e s ( I I ) i n c l u d e d 24 p a t i e n t s (15 men, 9 women; mean age 61. 0 ± 1 9 . 7 , ra ng e 23-92 y r s ) w i t h o u t a h i s t o r y o f n e u r o l o g i c a l o r p s y c h i a t r i c i l l n e s s . The u n d e r l y i n g c a u s e s o f d e a t h were i s ch ae mi c h e a r t d i s e a s e and v a r i o u s m a l i g n a n t neoplasms. S i x t e e n w e l l - d e f i n e d p a r t s o f t h e b r a i n were a n a l y z e d f o r DA a c c o r d i n g t o C a r l s s o n and L i n d q v i s t (1962). HVA c o n c e n t r a t i o n s were d e ter mi ne d in t h e same b r a i n p a r t s a c c o r d i n g t o Andén e t a l . (1963) and Korf e t a l . ( 1971) . F a c t o r s t h a t might i n f l u e n c e t h e l e v e l s o f t h e b i o g e n i c amines o r t h e i r m e t a b o l i t e s , such as s e x , a g e , drug t h e r a p y , b r a i n w e i g h t , m a l ig n a n c y , time between de at h and a u t o p s y , time between a u t o p s y and chemical a n a l y s i s and t h e d e g r ee o f a r t e r i o s c l e r o s i s in t h e ba sa l b r a i n v e s s e l s were r a t e d a c c o r d i n g t o a f o u r - s t a g e s c a l e (0, +, ++, +++; World F e d e r a t i o n o f Neurology, 1959).
The second s e r i e s ( I I I ) c o n s i s t e d o f 19 p a t i e n t s (6 men, 13 women; mean age 74.5 ± 7.2 y r s , range 59-84 y r s ) w i th a d i a g n o s i s o f dementia o f
Alzheimer t y p e . These p a t i e n t s had been r e s i d e n t in p s y c h o g e r i a t r i c o r l o n g - s t a y wards due t o t h e i r s e v e r e d e m e n t i a , which was r a t e d a c c o r d i n g t o a p s y c h o g e r i a t r i c r a t i n g s c a l e devel op ed by G o t t f r i e s and G o t t f r i e s (1968)
( s ee Appendix 1 in p a pe r I ) . The c o n c e n t r a t i o n s o f monoamines and t h e i r m e t a b o l i t e s were d e t er m i ne d in samples from d i f f e r e n t p a r t s o f t h e b r a i n . NA- and D A - c o nc en t r at i o ns were d e te r mi ne d in 10 a r e a s a c c o r d i n g t o t h e methods o f B e r t l e r e t a l . (1958) and Häggendahl (1963) f o r NA and C ar l s s o n and L i n d q v i s t (1962) f o r DA. 5-HT was d e t er m i ne d in 8 r e g i o n s a c c o r d i n g t o Anden and Magnusson (1967). 5-HIAA and HVA-concentrations were d e t er m i ne d in 4 r e s p e c t i v e l y 3 r e g i o n s a c c o r d i n g t o t h e methods o f J on ss on and Levander (1970) f o r 5-HIAA and Andén e t a l . (1963) and Korf e t a l . (1971) f o r HVA. The c o n c e n t r a t i o n o f t h e monoamines and t h e i r m e t a b o l i t e s were compared t o an age-matched c o n t r o l group (mean age
75.0 ± 7. 6 y r s ; n=40), w i t h o u t n e u r o l o g i c a l o r p s y c h i a t r i c i l l n e s s .
In t h e t h i r d p o s t mortem s e r i e s , 14 p a t i e n t s w i t h dement ia o f Alzheimer t y p e (6 men, 8 women; mean age 74.0 ± 2 . 0 y r s , range 66-84 y r s ; mean
d u r a t i o n o f i l l n e s s 5 . 5 ± 0 . 5 y r s ) were s e l e c t e d a t a u t o p s y . The MAO
a c t i v i t i e s were d e t er m i n e d in b r a i n samples from t h e h yp otha la mus, n u c l e u s c a u d a t u s , hippocampus and c o r t e x gyrus c i n g u l i and were compared w i t h 16 c o n t r o l s (8 men, 8 women; mean age 73. 0 ± 2 . 0 y r s , range 58-83 y r s ) . A f t e r removal from t h e s k u l l and d i s s e c t i o n , t h e samples were put i n t o a i r t i g h t packages and f r o z e n a t -70°C. The f r o z e n samples were t h e n p u l v e r i z e d in a m o r t a r which was f i l l e d wi th l i q u i d n i t r o g e n and p l a c e d in p l a s t i c t u b e s and were kept f r o z e n u n t i l t h e t i me f o r a n a l y s i s . The MAO a c t i v i t i e s were measured c o n c u r r e n t l y u s i n g a r a di o c h em i c a l method (Rot h, 1976) w it h
14 14 14
C-5-HT, C - t r y p t a m i n e and C - b e t a - p h e n e t h y l a m i n e as s u b s t r a t e s .
