INVITED ARTICLE AGING AND INFECTIOUS DISEASES

Kevin P. High, Section Editor

HIV Infection and Dementia in Older Adults

Victor Valcour1 and Robert Paul2
1
Hawaii AIDS Clinical Research Program and the Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu;
and 2Department of Psychiatry and Human Behavior, Brown Medical School, Providence, Rhode Island

Human immunodeficiency virus (HIV) infection in older patients is becoming increasingly common as seropositive individuals
live longer because of long-term antiretroviral treatment. Simultaneously, the development and expression of dementia among
HIV-infected patients is evolving in the era of highly active antiretroviral therapy (HAART) and immune reconstitution. How
long-term HAART interacts with chronic HIV infection and advanced age with regard to cognition is not fully understood.
This article provides an overview of HIV cognitive impairment as it relates to aging and presents some emerging issues in
the field. Particular emphasis is placed on describing the changing landscape of HIV-related cognitive impairment and
discussing possible concerns regarding the long-term effects of antiretroviral treatment. A brief discussion of potential
adjunctive therapies to reduce cognitive symptoms associated with HIV infection in older individuals is provided.

Historically, persons aged 150 years with HIV infection were
referred to as “older,” a classification supported by the relatively
bell-shaped demographic distribution of US HIV/AIDS cases
designated by the Centers for Disease Control and Prevention
(figure 1). Around 10% of HIV-infected individuals fall in this
older age group, which is a percentage that is roughly equivalent
to the percentage of the general population in their retirement
ages. Widespread use of antiretroviral therapy (ART) is begin-
ning to alter this somewhat arbitrary distinction. Because of
long-term survival of HIV-infected persons, the upper tail of
the epidemic is beginning to extend into the older age groups.
Currently, 160,000 HIV-infected individuals are 150 years old.
The number of HIV-infected individuals 165 years of age in-
creased from ∼1000 to 110,000 in the past decade [2]. The US
Senate Special Committee on Aging predicts that 50% of na-
tionally prevalent AIDS cases will fall into this older age group
by the year 2015 [3].
Older HIV-infected patients are either aging with HIV in-
fection or becoming newly infected at older ages. These dis-
tinctions may have clinical and prognostic implications. Cur-
rently, older HIV-infected individuals belong primarily to the
first group, having been infected in their 30s or 40s and living
Received 7 October 2005; accepted 27 January 2006; electronically published 13 April
2006.
Reprints or correspondence: Dr. Victor Valcour, Office of Neurology and Aging Research,
Sinclair 202, Leahi Hospital, 3675 Kilauea Ave., Honolulu, Hawaii 96816 (Vvalcour
@hawaii.edu).
Clinical Infectious Diseases 2006; 42:1449–54
 2006 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2006/4210-0017$15.00
with chronic HIV infection and prolonged ART. In the Hawaii
Aging with HIV Cohort, the mean self-reported duration since
the first HIV test result among individuals ⭓50 years old (mean
age, 54.6 years) is 11.8 years, compared with 7.2 years for
individuals !40 years old, which is roughly equivalent to the
mean duration reported by other groups [4]. Although the
Hawaii Aging with HIV Cohort is enrolled entirely in Hawaii,
it appears to be reasonably representative of the US HIV-in-
fected population, because the demographic constitution is
similar to that of the Multicenter AIDS Cohort Study and be-
cause most of the individuals were born and raised in the
continental United States. Exposure to ART is increased among
older individuals in the Hawaii Aging with HIV Cohort as well.
A mean of 5.1 years compared with a mean of 2.6 years of
nucleoside reverse-transcriptase inhibitor exposure was self-
reported by older participants, compared with younger partic-
ipants, respectively (P ! .001 ). The long-term consequences of
chronic infection and extended exposure to ART with respect
to the brain are not known.
Although it is currently less common, patients who develop
HIV infection in their older years represent a special issue for
health care providers, because it continues to be an invisible
problem. Diagnosis is often delayed, and risk behaviors may
be increasing in the absence of needed factors to support safer
sexual practices [5, 6]. Although most cases of HIV infection
among the older population occur in men, women account for
more new cases of infection in this group, and nearly 70% of
cases in older female persons occur among minority popula-
tions [7]. The magnitude of the problem may be understated,

AGING AND INFECTIOUS DISEASES • CID 2006:42 (15 May) • 1449


Figure 1. Estimated percent of persons living with HIV/AIDS in the
United States in 2003, by age group, based on Centers for Disease Control
and Prevention data [1].
because seniors are less likely to be tested for HIV. Newly
infected older individuals represent a group that is potentially
vulnerable to presenting with dementia as a sentinel HIV
event [8].
