Arq Neuropsiquiatr 2004;62(2-B):379-384
1Department of Neurology, University of São Paulo, São Paulo SP , Brazil;2Department of Internal Medicine (Neurology), Federal University of Rio Grande do Sul,
Porto Alegre RS,Brazil;3Institute of Neurology Deolindo Couto,Federal University of Rio de Janeiro,Rio de Janeiro RJ,Brazil;4AURUS-IEPE - Institute of Research
and Education on Aging,Belo Horizonte MG,Brazil;5Department of Neurology and Neurosurgery,Federal University of São Paulo,São Paulo SP ,Brazil;and 6Department
of Neurology,Psychiatry and Medical Psychology,University of São Paulo at Ribeirão Preto,Ribeirão Preto SP ,Brazil;7Appendix.This study was supported by Janssen-
Received 7 October 2003,received in final form 7 January 2004.Accepted 3 February 2004
Dr. Paulo Caramelli - Rua Itapeva 518/601 - 01332-000 São Paulo SP - Brasil. E-mail: email@example.com
EFFECTS OF GALANTAMINE ON ATTENTION AND MEMORY IN
ALZHEIMER’S DISEASE MEASURED BY COMPUTERIZED NEU-
Results of the Brazilian Multi-Center Galantamine Study (GAL-BRA-
Paulo Caramelli1, Márcia L.F. Chaves2, Eliasz Engelhardt3, João Carlos B. Machado4, Rodrigo R. Schultz5,
Francisco A.C. Vale6, Helenice Charchat-Fichman1, for the Brazilian Galantamine Study Group7
ABSTRACT - Objective:To investigate the effects of galantamine on the performance of patients with mild to moderate Alzheimer’s
disease (AD) in a computerized neuropsychological test battery (CNTB). Method:Thirty-three patients with probable AD were treat-
ed with galantamine for three months and evaluated in a prospective,open-label,multi-center study.The CNTB and the ADAS-Cog
were administered at baseline and after 12 weeks.The CNTB includes reaction time tests to evaluate attention,implicit and episod-
ic memory for faces and words. Statistical comparisons were performed between the results in week 12 versus baseline. Patients
who did not reach the therapeutic doses were excluded from the efficacy analysis. Results:Four patients (12.1%) were excluded
from the analysis either because of treatment discontinuation (n=3) or because a therapeutic dose was not reached (n=1).The remain-
ing 29 patients were treated with doses of 24 mg/day (n=22) and 16 mg/day (n=7).After 12 weeks,significant reductions in reac-
tion time were seen in the test of episodic memory for faces (p=0.023) and in the test of two-choice reaction time (p=0.039) of the
CNTB. Conclusion:Treatment with galantamine produced improvement in computerized tests of attention and episodic memory
after 12 weeks,leading to statistically significant reduction in the reaction times.
KEY WORDS:Alzheimer’s disease,clinical trial,galantamine,computerized neuropsychological tests,attention,memory.
Efeitos da galantamina sobre a memória e a atenção na doença de Alzheimer medidos por testes neuropsi-
cológicos computadorizados: resultados do Estudo Multicêntrico com Galantamina (GAL-BRA-01)
RESUMO - Objetivo:Investigar os efeitos da galantamina no desempenho de pacientes portadores de doença de Alzheimer (DA)
leve a moderada em uma bateria de testes neuropsicológicos computadorizados (BTNC). Método:Trinta e três pacientes com DA
provável receberam tratamento com galantamina por três meses em ensaio clínico multicêntrico aberto e prospectivo.A escala
BTNC e a ADAS-Cog foram administradas no início e ao final de 12 semanas.A BTNC incluiu testes de tempo de reação avaliando
atenção,memória implícita e memória episódica para palavras e faces.Comparações estatísticas foram realizadas entre os resul-
tados na 12ª semana versus a linha de base.Pacientes que não atingiram dose terapêutica foram excluídos da análise. Resultados:
Quatro pacientes (12,1%) foram excluídos por interrupção do tratamento (n=3) ou por não atingir dose terapêutica (n=1).Os 29
pacientes remanescentes foram tratados com doses de 24 mg/dia (n=22) e 16 mg/dia (n=7).Ao final de 12 semanas,reduções nos
tempos de reação foram observadas nos testes de memória episódica para faces (p=0,023) e no teste de tempo de reação de dupla
escolha (p=0,039) da BTNC. Conclusão:O tratamento com galantamina melhorou o desempenho em testes de atenção e memória
episódica,com redução estatisticamente significativa dos tempos de reação.
