epidos2

Association of Alzheimer’s Disease Onset WithGinkgo Biloba and Other Symptomatic Cognitive

Treatments in a Population of Women Aged 75 Yearsand Older From the EPIDOS Study

Sandrine Andrieu,1,2 Sophie Gillette,1,2 Karine Amouyal,1 Fati Nourhashemi,1,2 Emma Reynish,1

Pierre Jean Ousset,1 Jean Louis Albarede,1 Bruno Vellas,1 and Helene Grandjean2

1Department of Internal Medicine and Clinical Gerontology, Acute Unit for Alzheimer’s Patients, Toulouse, France.2Institut National de la Sante et de la Recherche Medicale (INSERM) U558, Toulouse, France.

Background. Peripheral C4A treatment (cerebral and peripheral vasotherapeutics) and especially Ginkgo bilobaextracts are prescribed for a number of symptoms, particularly memory impairment, in elderly patients. It is postulated thatbecause of its pharmacological actions, this treatment could prevent the decline of cognitive function, but no studies havebeen published to date to test its efficacy in prevention of Alzheimer’s disease. The potential association between use ofC4A treatments, in particular EGb 761 (standardized Ginkgo biloba extracts), and dementia of the Alzheimer type wasinvestigated.

Methods. A case-control study was nested in a cohort of 1462 community-dwelling elderly women aged over 75 years.Sixty-nine women with Alzheimer-type dementia were compared with 345 paired women whose cognitive functionremained normal. This study involved women whose cognitive function was evaluated at baseline by use of Pfeiffer’s testand whose medication history was taken. The onset of cognitive impairment was investigated over a 7-year follow-upperiod. In order to study the factors associated with the onset of dementia, the data concerning women with a score of >8on Pfeiffer’s test at inclusion, indicating normal cognitive function, were analyzed.

Results. A multivariate analysis including potential confounding factors showed that fewer women who developedAlzheimer’s dementia had been prescribed C4A treatment (including EGb 761) for at least 2 years (odds ratio 5 0.31,95% confidence interval 5 0.12–0.82, p 5 .018). Figures for EGb 761 alone were similar but did not reach statisticalsignificance (odds ratio 5 0.38, 95% confidence interval 5 0.08–1.76, p 5 .22).

Conclusion. These results suggest that C4A treatment may reduce the risk of developing Alzheimer’s dementia inelderly women. The potential preventive effect of C4A treatments, including EGb 761, requires further examination. Toestablish a causal relationship, these findings have to be confirmed with prospective studies.

ALZHEIMER’S disease (AD) is the most prevalent formof dementia, affecting 5% of people over 65 years old

and nearly 30% of people over 80 (1). It is essential to developtreatments that are effective in preventing the onset of thedisease. C4A treatments (cerebral and peripheral vasother-apeutics), including Ginkgo biloba extracts, are widely usedin Europe and in the United States, particularly for memoryimpairment in elderly persons. These medications are welltolerated and could have potential for preventing cognitivedecline. Research in this field is particularly important todaybecause of the relationship between cognitive decline andincreased risk of AD in elderly people (2).

A number of studies have investigated the efficacy ofstandardized Ginkgo biloba extracts (EGb 761) in patientswith altered cognitive function or AD. In a review of theliterature, Oken and colleagues identified four trials ofrigorous design (double blind, placebo controlled). Aftermeta-analysis, they concluded that treatment with EGb 761had a moderate but significant effect on cognitive function(3). More recently, two double-blind, randomized, placebo-controlled clinical trials reported conflicting results concern-ing the efficacy of EGb 761 in the treatment of AD (4,5).

In addition to its vasodilator properties (6), Egb 761 isalso an antioxidant. Oxidative stress is well recognized asone of the mechanisms involved in the development of AD(7,8), and because EGb 761 has antioxidant properties, itcould have a preventive effect on the onset of this disease.Prospective large-scale long-term randomized studies arenecessary to establish this effect. Prior to planning suchstudies, we had the opportunity to examine this hypothesisin an ongoing study, the EPIDOS (EPIDemiology ofOSteoporosis) study. In this multicenter study, women(>75 years) were assessed cognitively at baseline and werethen followed for 4 years, during which the history of theirprescribed drugs was recorded. At the end of the EPIDOSstudy the cognitive function of the participants from onecenter, Toulouse, was reassessed, allowing us to performa case-control study in this cohort.

