Neuropsychology

HIV and Age Underlie Specific Patterns of Brain

Abnormalities and Cognitive Changes in High
Functioning Patients
Agnieszka Pluta, Tomasz Wolak, Marta Sobańska, Natalia Gawron, Anna R. Egbert, Bogna
Szymańska, Andrzej Horban, Ewa Firląg-Burkacka, Przemysław Bieńkowski, Halina Sienkiewicz-
Jarosz, Anna Ścińska-Bieńkowska, Adela Desowska, Mateusz Rusiniak, Bharat B. Biswal, Stephen
Rao, Robert Bornstein, Henryk Skarżyński, and Emilia Łojek
Online First Publication, January 28, 2019. http://dx.doi.org/10.1037/neu0000504

CITATION
Pluta, A., Wolak, T., Sobańska, M., Gawron, N., Egbert, A. R., Szymańska, B., Horban, A., Firląg-
Burkacka, E., Bieńkowski, P., Sienkiewicz-Jarosz, H., Ścińska-Bieńkowska, A., Desowska, A.,
Rusiniak, M., Biswal, B. B., Rao, S., Bornstein, R., Skarżyński, H., & Łojek, E. (2019, January 28). HIV
and Age Underlie Specific Patterns of Brain Abnormalities and Cognitive Changes in High
Functioning Patients. Neuropsychology. Advance online publication.
http://dx.doi.org/10.1037/neu0000504
 Neuropsychology
© 2019 American Psychological Association 2019, Vol. 1, No. 999, 000
0894-4105/19/$12.00 http://dx.doi.org/10.1037/neu0000504

HIV and Age Underlie Specific Patterns of Brain Abnormalities and

Cognitive Changes in High Functioning Patients

Agnieszka Pluta Tomasz Wolak

University of Warsaw and Institute of Physiology and Pathology Institute of Physiology and Pathology of Hearing,
of Hearing, Nadarzyn, Poland Nadarzyn, Poland

Marta Sobańska and Natalia Gawron Anna R. Egbert

University of Warsaw University of Warsaw and New Jersey Institute of Technology
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
This document is copyrighted by the American Psychological Association or one of its allied publishers.

Bogna Szymańska, Andrzej Horban, Przemysław Bieńkowski

and Ewa Firla˛g-Burkacka Medical University of Warsaw
The Central Hospital for Infectious Diseases, Warsaw, Poland

Halina Sienkiewicz-Jarosz, Adela Desowska

and Anna Ścińska-Bieńkowska University of Warsaw
The Institute of Psychiatry and Neurology, Warsaw, Poland

Mateusz Rusiniak Bharat B. Biswal

Institute of Physiology and Pathology of Hearing, New Jersey Institute of Technology
Nadarzyn, Poland

Stephen Rao Robert Bornstein

The Cleveland Clinic, Cleveland, Ohio Ohio State University

Henryk Skarżyński Emilia Łojek

Institute of Physiology and Pathology of Hearing, University of Warsaw
Nadarzyn, Poland

Objective: Findings on the influence of age and HIV on brain and cognition remain equivocal,
particularly in aviremic subjects without other age or HIV-related comorbidities. We aimed to (a)
examine the effect of HIV status and age on structural brain measurements and cognition, and (b) apply
the machine learning technique to identify brain morphometric and cognitive features that are most
discriminative between aviremic subjects with HIV on stable combination antiretroviral therapy (cART)
and healthy controls. Method: Fifty-three HIV-seropositive patients and 62 healthy controls underwent
neuropsychological testing (executive functions, attention, memory, learning, psychomotor speed, flu-