C l i n i c a l s t u d i e s (IV, V)
Eleven p a t i e n t s w i t h dement ia o f Alzheimer t y p e (6 men, 5 women; mean age 6 5 . 0 ± 0 . 5 y r s , range 49-73 y r s ; mean d u r a t i o n o f i l l n e s s 6 . 7 ± 0. 5 y r s ) were s e l e c t e d from t h e i n - and o u t - p a t i e n t c l i e n t e l e a t t h e P s y c h i a t r i c
C l i n i c . A c o n t r o l group o f h e a l t h y v o l u n t e e r s , matched wi th t h e dement ia group f o r age and s e x , were used. Blood samples ( 4 . 5 ml) were t a k en from t h e two groups i n t o s i l i c o n i z e d V a c u t a i n e r t u b e s c o n t a i n i n g 0 . 5 ml o f 3.1 % sodium c i t r a t e s o l u t i o n . A f t e r 2-4 h rs s e d i m e n t a t i o n a t room t e m p e r a t u r e , a p p r o x i m a t e l y 1 ml o f t h e p l a t e l e t - r i c h plasma was t r a n s f e r r e d t o s i l i c o n i z e d t e s t t u b e s . P l a t e l e t c o un ts were d e t er m i ne d w i t h a C o u l t e r c o u n t e r ( C o u l t e r E l e c t r o n i c s , D u n s t a b l e , UK) and t h e p l a t e l e t - r i c h plasma s t o r e d a t -70°C. The samples were thawed and s o n i c a t e d a t low power f o r 60 s e c a t 4°C p r i o r t o t h e a s s a y f o r MAO a c t i v i t y . The MAO a c t i v i t y in a l l samples was e s t i m a t e d
14
14
( R o th , 1 9 7 6 ) .
Çerebrai_atroghY_and_intellectual__deterioration_in_dementia_of_Alzheimer
tYpe_(y)
T h i r t y - s i x p a t i e n t s (16 men, 20 women; mean age 6 5 . 8 ± 10.5 y r s , range 38-87 y r s ; mean d u r a t i o n o f i l l n e s s 4.1 ± 2.1 y r s ) w i t h a d i a g n o s i s o f dement ia o f Alzheimer t y p e were s e l e c t e d a t t h e p s y c h i a t r i c and n e u r o l o g i c d e p ar t m e n t s and from t h e p s y c h o g e r i a t r i c c l i n i c , U n i v e r s i t y H o sp i t a l o f Umeå. E v a l u a t i o n was made w i t h CT-scan, lumbar p u n c t u r e and p sy ch ome t ri c r a t i n g . CT-scan (160 x 160 m a t r i x ) was performed in 31 p a t i e n t s . The c e r e b r a l a t r o p h y was e s t i m a t e d as d e s c r i b e d by Huckman e t a l . ( 1 97 5) , Banna (1977) and Hahn and Rim (1 97 6) . CSF-samples were o b t a i n e d from 20 p a t i e n t s p r i o r t o and a f t e r t r e a t m e n t w i t h 1-dopa o r b r o m o c r i p t i n e . The c o n c e n t r a t i o n s o f HVA, 5-HIAA and 3 - m e t h o xy - 4- h y dr o xy p he n yl e ne - g ly c ol
(HMPG) were d et er mi ne d wi th gas chromatography-mass s p e c t r o m e t r y ( F ri e t a l . , 1974). Twenty-nine p a t i e n t s were r a t e d w i t h r e s p e c t t o t h e i r
i n t e l l e c t u a l , motor and emotional d e t e r i o r a t i o n ( G o t t f r i e s and G o t t f r i e s , 1968). The i n v e s t i g a t i o n was approved by t h e e t h i c a l c ommitte e, U n i v e r s i t y o f Umeå.
S t a t i s t i c s
RESULTS AND DISCUSSION
P r e v a l e n c e o f dement ia d i s o r d e r s ( I )
Twelvehundred and t h i r t y - n i n e o r 35. 2 % o f t h e i n s t i t u t i o n a l i z e d c l i e n t e l e were c o n s i d e r e d demented by t h e d e f i n i t i o n I 1 > 3 p o i n t s . R e l a t i n g t h i s number t o t h e whole p o p u l a t i o n in t h e c ount y aged 65 y e a r s o r more, a p r e v a l e n c e o f 3. 7 % was c a l c u l a t e d . However, t h i s i s an u n d e r e s t i m a t i o n o f t h e r e a l p r e v a l e n c e as t h e i n v e s t i g a t i o n d id n o t i n c l u d e pe op le w i th dementia l i v i n g a t home. In a r e c e n t i n v e s t i g a t i o n ( P e r s s o n , 1980) in t h e s out h o f Sweden t h e p r e v a l e n c e o f dement ia d i s o r d e r s in t h e 70 - 75 y e a r o l d p o p u l a t i o n l i v i n g a t home was 6 . 6 % f o r men and 3.1 % f o r women. I f t h e s e f i g u r e s a r e t r a n s f e r r e d t o t h e p r e s e n t c o n d i t i o n s in t h e c ounty o f V ä s t e r b o t t e n , t h i s would i n d i c a t e t h a t i n t h e 70 - 74 y e a r - o l d p o p u l a t i o n ( t o t a l number 4 657) an ap pr ox ima te r e l a t i o n s h i p between n o n - i n s t i t u t i o n a l i z e d vs i n s t i t u t i o n a l i z e d i s 1 : 1 . As t h e r e i s no r e a s o n t o b e l i e v e t h a t t h e o t h e r age groups above 65 y e a r s d i f f e r markedly in t h i s r e s p e c t , t h e c a l c u l a t e d r a t i o i s e x t r e m e l y low ( f i v e f o l d ) in comparison wi th o t h e r i n d u s t r i a l i z e d coun t r i e s . One o f t h e main r e a s o n s f o r t h i s i s o f c o u r s e t h e l a r g e r e s o u r c e a v a i l a b l e f o r w e l f a r e and h o s p i t a l c a r e in Sweden. C u l t u r a l d i f f e r e n c e s a r e p r o b a b l y a l s o c o n t r i b u t i n g f a c t o r s . This was e v i d e n t a l s o from t h i s i n v e s t i g a t i o n where t h e f r e q u e n c y o f i n s t i t u t i o n a l i z e d o l d p e opl e was h i g h e r in t h e c o a s t a l r e g i o n compared t o t h e i n l a n d , a l t h o u g h in t h e i n l a n d t h e mean age o f t h e p o p u l a t i o n was h i g h e r ( u n p u b l i s h e d d a t a ) . Although no d i f f e r e n c e in t h e d eg re e o f dement ia between men and women was f ound, t h e number o f i n s t i t u t i o n a l i z e d women outnumbered t h a t o f men in a l l i n s t i t u t i o n s (Table 1 ) , which c an n o t be e x p l a i n e d by t h e women t o men r a t i o in t h e c o u nt y. I t c ould be e x p l a i n e d by t h e h i g h e r p e r c e n t a g e o f women l i v i n g a l o n e in t h e s e age groups and perhaps a l s o by t h e g e n e r a l ass umption t h a t t h e men t a k e c a r e o f t h e i r women l e s s o f t e n t han women do f o r men.