DEMENTIA IN HIV-INFECTED PATIENTS
Existing definitional criteria for dementia and the epidemi-
ology of dementia associated with HIV. The American Acad-
emy of Neurology designates 2 main categories of HIV-related
cognitive impairment, including HIV-associated dementia
(HAD) and minor cognitive motor disorder (MCMD). In gen-
eral, a diagnosis of HAD necessitates an acquired abnormality
in at least 2 cognitive domains, with an additional abnormality
in either motor function or motivation and/or emotional con-
trol. Representing milder impairment, MCMD requires at least
2 cognitive and/or behavioral symptoms and an objective find-
ing of 1 acquired cognitive or motor abnormality. Both require
that cognitive difficulties reduce the ability to complete daily
activities or work. Determining functional decline due to cog-
nition can be problematic among older patients who are often
retired or have decreased their work load for medical reasons
and may not have reasonable insight into expected levels of
performance. Confidentiality issues and confounding of func-
tional capabilities due to other illnesses can produce further
barriers to functional assessment. Consequently, some centers
advocate objective assessments of function.
Before the widespread use of HAART, up to 30% of indi-
viduals with AIDS developed either HAD or MCMD [9]. Be-
cause advanced immune compromise is a major HAD risk
factor, a decrease in incidence was seen after the use of HAART
became widespread. However, HAD prevalence has not
changed, and an increased incidence of MCMD relative to HAD
has been noted. An increased proportion of individuals diag-
1450 • CID 2006:42 (15 May) • AGING AND INFECTIOUS DISEASES
nosed with dementia now have a CD4 cell count 1200 cells/
mm3 [10]. Incomplete neuropsychological improvement fol-
lowing HAART has been described [10, 11], and the rate of
HIV encephalitis at autopsy may be increasing [12]. Taken
together, there is evidence to suggest that the brain remains
vulnerable in the era of HAART, and significant cognitive dif-
ficulties may persist within the limits of current treatment
approaches.
Both epidemiological data and focused research initiatives
identify an increased rate of HAD among older patients [8, 13,
14]. The Multicenter AIDS Cohort Study identified a relative
hazard ratio for dementia of 1.60 per decade of life at AIDS
onset [15]. Similarly, after controlling for duration of infection,
use of HAART, and CD4 T lymphocyte count, older patients
are 3 times more likely to meet structured HAD criteria in a
research setting [13]. Whether there is an additive or synergistic
relationship between aging and HIV on neuropsychological
testing performance is not fully known, because discrepant re-
ports exist [4, 16–18].
Identifying the specific mechanisms related to increased risk
for HAD is not straightforward. The presence of coexisting
diseases, particularly neurodegenerative disorders, among older
patients limits our ability to identify HIV-specific etiologies
[19]. It is not known whether HIV infection, per se, increases
the risk for other age-related neurodegenerative disorders, per-
haps decreasing the age of onset. Such a relationship would
not be surprising, considering that other conditions, when co-
existing (e.g., cerebral infarction and Alzheimer’s disease),
lower the threshold for clinical expression of dementia [20].
The term “dementia in HIV” may be more appropriate for
older patients, given existing challenges in confidently exclude
contributing factors.
Characteristics of dementia among HIV-infected patients:
past and present. Dementia due to HIV infection is consid-
ered to be a “subcortical” dementia, because the cognitive
symptoms are predominately characterized by difficulties in
cognitive functions purportedly subserved by white matter
pathways and specific gray matter nuclei that lie deep in the
subcortical regions of the brain. Patients with HAD often ex-
hibit slowed response times, marked slowness in psychomotor
speed, poor cognitive flexibility, and emotional lability or ap-
athy. The impact on cortical brain regions may be more com-
mon in the era of HAART, altering the clinical expression of
cognitive impairment. Such changes have been identified in
neuropsychological testing profiles and in neuroimaging by
positron emission tomography [21, 22]. Milder cognitive ab-
normalities are more frequent, and HAD subtypes have been
introduced, reflecting chronic progressive, active, and nonpro-
gressive disease courses [23]. Markers of immune activation in
the CSF (e.g., b-2-microglobulin) that were classically described
with HAD may now have less specificity for active disease [24],
and current CD4 T lymphocyte count is less useful [10]. Mean-
while, markers that were classically associated with Alzheimer’s
disease may be emerging. Because disease severity is generally
milder, some discussion has ensued advocating greater reliance
on neuropsychological testing results to categorize asymptom-
atic, mild, moderate, and severe impairment rather than using
diagnostic categorization. This contention is supported by the
knowledge that milder degrees of impairment remain risks for
HIV disease progression, poor medication adherence (partic-
ularly among older adults), and encephalitis [25–27].