The Faculty of Psychology, University of Warsaw; Mateusz Rusiniak,

Agnieszka Pluta, The Faculty of Psychology, University of Warsaw,
and Institute of Physiology and Pathology of Hearing, Nadarzyn, Po-
land; Tomasz Wolak, Institute of Physiology and Pathology of Hearing;
Marta Sobańska and Natalia Gawron, The Faculty of Psychology,
University of Warsaw; Anna R. Egbert, The Faculty of Psychology,
University of Warsaw, and Department of Biomedical Engineering,
New Jersey Institute of Technology; Bogna Szymańska, Andrzej Hor-
ban, and Ewa Firla˛g-Burkacka, The Central Hospital for Infectious
Diseases, Warsaw, Poland; Przemysław Bieńkowski, Department of
Psychiatry, Medical University of Warsaw; Halina Sienkiewicz-Jarosz,
Department of Neurology, The Institute of Psychiatry and Neurology,
Warsaw, Poland; Anna Ścińska-Bieńkowska, Department of Pharma-
cology, The Institute of Psychiatry and Neurology; Adela Desowska,
Institute of Physiology and Pathology of Hearing; Bharat B. Biswal,
The Department of Biomedical Engineering, New Jersey Institute of
Technology; Stephen Rao, The Cleveland Clinic, Cleveland, Ohio;
Robert Bornstein, The College of Medicine, Ohio State University;
Henryk Skarżyński, Institute of Physiology and Pathology of Hearing;
Emilia Łojek, The Faculty of Psychology, University of Warsaw.
This study was supported by the Polish National Science Center
(UMO ⫺2012/06/M/H56/00316). We thank Katarzyna Cieśla for the valu-
able comments on the article.
Correspondence concerning this article should be addressed to Ag-
nieszka Pluta, The Faculty of Psychology, University of Warsaw,
Stawki 5/7, 00-183 Warsaw, Poland. E-mail: apluta@psych.uw.edu.pl

1
 2 PLUTA ET AL.

ency) and volumetric MRI scans. Voxel-based morphometry, ANCOVAs, machine learning, and mul-
tivariate regression were conducted to determine the between group differences in terms of relationship
of HIV status, age, and their interaction on neurocognitive and structural brain measures. Results:
Volume and gray matter (GM) thickness of the caudate, parahippocampus, insula, and inferior frontal
gyrus were smaller in seropositive subjects in comparison with healthy controls (HC). They also
performed worse in complex attention and cognitive fluency tasks. Support vector machine (SVM)
analysis revealed that the best between-groups classification accuracy was obtained based on cognitive
scores encompassing complex attention and psychomotor speed, as well as volumetric measures of white
matter and total gray matter; third, fourth, and lateral ventricles; amygdala; caudate; and putamen. Both
voxel-based morphometry (VBM) and regression analysis yielded that HIV and aging independently
increase brain vulnerability and cognitive worsening. Conclusion: Patients with HIV on effective cART
demonstrate smaller volumetric measures and worse cognitive functioning relative to seronegative
individuals. There is no interaction between HIV infection and aging.
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General Scientific Summary

This document is copyrighted by the American Psychological Association or one of its allied publishers.

In the cART era, HIV-infected subjects still show volumetric changes in cortical and subcortical
areas and slight deficits of complex attention and cognitive fluency. HIV does not accelerate brain
aging in aviremic subjects.