18 I n s t i t u t i o n Tot al No o f p a t i e n t s % o f popul > 65 base a t i o n y e a r s No Demented P e r c e n t a g e o f
Men Women Tot al
Home f o r t h e aged 1993 5 .9 340 14.6 17.6 17.1 Somatic l on g- s t a y ward 329 1. 0 194 55. 3 61. 4 59. 0 Nursing home 780 2. 2 439 51.7 58.9 56. 3 Mental h o s p i t a l 386 1.1 242 54.3 65.1 62. 7 Acute medical c l i n i c x 35 0.1 24 8 4. 5 59.0 68. 6 Tot al 3523 10.3 1239 S e l e c t e d g r ou p , see t e x t .
Table 1 T ot a l number of p a t i e n t s and f r e q u e n c y o f dement ia c o n d i t i o n s in t h e 65 and o l d e r p o p u l a t i o n in d i f f e r e n t i n s t i t u t i o n s .
The homes f o r t h e aged and t h e n u r s i n g homes c o n t r i b u t e d most (62 %) t o t h e t o t a l number o f t h e demented p a t i e n t s in t h e i n v e s t i g a t e d i n s t i t u t i o n s . The p e r c e n t a g e demented in d i f f e r e n t i n s t i t u t i o n s was, however, r a t h e r s i m i l a r , around 60 %, wi th t h e e x c e p t i o n f o r t h e homes f o r t h e aged ( s e e Table 1 ) , where a s u r p r i s i n g l y high p e r c e n t a g e (17 %) o f demented l i v e d . In s p i t e o f t h e l a c k of n u r s i n g c a r e in t h e homes f o r t h e a ged, o n ly a m i n o r i t y o f t h e s e p a t i e n t s c o n s t i t u t e d a heavy workload and needed t o be t r a n s f e r r e d t o more s u i t a b l e i n s t i t u t i o n a l c a r e . In p a r t i c u l a r , p a t i e n t s wi th a d i s t u r b i n g be h a v i o u r ( s e v e r e d e gr ee o f c o n f u s i o n , p s y c h o s i s , s u i c i d a l - o r v i o l e n t - a g g r e s s i v e b e ha v i o u r ) a r e , in a c c o r d a n c e w i th l o c a l p r a c t i c e , a d m i t t e d t o t h e mental h o s p i t a l . Other f a c t o r s s i g n i f i c a n t l y a f f e c t i n g a p a t i e n t ' s p l a c e of l i v i n g a r e s e v e r e memory l o s s , d e s o r i e n t a t i o n and l a c k o f i n s i g h t (Bergman, 1979). Thus, when p l a n ni ng t h e c a r e o f demented p e opl e t h e i r d i f f e r e n t symptom p r o f i l e s a r e o f g r e a t imp or tanc e in d e t e r m i n i n g t h e r i g h t l e v e l o f c a r e t a k i n g .
The p r o g r e s s i v e n a t u r e o f a dementing i l l n e s s s o o ne r o r l a t e r b r i n g s t h e p a t i e n t t o an i n s t i t u t i o n . Li ving w i th r e l a t i v e s o f t e n can d e l a y o r some t i me s even p r e v e n t i n s t i t u t i o n a l c a r e (Bergman e t a l . , 1 978) . N e v e r t h e l e s s , t h e r e i s a g r e a t burden on t h e r e l a t i v e s (Grad & Sa i ns bur y , 1 9 7 8 ) , who
f i n a l l y , a t l e a s t when t h e p a t i e n t r e q u i r e s c a r e a t a mental h o s p i t a l , reach a s t a g e when no a d d i t i o n a l s o c i a l o r medical s u p p o r t can p r e v e n t h i s a dmis
s i o n ( Ad ol f ss on e t a l . , 1980) .
