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Risk Factors for Cognitive Impairment in HIV-1–Infected Persons With Different Risk Behaviors
Diana De Ronchi, MD;
Irma Faranca, MD;
Domenico Berardi, MD;
Paolo Scudellari, MD;
Marco Borderi, MD;
Roberto Manfredi, MD;
Laura Fratiglioni, MD, PhD
Arch Neurol. 2002;59:812-818.
ABSTRACT
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Context Although it is well established that acquired immunodeficiency syndrome
dementia complex mainly develops in patients with advanced human immunodeficiency
virus 1 (HIV-1) infection and severe immunosuppression, other factors that
might increase the risk of early neuropsychological abnormalities are controversial.
Objective To identify risk factors for HIV-1–related cognitive impairment.
Design Case-control study.
Setting Division of Infectious Diseases, University of Bologna.
Participants We studied 272 consecutive individuals: 90 HIV-1–seronegative,
88 asymptomatic HIV-1–seropositive, and 94 symptomatic HIV-1–seropositive
persons.
Main Outcome Measures Cognitive impairment was defined as poor performance on at least 2 of
the 7 neuropsychological tests included in the battery. Cutoff scores for
poor performance on a test were established as 2 or more SDs lower than the
mean of the seronegative group in the corresponding risk behavior strata:
injecting drug users, hemophiliacs, and other risk behaviors. The following
risk factors were studied: age, sex, education, risk behaviors, HIV-1 stage,
lymphocyte count, and antiretroviral therapy.
Results Compared with individuals with higher levels of education, those with
less than 6 years of schooling had an odds ratio (OR) of 17.2 (95% confidence
interval [CI], 3.6-83.3) for cognitive impairment, independent of age, sex,
disease stage, antiretroviral therapy, and risk behavior. Compared with injecting
drug users, homosexual/bisexual and heterosexual participants had ORs of 9.6
(95% CI, 2.2-42.7) and 6.3 (95% CI, 2.2-18.3), respectively, for cognitive
impairment. Use of antiretroviral treatment (any vs none) was associated with
lower prevalence of cognitive impairment (OR, 0.1; 95% CI, 0.0-0.3). Compared
with persons with high CD4+ cell counts ( 500/µL), those
with low (<200/µL) and moderate (200-499/µL) CD4+
cell counts had adjusted ORs of 8.6 (95% CI, 1.0-71.0) and 6.9 (95% CI, 1.0-48.4),
respectively. The presence of prominent depressive symptoms did not change
the results.
Conclusions Low educational level, low CD4+ cell count, and homosexual/bisexual
and heterosexual risk behaviors are risk factors for cognitive impairment
in HIV-1–seropositive persons. Antiretroviral therapy exerts a beneficial
effect against cognitive impairment in symptomatic individuals. Homosexual/bisexual
and heterosexual persons who survive longer are expected to be the group at
highest risk for cognitive impairment. However, the protective effect of antiretroviral
therapy may balance this increased risk.
INTRODUCTION
HUMAN immunodeficiency virus 1 (HIV-1)–associated dementia complex
affects 16% of persons with acquired immunodeficiency syndrome (AIDS),1 but HIV-1–related cognitive impairment may be
even more common, as 20% to 30% of all individuals with AIDS are expected
to develop this condition.2 Although it is
well established that AIDS dementia complex mainly develops in patients with
advanced HIV-1 infection and severe immunosuppression,3-11
other factors that might increase the risk of early neuropsychological abnormalities
are controversial.12 Some researchers6, 13-14 have claimed that
injecting drug users (IDUs) are at a higher risk for AIDS dementia complex
than are individuals with other risk behaviors, but this finding has been
dismissed by others.7, 15-16
Because of the reported association between low educational level and
dementia of the Alzheimer type,17 special attention
has been given to this factor even in association with HIV-1–related
cognitive impairment. Four studies18-21
reported a higher prevalence of HIV-1–related cognitive impairment in
less-educated individuals. Two of these studies19, 21
included well-educated, middle class, asymptomatic homosexual men, and 1 included
asymptomatic IDUs.18 Only 1 study20
included different risk behaviors (including IDU), different disease severity,
and various educational levels. However, the study population was derived
from developing and developed countries, in which education may be an indicator
of different factors.