PALAVRAS-CHAVE:doença de Alzheimer,ensaio clínico,galantamina,testes neuropsicológicos computadorizados,atenção,memória.
Alzheimer’s disease (AD) is the leading cause of demen-
tia in the elderly,being responsible for more than 50% of the
dementia cases arising at ages 65 and over1,2.The disease leads
to substantial impairment in cognition and behavior, result-
ing in progressive functional dependence for the perform-
ance of daily activities.Long-term memory deficits,particular-
ly related to the episodic memory system,are usually the first
cognitive change to occur in AD.Attention is, in most cases,
the second cognitive domain to be affected,a feature that is
already present at mild stages of the disease and which is
responsible for part of the troubles with activities of daily liv-
ing3 .Three main subtypes of attention are described, name-
ly, divided, selective and sustained attention, which depend
upon distinct neuroanatomical structures. In AD, besides a
general slowness of the cognitive processing,that is also pres-
ent - although in less degree - in normal aging,specific selec-
tive and divided attention deficits become evident3 .
The pathological process involved in AD includes the accu-
mulation of neurofibrillary tangles and neuritic plaques espe-
cially in the hippocampal formation,basal forebrain,limbic cor-
tex and in cortical associative areas of the brain.This process
follows a usual temporal sequence, with involvement of the
entorhinal cortex and hippocampus in the earliest phases and
subsequent spreading to the limbic cortices and to the basal
forebrain nuclei,which represent the major cholinergic inner-
vation to the neocortex4.The basal forebrain cholinergic sys-
tem is represented by the nucleus basalis of Meynert, the
380 Arq Neuropsiquiatr 2004;62(2-B)
medial septum and the diagonal band of Broca.The spread-
ing of the AD pathology to these structures produces a signif-
icant reduction of the cholinergic innervation to the cortical
mantle,which has been related both to cognitive and non-cog-
nitive (neuropsychiatric) symptoms of the disease5-7
cognitive domain,attention deficits have been related to the
neuropathological involvement of the basal forebrain and its
consequent cholinergic deprivation8.
Treatment with cholinesterase inhibitors (AChEI) is the
current main pharmacological intervention available for treat-
ing AD patients9. Tacrine was the first AChEI approved for
clinical use.Nevertheless,although presenting unquestionable
efficacy,it is rarely prescribed nowadays because of the high
rate of adverse events (mainly hepatotoxicity). The second
generation of AChEI is represented by donepezil,galantamine
and rivastigmine.These three drugs have shown to be supe-
rior to placebo in many controlled clinical trials,with positive
effects on cognition, behavior and activities of daily living10-
15. Galantamine is a reversible inhibitor of acetylcholines-
terase and also exerts an allosteric modulation of the cholin-
ergic nicotinic receptors.These two complementary mechanisms
result in increase of the cholinergic neurotransmission in the
brain.Galantamine has shown to be effective in the sympto-
matic treatment of patients with AD, vascular dementia,AD
with cerebrovascular disease and dementia in Parkinson’s dis-
The present study reports the results from a Brazilian mul-
Appendix (GAL-BRA-01 participating centers and investigators).