The b e h a v i o u r d i s t u r b a n c e s and t h e impairment o f ADL-functions a r e i n t i m a t e l y r e l a t e d t o t h e d e g r ee o f dement ia ( Table 2) and t h e s u b j e c t i v e l y e x
p e r i e n c e d workload t h a t t h e s e p a t i e n t s c o n s t i t u t e . The workload was h i g h e s t in t h e s o mat i c l o n g - s t a v wards and i n t h e n u r s i n g homes ( Tabl e 3 ) . A r a t h e r high p e r c e n t a g e o f p a t i e n t s in t h e mental h o s p i t a l a c co un te d f o r a "maximal" workload which c a n n o t be e x p l a i n e d by t h e i r motor f u n c t i o n s b u t i s r a t h e r a s c r i b a b l e t o t h e i r i n c r e a s e d f r e q u e n c y o f b e h a v i o u r d i s t u r b a n c e s ( Tabl e 4 ) . ADL-function X2 d f P < U r i n a r y i n c o n t i n e n c e 261.3 20 0.001 Faecal i n c o n t i n e n c e 377.1 15 0.001 Hygiene 262.1 15 0.001 I n t a k e o f food 409.6 15 0.001 Dr es si ng a b i l i t y 210.7 15 0.001 Behaviourx 344.3 20 0.001 x D e s o r i e n t a t e d , d i s t u r b i n g and a g g r e s s i v e .
Table 2 X2- a n a l y s e s o f t h e r e l a t i o n s between de gr e e o f dementia ( I 1 > 3 p o i n t s ) and d i f f e r e n t ADL-f uncti ons.
20 I n s t i t u t i o n Workload None ( 0 - 1 ) L i t t l e ( 2 - 3 ) Moderate ( 4 - 8 ) Heavy ( 9- 2 2 ) Very heavy (23-36) Maximal (37- 42) Home f o r t h e 10.3 25 .0 32. 6 2 3 . 8 7 . 4 0 . 9 aged j 18.8 5 . 4 2 4. 4 4 3 . 5 7 . 9 0 . 0 Somatic l on g - 0 . 0 3.1 14. 9 30. 4 23.7 27.8 s t a y ward I 1. 5 0 . 0 2. 6 3 3. 0 56. 2 6 .7 Nursing home 0 . 5 2. 7 13.2 37. 6 2 8. 9 17.1 I 0 . 9 0 . 7 5. 5 3 7 . 8 4 9 . 0 6 . 2 Mental h o s p i t a l 0 . 0 5 . 0 24. 8 25. 6 17.4 27. 3 I 2 . 9 0 . 4 13.6 35.1 28. 5 19.4 Acute medical 0 . 0 4 . 2 16.7 20. 8 45. 8 12.5 c l i n i c I 0 . 0 0 . 0 8 . 3 29. 2 58.3 4 .2
Table 3 P e r c e n t a g e o f p a t i e n t s and t h e i r workload in d i f f e r e n t i n s t i t u t i o n s . Workload I i s a g l o b a l r a t i n g o f a p a t i e n t ' s workload on a 6 - s t e p s c a l e from "no workload" to "maximal w o rk l oa d ". The workload I I i s based upon t h e sum o f t h e f o l l o w i n g r a t e d f u n c t i o n s ( s e e appendix 2 ) : Motor f u n c t i o n s , i n c o n t i n e n c e , i n t a k e o f f o o d , d r e s s i n g a b i l i t y and t h e de gre e o f d i s o r i e n t a t i o n , r e s t l e s s n e s s and d i s t u r b i n g b e h a v i o u r . An X2- a n a l y s i s o f t h e r e l a t i o n between workload I and II showed s i g n i f i c a n c e (X2 = 1486.7, d f = 25, p < 0 . 0 0 1 ) .
The impor tan ce of a d e q u a t e a s s e s s m e n t o f p a t i e n t s in need o f i n s t i t u t i o n a l c a r e was shown by t h e work o f Kidd (1962) who i n v e s t i g a t e d t o what e x t e n t p s y c h o g e r i a t r i c p a t i e n t s were " mi s pl ac e d" w i t h i n t h e i n s t i t u t i o n a l c a r e s e c t o r . He r e p o r t e d t h a t 34 % in g e r i a t r i c u n i t s and 24 % in p s y c h i a t r i c u n i t s could be c l a s s i f i e d as e i t h e r d e f i n i t e l y o r p r o b a b