Apart from education, other factors have been sporadically associated
with a higher occurrence of dementia and cognitive impairment in HIV-1–infected
patients: increased age,1, 9, 14, 22
female sex,9 decreased hemoglobin levels,1, 3, 7, 23 lower
body mass index,1 vitamin B12 deficiency,24-26 previous traumatic
brain injury,27 and concurrent depressive symptoms.3, 14, 28 Conversely, antiretroviral
treatment has been found to protect against dementia and cognitive impairment.4, 13, 29-34
This study was designed to explore the role of all the previously suggested
risk factors for HIV-1–related cognitive impairment by using a risk
behavior–adjusted definition of cognitive impairment. The data are gathered
from a longitudinal study on HIV-1 infection that is ongoing in Bologna.
PARTICIPANTS AND METHODS
STUDY POPULATION
The study sample included consecutive outpatients examined at the Division
of Infectious Diseases, University of Bologna. Participants were recruited
between December 1, 1994, and December 1, 1997. Every person attending the
outpatient service was asked to participate. All patients underwent a neurological
examination before enrollment. We excluded from the sample individuals affected
by previous or current cerebral opportunistic infections or other neurological
diseases and psychiatric disorders (eg, schizophrenia and delusional, mood,
and anxiety disorders).
Informed consent was requested from all individuals before enrollment,
and the protocol of the research was approved by the ethical committee of
the University of Bologna. Confidentiality was strictly maintained: forms
that linked personal identifiers and data were available only to one of us
(D.D.), and these forms were kept in a locked file.
HIV-1 INFECTION
All participants were evaluated with HIV-1 serological tests using standardized
methods: enzyme-linked immunosorbent assay (Behring Enzygnost Anti-HIV 1/2
Plus; Behring, Marburg, Germany), confirmed by Western blot (Chiron Riba HIV-1/HIV-2
SIA; Chiron Corp, Emeryville, Calif). On the basis of this analysis, participants
were divided into HIV-1–seronegative and HIV-1–seropositive groups.
Staging in asymptomatic and symptomatic participants was performed according
to the Centers for Disease Control and Prevention (CDC) criteria,35 without taking into account the CD4+ cell
count. Information concerning CD4+ cell counts was available for
133 (73.1%) of 182 seropositive persons, who were grouped by CD4+
cell count36: less than 200/µL, 200 to
499/µL, and 500/µL or greater. Finally, according to self-reported
at-risk behavior, people were classified into 4 groups: (1) homosexuals/bisexuals,
(2) heterosexuals, (3) IDUs, and (4) hemophiliacs. Concerning IDUs, a "significant"
history of drug abuse was required, that is, abuse of psychoactive drugs for
more than 5 years, with a use frequency of at least 3 times per week.34 No individuals in our sample, according to self-reported
at-risk behavior, reported both homosexual/bisexual and IDU behaviors.
DATA COLLECTION
Individuals underwent a comprehensive clinical examination and then
evaluation by a neuropsychologist. The clinical examination included a semistructured
interview concerning sociodemographic variables; education, expressed in years;
medical history; personal psychiatric history, including previous and current
psychoactive substance use disorders; and previous and current antiretroviral
treatment. Data were obtained from an informant (usually a close relative)
when the participant was cognitively impaired. A medical and neurological
examination was performed, and neurological data were collected. Blood samples
were obtained for HIV-1 serological examination and CD4+ cell count.
During the second contact, a neuropsychological evaluation and a psychiatric
assessment were conducted by specialists (D.D. and I.F.). The HIV-1 serostatus
and any ongoing antiretroviral treatment were unknown to the examiners. Depression
was assessed using the Hamilton Depression Rating Scale,37
in which a score of at least 16 indicated the presence of prominent depressive
symptoms. The neuropsychological battery included tests that were used in
previous studies concerning HIV-1 and cognition38:
Verbal Fluency,39 the Rey 15 Words Short Term
and Long Term,40 and subtests of the Wechsler
Adult Intelligence Scale41 (digit span, digit
symbol, vocabulary, and block design). The neuropsychological battery was
administered in a fixed order.