METHODS

The EPIDOS StudyThe EPIDOS study was a prospective multicenter study

with the aim of investigating the risk factors for femoral

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Journal of Gerontology: MEDICAL SCIENCES Copyright 2003 by The Gerontological Society of America2003, Vol. 58A, No. 4, 372–377

neck fracture. From January 1992 to January 1994, 7598ambulatory women aged 75 years and over in 5 Frenchcities (Amiens, Lyon, Montpellier, Paris, and Toulouse)volunteered to participate in this study. The protocol hasbeen described in detail elsewhere (9).

At baseline, women were assessed for physical andfunctional capacities. Autonomy was assessed by threeitems concerning basic activities of everyday life (dressing,washing, and mobility) and Lawton’s Instrumental Activ-ities of Daily Living (IADL) scale (10). Cognitive functionwas determined by Pfeiffer’s test (short portable mentalstatus questionnaire), which yields scores ranging from0 to 10, with 10 representing the best performance (11). Thistest has good sensitivity and specificity for detecting casesof dementia compared with diagnosis by a clinician (12).Demographic data (age, education, family situation, andincome), medical history, life habits (social support,activities, lifestyle, accommodation, etc.), and treatmentswere recorded. As a way to assess treatment, subjects wereasked to bring their prescribed medications to the visit. Allperipheral treatments coded as C4A in the European Pharma-ceutical Marketing Research Association (EphMRA) clas-sification, from which the Anatomical Therapeutic Chemical(ATC) system originated (http://www.ephmra.org).

The study was approved by the local ethics committees,and all participating women signed informed consent forms.

Every 4 months, participants completed a questionnaireabout falls, fractures and other new conditions. At yearlyintervals, they also listed the medications they were taking.

Toulouse Cohort StudyTheToulousecohort (n51462)was followed-upat theUni-

versity Hospital and all cases of dementia of the Alzheimertype were recorded. All participants were invited to take partin an additional follow-up study. Those who had given in-formed consent were assessed either at home or at the Depart-ment of Internal Medicine and Clinical Geriatrics. Duringthis visit, demographic data and information on medicalconditions and prescribed drugs were recorded. Instrumentalactivities of daily living (IADL) and cognitive function werereassessed. Cognitive function was tested by use of Pfeiffer’stest (11), Folstein’s Mini-Mental State Examination (13),and the test from Grober and colleagues (14).

This information was analyzed independently bya geriatrician and a neurologist from the Department ofInternal Medicine and Clinical Geriatrics, who hadexpertise in AD and were unaware of medication taken.Diagnostic and Statistical Manual, 4th edition (DSM-IV)criteria were used to establish a clinical diagnosis ofdementia. AD was diagnosed according to the criteria ofthe NINCDS-ADRDA work group (15). When the twoassessors disagreed on a diagnosis, a joint decision wasreached after additional information was obtained from thegeneral practitioner. Subjects were then classified into fourgroups: normal cognitive function, mild cognitive impair-ment according to Petersen’s criteria (16), AD, and othertypes of dementia.

Initially, 1462 women were included in the EPIDOS studyin Toulouse. During the initial 4-year follow-up, 72 womenwere diagnosed with dementia of the Alzheimer type. Of the642 women who were followed up for 7 years, 450 wereconsidered as normal, 38 had dementia of the Alzheimertype, and 154 had other disturbances of cognitive function(mild cognitive impairment or another type of dementia,including mixed dementia). Thus, at the end of the study, dataon cognitive status were available for 714 women (48.8% ofthe initial cohort), of whom 110 had dementia of theAlzheimer type. Of the other 748 women, whose cognitivestatus remained undetermined, 25.8% (n 5 193) died duringfollow-up, 54.7% (n 5 414) were lost to follow-up, and18.9% (n 5 141) withdrew from the follow-up study.