1.Behavioral and Cognitive Neurology Unit,Department of Neurology,University of São Paulo School of Medicine
Paulo Caramelli (GAL-BRA-01 study coordinator and site’s principal investigator);Ricardo Nitrini (co-investigator);Helenice Charchat-Fichman (neu-
ropsychologist);Juliana Nery (site monitor)
2.Department of Internal Medicine (Neurology),Federal University of Rio Grande do Sul,Porto Alegre
Márcia Lorena Fagundes Chaves (site’s principal investigator);Eduardo Daura Ferreira (co-investigator);
Alberto Luiz Gricoli e Maia (co-investigator);Rachel Tavares de Laforete Padilha (co-investigator);
Vera Beatriz Delgado dos Santos (site monitor)
3.Institute of Neurology Deolindo Couto and Center of Alzheimer’s Disease,Institute of Psychiatry,Federal University of Rio de Janeiro
Eliasz Engelhardt (site’s principal investigator);Jerson Laks (co-investigator);Valeska Marinho (co-investigator);
Tatiana Quitério (co-investigator);Irene Moreira (neuropsychologist)
4.AURUS-IEPE - Institute of Research and Education on Aging,Belo Horizonte
João Carlos Barbosa Machado (site’s principal investigator);Daniel Gonçalves Rego (co-investigator);
Gustavo Vaz de Oliveira Moraes (co-investigator);Flávia Pinheiro Machado (neuropsychologist);
Érica de Araujo Brandão Couto (speech pathologist)
5.Department of Neurology and Neurosurgery,Federal University of São Paulo
Rodrigo Rizek Schultz (site’s principal investigator);Paulo Henrique Ferreira Bertolucci (co-investigator);
Ivan Hideyo Okamoto (co-investigator);Eliana Rysovas (neuropsychologist)
6.Department of Neurology,Psychiatry and Medical Psychology,University of São Paulo at Ribeirão Preto
Francisco A.C.Vale (site’s principal investigator);Maria Paula Foss (neuropsychologist)
ti-center open-label study to investigate the effects of galan-
tamine on the performance of mild to moderate AD patients
in computerized neuropsychological tests.The main goal of the
study was to investigate the effects of galantamine on atten-
tion and memory tests, especially focusing on the effects on
reaction time measures.
Population and eligibility criteria
Thirty-three patients (18 female), aged 75.1 ± 7.9 years (range
56-87), with educational level (mean ± SD) of 7.1 ± 4.4 years and
duration of symptoms (mean ± SD) of 36.7 ± 23.3 months,were includ-
ed in the study. All patients met the NINCDS-ADRDA criteria for
probable AD,with mild to moderate symptoms,as defined by scores
in a Brazilian version of the Mini-Mental State Examination (MMSE)18,19.
Regarding the latter,patients were recruited if the MMSE scores fell
between 14 and 24 points,both inclusive.
Appropriate laboratory blood tests (in order to fulfill the diag-
nostic criteria of probable AD) and neuroimaging assessment (com-
puterized tomography or magnetic resonance of the skull within a
period of 18 months preceding the beginning of the trial) were per-
formed in every study participant.Presence of two or more ischemic
lesions (either cortical and subcortical infarcts or lacunes), a single
strategically located infarct,or evidence of intense leukoaraiosis on
neuroimaging,excluded participation.Electrocardiogram was also per-
formed in order to rule out severe heart conduction abnormalities.
Subjects with previous treatment with AChEI were allowed to par-
ticipate in the trial only if the drug had been discontinued at least
60 days before inclusion.Patients had to live with or to receive reg-
ular visits (at least five days a week) from a caregiver,which should
be capable to provide all the necessary information about the patient.
The study has been approved by the Ethics Committee from all
the centers participating in the trial and all patients and the care-
givers signed the informed consent.
The study was conducted at six research centers from five dif-
ferent cities.A complete list of the participating centers and investi-
gators is provided at the end of the manuscript.
The study lasted 12 weeks.Galantamine was initiated at a dose
of 4mg bid for four weeks.At the end of the fourth week a medical
visit was scheduled,for clinical examination and safety evaluation.If
the initial drug regimen was well tolerated,the dose was increased to
8 mg bid for an additional four-week period.A similar procedure was
adopted at the end of the eighth week.The dose was then increased
to 12 mg bid for the final four-week period.Patients exhibiting mild
adverse events were maintained at 8 mg bid until the end of the tri-
Primary and secondary outcome efficacy measures were record-
ed at baseline and at week 12.The primary efficacy measure was the
performance in the computerized neuropsychological test battery
The CNTB was developed using the MEL professional software
(version 2.0)21.This software modifies the input and output systems
of the computer, allowing registration of reaction time in millisec-
onds.The tests were administered in a PC (IBM compatible) with a
Arq Neuropsiquiatr 2004;62(2-B)381
12’’ screen.A serial response box with five numbered buttons was
used as interface between patient and computer screen.The battery
administration lasted an average of 20 minutes.The CNTB includes
five reaction time tests evaluating attention,as well as episodic and
implicit memories,as follow:
a) Face Recognition test (episodic memory):Ten unfamiliar faces
were presented simultaneously on the computer screen for ten sec-
onds to be remembered.After this first presentation, a single face
was shown and the patient had to press button one if he/she remem-
bered or, otherwise, button five.The recognition test consisted in a
random presentation of ten pre-exposed faces and ten new faces as
b) Word Recognition and Learning test: similar to the Face
Recognition test procedure using Words.The recognition procedure
was repeated three times to evaluate a learning effect.
c) Simple reaction time test:The number one was presented in
the center of the computer screen and the patient had to press this
number in the response box as quickly as possible.This procedure
was repeated 100 times.The patient’s finger was put over button one
before the test begun.
d) Two-choice reaction time test:The numbers one or five were
presented in the center of the computer screen in a random order.