DEFINITION OF COGNITIVE IMPAIRMENT
Cognitive impairment related to HIV-1 has been defined on the basis
of a cognitive battery for which cutoff scores for each test were derived
from normative values19 or from HIV-1–seronegative
controls.20-21 However, a wide
range of neuropsychological deficits are associated with substance abuse,42-46
and hemophiliacs47-48 are more
likely to have cognitive deficits due to brain damage compared with homosexuals/bisexuals
and heterosexuals. In our sample, 3 seronegative hemophiliacs had had cerebral
vascular accidents, although with no permanent neurological deficits on neurological
examination.
Thus, risk behaviors were considered in the definition of cognitive
impairment. Cognitive impairment was defined as poor performance on at least
2 of the 7 neuropsychological tests included in the battery. Poor performance
on a test was considered as a score of 2 or more SD lower than the mean of
the seronegative group in the corresponding risk behavior strata (IDUs, hemophiliacs,
and other risk behaviors). Table 1
reports the mean ± 2 SD scores for each test, according to different
risk behaviors, in the seronegative group.
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Table 1. Performance of 90 HIV-1-Seronegative Individuals on
Each Test of the Cognitive Battery*
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DATA ANALYSIS
The association between putative risk factors and cognitive impairment
was analyzed by using odds ratios (ORs) from logistic regression models. Different
logistic regression models were performed for the entire population of HIV-1–seropositive
persons and separately for asymptomatic and symptomatic HIV-1–seropositive
individuals by using cognitive impairment as the dependent variable, dichotomized
into impaired vs not impaired.
Independent variables were entered into the models as follows: (1) age
as a continuous variable; (2) education as an indicator variable (<6 years,
6-8 years, and >8 years) and as a dichotomous variable (<6 years vs >5
years); (3) sex (female vs male); (4) risk behavior as an indicator variable
(homosexual/bisexual, heterosexual, IDU, and hemophiliac) and as a dichotomous
variable (IDU/hemophiliac vs homosexual/bisexual and heterosexual); (5) CD4+ cell count was used by contrasting low (<200/µL) and moderate
(200-499/µL) levels with high levels (500/µL); (6) stage of
HIV-1 infection (symptomatic vs asymptomatic); (7) presence of prominent depressive
symptoms; and (8) antiretroviral treatment (any vs none).
Finally, sensitivity analysis of missing CD4+ cell counts
was conducted by producing 2 extreme imputations. This analysis assumed that
all participants with missing CD4+ cell counts had counts of 499/µL
or less (imputation 1) or counts of 500/µL or greater (imputation 2).
All the analyses were repeated in these 2 imputations.
RESULTS
Between December 1, 1994, and December 1, 1997, 272 consecutive outpatients
were examined and did not have any of the exclusion criteria (such as schizophrenia,
delusional disorders, mood disorders, or anxiety disorders). Of these, 90
(33%) were HIV-1 seronegative and 182 (67%) were HIV-1 seropositive (88 asymptomatic
and 94 symptomatic persons).
Concerning the sociodemographic characteristics of HIV-1–seronegative
individuals, there were no significant differences in the various risk behaviors
on age (almost half of the persons were aged <28 years). All the HIV-1–seronegative
hemophiliacs were obviously men, but between homosexuals/bisexuals and heterosexuals
and IDUs, no significant differences were found on sex. Conversely, 86% of
the homosexuals/bisexuals and heterosexuals had more than 8 years of education,
whereas only 30% of IDUs and 63% of hemophiliacs were highly educated.
Among HIV-1–seropositive persons, on the basis of performance
on the neuropsychological battery, 37 seropositive individuals were classified
as cognitively impaired and 145 as non–cognitively impaired. The prevalence
of cognitive impairment according to sociodemographic, clinical, and immunological
characteristics of HIV-1–seropositive persons is reported in Table 2. Prevalence was higher in participants
with less than 6 years of education than in more highly educated people, in
persons with no antiretroviral treatment than in treated people, and in heterosexuals
than in IDUs and hemophiliacs.