l y m i s p l a c e d a c c o r d i n g to h i s c r i t e r i a . At f o l l o w - u p he c l ai med t h a t t h e m i s p l a c e d e x p e r i e n c e d a h i g h e r m o r t a l i t y r a t e and l o n g e r s t a y s in both t y p e s o f h o s p i t a l t ha n t h o s e who had been c o r r e c t l y p l a c e d . Although many y e a r s have p a s s ed s i n c e Ki dd' s o b s e r v a t i o n s , we s t i l l b e l i e v e to da y t h a t u n c r i t i c a l d e c e n t r a l i z a t i o n w i t h o u t p r o p e r
4 -o 4-5 c CD fö Q-4-5 3 O ZI 4-5 5 X fÖ 4-> • i— 2= C/) 4-5 c: CD 4-5 fÖ Cl. 45 X 3 X O CO CD i— r^- co zz • • • • • =3 4-5 CO 1— co 0 0 o •|— r— [— r— •1— > fÖ zz X r— CVJ i— o co CD fÖ • • • • • GQ z C\J co CVJ 'Ö- 0 0 «— CVJ X c o 45 • 1— 3 4-5 O o cd i— CO o O _c • • • • • c 45 o co CVJ 1— LO 13 • r— CO 1— evi co CVJ <4- 3 : <J • r - s-o CO 1— CD 0 0 4-5 X • • • • • O fÖ LO cd i— CD LO zz co co CVJ 3 o c •1— o 4-> > 3 fÖ 4-5 O LO 0 0 o co co zz O zz • • • • • CD c 4-5 r— 0 0 co CD co _Q 3 • r— CVJ CVJ co 4- CD > 1— •i— CD 0 0 co evi co CVJ CO 3ï X • • • • • co o fÖ co CVJ CD CVJ <3- CD 0Û LO co LO S-CD CD fÖ c o 4-5 no 3 C O evi CVJ o co co fÖ O zz • • • • • c 4-5 co co co CVJ 0 0 CD 13 • i— LO 1— evi C 4 - •i— JD >> S-S- 3 fÖ 4-5 c CO cvj LO c o CVJ CO •1— X • • • • • •1— fö LO LO CD CD T3 ZD z CVJ CVJ c o CVJ CZ • o >*> CD •1— - P 4-5 > 4-5 •i— 3 •1— fÖ ,— O co o co o co 4-5 • i— ZZ • • • • • co SZ _Q 4-5 LO c o o CD CD
fÖ •i— •vi CVJ S- •i—
31 CD S-CD CD o C fÖ co •i— CD CO ”O “O CO er» o LO r-. c CD X • • • • • fÖ 4-5 s- fÖ *0" 1— LO co 3 Q z: CVJ 0 0 0 0 LO co CD O sz ZZ • I— 4-5 JD • r— “O 4-5 • s-O 3 sz 3 O O co LO c o CD 4-5 CD 4 - ZZ • • • • • TJ CO c--- P o o co co r—*- T3 •r— _Q 4- •r - co LO LO LO • 1— T3 fÖ O 3: o "O •1— CD CD "O c -X ZD CD 3 fÖ <0- LO co CO CVJ 4-> E 4> X • • • • • T3 fÖ E C fÖ CVJ LO co CD cz 4 5 O i—i z : co CVJ CVJ CVJ fÖ sz CJ CD 1 •i— >> •1— o •1— 1 1— fÖ co co CD CD <D fÖ zz CD fÖ c ZI £Z E CJ o O LU o 4 5 o o •1—
• r— i— “O zz "O II II II
4 5 4 4 1— CD =3 o O fÖ CD (Ö E 4-5 4-5 4 - •r - c r— 4 5 o X X 3 •1— 4-> •1— fÖ -I— CD T - fö fÖ O 4 5 CD “O fÖ >> co 4-5 CL 4-5 SZ 2 1 z o : CO E CD E fÖ s^. £Z CO 3 T- 4-5 C O CD O 4-5 3 CD O L > r - X X •1— i—i m fö U1 CO z z: zz <c o X 3 : Tab le 4 P e rc e n ta g e d em en te d patie nts in d if fe re n t in s ti tu ti o n s w it h m ax im al an d w it h o u t im p a ir m e n t of A D L -f u n c ti o n s a c c o rd in g to th e ra ti n g sc a le (a p p e n d ix I I ) .
22
a s s e s s m e n t can have consequences f o r t h e p a t i e n t . Moreover, a t ho ro ug h i n v e s t i g a t i o n e n a b l e s p o t e n t i a l l y t r e a t a b l e c a s e s o f dement ia t o be
d i s c o v e r e d (Mardsen & H a r r i s s o n (1978). Adequate i n v e s t i g a t i o n o f i n d i v i d u a l p a t i e n t s ' needs r e q u i r e s i nvolvement o f both g e r i a t r i c i a n s and p s y c h i a t r i s t s . The i n s t i t u t i o n o f j o i n t p s y c h o g e r i a t r i c a s s e s s m e n t u n i t s could be an
i m p o r t a n t c o r n e r s t o n e in p s y c h o g e r i a t r i c c a r e (Robinson, 1977).