In contrast to most other types of dementia, temporal fluc-
tuation in cognitive deficits have been seen in contemporary
cohorts of HIV-infected patients [23]. This fluctuation may
represent a relapsing and/or remitting pattern of cognitive im-
pairment and would not be surprising, because cognitive find-
ings are believed to reflect inflammatory processes that may
fluctuate over time and because vacillation occurs in a number
of secondary factors, such as degree of viral suppression, med-
ication adherence, treatment regimens, and drug toxicities. One
study demonstrated a relationship between CSF oxidative stress
and a progressive disease course [28], and another suggested
that undetectable CSF b-2-microglobulin and undetectable CSF
HIV RNA do not preclude active disease [24]. From a clinical
perspective, it is important to note that cognitive abnormalities
remain prevalent and, though less severe, remain risk factors
for meaningful outcomes in the era of HAART.
EMERGING ISSUES AND CONTROVERSIES
RELATING TO HIV INFECTION AND DEMENTIA
IN OLDER PATIENTS
Immune reconstitution. Having a low CD4 lymphocyte count
increased the risk for HAD in the pre-HAART era, likely
through indirect means. After the advent of HAART, the mean
CD4 cell count in patients diagnosed with HAD increased sub-
stantially [10, 22], rendering CD4 cell counts less clinically
useful. Nadir CD4 cell count, the lowest CD4 cell count ever
achieved, may have diagnositc utility in the short-term. Nadir
CD4 cell count correlates to prevalent distal symmetric poly-
neuropathy among older (but not younger) individuals [29]
and to neurocognitive impairment [30]. This marker may be
particularly relevant to individuals who were infected before
HAART was readily available or who sustain low CD4 cell
counts before diagnosis of HIV infection—2 situations that are
more common among older patients.
There is some speculation that age-related changes in im-
mune function may negatively influence HIV disease outcome
among older individuals. Age-related changes in immune func-
tion include decreased ability to respond to novel pathogens
and decreased proliferation of T lymphocytes [31, 32]. Several
investigators have posited that immunosenesence will result in
accelerated HIV disease progression in older patients [31, 33].
On the other hand, the overall impact of these changes may
be partly mitigated by enhanced adherence to ART [34].
Control of HIV viremia. HIV is thought to enter the CNS
early in infection [35]. Mild cognitive abnormalities have been
identified early in infection using sensitive neuropsychological
measures (reviewed in [36]) and functional neuroimaging [37].
Nevertheless, great variability in the timing of clinically signif-
icant cognitive difficulties is seen. It is likely that the indirect
effects of HIV, particularly inflammatory responses, are vitally
important (reviewed in [38]). Controlling plasma viremia is
the standard of care for individuals with low CD4 cell counts.
One might surmise that this would control cognitive sequelae
among successfully treated individuals. There are several im-
portant caveats, however, resulting in markedly dampened op-
timism, and clinical experience mandates continued vigilance.
First, there is evidence to suggest that CNS compartmen-
talization of the virus occurs. Phylogenetic analyses and HIV
resistance profiles from the brains of dementia patients support
this concept [39, 40]. Plasma HIV RNA levels are not necessarily
reflective of brain parenchymal exposure and vulnerability. Be-
cause of proximity, CSF may serve as a better marker of brain
vulnerability, although it is not necessarily reflective of degree
of parenchymal infection. Some studies indicate that CSF vi-
remia may reflect risk for cognitive impairment [41, 42].
The clinical implications are immediately evident. Although
it is not possible to measure the degree of brain parenchymal
infection, measurement of CSF HIV RNA can be done and
may provide some clinical utility, particularly among patients
who deteriorate during successful peripheral control of virus
[43]. This may suggest treatment approaches, because some
antiretrovirals are thought to have better activity in the CNS,
whereas others are actively transported out [44]. It is not yet
known whether ART regimens with profiles that suggest high
levels of CNS penetration should be broadly recommended,
because limited data exist. There is sufficient evidence from
cross-sectional studies and case reports to suggest individual-
ized decisions regarding ART choice and CSF HIV RNA mon-
itoring among selected cases [43, 45, 46].
Eradicating HIV from PBMCs may be important as well. A
leading hypothesis for HIV entry into the brain relates to traf-
ficking of monocytes from the periphery into the CNS (i.e.,
the Trojan horse effect). Intracellular levels of HIV DNA in
PBMCs relate to both HIV disease progression [47] and prev-
alent HAD [48], with the relationship to HAD remaining sig-
nificant among individuals with undetectable plasma HIV RNA.