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Table 2. Number of Subjects, Number of Cases, and Prevalence of Cognitive
Impairment According to Sociodemographic, Clinical, and Immunological Characteristics
of 182 HIV-1-Seropositive Persons*
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Results of 4 logistic regression models, in which different putative
risk factors were entered one by one into the first block of variables (age,
sex, and education), are reported in Table
3. Participants with low educational levels had high ORs in all
4 models. In Italy, the first degree of education is achieved after 5 years
of schooling, and the second level after 3 more years. Therefore, 3 categories
of education were chosen: (1) less than 6 years, (2) 6 to 8 years, and (3)
more than 8 years. Adjusted ORs for HIV-1–related cognitive impairment
were 18.9 (95% confidence interval [CI], 3.7-97.6) in participants with less
than 6 years of education and 1.3 (95% CI, 0.5-3.2) in subjects with 5 to
8 years of education compared with individuals with 9 or more years of education.
Based on these results, we further analyzed education, contrasting individuals
with less than 6 years of education with those with more than 5 years of education.
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Table 3. Adjusted Odds Ratios for HIV-1-Related Cognitive Impairment
From 4 Logistic Regression Models*
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When antiretroviral treatment and risk behavior were introduced into
the fourth logistic regression model (Table
3), the OR for low educational level more than doubled. Antiretroviral
therapy (Table 3, models 3 and
4) was consistently inversely associated with cognitive impairment. A high
OR for HIV-1–related cognitive impairment in homosexual/bisexual and
heterosexual risk behaviors compared with IDU risk behavior (Table 3, model 4) was detected. All previous results were confirmed
when the data were adjusted for prominent depressive symptoms.
Analyses were repeated separately for symptomatic and asymptomatic persons
(Table 4). The results for symptomatic
individuals were similar to those for the entire population. For asymptomatic
individuals, although a similar trend was observed for all the risk factors,
only homosexual/bisexual and heterosexual risk behaviors emerged as significantly
associated with cognitive impairment (OR, 15.7; 95% CI, 3.1-78.9; P = .001).
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Table 4. Adjusted Odds Ratios for HIV-1-Related Cognitive Impairment
According to CDC Stage From 4 Logistic Regression Models*
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The CD4+ cell counts were available for 133 HIV-1–seropositive
persons (73%). Results of logistic regression analysis, in which the lack
of CD4+ cell count was the dependent variable, showed that persons
without CD4+ cell counts were more frequently women (OR, 2.2; 95%
CI, 1.0-4.5) and also more frequently non–cognitively impaired (OR,
0.3; 95% CI, 0.1-0.9). Participants with and without CD4+ cell
counts did not differ regarding other sociodemographic and clinical aspects.
Among individuals with CD4+ cell counts, 46% of IDUs and hemophiliacs
had low CD4+ cell counts vs only 23% of homosexuals/bisexuals and
heterosexuals ( 2 = 7.0; P = .03).
When CD4+ cell count was used instead of CDC stage in regression
models equal to those reported in Table
3, the adjusted OR for HIV-1–related cognitive impairment
among individuals with low CD4+ cell counts was 8.6 (95% CI, 1.0-71.0),
and in individuals with moderate CD4+ cell counts the OR was 6.9
(95% CI, 1.0-48.4) compared with persons with high CD4+ cell counts.
The ORs for the other risk factors were similar to those reported in Table 3.
Finally, sensitivity analysis of missing CD4+ cell counts
was performed. When the relation between HIV-1–related cognitive impairment
and age, sex, educational level, CDC stage, antiretroviral treatment, risk
behavior, and CD4+ cell count was analyzed using the method reported
in the "Data Analysis" subsection, the following results were obtained:
- Imputation 1 (all participants with missing CD4+ cell
counts were assumed to have counts
 499/µL): ORs in relation to increasing
age, female sex, low educational level, antiretroviral treatment, IDU and
hemophiliac risk behavior, and low CD4+ cell count were 1.0, 1.7,
16.4, 0.1, 0.1, and 4.5, respectively.
- Imputation 2 (all participants with missing CD4+ cell
counts were assumed to have counts 500/µL): ORs in relation to increasing
age, female sex, low educational level, antiretroviral treatment, IDU and
hemophiliac risk behavior, and low CD4+ cell count were 1.0, 2.0,
19.5, 0.1, 0.1, and 3.6, respectively.
COMMENT
The main findings from this study are summarized as follows:
- Low educational level emerged as an independent
risk factor for HIV-1–related cognitive impairment.
