- Email: [email protected]
Effect of the cholinesterase inhibitor huperzine A (HUP-A) on central cholinergic parameters in the rat
348
N E U R O B I O L O G Y O F A G I N ( L 'vOLUMt= ] i , t~)'=)o A B S I R A C ] ' S OF SE(IOND IN] E R N A T I O N A L C O N F E R E N C E ON A L Z H E 1 M E R ' S DISEASE CURRENT THERAPIES & II T U R E DIRECTIONS g i v e n f o r 3 months f o l l o w e d by a wash-out of 4 weeks and cross-over to the other treatment condition. Results of the efficacy of the treatment will not be known until shortly before the meeting when the code will be broken, There were however relatively few dropouts on account of invariably reversible Increases in liver enz~nes. Parallel experiments(Hodges et al. 1990) on tats wlth septal lesions produced a marked Improvement in performance on a radial maze task with no associated changes In acetyl choline levels and only ~ild choline esterase inhibition. Conclusion: Should improvement be found in humans tt is suggested that this may be related to some of the other effects of the drug e.g. K-channel blockade, nlcotinlc receptor stimulation or monoamineoxldase inhibition or possibly to a combination of these. Hodges, H., Rlbeiro, A.M,, Gray, J.A. & Marshbanks, R.~.(1990). Low dose THA improves cognitive function but does not affect brain acetyl choline In rats. Pharmacology, Biochemistry & Behaviour. (in press)
For the evaluation of treatment effects, psychological ruling scales and psychometric tests were performed at day 0 and 84 in [)AT patients, who did not respond to placebo therapy during a precedent 14 days wash-out period, randomly assigned to three treatment groups. Double blind treatment consisted of once daily intranasal administration of either 0.5 mg Org 5667. 2.0 mg Org 5667 or placebo. Chi-square tests showed no significant differences between the three treatment groups with respect to medical, psychiatric, social and demographic characteristics, except for sex distribution. For the evaluation of clinical treatment effects, a total of 53 variables were statistically analysed. Clinical evaluation revealed no significant differences between the various groups in non-parametric pairwise Wilcoxon tests, except for the item "speech' in the two active treatment groups. In accordance the variables in various cognitive functions showed also only some randomly scattered differences. The number of significant differences conform what one would expect in case no real differences between treatments do exist. In respect to the group size, it may be concluded that any clinically meaningful difference from placebotreatment would have been detected with high probability. The investigated dose-regimen resulted in measurable levels of DGAVP in human cerebrospinal fluid, so the treatment will have had access to the brain.
Summary: in a homogeneous group early DAT patients no favourable effects of daily intranasally treatment with DGAVP could be established. Vasopressin-like peptides seem not satisfactory therapeutic agents in DAT.
390 ORAL TETRAHYDROAMINOACRIDINEAND LECITHIN T R E A T M E N T OF ALZHEIMER'S DISEASE. L. Minthon, G. Dalfelt, L. Gustafson, B. Hagberg, I. Ros~n and J.Risberg Departments of Psychogeriatrics and Clinical Neurophysiology and Gerontology Research Center, University Hospital, P.O. 638, S-220 06 Lund, Sweden Previous studies of physostigmin and tetrahydroaminoacridine (THA) treatment of dementia of Alzheimer type (DAT) have indicated positive effects on cognition and neurophysiological measures. The present study evaluated oral THA-treatment with and without lecithin compared to placebo in patients with presenile DAT. Seventeen patients (8 women and 9 men) with a mean age of 63 + 7 (range 52-77) years were selected for the study. The patients were outpatients who except for pre-treatment assessment and dose-adjustmet periods in the hospital, lived with their families. The study had a double-blind crossover design with three 6-week treatment periods with two drugfree weeks inbetween. The sequence of treatments, THA+lecithin, THA+placebo and placebo+placebo, was randomized. The patients first went through a neuropsychiatric investigation including regional cerebral blood flow (rCBF) measurements, EEG, cerebral spinal fluid (CSF) analyses and in most cases CT. RCBF was measured with the non-traumatic 133 Xe inhalation tehnique using a high resolution equipment (Cortexplorer) with 254 detectors. The clinical diagnosis was based on these findings and a differential diagnostic scoring. Degree and kind of dementia was measured using a neuropsychological test battery. The best dose of THA was titrated during the dose adjustment phase, when also T ~ was calculated. The amount of lecithin was 22 g/d = 4 g Epycyron 200 (Lucas Meyer). The first treatment period started after a 2 week washout period. The clinical effects were measured at baseline and after 3 and 6 weeks during each treatment period. The evaluation was based on the organic brain syndrome (OBS) scale, a rating scale for side effects, the psychometric testhattery, rCBF measurement, EEG and laboratory tests. All 17 patients went through the full design of the study. The mean dose of T H A given was 101 ± 26 rag/day (range 50-125). The serum concentration of T H A indicated a satisfactory absorption of the drug. Two patients had elevations of A L T and AST which returned to normal range following dose reduction. The blinding has just been broken. The increase of liverenzymes were found during T H A treatment. The patients did not report or show any significant side effects during drug treatment compared to placebo. Nine patients have chosen to continue treatment with THA in an open trial. The analyses of clinical, psychometric and neurophysiological variables is in progress.