HAART neurotoxicity. The neurotoxicities of some anti-
retrovirals have been demonstrated [49, 50]. Newer antiret-
rovirals appear to have improved toxicity profiles; however,
older patients have often survived extensive past exposure to
more toxic antiretrovirals, and others continue the regimen
because of resistance profiles. Although speculative, long-term
AGING AND INFECTIOUS DISEASES • CID 2006:42 (15 May) • 1451
treatment in a more vulnerable host (e.g., older individuals)
may expose cognitive consequences.
Particular concern can be raised for the metabolic changes
related to HAART. Lipid abnormalities, glucose intolerance, and
a condition akin to the metabolic syndrome are associated with
HAART [51] and relate to cardiovascular sequelae [52]. Among
the seronegative population, these risk factors relate to cere-
brovascular disease and cognitive impairment. To date, this
relationship has not been uniformly demonstrated in HIV-in-
fected patients [53, 54]; however, cerebrovascular endothelial
changes have been identified in patients with lipodystrophy
[55], and diabetes has been linked to HAD [56]. These findings
suggest continued vigilance is required.
Aging and contributing causes to dementia. Historically,
there was little need to consider age-related neurodegenerative
diseases as contributing causes to cognitive impairment in HIV
infection, because infection existed almost exclusively among
younger individuals. This supposition no longer exists, raising
new issues regarding the diagnosis and treatment of HAD. Cur-
rently, there is little formal basis on which a clinician can con-
fidently determine the etiology of cognitive impairment in an
older HIV-infected patient. Relying on signs, symptoms, and
neuropsychological profiles may be problematic in the face of
newly identified changes in the presentation and course of
HAD. If HIV infection lowers the threshold for the clinical
presentation of other neurodegenerative disease (cerebral re-
serve hypothesis), then these challenges may even impact mid-
dle-aged patients.
Existing data suggest that an overlap in neuropathology is
reasonable to consider. The pathology typically attributed to
Alzheimer disease has now been reported in HIV-infected pa-
tients, including increased brain b-amyloid deposition [57],
increased extracellular amyloid plaques [58], and decreased CSF
b-amyloid levels [22]. Neprolysin, an enzyme responsible for
amyloid degradation in the extracellular environment, is in-
hibited by Tat [59]. Similar to Alzheimer disease, the existence
of an apolipoprotein e4 allele correlates to HAD [60], possibly
in an age-dependent fashion [61]. Parkinson disease may be
another particularly vulnerable disease for older HIV-infected
patients, given the importance of the basal ganglia and dopa-
minergic pathways in both diseases [62, 63].
TREATMENT OPTIONS: PAST, PRESENT,
AND FUTURE
Currently, the mainstay of HAD treatment is the initiation of
HAART and maintenance of undetectable plasma viremia.
There is little basis on which to make recommendations for
individuals who experience cognitive deterioration while on
HAART with adequate plasma and CSF viral control [43]. Some
controversy remains as to whether this does occur; however,
there are limited data supporting the contention that progres-
1452 • CID 2006:42 (15 May) • AGING AND INFECTIOUS DISEASES
sion can occur within the context of current treatment param-
eters [24, 64]. The existence of confounding factors and a pau-
city of molecular markers are notable research disadvantages
for identifying treatment options for HAD. The hypothesis that
“actively progressive HIV dementia” [28, p. 176] is associated
with ongoing oxidative stress has received some attention. Two
studies evaluating the efficacy of selegiline (enrollment com-
plete) and minocycline (in development) are underway.
Selegiline is a dopamine agonist used in the treatment of
Parkinson disease. The drug exhibits supportive trophic effects
on damaged neurons as well as antioxidant qualities. In pre-
liminary studies, HIV-seropositive individuals receiving sele-
giline for 10 weeks experienced improvement in memory and
fine motor speed [65]; although early reports from the larger
placebo-controlled study have been disappointing [66]. Min-
ocycline is an antibiotic with anti⫺inflammatory effects and
good brain penetration at tolerable doses. In a pigtail macaque
model of simian immunodeficiency virus encephalitis with rap-
idly progressive disease, minocycline was associated with de-
creased inflammatory markers, intermediates of neuronal ap-
optosis, and simian immunodeficiency virus concentrations in
brain aggregates [67]. These effects were observed at doses that
would be considered tolerable in humans, suggesting that min-
ocycline may be a useful adjunctive therapy.