Statistical AnalysisAnalysis was performed with SAS software (SAS Version

8.0; SAS Institute, Inc., Cary, NC). Bivariate analyses werebased on conventional tests comparing means for quantita-tive variables (analysis of variance), and frequency distribu-tions for qualitative variables (chi-square test or Fisher exacttest, according to sample size). Comparisons were madebetween AD patients and a control group consisting of fivecontrols for one case. For all cases, medication history wasavailable from six follow-up consultations: baseline (T0),each year of follow-up study (T1, T2, T3, and T4), and at thefinal examination (T7). For the cases diagnosed as ADduring follow-up and for their five corresponding controls,only data preceding the diagnosis were used. In order tostudy the factors associated with the onset of dementia, onlydata for women with a score >8 on Pfeiffer’s test at baseline(17,18), who were thus considered as cognitively normal,were used. The analysis included 69 women with AD of the110 women who were diagnosed with AD, and 345 controlswith normal cognitive evaluation.

To account for potential confounding factors, thevariables statistically related to AD and those related toexposure to C4A treatment, with a value of p , .25, wereincluded in the logistic regression model, with Alzheimer’sdementia as a dependent variable. The model was fitted byusing the Hosmer–Lemeshow test (19).

RESULTS

Those patients lost to follow-up were initially in worsehealth than those included in the study. However, there were

Table 1. Peripheral Treatments Coded as C4A

1. Ginkgo biloba extracts

2. Other C4A drugs

Naftidrofuryl

Vinburnine

Raubasine-Almitrine

Nicergoline

Ergot alkaloids

Piribedil

Ifenprodil

Buflomedil

Cinnarizine

Pentoxifylline

Vincamine

Moxisylyte

Cyclandelate

Papaverine

373C4A TREATMENT AND RISK OF ALZHEIMER’S DISEASE

no differences concerning C4A prescription between the748 women lost to follow-up and the 714 women for whomfollow-up data were available (38.8% vs 39.0%).

Exposure to C4A MedicationsIn the study population, 50.7% (n 5 210) of women

reported having taken a C4A medication (Table 1); 32.9%(n 5 69) of this subgroup had been given EGb 761, 55.7%(n 5 117) had been given another C4A medication, and11.4% (n 5 24) had been given both types of treatment.

Factors Associated With ADWomen diagnosed with AD during follow-up were

considerably older at inclusion than nondemented subjects(80.8 6 4.1 years vs 79.2 6 3.4 years; p 5 .02). Theygenerally had lower financial status and level of education,and poorer perception of their health with difficultyperforming activities of daily living (ADL) (Tables 2 and 3).They also performed slightly less well on the Pfeiffer test(8.9 6 0.9 vs 9.3 6 0.7; p 5 .03). Analysis of the medi-cation histories of patients with AD showed they were lesslikely to have taken C4A treatments for three consecutiveperiods, but there were no other significant differences re-garding other treatments (aspirin, calcium channel blockers,

mineral supplements, or nonsteroidal anti-inflammatorydrugs).

Factors Associated With C4A TreatmentWomen who had received C4A treatment were older at

inclusion (79.8 6 4.0 years vs 78.9 6 3.0 years; p 5 .01),but they were otherwise not significantly different from theuntreated group (Table 4).

Logistic RegressionTable 5 shows the results of the final model. Three

variables were excluded, using the stepwise process model(ADL, IADL, and education level). Logistic regressionshowed that women with dementia appeared to have beenregularly exposed to C4A treatment less often than hadothers (odds ratio 5 0.31, 95% confidence interval [CI]0.12–0.82, p 5 .018). In an additional analysis, the variable‘‘C4A exposure’’ was replaced with ‘‘EGb or Ginkgo ex-posure.’’ The results were similar but did not reach statisti-cal significance with odds ratio 5 0.78, 95% CI 5 0.32–1.91, and p 5 .59; odds ratio 5 0.51, 95% CI 5 0.11–2.51,and p 5 .41; and odds ratio 5 0.38, 95% CI 5 0.08–1.76,and p 5 .22 for at least one exposure, two consecutiveexposures, and at least three consecutive exposures, re-spectively.