391 DOUBLE-BLIND PLACEBO-CONTROLLED DGAVP IN EARLY ALZHEIMER'S DISEASE PATIENTS
Wolters E.Ch., Riekkinen P, Lowenthat A, et at. DGAVP (ORG 5667) in early Aizhein~er's disease patients: An internationaldouble-btind placebo-controlledmu{ti-centertrial. Neurology 1990: in press.
392 THE EFFECTS OF ALZHEIHER'S DISEASE ON DRIVING-RELATED ABILITIES. *F.W. Bylsma, G.W. Rebok, P.M. Key]. The Johns Hopkins University, Baltimore, Naryland, 21205 USA. l.lany cognitive and behavioral impairments of Alzheimer's disease (AD) have the potential to interfere ~dth safe driving, but this issue has not been systematically investigated. This study investigated the relationship of cognitive deficits to driving-related abilities in iO AD
p a t i e n t s and 12 nondemented e l d e r l y age- and educationmatched c o n t r o l s . A l l subjects ~ere c u r r e n t l y d r i v i n g or had stopped ~dthin six months p r i o r to assessment. Subjects were administered tests of v i s u a l - s p a t i a l r e c o g n i t i o n , verbal and visual memory, l o g i c a l t h i n k i n g , and verbal fluency, and t~o d r i v i n g - r e l a t e d performance assessments: ( i ) the Driver Performance Test (DPT), a videotaped presentation of 40 d r i v i n g s i t u a t i o n s with varying degrees of hazard or danger, and {2) the Driving Advisement System (DAS), a computer'based assessment of reaction time (RT) and visuomotor tracking abilities. AD p a t i e n t s scored s i g n i f i c a n t l y loller than c o n t r o l s and had below average performance on DPT tests i n v o l v i n g search of the d r i v i n g environment, i d e n t i f i c a t i o n of s p e c i f i c d r i v i n g hazards, and execution of appropriate evasive actions. However, AD p a t i e n t s performed s i m i l a r l y to c o n t r o l s in two s p e c i f i c s k i l l areas - p_redic_ti~ ~hat w i l l happen in a given d r i v i n g s i t u a t i o n and decidinc L on appropriate hazard avoidance actions - where p a t i e n t s ' performance f e l l w i t h i n the average range. On the DAS, AD p a t i e n t s ' RT scores svere not only s i g n i f i c a n t l y longer than c o n t r o l s ' , but f e l l above the 95th p e r c e n t i l e f o r a sample of gO safe d r i v e r s p r e v i o u s l y assessed. I n t e r e s t i n g l y , AD p a t i e n t s became d i s p r o p o r t i o n a t e l y slower as task complexity increased. The AD p a t i e n t s performed more poorly than c o n t r o l s on the neuropsychological measures, and these measures c o r r e l a t e d with performance on the DPT and DAS measures. S p e c i f i c a l l y , visual and verbal memory was related to poor performance on the DPT and response s e l e c t i o n e r r o r s on the DAS. These r e s u l t s suggest that AD p a t i e n t s ' d r i v i n g a b i l i t i e s are adversely a f f e c t e d by the disease, and neuro, psychological measures may be useful in monitoring and p r e d i c t i n g the impact of AD on d r i v i n g a b i l i t i e s . Hore research is needed before such tests can be used f o r making recommendations about continuation or cessation of d r i v i n g in AF).
*E.Ch. Wolters, P. Riekkinen, A. Lowenthal, C. Sennef. Depts. of Neurology, Free University Amsterdam (The Netherlands), University of Kuopio (Finland), University of Antwerp (Belgium), and Akzo Organon, Oss, The Netherlands.
393
Beneficial effects of a vasopressin-related peptide, DGAVPcitrate (OrB 5667) on learning and memory processes were reported for healthy volunteers and occasionally for patients with dementia of the Alzheimer type (DAT), but patient-studies were small, often uncontrolled, and included severely affected patients. A double-blind placebo-controlled studie of DGAVP-citrate was carried out in 115 patients with mild DAT.