- Homosexuals/bisexuals and heterosexuals had higher
risk for HIV-1–related cognitive impairment than did IDUs, even after
adjustment for CD4+ cell count.
- Antiretroviral therapy was consistently inversely
associated with cognitive impairment.
- Persons who were seropositive for HIV-1 and had
severe immunosuppression showed a higher risk of cognitive impairment.
EDUCATION AND HIV-1–RELATED COGNITIVE IMPAIRMENT
In agreement with Stern,19 Maj,20 and Satz21 and their
colleagues, our findings suggest that low educational level (<6 years)
increases the risk of HIV-1–related cognitive impairment in HIV-1–seropositive
persons (asymptomatic and symptomatic). The association between low educational
level and HIV-1–related cognitive impairment was independent of all
other putative risk factors.
Analogous to Alzheimer disease, these findings regarding education may
be interpreted according to the cerebral reserve hypothesis.49
Higher education might delay the onset of cognitive impairment by providing
extra brain reserve that allows an individual to cope longer before cognitive
impairment is expressed clinically. However, the alternative hypothesis, that
the deleterious effects of low educational levels may be due to other related
factors,17, 20, 50-51
is also likely. In effect, less-educated individuals are more likely to belong
to a low socioeconomic level, where factors not considered in our study, such
as other infectious diseases and malnutrition, may, per se, affect cognition.
RISK BEHAVIOR AND HIV-1–RELATED COGNITIVE IMPAIRMENT
In our study, homosexuals/bisexuals and heterosexuals had a higher risk
for HIV-1–related cognitive impairment than did IDUs. This finding is
in disagreement with the suggested hypothesis that IDUs, for multiple reasons,
could have more rapid progression to HIV-1–related cognitive impairment
than persons with other risk behaviors.6, 13-14
A first explanation for the discrepancy lies in the cognitive impairment definition
adopted in this study. In fact, including risk behavior in the definition
of cognitive impairment discounts the effect of other factors related to the
IDU risk behavior, which could lead to cognitive deficits per se. Moreover,
individuals with IDU risk behavior have higher mortality rates than patients
with other risk behaviors.52 This might reduce
the number of IDUs with cognitive impairment in the pool of prevalent cases.
Alternatively, because of the high mortality rates, persons with IDU risk
behavior have reduced survival time after HIV-1 infection, which might be
proportionally related to the risk of cognitive impairment. Finally, IDUs
are less likely to receive or follow new antiretroviral measures.52
IMMUNOLOGICAL STATUS AND ANTIRETROVIRAL THERAPY IN RELATION TO HIV-1–RELATED
COGNITIVE IMPAIRMENT
Individuals seropositive for HIV-1 who had severe immunosuppression
showed a higher risk of cognitive impairment, in agreement with results of
other studies.3-11
This association is supported by a neuroimaging study53
in which, within the gray matter, cerebral volume loss was related to a low
CD4+ cell count. Conversely, we did not observe any significant
difference in cognitive impairment prevalence related to CDC stage criteria.
This result could be explained by the fact that the CD4+ cell count
represents a more sensitive indicator of immunological progression of HIV-1
infection than CDC stage.23 It has been suggested6 that a low CD4+ cell count may be a reliable
marker of rapid AIDS dementia complex progression, indicating high viral and
central nervous system seeding. Limited information was available in our study
concerning disease duration because for most participants the date of the
onset of infection was unknown. Adjustment for CD4+ cell count
partially adjusts for the duration of infection.
Our finding of a protective effect of antiretroviral therapy for cognitive
impairment is in agreement with most studies4, 13, 29-34
and in line with clinical trials suggesting that antiretroviral therapy is
effective in increasing the CD4+ cell count. We found that this
is true for symptomatic individuals.
AGE AND SEX AS POSSIBLE RISK FACTORS FOR HIV-1–RELATED COGNITIVE
IMPAIRMENT
We did not observe increasing age as a risk factor for cognitive impairment.
This result is inconsistent with other studies of HIV-1–associated dementia
complex.1, 9, 14, 22
One reason for a lack of association in the present study may be because of
the high degree of homogeneity in age of the sample and the high proportion
of IDUs, who have lower mean age than individuals with other risk behaviors
in our population.