The patient had to press the correspondent button in the response
box as quickly as possible.This procedure was repeated 100 times.
The patient’s right finger was put over button five and the left fin-
ger over button one before the test begun.
e) Serial reaction time test:The numbers one,two,three,four or
five were presented in the center of the computer screen and the
patient had to press the correspondent button in the response box
as quickly as possible.This test was divided in five blocks, with 50
trials each.In blocks 1,2,3 and 4 the numbers were presented in a
fixed order and in block 5,in a random order.The reaction time dif-
ferences between blocks 1 - 4 and 4 - 5 were considered implicit learn-
The CNTB was administered by neuropsychologists working in
each of the sites,who had been previously trained in the procedure.
The training session was carried out during the investigator’s meet-
ing, lasting four hours. In the following weeks, the neuropsycholo-
gists performed three pilot evaluations with patients that would not
be included in the trial.
The secondary efficacy measure was the performance in the
Brazilian version of the Alzheimer’s disease Assessment Scale Cognitive
Subscale (ADAS-Cog)22.The ADAS-Cog is widely used in clinical tri-
als for the evaluation of treatment effects in AD.It is an 11-item scale
that evaluates memory, language, orientation and praxis, taking
about 40 minutes to be administered.
Safety evaluations were performed at weeks 4,8 and 12,includ-
ing physical examination and vital signs.
All patients that received at least one dose of galantamine were
included in the demographic characterization of the sample and in the
safety report.All efficacy analysis was based on the intent-to-treat pop-
ulation, defined as all patients who received medication (8mg or 12
mg bid) for at least two months and for which any of the efficacy meas-
ures (CNTB or ADAS-Cog) were available.
The primary efficacy measure was the variation in the performance
at the CNTB at week 12 in comparison with baseline,with analysis of
the percentage of correct responses and the reaction times.The second-
ary efficacy measure was the variation in the total and in the individ-
ual item scores of the ADAS-Cog between weeks 12 and baseline.The
percentage of responders to galantamine treatment based on the
changes in the ADAS-Cog scores was also determined (≥0 vs < 0,≥4
vs < 4,and ≥ 7 vs < 7).
The Wilcoxon non-parametric test for related samples was used
in the analysis of both the CNTB and the ADAS-Cog data.The paired
t-test was used for the comparisons of the safety parameters between
baseline and the last evaluation.
Thirty-three patients were included in the trial, with a
mean MMSE score of 19.9 points at baseline. Twenty-two
patients (66.7%) reported no previous use of AChEI,while 11
(33.3%) referred usage of at least one agent from this class.
Four (12.1%) out of the 33 patients were excluded from
the efficacy analysis: two (6.1%) because of adverse events
(nausea, vomiting and dizziness) and two for other reasons
non-related to the study medication.
The remaining 29 patients were treated with galantamine
at doses of 24 mg/day (n=22) and 16 mg/day (n=7). Data
regarding performance in the CNTB and in the ADAS-Cog
were available from all these patients.
Statistically significant differences emerged between the
performances of patients at week 12 versus baseline in the
CNTB, particularly in the reaction times. In the face recogni-
tion test, the mean reaction time fell from 5,543.1 millisec-
onds at baseline to 4,750.5 milliseconds at week 12 (p=0.023;
Figure 1). In the test of two-choice reaction time, the mean
reaction time fell from 1,024.1 milliseconds at baseline to
908.5 milliseconds at week 12 (p=0.039;Figure 2).A trend for
reduction of the reaction time in the block 2 of the serial reac-
382 Arq Neuropsiquiatr 2004;62(2-B)
tion time test was also observed (p=0.053).No difference in
the percentage of correct responses was observed in any of
the CNTB tests.