Several other agents have been considered. A study evaluating
the efficacy of memantine, a low-to-moderate affinity N-
methyl-d-aspartate receptor antagonist, has been completed
based on in vitro evidence that memantine blocks neuronal
injury resulting from gp120 and Tat [68] and improves hip-
pocampal function in a mouse model of HIV encephalitis [69].
Results of the clinical trial are not yet published. Use of the
CNS stimulant modafanil resulted in improved performance
in neuropsychological testing profiles in an open-label, 4-week
evaluation [70]. A placebo-controlled study is under consid-
eration. Additional adjunctive targets have been proposed [71],
including neurotropic factors (e.g., brain-derived neurotropic
factor, nerve growth factor, and insulin growth factor) and anti-
inflammatory agents (e.g., IL-4, IL-10, and erythropoietin). A
particularly interesting approach focuses on GSK-3b, an en-
zyme that is expressed in the brain and may play a role in
cellular signaling. To our knowledge, evaluation of these the-
oretical targets remains preclinical.
Providing treatment approaches that are specific to older
HIV-infected patients is problematic, given a paucity of research
addressing this issue. An algorithmic approach for all ages has
been proposed and has broad applicability to older patients
[43]. It may be warranted to broaden the differential of alter-
native etiologies for impairment among older patients. It is
reasonable to speculate that medications known to abate Alz-
heimer disease symptoms may have some efficacy in older pa-
tients when a combination of neurodegenerative etiologies may
underlie the clinical syndrome. However, there are no clinical
trials on which to base such recommendations. It is important
to have a high level of suspicion for HIV infection in older
individuals newly identified to have dementia and thought to
be HIV-seronegative. This concern would be most warranted
if the dementia has predominantly subcortical features, if con-
comitant constitutional symptoms exist, or if the patient is
relatively young (perhaps in their 60s) for the typical age of
onset of common neurodegenerative disorders.
SUMMARY
There is little question that the natural history of HIV infection
is changing in the contemporary era, and advanced age will
likely be an important moderator of clinical outcome associated
with the disease. The observation that HIV, advanced age, and
concomitant neurodegenerative disorders may interact in ad-
ditive or synergistic ways raises many questions regarding best
practice among this population. To date, no consensus has been
established regarding optimal approaches, and no clinical trials
have specifically addressed older HIV-infected patients. It is
likely that HIV will represent the most common infectious
etiology of dementia until a cure for HIV infection is identified.
Clinicians are encouraged to consider HIV infection a primary
contributor to cognitive impairment in older individuals
thought to be HIV-seronegative and to integrate the possibility
that age-related cognitive disorders may contribute to clinical
findings in older HIV-infected patients.
Acknowledgments
Financial support. National Institute of Neurological Disorders and
Stroke (grant 1U54NS43049 to V.V.); the National Institute of Allergy and
Infectious Diseases (grant 5U01 A134853 to V.V.), and the National Institute
of Mental Health (grant K23MH065857 to R.P.).
Potential conflicts of interest. V.V. and R.P.: no conflicts.
References
1. Centers for Disease Control and Prevention (CDC). HIV/AIDS Sur-
veillance Report, 2003. Atlanta: US Department for Health and Human
Services, CDC, 2004:17. Available at: http://www.cdc.gov/hiv/topics/
surveillance/resources/reports/index.htm. Accessed 13 April, 2006.
2. Stoff DM, Khalsa JH, Monjan A, Portegies P. Introduction: HIV/AIDS
and aging. AIDS 2004; 18(Suppl 1):S1–2.
3. Smith G. Statement of Senator Gordon H. Smith. Aging hearing: HIV
over fifty, exploring the new threat. Senate Committee on Aging. Wash-
ington, DC:2005. Available at: http://www.aging.senate.gov/public/
_files/hr141gs.pdf. Accessed 13 April 2006.
4. Cherner M, Ellis RJ, Lazzaretto D, et al. Effects of HIV-1 infection and
aging on neurobehavioral functioning: preliminary findings. AIDS
2004; 18(Suppl 1):S27–34.
5. el-Sadr W, Gettler J. Unrecognized human immunodeficiency virus
infection in the elderly. Arch Intern Med 1995; 155:184–6.
6. Zablotsky D, Kennedy M. Risk factors and HIV transmission to midlife
and older women: knowledge, options, and the initiation of safer sexual
practices. J Acquir Immune Defic Syndr 2003; 33(Suppl 2):S122–30.
7. Waysdorf SL. The aging of the AIDS epidemic: emerging legal and
public health issues for elderly persons living with HIV/AIDS. Elder
Law J 2002; 10:47–89.