Monoamines, monoamine m e t a b o l i t e s and MAO a c t i v i t y in t h e b r a i n in normal aging and in dementia o f Alzheimer t y p e ( I I , I I I , IV)
A g e - r e l a t e d h i s t o p a t h o l o g i c a l changes w i th a gradual neuron and g l i a l c e l l l o s s a r e known t o o c c u r in t h e normal b r a i n (Henderson e t a l . , 1980). We found a gradual d e c r e a s e in t h e l e v e l s o f DA in normal a gi ng (Table 5) ( I I ) , p r o b a b l y p a r t l y due t o t h e l o s s o f monoamin e r g i c neurons o b s e r v e d morpho l o g i c a l l y . The age dependence was s t r o n g e s t in t h e n u c l eu s c a u d a t u s , globus p a l l i d u s , me se nc epha lon, hippocampus and in t h e c o r t e x gyrus hippocampus, r e g i o n s known t o be a f f e c t e d in P a r k i n s o n ' s d i s e a s e and dement ia o f
Alzheimer t y p e ( B o i l e r e t a l . , 1979). I t has been s u g g e s t e d t h a t t h e age- r e l a t e d d e c r e a s e in t h e DA c o n c e n t r a t i o n c ou ld be one o f t h e e t i o l o g i c f a c t o r s c o n t r i b u t i n g t o t h e o bs er v ed i n c r e a s e d f r e q u e n c y o f P a r k i n s o n ' s d i s e a s e and a f f e c t i v e d i s o r d e r s w i th age (F i nc h, 1973), which c o u l d
t h e o r e t i c a l l y a l s o p l a y a r o l e in t h e development o f d ement ia o f Alzheimer t y p e . Thi s would be s u p p o r t e d by t h e biochemical s i m i l a r i t i e s in normal agi ng and in dementia o f Alzheimer t y p e (Table 6 ) . On t h e o t h e r hand, s e v e r a l o t h e r biochemical markers show pronounced d i f f e r e n c e s between dementia o f Alzheimer t y p e and normal a gi ng (Bowen, 1 9 7 9) , so t h e r o l e o f aging p e r s e in t h e p r o c e s s o f t h i s p a r t i c u l a r d ement ia d i s o r d e r i s a t p r e s e n t not known. F u r t h e r m o r e , any one o f t h e r e p o r t e d biochemical
f i n d i n g s o t h e r th a n DA p r e s e n t e d in Table 6 , c o ul d be o f imp or tanc e in t h e i n i t i a t i o n and t h e development o f dement ia o f Alzheimer t y p e .
DA/age HVA/age
P a r t o f b r a i n r n r n
Hypothalamus - 0 . 1 8 24 0 .16 19
Nucleus c au da tu s - 0 . 33X 23 - 0. 01 44
Putamen - 0 . 1 9 24 0.06 44
Globus pal 1 i dus - 0 . 4 1 X 18 0. 28 18
Thai amus - 0 . 0 8 18 - 0 . 2 7 18 Mesencephalon - 0 . 4 1 X 18 - 0 . 3 4 17 Pons 0 .1 7 18 0. 09 17 Medulla o b l o n g a t a 0 .34 18 0. 03 18 Hi ppocampus - 0 . 37X 18 - 0 . 0 4 18 Cortex gyrus f r o n t a l i s - 0 . 2 5 18 0. 35 18 Cortex gyrus p a r i e t a l i s 0. 04 18 0. 23 18 Cortex gyrus t e m p o r a l i s - 0 . 0 3 18 -0.01 19 Cortex gyrus o c c i p i t a l i s - 0 . 2 4 18 -0.01 18
Cortex gyrus hippocampus - 0 . 38X 18 0. 36 18
Cortex gyrus c i n g u l i 0 .1 0 18 0.11 18
Cortex c e r e b e l l a r i s 0.05 18 0.14 18
xp < 0 .05
Table 5 Product-moment c o r r e l a t i o n s between t h e c o n c e n t r a t i o n s o f dopamine (DA) ( y g / g wet t i s s u e ) and h o m o v a n i l l i c a c i d (HVA)
(yg/g wet t i s s u e ) and a ge. The b r a i n samples were o b t a i n e d a t a u t o p s y from normal c o n t r o l s .
24 Normal a gi ng S e n i l e dementia T y r o s i n e h yd ro x y l a s e 4 44 DOPA-decarboxylase 4 44 Dopamine b e t a h y d r o x y l a s e 4 44 Dopamine 4 44 Homovanillic a c i d 4 44 N o r a d r e n a l i ne 4 44 4-Hydroxy-3-Methoxy- p h e n y l en e gl y c ol (HMPG) - 4
5-Hydr oxyt r ypt ami ne (5-HT) - 44
5 - H y d r o x y i n d o l e a c e t i c a c i d (5-HIAA) - 4 Monoamine o x i d a s e B (MAO-B) 4 44 Choline a c e t y l t r a n s f e r a s e (CAT) 4 44 M us c a r i n i c b i n d i n g s i t e s 4
-Table 6 Summary o f reported changes in transmitters and related enzymes
in the brain in normal aging and dementia o f Alzheimer tvDe.
When i n t e r p r e t i n g p o s t mortem d a t a , a n t e mortem f a c t o r s such as s e x , time o f d e a t h , drug t r e a t m e n t and c au s e o f d e a t h must be c a r e f u l l y c o n t r o l l e d .
Pos t mortem f a c t o r s i n c l u d e t h e time i n t e r v a l from d e at h t o a u t o p s y and s t o r a g e time u n t i l chemical a n a l y s i s . DA and HVA l e v e l s a r e l a r g e l y u n a f f e c t e d w i t h i n t h e time i n t e r v a l 6 - 6 6 hours between d e at h and
a u t o p s y (Table 7) and a l s o unchanged by l o n g - t e r m s t o r a g e a t -20°C (18 - 281 days) ( I I ) . S i m i l a r r e s u l t s were r e p o r t e d in animal (Chase e t a l . , 1974; Wiesel and S e d v a l l , 1974) and in human b r a i n (Vogel e t a l . , 1969; Fahn e t a l . , 1971; C a r l s s o n and Winblad, 1976; Spokes, 1979). The c r i t i c a l p e r i o d , as j ud ge d from animal e x p e r i m e n t s , i s t h e f i r s t hours a f t e r d e a t h , when s i g n i f i c a n t d e c r e a s e in t h e c o n c e n t r a t i o n s (30-40 %) were found
c a s e s i n c l u d e d in t h i s s t u d y ( I I ) , DA c o n c e n t r a t i o n i s f a i r l y s t a b l e . Thus, DA l e v e l s measured in human b r a i n p o s t mortem do not r e p r e s e n t f r e s h t i s s u e v a l u e s . The r e d u c t i o n o f t h e DA l e v e l s can p a r t l y be a t t r i b u t e d t o t h e f a c t t h a t DA i s c o n v e r t e d t o 3 -me t ho xy- t yr am in e a f t e r d e at h ( C a r l s s o n and
Winblad, 1976). Thus, t h e sum o f t h e c o n c e n t r a t i o n s o f DA and 3-methoxy- t y r a m i n e p ro b a b l y more a c c u r a t e l y r e f l e c t t h e p o s t mortem DA c o n c e n t r a t i o n . The p o s t mortem s t a b i l i t y o f NA and 5-HT i s e s s e n t i a l l y t h e same as t h a t f o r
DA (Mackay e t a l . , 1978; Bucht e t a l . , 1980).