EF'FI~CI" OF THE CHOUNESTEI~E INHIBITOR HUPEBZlNE A (HUP-A) ON OENI~ (~-K)UN~O P~'I"~ IN THE RAT. $. L ~ , J, ~ , ~C. Tang, E. ~ahWIWm"and i. Hanln, Loyola Unlvem~y of Chicago, Ma~a~mmd,II BO1~ and "UCB ma., Phamm(wm~k~ ~ c ~ . Hup-A Is a natur~ acetylchollne~erase (ACHE) inhibitor isolated from a Lycopodlurn speciesfound in China. It has been reported to Irw:~ a long lasllng
N E U R O B I O L O G Y OF A G I N G , V O L U M E 11, 1990 A B S T R A C T S OF S E C O N D I N T E R N A T I O N A L C O N F E R E N C E ON A L Z H E I M E R ' S D I S E A S E CURRENT THERAPIES & FUTURE DIRECTIONS
(houm) Increase in levis d ace~ch~ine ~Ch) in the brain by up to 40%, and has been ~oposed as a pallmt~e treatment in Alzheimer's dementm. (Tang ~ al, J. Neuroscl. Res. 24:276, 1989). In vtvo ac=e =udles. We a~essed the high affin~ ch~ine tmnspo~ (HACh~ on syna~eaornal fra~lons from male Spmgue Da~ey rats ~25~25 g) that had receNed a single I~ectlon ~ Hup-A ~.1 and 0.5 mg/kg, i.p.), 45 or 90 min eadier. 0.5 mg/kg, hlppocampal (H) HAChT was signfficamly decreased by 20% ~ 45 min, b~ this Inhlb~ion was come.ely revemed by 90 min. This effe~ was n~ seen = the lower d o ~ ~ Hu~A 0.1 mg/kg), nor in =ri~al ($tr) syna~osomes, = any dose. ~though Hup-A showed a pote~ inhib~ion ~ AChE in homogenates ~ H (-10%), ~r (-20%) and ~ u m (S~, ~5%), k had no effect on choline a c ~ t m n ~ e ~ (ChA~ a~lvlty In these seme areas. In v~o chronic =ndies. R~s were tre~ed with Hup-A ~.1 or 0.5 mg/kg i.p., twice a day) ~ r 4-5 d a ~ and ~cr~iced 45 min affer the ~h and la= i~ect~n. The ree~ts showed a consi~ent redu~ion ~ AChE a c t ~ in homogenates ~: H (~3%), ~ r (-20%), 8 ~ (-20%) and codex (-19%). HAChT activi~ was reduced in H after chmn~ treatme~ w~h Hu~A (p<0.025, 0.5 mg/kg), b~ n~ in Str. Again, them was no effect ~ Hu~A on ChAT a ~ y in any ~ the four brain regions ~udied. tn v~ro =ndles. To d~ermine wh~her the reduction in HAChT a c t ~ seen above mlg~ be due to a direct inhib~o~ effect on HAChT, hippocampal syna~osomes were Incubated in the presence ~ Hup-A (10"z to ' ~ M), and HAChT was measured affer 5, 15 and 45 rain @ incubation. Results ~ this ~ndy Indicated ~eady the absence ~ any m vitro effect ~ Hup~ on HAChT. These combined d~a indicate that: 1) t~emnce to Hup-A does n~ occur after chronic adminl~ration; 2) Hu~A does n~ i~em~ dire~ly w~h the high affin~ transporter ~ ch~lne; and 3) Hup-A might affe~ the regul~ion ~ HAChT in the hippocampus v~ a pre-wna~ic muscarinic feedback mechanism, possi~y triggered by tmnsie~ changes in central ACh m~abolism. SuppoSed by NIA Grant #AGO7591 and by UCB, s.a., Bruss~s.
394 R E G I O N A L A L Z H E I M E R ' S D I S E A S E PROGRAM: D E V E L O P M E N T OF A M O D E L C E N T E R FOR A R E L A T I V E L Y UNDE~SERVED P O P U L A T I O N IN THE C E N T R A L U N I T E D STATES. * G a r y D. Miner. The A l z h e i m e r ' s F o u n d a t i o n , Tulsa, O k l a h o m a , 74137, U.S.A. T h e r e is a need for c o o p e r a t i v e r e s e a r c h and e d u c a t i o n a l e f f o r t s for A l z h e i m e r ' s d i s e a s e in a r e a s of r e l a t i v e l y low p o p u l a t i o n density. Such a cooperative effort to develop facilities for research, health care worker training, and dissemination of public information about A l z h e i m e r ' s d i s e a s e has b e e n d e v e l o p e d in the f o u r state region including Oklahoma, Kansas, s o u t h w e s t e r n Missouri, and n o r t h w e s t e r n Arkansas. P r i o r to d e v e l o p i n g this c o n s o r t i u m , this four s t a t e region, w h i c h is g e o g r a p h i c a l l y isolated with a d i s p e r s e d and a g r o w i n g r e t i r e m e n t age p o p u l a t i o n , had no c o o r d i n a t e d program. B a s e d on the m o m e n t u m gained from International Symposia and recently p u b l i s h e d b o o k s [Miner, et al. , F A M I L I A L A L Z H E I M E R ' S DISEASE: MOLECULAR GENETICS AND CLINICAL PERSPECTIVES, NY: Marcel Dekker, Inc., 1989; Miner, et al. , C A R I N G FOR A L Z H E I M E R ' S PATIENTS: A GUIDE FOR F A M I L Y AND HEALTHCARE PROVIDERS, NY: P l e n u m Press, 1989] t h e r e is i n c r e a s e d c o m m u n i c a t i o n and i n t e r a c t i o n s a m o n g the d i s p e r s e d p r o f e s s i o n a l and c l i n i c a l p o p u l a t i o n s . This has e n h a n c e d the a b i l i t y to d e v e l o p d r u g t r i ~ s , community education programs, interactions with state Alzheimer's d i s e a s e t a s k forces, and l e g i s l a t i v e efforts. This r e g i o n a l c e n t e r c a n s e r v e as a m o d e l for p r o g r a m s in o t h e r g e o g r a p h i c locations.