8. Janssen RS, Nwanyanwu OC, Selik RM, Stehr-Green JK. Epidemiology
of human immunodeficiency virus encephalopathy in the United
States. Neurology 1992; 42:1472–6.
9. McArthur JC, Sacktor N, Selnes O. Human immunodeficiency virus-
associated dementia. Semin Neurol 1999; 19:129–50.
10. Sacktor N, Lyles RH, Skolasky R, et al. HIV-associated neurologic dis-
ease incidence changes: Multicenter AIDS Cohort Study, 1990–1998.
Neurology 2001; 56:257–60.
11. Tozzi V, Balestra P, Galgani S, et al. Changes in neurocognitive per-
formance in a cohort of patients treated with HAART for 3 years. J
Acquir Immune Defic Syndr 2001; 28:19–27.
12. Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE. Influence
of HAART on HIV-related CNS disease and neuroinflammation. J
Neuropathol Exp Neurol 2005; 64:529–36.
13. Valcour V, Shikuma C, Shiramizu B, et al. Higher frequency of dementia
in older HIV-1 individuals: the Hawaii Aging with HIV-1 Cohort.
Neurology 2004; 63:822–7.
14. Chiesi A, Vella S, Dally LG, et al. Epidemiology of AIDS dementia
complex in Europe: AIDS in Europe Study Group. J Acquir Immune
Defic Syndr Hum Retrovirol 1996; 11:39–44.
15. McArthur JC, Hoover DR, Bacellar H, et al. Dementia in AIDS patients:
incidence and risk factors. Multicenter AIDS Cohort Study. Neurology
1993; 43:2245–52.
16. Becker JT, Lopez OL, Dew MA, Aizenstein HJ. Prevalence of cognitive
disorders differs as a function of age in HIV virus infection. AIDS
2004; 18(Suppl 1):S11–8.
17. van Gorp WG, Miller EN, Marcotte TD, et al. The relationship between
age and cognitive impairment in HIV-1 infection: findings from the
Multicenter AIDS Cohort Study and a clinical cohort. Neurology
1994; 44:929–35.
18. Kissel EC, Pukay-Martin ND, Bornstein RA. The relationship between
age and cognitive function in HIV-infected men. J Neuropsychiatry
Clin Neurosci 2005; 17:180–4.
19. Skiest DJ. The importance of co-morbidity in older HIV-infected pa-
tients. AIDS 2003; 17:1577.
20. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Mar-
kesbery WR. Brain infarction and the clinical expression of Alzheimer
disease: the Nun Study. JAMA 1997; 277:813–7.
21. Cysique LA, Maruff P, Brew BJ. Prevalence and pattern of neuropsy-
chological impairment in human immunodeficiency virus–infected/
acquired immunodeficiency syndrome (HIV/AIDS) patients across pre-
and post-highly active antiretroviral therapy eras: a combined study
of two cohorts. J Neurovirol 2004; 10:350–7.
22. Brew BJ. Evidence for a change in AIDS dementia complex in the era
of highly active antiretroviral therapy and the possibility of new forms
of AIDS dementia complex. AIDS 2004; 18(Suppl 1):S75–8.
23. McArthur JC, Haughey N, Gartner S, et al. Human immunodeficiency
virus–associated dementia: an evolving disease. J Neurovirol 2003; 9:
205–21.
24. Cysique LA, Brew BJ, Halman M, et al. Undetectable cerebrospinal
fluid HIV RNA and beta-2 microglobulin do not indicate inactive AIDS
dementia complex in highly active antiretroviral therapy-treated pa-
tients. J Acquir Immune Defic Syndr 2005; 39:426–9.
25. Heaton RK, Marcotte TD, Mindt MR, et al. The impact of HIV-as-
sociated neuropsychological impairment on everyday functioning. J Int
Neuropsychol Soc 2004; 10:317–31.
26. Cherner M, Masliah E, Ellis RJ, et al. Neurocognitive dysfunction pre-
dicts postmortem findings of HIV encephalitis. Neurology 2002; 59:
1563–7.
27. Hinkin CH, Hardy DJ, Mason KI, et al. Medication adherence in HIV-
infected adults: effect of patient age, cognitive status, and substance
abuse. AIDS 2004;18(Suppl 1):S19–25.
28. Sacktor N, Haughey N, Cutler R, et al. Novel markers of oxidative
stress in actively progressive HIV dementia. J Neuroimmunol 2004;
157:176–84.
AGING AND INFECTIOUS DISEASES • CID 2006:42 (15 May) • 1453
29. Watters MR, Poff PW, Shiramizu BT, et al. Symptomatic distal sensory
polyneuropathy in HIV after age 50. Neurology 2004; 62:1378–83.