No difference between total scores at the ADAS-Cog
between weeks 12 and baseline was found (p=0.673).A sig-
nificant reduction (improvement) in the sub-item “Word-find-
ing difficulties in spontaneous speech” was observed at the
end of the trial (p=0.008).
In the responder analysis of the ADAS-Cog, 10 (34.5%)
patients showed signs of mild improvement (total score vari-
ation between 0 and 3 points,both inclusive),8 (27.6%) pre-
sented moderate improvement (total score variation between
4 and 6 points, both inclusive) and 2 (6.9%) had marked
improvement (total score variation ≥7 points),while 9 (31.0%)
did not improve.
The present study reports the results from the first Brazilian
multi-center trial with galantamine in the treatment of patients
with mild to moderate AD.Patients were treated for 12 weeks
and positive effects were seen at the end of the treatment peri-
od in specific cognitive measures,namely the performance in
computerized neuropsychological tests of attention and mem-
Previous clinical trials have shown that galantamine leads
to significant improvement of the cognitive, behavioral and
functional impairment both in AD and in vascular demen-
tia12,13,16.Moreover,in one of this trials,36 to 37% of patients
treated with the drug improved ≥ 4 points in the ADAS-Cog
and thus could be considered as “responders”13.Similarly,in
our study the analysis of the ADAS-Cog performance profile
shows that 34.5% of the patients showed moderate to marked
In the current trial galantamine treatment effects were
Fig 1. Changes in the reaction times in the episodic memory tests of the CNTB
(face and word recognition tests).
Fig 2. Changes in the reaction times in the tests of attention of the CNTB (sin-
gle, two-choice and five-choice reaction time).
measured through a computerized neuropsychological test
battery.The major advantages of this computer-based cogni-
tive examination are the precise time control of stimuli pres-
entation and the accurate measurement of the reaction time.
This level of accuracy and resolution is practically unattainable
using the classic paper-and-pencil tests, even in the use of a
chronometer .Furthermore,this approach allows the generation
and use of multiple versions of a single test,thus reducing the
interference of a learning effect23. These features place the
computerized evaluation in a privileged position for measur-
ing the effects of any sort of symptomatic treatment for demen-
Reaction time measures in computerized tests have been
previously used as efficacy variables in very few dementia tri-
als,such as a recent study with rivastigmine in the treatment
of patients with Lewy-body dementia,with positive results on
Despite the small number of patients included in the cur-
rent trial, the performance in the CNTB improved at the end
of the study,with significant reductions of the reaction times
in the tests of episodic memory for faces and attention (two-
choice reaction time).These findings suggest that the bene-
fits produced by galantamine were more marked within the
domain of attention,since even for the episodic memory task
the reaction time was the variable influenced by the treatment,
while the percentage of correct responses was not.
Attention deficits are frequent in AD,already present in the
early stages of the disease3.In the CNTB,the two-choice reac-
tion time task,which has been consistently reduced with galan-
tamine treatment,focus on the selective attention subcompo-
nent. Lined with this observation, a recent PET study with
healthy elderly subjects found that action on nicotinic receptors
modulated arousal and selective attention to a visual task25.Thus,
improvement in this aspect of cognition can be regarded as a
truly positive effect, also because enhancement of the atten-
tional tonus may lead to benefits in other neuropsychological
functions,especially memory,with also some positive effects on
Since the current trial was not placebo controlled (for eth-
ical reasons), one could argue that the reduction in reaction
time at week 12 in comparison with baseline could represent
only a reflex of implicit (procedural) learning rather than a real
benefit.If this was indeed the case,we should have observed
a reduction of the reaction time in all the CNTB tests, espe-
cially in the simple reaction time task, which consists on an
objective measure of motor speed.However,improvement in
these other tasks did not occur.
Galantamine treatment was well tolerated, with 29/33
(87.8%) patients reaching a therapeutic dose.Only two patients
had to discontinue the drug due to adverse events (mainly gas-
trointestinal effects). This discontinuation rate is similar to
what has been previously described in other galantamine tri-
Arq Neuropsiquiatr 2004;62(2-B)383
In conclusion,treatment with galantamine at doses 16 to
24 mg/day in patients with mild to moderate AD produced
improvement in their performance in computerized tests of
episodic memory and attention after 12 weeks,leading to sta-
tistically significant reduction in the reaction times.
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