349
LC/MS including l-hydroxy-tacrine and several dihydroxylated metabolites. Using the Ellman method, tacrine was found to i n h i b i t ra t c o r t i c a l AcChE with an IC5n of 0.21~M and r a t plasma BuChE with a value of 0.06~M. I-Hydroxy-tacrine was less potent with ICanS of 0.68~M and 0.44~M respectively, while 2-hydroxy-tacfTne and 4-hydroxy-tacrine were also weaker than tacrine in both assays. Thus, while several metabolites have ChE i n h i b i t o r y properties, t h e i r reduced potency lessens the potential f o r these compounds to cont r i b u t e to the overall pharmacological p r o f i l e of tacrine in both humans and animals. 8
NH2 9
6
1
3
Tacrine
396 INNOVATIVE
RESEARCH METHODOLOGIES IN NORMAL AGING MEMORY: AN INTERNATIONAL SURVEY. *O. Zappal&, B.D. Lebowitz, L.A. Amaducci, T.H. Crook, D. M a s s a r i , F.J. Pirozzolo. Progetto Memoria: CNR (Rome), NIMH (Bethesda), F I D I A (Abano Terme). One of the roles of neuropsychology, among others, is to offer safer and m o r e s o p h i s t i c a t e d assessment tools to monitor the efficacy of available pharmacological t r e a t m e n t s and to p r o v i d e more clues for future drug developments in age r e l a t e d m e m o r y d i s f u n c t i o n and n e u r o d e g e n e r a t i o n . R e s e a r c h in n e u r o b i o l o g y of aging and psychogeriatric pharmacology is h e a v i l y i n t e r d i s c i p l i n a r y and it relies on p r o g r e s s m a d e in several different fields of current neurosciences, including cooperative e f f o r t s a m o n g g o v e r n m e n t s , academia and pharmaceutical industry. It is in fact a c o m m o n need, b o t h for e x p e r i m e n t a l neuroscience and drug developing companies to transfer t h e i r k n o w l e d g e from basic research to more clinically oriented a c t i v i t i e s and programs. We will report on an innovative and o r i g i n a l research named PROGETTO MEMORIA which involves the Italian National Research Council, the National I n s t i t u t e of M e n t a l Health (USA), and the Memory R e s e a r c h C e n t e r of F I D I A P h a r m a c e u t i c a l s . The Progetto Memoria is a neuroepidemiological survey c u r r e n t l y u n d e r w a y which aims at assessing memory performance of normal h e a l t h y s u b j e c t s w h o s e age ranges from 20 to 79. Such study combines the innovative concepts of ecologically oriented measures recently developed at M e m o r y Assessment C l i n i c s (Bethesda), w i t h the use of a mobile unit which enables us to test only randomly selected populations. The replicability of such research program and its p o t e n t i a l for l o n g i t u d i n a l studies m i g h t offer significant hints to the problem of assessing cognitive performance of p o p u l a t i o n s of d i f f e r e n t n a t i o n s and d i f f e r e n t ethnic groups. AND
395 THE EFFECT OF TACRINE AND SELECTED METABOLITES ON RAT ACETYL- AND BUTYRYLCHOLINESTERASE ACTIVITY. *R.D. Schwarz, T. Chang, R.E. Davis, W.H. Moos, M. Pavia, C.J. Spencer, and A.J. Thomas. Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, MI, 48105 USA. The loss of cognitive function associated with aging and neurodegenerative disorders such as Alzheimer's disease (AD) appears to be due in part to a l t e r a t i o n s in central c h o l i nergic neurotransmission. Acetylcholinesterase (AcChE) i n h i b i t o r s , such as tacrine and physostigmine, may a l l e v i a t e this reduction in cognitive a b i l i t i e s by preventing acetylcholine breakdown in the synaptic c l e f t . Since tacrine is currently undergoing c l i n i c a l investigation, the present study examined tacrine and several of i t s metabolites on AcChE and butyrylcholinesterase (8uChE) a c t i v i t y . In rats, tacrine was eliminated p r i m a r i l y by hepatic metabolism and several metabolites have been i d e n t i f i e d by
397 EFFECTS OF SCOPOLAMINE ON LATERALIZATIONOF 40Hz EEG Ac:TIVITY 1N YOUNG HEALTIIYVOLUNTEERS. ¢~D. G u r e v i c h , M. K u s h n i r , M.S. Dumlao, C.A. Bagne, A.S. Dumlao, D.E. Sheer 1. Wayne S t a t e U n i v . , Dept. of P s y c h i a t r y , L a f a y e t t e C l i n i c , D e t r o i t : , M[ 48207 HSA and Univ. of }touston, Dept. of P s y c h o l o g y , Houston, TX 77004 ]!SA1. Dementia of A l z h e i m e r ' s t y p e (DAT) is c h a r a c t e r i z e d by i m p a i r menL of memory and a t t e n t i o n . A s u b s t a n t i a l body of e v i d e n c e s u g g e s t s t h a t r e d u c e d c h o l i n e r g J c a c t i v i t y i s c o r r e l a t e d with cognitive deficits. S c o p o l a m i n e , an a n t i c h o t i n e r g i c agent:, i s known to c a u s e c o g n i t i v e d e f i c i t s . We have been e v a l u a t i n g t h e e f f e c t s of Scopolamine on t a s k - d e p e n d e n t l a t e r a l i z a t i o n ot 40Hz PEG a c t i v i t y (35-45Hz band) in an ongoing s t u d y . Young h e a l t h y c o l t e g e - s t u d e n t v o l u n t e e r s were g i v e n s c o p o l a m i n e (3~g/kg and 6Dg/kg, IV) and p l a c e b o i n a 3 s e s s i o n , s i n g l e b l i n d , randomized design. EEG was r e c o r d e d o v e r t h e r i g h t and l e f t h e m i s p h e r e s a t t h e P3-O1 T5 and P4-O2-T6 of t h e i n t e r n a t i o n a l 10-20 s y s t e m with