30. Tozzi V, Balestra P, Lorenzini P, et al. Prevalence and risk factors for
human immunodeficiency virus–associated neurocognitive impair-
ment, 1996 to 2002: results from an urban observational cohort. J
Neurovirol 2005; 11:265–73.
31. Goodkin K, Wilkie FL, Concha M, et al. Aging and neuro-AIDS con-
ditions and the changing spectrum of HIV-1-associated morbidity and
mortality. J Clin Epidemiol 2001; 54(Suppl 1):S35–43.
32. Murasko DM, Weiner P, Kaye D. Decline in mitogen induced prolif-
eration of lymphocytes with increasing age. Clin Exp Immunol 1987;70:
440–8.
33. Adler WH, Baskar PV, Chrest FJ, Dorsey-Cooper B, Winchurch RA,
Nagel JE. HIV infection and aging: mechanisms to explain the accel-
erated rate of progression in the older patient. Mech Ageing Dev
1997; 96:137–55.
34. Murphy DA, Marelich WD, Hoffman D, Steers WN. Predictors of
antiretroviral adherence. AIDS Care 2004; 16:471–84.
35. Gartner S. HIV infection and dementia. Science 2000; 287:602–4.
36. White DA, Heaton RK, Monsch AU. Neuropsychological studies of
asymptomatic human immunodeficiency virus-type-1 infected indi-
viduals. The HNRC Group. HIV Neurobehavioral Research Center. J
Int Neuropsychol Soc 1995; 1:304–15.
37. Chang L, Tomasi D, Yakupov R, et al. Adaptation of the attention
network in human immunodeficiency virus brain injury. Ann Neurol
2004; 56:259–72.
38. Lawrence DM, Major EO. HIV-1 and the brain: connections between
HIV-1-associated dementia, neuropathology and neuroimmunology.
Microbes Infect 2002; 4:301–8.
39. Salemi M, Lamers SL, Yu S, de Oliveira T, Fitch WM, McGrath MS.
Phylodynamic analysis of human immunodeficiency virus type 1 in
distinct brain compartments provides a model for the neuropatho-
genesis of AIDS. J Virol 2005; 79:11343–52.
40. Gonzalez-Scarano F, Martin-Garcia J. The neuropathogenesis of AIDS.
Nat Rev Immunol 2005; 5:69–81.
41. Ellis RJ, Hsia K, Spector SA, et al. Cerebrospinal fluid human im-
munodeficiency virus type 1 RNA levels are elevated in neurocogni-
tively impaired individuals with acquired immunodeficiency syndrome.
HIV Neurobehavioral Research Center Group. Ann Neurol 1997; 42:
679–88.
42. De Luca A, Ciancio BC, Larussa D, et al. Correlates of independent
HIV-1 replication in the CNS and of its control by antiretrovirals.
Neurology 2002; 59:342–7.
43. McArthur JC, Brew BJ, Nath A. Neurological complications of HIV
infection. Lancet Neurol 2005; 4:543–55.
44. Taylor EM. The impact of efflux transporters in the brain on the
development of drugs for CNS disorders. Clin Pharmacokinet 2002;
41:81–92.
45. Tyler KL, McArthur JC. Through a glass, darkly: cerebrospinal fluid
viral load measurements and the pathogenesis of human immuno-
deficiency virus infection of the central nervous system. Arch Neurol
2002; 59:909–12.
46. Wendel KA, McArthur JC. Acute meningoencephalitis in chronic hu-
man immunodeficiency virus (HIV) infection: putative central nervous
system escape of HIV replication. Clin Infect Dis 2003; 37:1107–11.
47. Rouzioux C, Hubert JB, Burgard M, et al. Early levels of HIV-1 DNA
in peripheral blood mononuclear cells are predictive of disease pro-
gression independently of HIV-1 RNA levels and CD4+ T cell counts.
J Infect Dis 2005; 192:46–55.
48. Shiramizu B, Gartner S, Williams A, et al. Circulating proviral HIV
DNA and HIV-associated dementia. AIDS 2005; 19:45–52.
49. Clifford DB, Evans S, Yang Y, et al. Impact of efavirenz on neuropsy-
chological performance and symptoms in HIV-infected individuals.
Ann Intern Med 2005; 143:714–21.
50. Verma S, Estanislao L, Simpson D. HIV-associated neuropathic pain:
epidemiology, pathophysiology and management. CNS Drugs 2005;
19:325–34.
1454 • CID 2006:42 (15 May) • AGING AND INFECTIOUS DISEASES
51. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipo-
dystrophy, hyperlipidaemia and insulin resistance in patients receiving
HIV protease inhibitors. AIDS 1998; 12:F51–8.