On t h e c o n t r a r y , enzyme a c t i v i t i e s measured p o s t mortem, e . g . MAO (IV) and c h o l i n e a c e t y l t r a n s f e r a s e , a r e remarkably s t a b l e in human b r a i n d u r i ng r o u t i n e p o s t mortem t e c h n i q u e s (McGeer & McGeer, 1976).
The t h r e e n e u r o t r a n s m i t t e r s y s t e m s , DA, NA and 5-HT were a l l found t o be a f f e c t e d in dement ia o f Alzheimer t y p e ( I I I ) , t h e p r i n c i p a l f i n d i n g s
be in g d e c r e a s e d c o n c e n t r a t i o n s . Although t h e d e c r e a s e o f t h e D A -c o n c e n t r a t i o n s were moderate in t h e dementia g r o u p , t h e r e d u c t i o n in t h e HVA-concentrations
in t h e putamen and n u c l eu s c a u d a t u s were h i g h l y s i g n i f i c a n t (Table 8 ) . The d i f f e r e n c e s o b s er v ed were n ot a t t r i b u t a b l e t o a n t e o r p o s t mortem f a c t o r s and c ou ld n o t be e x p l a i n e d by age d i f f e r e n c e s between t h e two gro u ps . NA- c o n c e n t r a t i o n was lower in e ve r y r e g i on a n a l y z e d , be ing s i g n i f i c a n t in t h e putamen and c o r t e x gyrus f r o n t a l i s (Table 9 ) . 5-HT c o n c e n t r a t i o n was lower in 7 o f 9 a n al yz e d r e g i o n s , a l t h o u g h not s i g n i f i c a n t l y . 5-HIAA c o n c e n t r a t i o n , a n a l y z e d in t h r e e c o r t i c a l a r e a s , was s i g n i f i c a n t l y d e c r e a s e d in t h e c o r t e x gyrus hippocampus and c i n g u l i (Table 10).
26 P a r t o f b r a i n DA/time d e a t h - a u t o p s y HVA/time d e a t h - a u t o p s y k n k n Hypothalamus - 0 . 2 8 24 0 . 24 19 Nucleus c a u da t u s -0. 21 23 - 0 . 1 5 44 Putamen - 0 . 1 7 24 - 0 . 1 9 44
Globus pal 1i dus 0. 12 18 0.11 18
Thaiamus 0. 10 18 - 0 . 2 5 18 Mesencephalon - 0 . 0 7 18 - 0 . 2 6 17 Pons - 0 . 1 3 18 0 .16 17 Medulla o b l o n g a t a 0. 07 18 0 . 1 8 18 Hi ppocampus 0 . 0 8 18 0. 14 18 Cortex gyrus f r o n t a l i s 0. 04 18 -0.11 18 Cortex gyrus p a r i e t a l i s 0.21 18 0 .25 18 Cortex gyrus o c c i p i t a l i s 0 . 4 2 x 18 - 0 . 0 6 18 Cortex t e m p o r a l i s 0 .2 6 18 -0.31 19 Cortex c e r e b e l l a r i s 0.11 18 - 0 . 0 2 18
Corte x gyrus hippocampus 0 .1 9 18 - 0 . 0 3 18
Cortex gyrus c i n g u l i 0 . 5 7 XX 18 0 .09 18
Xp < 0 . 0 5 ; XXp < 0.01
Table 7 Product-moment c o r r e l a t i o n s (k) between t h e c o n c e n t r a t i o n s o f dopamine (DA) and h o m o v a n i l l i c a c i d (HVA) (yg/ g wet t i s s u e ) and time between de ath and a u t o p s y . The p a t i e n t s had no n e u r o l o g i c o r p s y c h i a t r i c i l l n e s s . n=number o f c a s e s .