N E U R O B I O L O G Y O F A G I N ( L 'vOLUMt= ] i , t~)'=)o A B S I R A C ] ' S OF SE(IOND IN] E R N A T I O N A L C O N F E R E N C E ON A L Z H E 1 M E R ' S DISEASE CURRENT THERAPIES & II T U R E DIRECTIONS g i v e n f o r 3 months f o l l o w e d by a wash-out of 4 weeks and cross-over to the other treatment condition. Results of the efficacy of the treatment will not be known until shortly before the meeting when the code will be broken, There were however relatively few dropouts on account of invariably reversible Increases in liver enz~nes. Parallel experiments(Hodges et al. 1990) on tats wlth septal lesions produced a marked Improvement in performance on a radial maze task with no associated changes In acetyl choline levels and only ~ild choline esterase inhibition. Conclusion: Should improvement be found in humans tt is suggested that this may be related to some of the other effects of the drug e.g. K-channel blockade, nlcotinlc receptor stimulation or monoamineoxldase inhibition or possibly to a combination of these. Hodges, H., Rlbeiro, A.M,, Gray, J.A. & Marshbanks, R.~.(1990). Low dose THA improves cognitive function but does not affect brain acetyl choline In rats. Pharmacology, Biochemistry & Behaviour. (in press)
For the evaluation of treatment effects, psychological ruling scales and psychometric tests were performed at day 0 and 84 in [)AT patients, who did not respond to placebo therapy during a precedent 14 days wash-out period, randomly assigned to three treatment groups. Double blind treatment consisted of once daily intranasal administration of either 0.5 mg Org 5667. 2.0 mg Org 5667 or placebo. Chi-square tests showed no significant differences between the three treatment groups with respect to medical, psychiatric, social and demographic characteristics, except for sex distribution. For the evaluation of clinical treatment effects, a total of 53 variables were statistically analysed. Clinical evaluation revealed no significant differences between the various groups in non-parametric pairwise Wilcoxon tests, except for the item "speech' in the two active treatment groups. In accordance the variables in various cognitive functions showed also only some randomly scattered differences. The number of significant differences conform what one would expect in case no real differences between treatments do exist. In respect to the group size, it may be concluded that any clinically meaningful difference from placebotreatment would have been detected with high probability. The investigated dose-regimen resulted in measurable levels of DGAVP in human cerebrospinal fluid, so the treatment will have had access to the brain.
Summary: in a homogeneous group early DAT patients no favourable effects of daily intranasally treatment with DGAVP could be established. Vasopressin-like peptides seem not satisfactory therapeutic agents in DAT.
390 ORAL TETRAHYDROAMINOACRIDINEAND LECITHIN T R E A T M E N T OF ALZHEIMER'S DISEASE. L. Minthon, G. Dalfelt, L. Gustafson, B. Hagberg, I. Ros~n and J.Risberg Departments of Psychogeriatrics and Clinical Neurophysiology and Gerontology Research Center, University Hospital, P.O. 638, S-220 06 Lund, Sweden Previous studies of physostigmin and tetrahydroaminoacridine (THA) treatment of dementia of Alzheimer type (DAT) have indicated positive effects on cognition and neurophysiological measures. The present study evaluated oral THA-treatment with and without lecithin compared to placebo in patients with presenile DAT. Seventeen patients (8 women and 9 men) with a mean age of 63 + 7 (range 52-77) years were selected for the study. The patients were outpatients who except for pre-treatment assessment and dose-adjustmet periods in the hospital, lived with their families. The study had a double-blind crossover design with three 6-week treatment periods with two drugfree weeks inbetween. The sequence of treatments, THA+lecithin, THA+placebo and placebo+placebo, was randomized. The patients first went through a neuropsychiatric investigation including regional cerebral blood flow (rCBF) measurements, EEG, cerebral spinal fluid (CSF) analyses and in most cases CT. RCBF was measured with the non-traumatic 133 Xe inhalation tehnique using a high resolution equipment (Cortexplorer) with 254 detectors. The clinical diagnosis was based on these findings and a differential diagnostic scoring. Degree and kind of dementia was measured using a neuropsychological test battery. The best dose of THA was titrated during the dose adjustment phase, when also T ~ was calculated. The amount of lecithin was 22 g/d = 4 g Epycyron 200 (Lucas Meyer). The first treatment period started after a 2 week washout period. The clinical effects were measured at baseline and after 3 and 6 weeks during each treatment period. The evaluation was based on the organic brain syndrome (OBS) scale, a rating scale for side effects, the psychometric testhattery, rCBF measurement, EEG and laboratory tests. All 17 patients went through the full design of the study. The mean dose of T H A given was 101 ± 26 rag/day (range 50-125). The serum concentration of T H A indicated a satisfactory absorption of the drug. Two patients had elevations of A L T and AST which returned to normal range following dose reduction. The blinding has just been broken. The increase of liverenzymes were found during T H A treatment. The patients did not report or show any significant side effects during drug treatment compared to placebo. Nine patients have chosen to continue treatment with THA in an open trial. The analyses of clinical, psychometric and neurophysiological variables is in progress.