52. Friis-Moller N, Sabin CA, Weber R, et al. Combination antiretroviral
therapy and the risk of myocardial infarction. N Engl J Med 2003;
349:1993–2003.
53. Qureshi AI, Janssen RS, Karon JM, et al. Human immunodeficiency
virus infection and stroke in young patients. Arch Neurol 1997;54:
1150–3.
54. d’Arminio A, Sabin CA, Phillips AN, et al. Cardio- and cerebrovascular
events in HIV-infected persons. AIDS 2004; 18:1811–7.
55. Concha M, Symes S, Goodkin K, et al. Risk of cerebrovascular disease
in HIV-1–infected subjects with lipodystrophy syndrome and long-
term exposure to protease inhibitors [abstract P123]. In: Program and
abstracts of the 28th International Stroke Conference (Phoenix). 2003.
56. Valcour VG, Shikuma CM, Shiramizu BT, et al. Diabetes, insulin re-
sistance, and dementia among HIV-1-infected patients. J Acquir Im-
mune Defic Syndr 2005; 38:31–6.
57. Green DA, Masliah E, Vinters HV, Beizai P, Moore DJ, Achim CL.
Brain deposition of beta-amyloid is a common pathologic feature in
HIV positive patients. AIDS 2005; 19:407–11.
58. Achim C, Masliah E, Vinters H, Schindelar J, Green D. Beta-amyloid
in the HIV brain. Society of Neuroscience (Washington, DC). 2004.
59. Rempel HC, Pulliam L. HIV-1 tat inhibits neprilysin and elevates am-
yloid beta. AIDS 2005; 19:127–35.
60. Corder EH, Robertson K, Lannfelt L, et al. HIV-infected subjects with
the E4 allele for APOE have excess dementia and peripheral neuropathy.
Nat Med 1998; 4:1182–4.
61. Valcour V, Shikuma C, Shiramizu B, et al. Age, apolipoprotein E4, and
the risk of HIV dementia: the Hawaii Aging with HIV Cohort. J Neu-
roimmunol 2004; 157:197–202.
62. Vargas D, Nascimbene C, Lee A, Williams J, McArthur J, Pardo C.
Chemokine and cytokine profiling by protein array technology shows
the basal ganglia as the most affected area in HIV dementia. In: Pro-
gram and abstracts of the 12th Conference on Retroviruses and Op-
portunistic Infections (Boston). 2005.
63. Berger JR, Arendt G. HIV dementia: the role of the basal ganglia and
dopaminergic systems. J Psychopharmacol 2000; 14:214–21.
64. Ellis RJ, Moore DJ, Childers ME, et al. Progression to neuropsycho-
logical impairment in human immunodeficiency virus infection pre-
dicted by elevated cerebrospinal fluid levels of human immunodefi-
ciency virus RNA. Arch Neurol 2002; 59:923–8.
65. Sacktor N, Schifitto G, McDermott MP, Marder K, McArthur JC, Kie-
burtz K. Transdermal selegiline in HIV-associated cognitive impair-
ment: pilot, placebo-controlled study. Neurology 2000; 54:233–5.
66. Schifitto G, Sacktor N, Zhang J, et al. A phase II, placebo-controlled
double-blind study of the selegiline transdermal system in the treat-
ment of HIV-associated cognitive impairment: the ACTG 5090 team
[poster 364]. In: Program and abstracts of the 13th conference on
retroviruses and opportunistic infections (Denver). 2006.
67. Zink MC, Uhrlaub J, DeWitt J, et al. Neuroprotective and anti-human
immunodeficiency virus activity of minocycline. JAMA 2005; 293:
2003–11.
68. Nath A, Haughey NJ, Jones M, Anderson C, Bell JE, Geiger JD. Syn-
ergistic neurotoxicity by human immunodeficiency virus proteins Tat
and gp120: protection by memantine. Ann Neurol 2000; 47:186–94.
69. Anderson ER, Gendelman HE, Xiong H. Memantine protects hippo-
campal neuronal function in murine human immunodeficiency virus
type 1 encephalitis. J Neurosci 2004; 24:7194–8.
70. Rabkin JG, McElhiney MC, Rabkin R, Ferrando SJ. Modafinil treatment
for fatigue in HIV+ patients: a pilot study. J Clin Psychiatry 2004; 65:
1688–95.
71. Dou H, Kingsley JD, Mosley RL, Gelbard HA, Gendelman HE. Neu-
roprotective strategies for HIV-1 associated dementia. Neurotox Res
2004; 6:503–21.