C o n tr o ls D em en te d C o n tr o ls D e m e n te d X X X CO CO o C\J LO d--p • • • CO OJ o 1 r>- OJ o LO OJ to r^-i— Q LO LO o to • • • 1 o OJ o C\J +i +1 +1 1— OJ OJ CO II o LO LO E o o o z • • • OJ LO o co 00 o d* d- O'» d-C\J o CO LO o CO • • • 1 •— OJ o o +1 +1 +1 r— LO CO h CO O'» d -E OJ 1— o • • • CO r-- o X X OJ 0J OJ to LO i— 00 d - d- d -4-> CO r-. to LO O'» OJ o OJ to OJ • • • • • • • • • • o 1 o1 OJ o o1 OJ o O' d- 00 r>- or CO 0J 0J CO 00 er» r— o 1— r— OJ OJ OJ 1— CO 1— O to d" 1— o o O o o o o to • • • • • • • • • • 1 o o o o o o o o o LO +1 + 1 +1 +1 +1 +1 +1 +1 +1 +! 1--LO LO or OJ OJ 00 OJ 00 0J d-II OJ to 00 1— OJ CO OJ ,— 1— OJ E o LO o o o o o o o o z • • • • • • • • • • 1 l—’ o o o o o o o o CO CD —s o or LO OJ o C"- CO 1— LO 1— CO OJ d- ,— 1— d- O' OJ LO LO OJ CO fÖ 1— Q LO CO 1— o er) o o o o o o to • • • • • • • • • • 1 o o o o o o o o o o o o +1 +1 +1 +1 +1 +1 +1 +1 +1 +1 1— s-«id CO O'» o to OJ CO d- 0>- CD II LO eo to CO d- CO LO CO OJ 0J _Q E CO• OJ• o• o• o• o• o• o• o• o• E 3 — «— «— o o o o o o o o c. II CO JO 3 CO CL • •1— E 1— 1— fÖ • 1— o fö o 1— • -p o 3 o c CL cn CO o CL c V =3 s- •1— •1— -P <p -£= CJ CL fö c X "O CO o co CO to X 3 =3 to 13 3 3 rö E 13 fÖ S- s- • #\ O fÖ CL _£Z >> >> >> LO 1— CO E CL CD cn cn o to c fÖ 13 fÖ CD • 13 CD E o o X X X o CD E -p fÖ o o CD CD CL) i—- rö o 1— Cl CD CO -p -p -p V O 4-> Ql fö CL CO £Z S-3 13 >> JO • 1— <D o o o o CL Q- J O \— nr Cl CJ o o X Tab le 8 M ea n an d st a n d a rd d e v ia ti o n of th e co nc en tr at io n of d o p am in e (D A ) (y g /g w et ti s s u e ) an d ho m ov a n ill ic ac id (H V A ) (y g /g w et ti s s u e ) in d em en te d pa ti en ts of A lz h e im e r ty p e an d in a g e -m a tc h e d c o n tr o ls . D if fe re n c e s ar e a n a ly z e d by Stu dent's t -t e s t .
28 C o n t r o l s Demented (N - 10 - 21) (N = 15 - 18) P a r t o f b r a i n m SD m SD t Nucleus c au d at us 0. 020 ± 0..012 0.,015 + 0..012 1 .35 Putamen 0. 043 + 0,.031 0..021 + 0,.019 3,.45X Hypothalamus 0. 749 ± 0..398 0..440 + 0..508 1,.83 Thalamus 0. 071 ± 0..048 0.,067 + 0..097 0 .19 Hippocampus 0. 013 + 0..012 0.,008 ± 0.,007 1 .46 Mesencephalon 0. 117 + 0.,059 0.,088 + 0..052 1 .55 Pons 0. 046 + 0..010 0..011 + 0.,007 1 .45 Cortex gyrus f r o n Y t a l i s 0. 018 ± 0.,024 0.,005 + 0.,006 2 .18 Cortex gyrus hi ppocampus 0. 014 + 0.,012 0..010 + 0.,011 0,.80 Cortex gyrus c in gul i 0. 019 + 0.,016 0.,013 ± 0.,016 0,.84 xp < 0.05
Table 9 Mean and s t a n d a r d d e v i a t i o n o f t h e c o n c e n t r a t i o n s o f n o r a d r e n a l i n e (NA) (ug/ g wet t i s s u e ) in t h e b r a i n in demented p a t i e n t s o f
Alzheimer t y p e and in a ge- matched c o n t r o l s . N = number o f c a s e s . S t u d e n t ' s t - t e s t .
I t must be emphasized t h a t a l l p a t i e n t s wi th dementia in t h i s s e r i e s were s e v e r e l y a f f e c t e d by t h e i r d i s e a s e , and were l o n g - s t a y r e s i d e n t s . The d i s e a s e most o f t e n had l e d t o a s e v e r e s t a t e o f c a c h e x i a and t h e i r mode o f d eat h was p r o t r a c t e d . Dying a t h o s p i t a l in a p r o t r a c t e d way, however, does n o t seem t o i n f l u e n c e t h e monoamine l e v e l s (Spokes, 1979). The u n d e r l y i n g mechanisms f o r t h e lower c o n c e n t r a t i o n s o f monoamines found
in dement ia o f Alzheimer t ype a r e most l i k e l y due t o neuronal d e g e n e r a t i v e c h a n g e s .
C o n tr o ls D em en te d C o n tr o ls D e m e n te d T ab le 10 M ea n an d s ta n d a rd d e v ia ti o n of th e con ce nt ra ti on of 5 -h y d ro x y tr y p ta m in e (5 -H T ) (y g /g w et ti s s u e ) a n d 5-hy droxyindoleacetic ac id (5 -H IA A ) (y g /g w et ti s s u e ) in th e b ra in in pati ents w it h d e m e n ti a of A lz h e im e r ty p e an d a g e -m a tc h e d c o n tr o ls . D if fe re n c e s ar e a n a ly z e d by St ud ent 's t -t e s t .