Keywords: HIV, aging, structural imaging, cognitive functions

Supplemental materials: http://dx.doi.org/10.1037/neu0000504.supp

During the early years of the HIV epidemic, HIV-associated
encephalopathy and dementia were among the most common
diagnoses in people with AIDS at the time of death, which on
average occurred 11 months after the onset of illness. The intro-
duction of combination antiretroviral therapy (cART) has changed
AIDS from a lethal to a long-term condition, with nearly normal
life expectancy in optimally treated patients (Deeks, Lewin, &
Havlir, 2013; Teeraananchai, Kerr, Amin, Ruxrungtham, & Law,
2017). Effective cART suppresses the viral load, leading to the
restoration of immune function. As individuals with HIV have
longer life expectancies, the prevalence of cognitive and brain
abnormalities (resulting from HIV alone or age) might increase
despite treatment. This is likely related to the duration of HIV
infection (older adults might be infected with HIV longer) and
aging-related comorbidities that might be exacerbated or acceler-
ated by HIV-induced neurotoxicity (Cohen, Seider, & Navia,
2015; Cole et al., 2017; Holt, Kraft-Terry, & Chang, 2012).
Studies have demonstrated lower cognitive outcomes in HIV-
positive patients in comparison with controls, despite improved
viral suppression and immune reconstitution with cART (Cohen et
al., 2015). According to Heaton et al. (2011), a common neuro-
psychological pattern includes impaired executive functioning,
motor skills, speed of information processing, and learning, as well
as intact memory retention, most language skills, and visuospatial
functioning. The prevalence of cognitive impairment is expected to
increase in older populations with HIV because of longer duration
of HIV infection (Scott et al., 2011).
Brain atrophy has been extensively reported in HIV subjects
both in the pre- and postcART era (Becker et al., 2012; Stout et al.,
1998; Thompson & Jahanshad, 2015). Recent neuroimaging stud-
ies demonstrate reductions of the global cerebral brain volume as
well as a number of cortical and subcortical structures in patients
on cART (see Holt et al., 2012 for a review; Wilson et al., 2015).
The study of Li, Li, Gao, Yuan, and Zhao (2014) has shown gray
matter (GM) atrophy of the frontal and temporal regions, including
the anterior cingulate cortex, left inferior frontal gyrus, right mid-
dle frontal gyrus, and left superior temporal gyrus in HIV-positive
patients without cognitive impairment according to the Interna-
tional HIV Dementia Scale (Li et al., 2014). However, out of 36
subjects with HIV, only 11 were on cART. Consistently, Tow-
good, et al. (2012) reported GM reductions in medial and superior
frontal gyri in asymptomatic HIV-infected participants, suggesting
that brain atrophy may precede neuropsychological decline. Ac-
cording to Ragin et al. (2015), structural reductions may already
occur within the first year of disease, which is in line with an
animal model of HIV indicating that brain changes may already
occur within 15 days of infection (Lackner & Veazey, 2007).
Epidemiological trends have made the effect of HIV and age on
the brain a subject of great concern (Thompson & Jahanshad,
2015). However, whether HIV and age interactively affect the
brain and neurocognitive functions or contribute separately to
brain atrophy and cognitive impairments remains an open question
(Cohen et al., 2015). Evidence for and against accelerated aging in
HIV subjects exists in the literature. For example, the recent study
of Seider et al. (2016) revealed synergetic effects of age and HIV
on white matter integrity. Specifically, older HIV-positive subjects
had greater white matter hypointensities and lower white matter
integrity in the anterior corona radiata, internal capsules, and
cerebral peduncles (Seider et al., 2016). Although interesting, the
findings should be treated with caution, because the group was
heterogeneous regarding the treatment regimen (not all partici-
pants were on cART), HCV coinfection (in ⬎1/three subjects),
detectable or undetectable amounts of plasma HIV RNA, and
AIDS history. Other studies have reported independent effects of
HIV and aging on brain structures. For example, Becker et al.
(2012) reported age-associated volumetric reductions in the infe-
rior frontal, superior temporal, medial temporal, and cingulate
areas as well as independent HIV-related thickenings in the tem-
 BRAIN AND COGNITIVE CHANGES IN SUBJECTS WITH HIV
poral lobes, parietal lobes, and cerebellum (Becker et al., 2012).
Similarly, Ances, Ortega, Vaida, Heaps, and Paul (2012) revealed
atrophy in subcortical regions (amygdala, caudate, corpus callo-
sum) in HIV subjects, despite being on a cART regimen (subjects
on vs. not on cART had similar volumetric measures). No inter-
action between age and HIV status was confirmed in the above-
mentioned study (Ances et al., 2012). The study of Cole et al.
(2017) conducted on 162 aviremic HIV-positive adults yielded
similar results. Authors revealed increased brain aging marked by
brain volume reductions but no interaction between HIV and age.
Some studies revealed interactive or synergistic effects of HIV
and age on cognition. Such evidence is limited and was reported in
the domain of verbal memory. In the study of Seider et al. (2014),
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when tested twice over 1 year, older HIV-positive patients dem-
This document is copyrighted by the American Psychological Association or one of its allied publishers.
onstrated greater impairments in verbal memory and learning