Rates of cognitive impairment were higher for women, in agreement with
the findings of Chiesi et al,9 who reported
higher rates of AIDS dementia complex among women. However, when risk behaviors
were introduced into the model, the association between sex and cognitive
impairment was not present. Previous reporting of female sex as a risk factor
for AIDS dementia complex may be because the latter study9
did not adjust for risk behaviors in the definition of cognitive impairment.
In conclusion, low educational level, low CD4+ cell count,
and homosexual/bisexual and heterosexual risk behaviors are risk factors for
cognitive impairment in HIV-1–seropositive persons. Antiretroviral therapy
exerts a beneficial effect against cognitive impairment in symptomatic individuals.
The generalizability of these findings may be questioned, as the extent
to which our participants are representative of persons with different risk
behaviors or HIV-1 infection is unknown. For instance, the exclusion of persons
affected by previous or current psychiatric disorders may limit the generalizability
of our results. Nevertheless, our sample may be considered representative
of at least Italian HIV-1–seropositive persons because a similar distribution
in age, sex, and risk behaviors has been reported by Chiesi et al54 for the inception cohort of the Italian National
AIDS Registry.
We are aware that even missing a few cognitively impaired individuals,
because of small numbers in some education strata, may modify the finding
concerning education and cognitive impairment. Nevertheless, we feel confident
in our findings, as selection bias due to dropouts, if present, was minimal.
Indeed, there were only 2 dropouts in the whole sample. Diagnostic bias was
minimized by the use of a reliable neuropsychological battery and by the fact
that risk behaviors were considered in the definition of cognitive impairment,
which also adjusted indirectly for education. Last, contrary to many previous
investigations conducted in the research field, persons were consecutively
recruited from outpatient units to which they had been referred for medical
advice.
Major changes in the AIDS epidemic have taken place in recent years,
and our findings have important implications for HIV-1 surveillance programs.
Our findings suggest that homosexual/bisexual and heterosexual persons who
survive longer are expected to be the group at highest risk for cognitive
impairment. However, the protective effect of antiretroviral therapy may balance
this increased risk. Further studies based on larger populations and incident
cognitive impairment cases are needed to confirm these data and to understand
if some years of education can decrease the risk of HIV-1–related cognitive
impairment or whether other factors, acting in the first decade of life, are
the real determinants.
AUTHOR INFORMATION
Accepted for publication September 25, 2001.
Author contributions: Study concept and design (Drs De Ronchi and Fratiglioni); acquisition of data (Drs De Ronchi, Faranca, Borderi, and Manfredi); analysis
and interpretation of data (Drs De Ronchi, Berardi, Scudellari,
and Fratiglioni); drafting of the manuscript (Drs
De Ronchi and Fratiglioni); critical revision of the manuscript for
important intellectual content (Drs De Ronchi, Faranca,
Berardi, Scudellari, Borderi, Manfredi, and Fratiglioni); statistical
expertise (Drs De Ronchi and Fratiglioni); obtained
funding (Dr De Ronchi); administrative, technical,
and material support (Drs De Ronchi, Faranca, Scudellari,
Borderi, and Fratiglioni); study supervision (Drs
De Ronchi, Berardi, Scudellari, Manfredi, and Fratiglioni).
This study was supported by grants (ex-quota 60%, E.F. 1998, 1999, 2000)
from the Ministry of University and Scientific Research and Technology, Rome,
Italy.
We thank all the patients who participated in the survey and all the
members of the HIV-1–Related Cognitive Impairment and AIDS Dementia
Complex Project Study Group of Bologna.
Corresponding author and reprints: Diana De Ronchi, MD, Stockholm
Gerontology Research Center—The Kungsholmen Project, BOX 6401, S-113
82 Stockholm, Sweden (e-mail Diana.de.Ronchi{at}cnsf.ki.se).
From the Institute of Psychiatry (Drs De Ronchi, Faranca, Berardi,
and Scudellari) and the Division of Infectious Diseases, Department of Clinical
and Experimental Medicine (Drs Borderi and Manfredi), University of Bologna,
Bologna, Italy; and the Division of Geriatric Epidemiology, NEUROTEC, Karolinska
Institutet, Stockholm, Sweden (Drs De Ronchi and Fratiglioni).
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