Table 2. Characteristics of Women With and Without ATD

Baseline Parameters

Non-ATD

No. (%)

ATD

No. (%) p OR 95% CI

Age .0292

<80 y 247 (71.6) 40 (57.9) — 1 —

81–85 79 (22.9) 20 (29.0) .1401 1.56 0.86–2.83

.85 yr 19 (5.5) 9 (13.1) .0145 2.93 1.24–6.92

End of primary school certificate

No (,5 y) 29 (8.4) 11 (15.9) — 1 —

Yes (.5 y) 316 (91.6) 58 (84.1) .0531 0.48 0.23–1.02

Income (euros/mo) .0005

.915 173 (50.1) 17 (24.6) — 1 —

457–915 80 (23.2) 26 (37.7) .0045 2.70 1.36–5.35

,457 9 (2.6) 4 (5.8) .0207 4.52 1.26–16.25

Unknown 83 (24.1) 22 (31.9) .0004 3.31 1.70–6.44

Perceived health

Good 284 (85.5) 46 (66.7) — 1 —

Poor 48 (14.5) 23 (33.3) .0002 2.96 1.65–5.32

Marital status .3125

Married 100 (29.0) 14 (20.3) — 1 —

Widowed 190 (55.1) 41 (59.4) .1942 1.54 0.80–2.96

Divorced 20 (5.8) 7 (10.1) .0802 2.50 0.90–7.00

Single 35 (10.1) 7 (10.1) .4781 1.43 0.53–3.83

Washing, dressing, & walking

Independent 329 (95.4) 60 (87.0) — 1 —

Dependent 16 (4.6) 9 (13.0) .0219 3.08 1.30–7.30

IADL

0 incapacity 315 (91.3) 56 (81.2) — 1 —

>1 incapacity 30 (8.7) 13 (18.8) .0117 2.44 1.20–4.96

Depression

No 309 (89.8) 59 (85.5) — 1 —

Yes 35 (10.2) 10 (14.5) .2934 1.50 0.70–3.19

Hearing problem

No 158 (45.8) 37 (53.6) — 1 —

Yes 187 (54.2) 32 (46.4) .2345 1.73 0.44–1.22

Notes: ATD 5 Alzheimer’s-type dementia; OR 5 odds ratio; CI 5 confidence interval; IADL 5 instrumental activities of daily living. Non-ATD = 345

(83.33%); ATD 5 69 (16.67%).

374 ANDRIEU ET AL.

DISCUSSION

Alzheimer’s dementia is a neurodegenerative disease withlong-term evolution before definitive lesions. With anunprecedented demographic change in the Western pop-ulation, prevention and effective treatment of age-dependentdisease is a public health priority. Many elderly peopleworried about cognitive impairment are requesting therapy,and millions of people in Europe and the United States areregularly taking Ginkgo biloba extracts. The value of thistreatment deserves study.

Our objective was to investigate the potential associationbetween use of C4A treatments, in particular EGb 761(standardized Ginkgo biloba extracts), and Alzheimer’sdementia onset in elderly women. We found that womenregularly taking C4A treatment were three times morenumerous in the group without dementia than in the groupwith dementia. The odds ratio for EGb 761 was similar butdid not reach statistical significance.

Women participating in the EPIDOS study were volun-teers and therefore not representative of the general popula-tion. Cognitive status was evaluated in only 50% of theinitial population, so we could not study the relative risk ofAD associated with C4A prescription. However, our studywas prospective and could precisely determine the cognitive

status of the women (normal or AD). Therefore, a case-control study nested in the cohort was possible. One of thestrong points of the study is the fact that the population hadcognitive assessments at the outset by the Pfeiffer test andonly those with scores of 8 or more were included. BecauseC4A treatments are physician prescribed, we could be surethat all patients received the standardized extract of Ginkgobiloba. The medication history was recorded each year, sowe assumed patients who had three consecutive recordingsof C4A medication received the treatment long term. It wasthis group of patients who showed significant results.However, in the early stages of dementia, women couldhave forgotten whether they had taken specific medication.We postulate that they were not more likely to have forgottentheir C4A treatment than their other treatments, and yet therewas no difference in the two groups for any other type ofmedication (aspirin, calcium channel blockers, mineralsupplements, nonsteroidal anti-inflammatory drugs).