compared with younger HIV-positive subjects as well as compared
with younger and older HIV-negative controls. Such findings
support the hypothesis that HIV accelerates the effects of age on
cognition. On the other hand, cross-sectional studies exploring the
combined effects of HIV and aging on cognitive functions have
not reported significant interactions (Ciccarelli et al., 2012; Val-
cour, Paul, Neuhaus, & Shikuma, 2011). Ciccarelli et al. (2012)
demonstrated that older HIV-positive participants performed lower
in verbal learning than younger HIV-positive subjects and healthy
controls, but the HIV-positive groups did not differ in primacy and
recency effects on words recalled. Valcour, Paul, Neuhaus, and
Shikuma (2011) also failed to demonstrate HIV and age interac-
tions on neuropsychological performance and hypothesized that
they were minimized by careful matching of groups on age,
gender, and IQ; thereby, eliminating additional sources of vari-
ance.
In all, studies report slight HIV-related cognitive and brain
abnormalities. The pattern of cognitive effects varies across stud-
ies. Moreover, the severity and location of brain abnormalities is
not consistent. While previous studies reported structural changes
mainly in basal ganglia, with caudate being preferentially affected
(Ances et al., 2006), more recent studies are not so coherent and
report regions which were not typically affected by HIV in pre-
cART era, as for example the amygdala (Ances et al., 2012),
orbitofrontal cortex or insula (Kallianpur et al., 2012). The find-
ings on the influence of age and HIV on brain and cognition
remain equivocal. This may partly result from heterogeneity across
the investigated patient groups in terms of the medication regimen,
lifetime substance abuse, HIV or age comorbidities (e.g., cardio-
vascular, renal, hepatic and/or pulmonary disease, cancer, physical
frailty), varied education levels and medical condition (only HIV
vs. AIDS/prior clinical AIDS, different CD4 load or viremia). All
these factors may influence aging in HIV-infected individuals
(Holt et al., 2012); therefore, further investigation is required to
derive a clear understanding of how HIV and age influence brain
and cognition in aviremic subjects without other age or HIV-
related comorbidities.
Accordingly, there might be a need to reinvestigate brain struc-
tures and cognitive domains that may be affected by HIV in highly
functioning aviremic subjects who are otherwise healthy. Espe-
cially that new advanced methods of complex data have been
recently developed. To date, only several studies have sought to
identify patterns of brain abnormalities in subjects with HIV by
employing multivariate analysis methods, such as support vector
3
machines (SVMs; Cao, Kong, Kettering, Yu, & Ragin, 2015;
Keltner et al., 2014). An SVM allows statistical inferences to be
made at an individual level based on regularities detected in
high-dimensional data (Cao et al., 2014). As an example, the use
of multivariate data analysis has recently demonstrated the poten-
tial of using structural MRI data for identification of HIV-positive
patients at different periods of disease development (Cao et al.,
2015). Furthermore, Cysique, Murray, Dunbar, Jeyakumar, and
Brew (2010) effectively utilized SVMs to identify HIV-positive
subjects with high risk of HIV-associated neurocognitive disorder
(HAND) based on a noncognitive set of predictors. According to
the authors, an algorithm used during routine clinical visits might
help clinicians quickly identify patients who might need more
complex neuropsychological assessment.
The aim of the present study was twofold. We examined highly
functioning subjects with HIV, representing a wide range of age
groups, who were otherwise healthy and therefore may present
different patterns of structural and cognitive abnormalities than
populations studied previously. Therefore, we sought to (a) exam-
ine the independent and/or combined effect of HIV status and age
on cognition and the brain (volumetric and morphometric mea-
surements) in subjects with HIV on effective cART; and (b)
reinvestigate brain structures and cognitive domains that may be
affected by HIV (using SVM). To provide most comprehensive
evidence, we applied multiple approaches to data analysis: explor-
atory (voxel-based morphometry [VBM]), hypothesis-driven
(SVM) and data-driven (regression analysis based on SVM re-
sults). We applied the machine learning technique of SVMs based
on brain morphometry and cognitive measures to identify features
that were most discriminative between seropositive and seroneg-
ative groups.
In accordance with previous studies we hypothesized that:
• HIV-positive participants would perform worse on neuro-
psychological testing, especially in the domains of mem-
ory, attention, and psychomotor speed.
• HIV and age would be associated with subcortical and
cortical GM (mainly in basal ganglia, frontal, temporal
and parietal lobes, ventricles) volume changes.
• In subjects on stable therapy, HIV and age would have
additive effects on brain structures and cognitive func-
tions.
• The optimal feature set revealed by SVM would include
cognitive scores as well as subcortical and cortical measures.
Method
Study Design and Participants
The study was approved by the Ethics Committee of the Uni-
versity of Warsaw (Poland). Written informed consent was ob-
tained from each participant. The presented study is part of a larger
research project—Harmonia-3. A total of 115 volunteers took part
in this part of the research, during the period from 2014 to 2016.