391 DOUBLE-BLIND PLACEBO-CONTROLLED DGAVP IN EARLY ALZHEIMER'S DISEASE PATIENTS
Wolters E.Ch., Riekkinen P, Lowenthat A, et at. DGAVP (ORG 5667) in early Aizhein~er's disease patients: An internationaldouble-btind placebo-controlledmu{ti-centertrial. Neurology 1990: in press.
392 THE EFFECTS OF ALZHEIHER'S DISEASE ON DRIVING-RELATED ABILITIES. *F.W. Bylsma, G.W. Rebok, P.M. Key]. The Johns Hopkins University, Baltimore, Naryland, 21205 USA. l.lany cognitive and behavioral impairments of Alzheimer's disease (AD) have the potential to interfere ~dth safe driving, but this issue has not been systematically investigated. This study investigated the relationship of cognitive deficits to driving-related abilities in iO AD
p a t i e n t s and 12 nondemented e l d e r l y age- and educationmatched c o n t r o l s . A l l subjects ~ere c u r r e n t l y d r i v i n g or had stopped ~dthin six months p r i o r to assessment. Subjects were administered tests of v i s u a l - s p a t i a l r e c o g n i t i o n , verbal and visual memory, l o g i c a l t h i n k i n g , and verbal fluency, and t~o d r i v i n g - r e l a t e d performance assessments: ( i ) the Driver Performance Test (DPT), a videotaped presentation of 40 d r i v i n g s i t u a t i o n s with varying degrees of hazard or danger, and {2) the Driving Advisement System (DAS), a computer'based assessment of reaction time (RT) and visuomotor tracking abilities. AD p a t i e n t s scored s i g n i f i c a n t l y loller than c o n t r o l s and had below average performance on DPT tests i n v o l v i n g search of the d r i v i n g environment, i d e n t i f i c a t i o n of s p e c i f i c d r i v i n g hazards, and execution of appropriate evasive actions. However, AD p a t i e n t s performed s i m i l a r l y to c o n t r o l s in two s p e c i f i c s k i l l areas - p_redic_ti~ ~hat w i l l happen in a given d r i v i n g s i t u a t i o n and decidinc L on appropriate hazard avoidance actions - where p a t i e n t s ' performance f e l l w i t h i n the average range. On the DAS, AD p a t i e n t s ' RT scores svere not only s i g n i f i c a n t l y longer than c o n t r o l s ' , but f e l l above the 95th p e r c e n t i l e f o r a sample of gO safe d r i v e r s p r e v i o u s l y assessed. I n t e r e s t i n g l y , AD p a t i e n t s became d i s p r o p o r t i o n a t e l y slower as task complexity increased. The AD p a t i e n t s performed more poorly than c o n t r o l s on the neuropsychological measures, and these measures c o r r e l a t e d with performance on the DPT and DAS measures. S p e c i f i c a l l y , visual and verbal memory was related to poor performance on the DPT and response s e l e c t i o n e r r o r s on the DAS. These r e s u l t s suggest that AD p a t i e n t s ' d r i v i n g a b i l i t i e s are adversely a f f e c t e d by the disease, and neuro, psychological measures may be useful in monitoring and p r e d i c t i n g the impact of AD on d r i v i n g a b i l i t i e s . Hore research is needed before such tests can be used f o r making recommendations about continuation or cessation of d r i v i n g in AF).
*E.Ch. Wolters, P. Riekkinen, A. Lowenthal, C. Sennef. Depts. of Neurology, Free University Amsterdam (The Netherlands), University of Kuopio (Finland), University of Antwerp (Belgium), and Akzo Organon, Oss, The Netherlands.
393
Beneficial effects of a vasopressin-related peptide, DGAVPcitrate (OrB 5667) on learning and memory processes were reported for healthy volunteers and occasionally for patients with dementia of the Alzheimer type (DAT), but patient-studies were small, often uncontrolled, and included severely affected patients. A double-blind placebo-controlled studie of DGAVP-citrate was carried out in 115 patients with mild DAT.