Epidemiological studies should help to identify risk factorsfor AD. Our study has once again identified age attained as anindependent risk factor. It has not, however, shown anyrelationship between aspirin or nonsteroidal anti-inflam-matory treatment and risk for AD. This may be due to the re-latively infrequent use of these drugs in the study population.

Table 3. More Characteristics of Women With and Without ATD

Treatment

Non-ATD

No. (%)

ATD

No. (%) p OR 95% CI

Estrogens

No 342 (99.1) 68 (98.6) — 1 —

Yes 3 (0.9) 1 (1.4) .5192 1.68 0.17–16.4

Mineral supplements .8006

Not exposed 249 (72.2) 50 (72.5) — 1 —

Nonconsecutive exposure(s) 77 (22.3) 14 (20.3) .2181 0.91 0.48–1.73

2 consecutive exposures 12 (3.5) 4 (5.8) .9240 1.66 0.51–5.36

>3 consecutive exposures 7 (2.0) 1 (1.4) .2743 0.71 0.09–5.91

Calcium antagonist .3634

Not exposed 242 (70.1) 49 (71.0) — 1 —




Aspirin .9078

Not exposed 232 (67.2) 44 (63.8) — 1 —




NSAIDs .1811

Not exposed 270 (78.3) 51 (73.9) — 1 —




C4A treatment .0289

Not exposed 169 (49.0) 35 (50.7) — 1 —




EGb or Ginkgo .5254

Not exposed 264 (76.5) 57 (82.6) — 1 —




Notes: ATD5 Alzheimer’s-type dementia; OR 5 odds ratio; CI 5 confidence interval; NSAIDs 5 nonsteroidal anti-inflammatory drugs; C4A 5 cerebral and

peripheral vasotherapeutics; EGb 5 standardized Ginkgo biloba extracts.


ConclusionIn conclusion, our study including 414 patients over 75

years old showed that women with diagnosed dementia hadbeen less frequently exposed to chronic use of C4Atreatment. This effect remained significant after adjustmentfor potential confounding effects. Although these resultsshould be interpreted with caution because of the studydesign, the evidence for the protective effects of othertreatments was not stronger than that shown for C4Atreatment. Primary prevention trials should be undertaken toconfirm these findings. In fact, large interventional studiesare ongoing with EGb 761 in North America and Europe todetermine the preventive effect of these treatments, butresults will not be available for 6 to 7 years. A recent studywith Ginkgo extract treatment has shown no effects onmemory (20); however, this study was done in youngerpeople (68.5 years) with no cognitive complaints and withonly 6 weeks of treatment. The effect of Ginkgo onoxidative stress and on vascular function will require muchlonger time review to be effective. Following our long-termobservational study, some long-term placebo-controlledstudies are on the way over a 1-year period to preventdementia in older elderly persons (more than 75 years) withcognitive complaints.

However, a preliminary study of the effect on memory of6 weeks of treatment with Ginkgo gave negative results(20). If the protective effect of C4A treatment is confirmed,this class of medication is a strong contender for widespread

Table 4. Bivariate Analysis: Characteristics of Women According to Exposure to C4A Treatment at the Time of Diagnosis

C4A Treatments

Baseline Parameters

Not Exposed

No. (%)

1 Exposure

No. (%)

2 Exposures

No. (%)

>3 Exposures

No. (%) p

Age .01

<80 y 154 (75.5) 43 (58.9) 37 (72.6) 53 (61.6)

81–85 44 (21.6) 21 (28.8) 10 (19.6) 24 (27.9)

.85 y 6 (2.9) 9 (12.3) 4 (7.8) 9 (10.5)

End of primary school certificate .20

No 16 (7.8) 12 (16.4) 5 (9.8) 7 (8.1)

Yes 188 (92.2) 61 (83.6) 46 (90.2) 79 (91.9)

Income euros/mo) .50

.915 91 (44.6) 29 (39.7) 23 (45.1) 47 (54.7)

457–915 54 (26.5) 23 (31.5) 12 (23.5) 17 (19.8)

,457 6 (2.9) 3 (4.1) 0 (0.0) 4 (4.7)

Unknown 53 (26.0) 18 (24.7) 16 (31.4) 18 (20.9)

Perceived health .25

Good 163 (82.7) 54 (76.1) 39 (79.6) 74 (88.1)

Poor 34 (17.3) 17 (23.9) 10 (20.4) 10 (11.9)

Marital status .42

Married 63 (30.9) 17 (23.3) 15 (29.4) 19 (22.1)

Widowed 110 (53.9) 43 (58.9) 32 (62.7) 46 (53.5)

Divorced 13 (6.4) 5 (6.8) 1 (2.0) 8 (9.3)

Single 18 (8.8) 8 (11.0) 3 (5.9) 13 (15.1)

Washing, dressing, & walking .17

Independent 194 (95.1) 67 (91.8) 45 (88.2) 83 (96.5)

Dependent 10 (4.9) 6 (8.2) 6 (11.8) 3 (3.5)

Binary IADL .97

0 incapacity 183 (89.7) 65 (89.0) 45 (88.2) 78 (90.7)

>1 incapacity 21 (10.3) 8 (11.0) 6 (11.8) 8 (9.3)

Hearing problem .07

No 108 (52.9) 33 (45.2) 23 (45.1) 31 (36.1)

Yes 96 (47.1) 40 (54.8) 28 (54.9) 55 (63.9)

Depression .18

No 177 (86.8) 69 (94.5) 47 (94.0) 75 (87.2)

Yes 27 (13.2) 4 (5.5) 3 (6.0) 11 (12.8)

Notes: C4A 5 cerebral and peripheral vasotherapeutics; not exposed, n 5 204 (49.3%); 1 exposure, n 5 73 (17.6%); 2 exposures, n 5 51 (12.3%); >3 expo-

sures, n 5 86 (20.8%). IADL 5 instrumental activities of daily living.

Table 5. Multivariate Analysis (Logistic Regression)

Model

Variable to be Explained p OR 95% CI

Pfeiffer test in 1992 .0082 0.60 0.41–0.87

Age (y) .0004 1.16 1.07–1.26

Income (ref: .915 euros) .0063

457–915 .0033 2.91 1.43–5.94

,457 .0168 5.56 1.36–22.70

Unknown .0106 2.62 1.25–5.47

Perceived health (poor vs good) .0333 2.02 1.06–3.86

Hearing problem .0765 0.58 0.32–1.06

C4A treatment (ref: not exposed) .0698

Nonconsecutive exposure(s) .7261 0.87 0.41–1.86

2 consecutive exposures .4915 1.34 0.59–3.04

>3 consecutive exposures .0180 0.31 0.12–0.82

Adequacy of the model

(Hosmer–Lemeshow test)

.7175

Notes: For variable to be explained, dementia of the Alzheimer’s type

(n 5 69) is versus dementia not of the Alzheimer’s type (n 5 332). OR

5 odds ratio; CI 5 confidence interval.

376 ANDRIEU ET AL.

preventive treatment use because of its minimal side effectscompared with others such as nonsteroidal anti-inflamma-tory drugs or estrogens.

ACKNOWLEDGMENTS

This work was part of the EPIDOS study supported by an InstitutNationale de la Sante et de la Recherche Medicale (INSERM)/MSD-Chibret contract. Additional follow-up was supported by an INSERM/Beaufour Ipsen contract. EPIDOS study participants included coordinatorsG. Breart, P. Dargent-Molina, P. J. Meunier, A. M. Scott, D. Hans, and P.D. Delmas, and principal investigators C. Baudoin and J. L. Sebert(Amiens), M. C. Chapuy and A. M. Scott (Lyon), F. Favier and C. Marcelli(Montpellier), C. J. Menkes, C. Cormier, and E. Hausherr (Paris), and H.Grandjean and C. Ribot (Toulouse).

The authors thank Ms. Christelle Cantet for her collaboration in thisstudy.

Address correspondence and to Sandrine Andrieu, MD, PhD, De-partment of Internal Medicine and Clinical Gerontology, Acute Unit forAlzheimer’s Patients, 170 Chemin de Casselardit, 31059 Toulouse Cedex03, France. E-mail: [email protected]

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Received May 15, 2002Accepted October 18, 2002


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