EF'FI~CI" OF THE CHOUNESTEI~E INHIBITOR HUPEBZlNE A (HUP-A) ON OENI~ (~-K)UN~O P~'I"~ IN THE RAT. $. L ~ , J, ~ , ~C. Tang, E. ~ahWIWm"and i. Hanln, Loyola Unlvem~y of Chicago, Ma~a~mmd,II BO1~ and "UCB ma., Phamm(wm~k~ ~ c ~ . Hup-A Is a natur~ acetylchollne~erase (ACHE) inhibitor isolated from a Lycopodlurn speciesfound in China. It has been reported to Irw:~ a long lasllng
N E U R O B I O L O G Y OF A G I N G , V O L U M E 11, 1990 A B S T R A C T S OF S E C O N D I N T E R N A T I O N A L C O N F E R E N C E ON A L Z H E I M E R ' S D I S E A S E CURRENT THERAPIES & FUTURE DIRECTIONS
(houm) Increase in levis d ace~ch~ine ~Ch) in the brain by up to 40%, and has been ~oposed as a pallmt~e treatment in Alzheimer's dementm. (Tang ~ al, J. Neuroscl. Res. 24:276, 1989). In vtvo ac=e =udles. We a~essed the high affin~ ch~ine tmnspo~ (HACh~ on syna~eaornal fra~lons from male Spmgue Da~ey rats ~25~25 g) that had receNed a single I~ectlon ~ Hup-A ~.1 and 0.5 mg/kg, i.p.), 45 or 90 min eadier. 0.5 mg/kg, hlppocampal (H) HAChT was signfficamly decreased by 20% ~ 45 min, b~ this Inhlb~ion was come.ely revemed by 90 min. This effe~ was n~ seen = the lower d o ~ ~ Hu~A 0.1 mg/kg), nor in =ri~al ($tr) syna~osomes, = any dose. ~though Hup-A showed a pote~ inhib~ion ~ AChE in homogenates ~ H (-10%), ~r (-20%) and ~ u m (S~, ~5%), k had no effect on choline a c ~ t m n ~ e ~ (ChA~ a~lvlty In these seme areas. In v~o chronic =ndies. R~s were tre~ed with Hup-A ~.1 or 0.5 mg/kg i.p., twice a day) ~ r 4-5 d a ~ and ~cr~iced 45 min affer the ~h and la= i~ect~n. The ree~ts showed a consi~ent redu~ion ~ AChE a c t ~ in homogenates ~: H (~3%), ~ r (-20%), 8 ~ (-20%) and codex (-19%). HAChT activi~ was reduced in H after chmn~ treatme~ w~h Hu~A (p<0.025, 0.5 mg/kg), b~ n~ in Str. Again, them was no effect ~ Hu~A on ChAT a ~ y in any ~ the four brain regions ~udied. tn v~ro =ndles. To d~ermine wh~her the reduction in HAChT a c t ~ seen above mlg~ be due to a direct inhib~o~ effect on HAChT, hippocampal syna~osomes were Incubated in the presence ~ Hup-A (10"z to ' ~ M), and HAChT was measured affer 5, 15 and 45 rain @ incubation. Results ~ this ~ndy Indicated ~eady the absence ~ any m vitro effect ~ Hup~ on HAChT. These combined d~a indicate that: 1) t~emnce to Hup-A does n~ occur after chronic adminl~ration; 2) Hu~A does n~ i~em~ dire~ly w~h the high affin~ transporter ~ ch~lne; and 3) Hup-A might affe~ the regul~ion ~ HAChT in the hippocampus v~ a pre-wna~ic muscarinic feedback mechanism, possi~y triggered by tmnsie~ changes in central ACh m~abolism. SuppoSed by NIA Grant #AGO7591 and by UCB, s.a., Bruss~s.
394 R E G I O N A L A L Z H E I M E R ' S D I S E A S E PROGRAM: D E V E L O P M E N T OF A M O D E L C E N T E R FOR A R E L A T I V E L Y UNDE~SERVED P O P U L A T I O N IN THE C E N T R A L U N I T E D STATES. * G a r y D. Miner. The A l z h e i m e r ' s F o u n d a t i o n , Tulsa, O k l a h o m a , 74137, U.S.A. T h e r e is a need for c o o p e r a t i v e r e s e a r c h and e d u c a t i o n a l e f f o r t s for A l z h e i m e r ' s d i s e a s e in a r e a s of r e l a t i v e l y low p o p u l a t i o n density. Such a cooperative effort to develop facilities for research, health care worker training, and dissemination of public information about A l z h e i m e r ' s d i s e a s e has b e e n d e v e l o p e d in the f o u r state region including Oklahoma, Kansas, s o u t h w e s t e r n Missouri, and n o r t h w e s t e r n Arkansas. P r i o r to d e v e l o p i n g this c o n s o r t i u m , this four s t a t e region, w h i c h is g e o g r a p h i c a l l y isolated with a d i s p e r s e d and a g r o w i n g r e t i r e m e n t age p o p u l a t i o n , had no c o o r d i n a t e d program. B a s e d on the m o m e n t u m gained from International Symposia and recently p u b l i s h e d b o o k s [Miner, et al. , F A M I L I A L A L Z H E I M E R ' S DISEASE: MOLECULAR GENETICS AND CLINICAL PERSPECTIVES, NY: Marcel Dekker, Inc., 1989; Miner, et al. , C A R I N G FOR A L Z H E I M E R ' S PATIENTS: A GUIDE FOR F A M I L Y AND HEALTHCARE PROVIDERS, NY: P l e n u m Press, 1989] t h e r e is i n c r e a s e d c o m m u n i c a t i o n and i n t e r a c t i o n s a m o n g the d i s p e r s e d p r o f e s s i o n a l and c l i n i c a l p o p u l a t i o n s . This has e n h a n c e d the a b i l i t y to d e v e l o p d r u g t r i ~ s , community education programs, interactions with state Alzheimer's d i s e a s e t a s k forces, and l e g i s l a t i v e efforts. This r e g i o n a l c e n t e r c a n s e r v e as a m o d e l for p r o g r a m s in o t h e r g e o g r a p h i c locations.
349
LC/MS including l-hydroxy-tacrine and several dihydroxylated metabolites. Using the Ellman method, tacrine was found to i n h i b i t ra t c o r t i c a l AcChE with an IC5n of 0.21~M and r a t plasma BuChE with a value of 0.06~M. I-Hydroxy-tacrine was less potent with ICanS of 0.68~M and 0.44~M respectively, while 2-hydroxy-tacfTne and 4-hydroxy-tacrine were also weaker than tacrine in both assays. Thus, while several metabolites have ChE i n h i b i t o r y properties, t h e i r reduced potency lessens the potential f o r these compounds to cont r i b u t e to the overall pharmacological p r o f i l e of tacrine in both humans and animals. 8
NH2 9
6
1
3
Tacrine
396 INNOVATIVE
RESEARCH METHODOLOGIES IN NORMAL AGING MEMORY: AN INTERNATIONAL SURVEY. *O. Zappal&, B.D. Lebowitz, L.A. Amaducci, T.H. Crook, D. M a s s a r i , F.J. Pirozzolo. Progetto Memoria: CNR (Rome), NIMH (Bethesda), F I D I A (Abano Terme). One of the roles of neuropsychology, among others, is to offer safer and m o r e s o p h i s t i c a t e d assessment tools to monitor the efficacy of available pharmacological t r e a t m e n t s and to p r o v i d e more clues for future drug developments in age r e l a t e d m e m o r y d i s f u n c t i o n and n e u r o d e g e n e r a t i o n . R e s e a r c h in n e u r o b i o l o g y of aging and psychogeriatric pharmacology is h e a v i l y i n t e r d i s c i p l i n a r y and it relies on p r o g r e s s m a d e in several different fields of current neurosciences, including cooperative e f f o r t s a m o n g g o v e r n m e n t s , academia and pharmaceutical industry. It is in fact a c o m m o n need, b o t h for e x p e r i m e n t a l neuroscience and drug developing companies to transfer t h e i r k n o w l e d g e from basic research to more clinically oriented a c t i v i t i e s and programs. We will report on an innovative and o r i g i n a l research named PROGETTO MEMORIA which involves the Italian National Research Council, the National I n s t i t u t e of M e n t a l Health (USA), and the Memory R e s e a r c h C e n t e r of F I D I A P h a r m a c e u t i c a l s . The Progetto Memoria is a neuroepidemiological survey c u r r e n t l y u n d e r w a y which aims at assessing memory performance of normal h e a l t h y s u b j e c t s w h o s e age ranges from 20 to 79. Such study combines the innovative concepts of ecologically oriented measures recently developed at M e m o r y Assessment C l i n i c s (Bethesda), w i t h the use of a mobile unit which enables us to test only randomly selected populations. The replicability of such research program and its p o t e n t i a l for l o n g i t u d i n a l studies m i g h t offer significant hints to the problem of assessing cognitive performance of p o p u l a t i o n s of d i f f e r e n t n a t i o n s and d i f f e r e n t ethnic groups. AND
395 THE EFFECT OF TACRINE AND SELECTED METABOLITES ON RAT ACETYL- AND BUTYRYLCHOLINESTERASE ACTIVITY. *R.D. Schwarz, T. Chang, R.E. Davis, W.H. Moos, M. Pavia, C.J. Spencer, and A.J. Thomas. Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, MI, 48105 USA. The loss of cognitive function associated with aging and neurodegenerative disorders such as Alzheimer's disease (AD) appears to be due in part to a l t e r a t i o n s in central c h o l i nergic neurotransmission. Acetylcholinesterase (AcChE) i n h i b i t o r s , such as tacrine and physostigmine, may a l l e v i a t e this reduction in cognitive a b i l i t i e s by preventing acetylcholine breakdown in the synaptic c l e f t . Since tacrine is currently undergoing c l i n i c a l investigation, the present study examined tacrine and several of i t s metabolites on AcChE and butyrylcholinesterase (8uChE) a c t i v i t y . In rats, tacrine was eliminated p r i m a r i l y by hepatic metabolism and several metabolites have been i d e n t i f i e d by
397 EFFECTS OF SCOPOLAMINE ON LATERALIZATIONOF 40Hz EEG Ac:TIVITY 1N YOUNG HEALTIIYVOLUNTEERS. ¢~D. G u r e v i c h , M. K u s h n i r , M.S. Dumlao, C.A. Bagne, A.S. Dumlao, D.E. Sheer 1. Wayne S t a t e U n i v . , Dept. of P s y c h i a t r y , L a f a y e t t e C l i n i c , D e t r o i t : , M[ 48207 HSA and Univ. of }touston, Dept. of P s y c h o l o g y , Houston, TX 77004 ]!SA1. Dementia of A l z h e i m e r ' s t y p e (DAT) is c h a r a c t e r i z e d by i m p a i r menL of memory and a t t e n t i o n . A s u b s t a n t i a l body of e v i d e n c e s u g g e s t s t h a t r e d u c e d c h o l i n e r g J c a c t i v i t y i s c o r r e l a t e d with cognitive deficits. S c o p o l a m i n e , an a n t i c h o t i n e r g i c agent:, i s known to c a u s e c o g n i t i v e d e f i c i t s . We have been e v a l u a t i n g t h e e f f e c t s of Scopolamine on t a s k - d e p e n d e n t l a t e r a l i z a t i o n ot 40Hz PEG a c t i v i t y (35-45Hz band) in an ongoing s t u d y . Young h e a l t h y c o l t e g e - s t u d e n t v o l u n t e e r s were g i v e n s c o p o l a m i n e (3~g/kg and 6Dg/kg, IV) and p l a c e b o i n a 3 s e s s i o n , s i n g l e b l i n d , randomized design. EEG was r e c o r d e d o v e r t h e r i g h t and l e f t h e m i s p h e r e s a t t h e P3-O1 T5 and P4-O2-T6 of t h e i n t e r n a t i o n a l 10-20 s y s t e m with