All volunteers were Polish males aged between 24- and 75-years-
old (mean age 42.4 ⫾ 12.1 years). For Harmonia-3, HIV-infected
participants were recruited from the patients of the Central Hos-
pital for Infectious Diseases in Warsaw. They were infected
through sexual transmission (men who have sex with men [MSM])
 4 PLUTA ET AL.
at least 1 year prior to the study and were receiving antiretroviral
treatment as well as stabilized on medication at the time of par-
ticipation in the study for at least 6 months. Highly age and
education comparable control subjects were recruited from local
organizations for homosexual men via advertisements and an-
nouncements on social media. The exclusion criteria were as
follows: education below high school graduation; developmental
learning disorders; current psychosis, anxiety, or depressive symp-
toms; untreated hypertension; history of head trauma or brain
injury, a period of unconsciousness ⬎30 min; cancer, diabetes,
liver or renal dysfunction/failure; chronic or progressive neurolog-
ical disorders such as epilepsy, stroke, Alzheimer’s or Parkinson’s
disease; laryngeal disorders; illicit substance use within the last 5
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years; alcohol consumption above three units per day; and in the
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case of controls, HIV-seropositive blood test result (ELISA and
Western blot). Subjects received small financial compensation for
their participation.
In total, we acquired data from 53 HIV-seropositive patients
(mean age 41.3 ⫾ 12.0 years; mean years of education 16.2 ⫾ 2.7)
and 62 control group participants (mean age 43.3 ⫾ 12.1 years;
mean years of education 16.6 ⫾ 2.9). There were no significant
differences between the groups for age (t ⫽ 0.89, ns) nor for years
of education (t ⫽ 0.75, ns). Most of the subjects in each group
were employed: a total of 41 of HIV-positive patients (79%) and
a total of 54 healthy participants (87%). The rest of them were
students, retired/living on pension, or unemployed.
Neuropsychological and Clinical Evaluations
Certified neuropsychologists administered a comprehensive bat-
tery of neurocognitive tests (adapted and standardized for the
Polish population). The Mini Mental State Examination (Stanczak,
2010) was used to screen for cognitive impairment and subjects
who scored below 27 points were not included in the study. The
following domains were evaluated: spatial (block-tapping task)
and verbal (digit span of WAIS-PL(R)) short-term memory
(STM); verbal memory and learning (California Verbal Learning
Test [CVLT]); psychomotor speed (Color Trails Test—Trial 1,
Grooved Pegboard Test); executive functions (Ruff Figural Flu-
ency Test, WI Card Sorting Test, Color Trails Test—Trial 2);
verbal fluency (participants were asked to produce words starting
with a particular letter: K, P, and M, and then in a given category:
animals, masculine names, and plants); and long-term semantic
memory (Vocabulary of WAIS-PL(R)). Subjects also completed
the Centre for Epidemiological Studies Depression Scale (CES-D),
a 20-item self-reported measure of depression, with a maximum
score of 60 and a cut-off of 16 and above indicating significant
Table 1
Clinical Characteristics of Participants With HIV (N ⫽ 53)
Clinical and treatment-related variables
Years postinfection
Years on cART
CD4 nadir (cells/mm3)
CD4 count at time of assessment (cells/mm3)
Highest viral load (cells/mm3)
Viral load at time of assessment (cells/mm3)
CPE (n ⫽ 47) Data not provided (n ⫽ 6)
depressive symptoms (Schein & Koenig, 1997); and the Patient
Assessment of Own Functioning Inventory (PAOFI; Chelune,
Heaton, & Lehman, 1986), a questionnaire exploring the frequency
with which participants experience sensorimotor and cognitive
difficulties in everyday life.
The following variables were assessed in HIV-positive subjects:
type of seroconversion (MSM, 51 patients; heterosexual, two
patients), month and year of HIV detection, duration of cART
treatment, CD4 nadir, CD4 count at time of assessment, highest
viral load, viral load at the time of assessment, and the CNS
Penetration-Effectiveness (CPE) Index. The CPE index quantifies
the effectiveness of the implemented antiretroviral medication
regimen (Letendre et al., 2008). We calculated the CPE index
according to the previously published CPE ranking scale (Letendre
et al., 2008). The outcome score is a sum of ranks assigned to each
individual medication in the prescribed regimen.
A total of eight seropositive subjects and none of the control
group participants had an HIV/HCV coinfection. All 53 partici-
pants were aviremic (viral load was categorized as not de-
tected, ⬍50 copies/mL). Clinical characteristics of the study par-
ticipants are presented in Table 1.
HAND was diagnosed by published criteria (Antinori et al.,
2007). The majority of the patients (83%) did not exhibit HAND
(see Table 2).
As all HIV-positive participants in our study were aviremic, only a
few were diagnosed with HAND and most of them had an employ-
ment. Therefore, we described the group as high-functioning.
MRI Data Acquisition
The structural magnetic resonance images (MRIs) of the subjects
were acquired using a 3T Siemens TIM TRIO VB17 whole-body
magnetic resonance scanner with a 12-channel head matrix coil.
T1-weighted images were acquired with the following acquisition
parameters: TE ⫽ 2.21 ms, TR ⫽ 1,900 ms, TI ⫽ 900 ms, flip
angle ⫽ 9°, field of view ⫽ 260 mm ⫻ 288 mm, slice thickness ⫽
0.9 mm, number of slices ⫽ 208, image matrix ⫽ 290 ⫻ 320, which
gives an isotropic voxel size of 0.9 mm ⫻ 0.9 mm ⫻ 0.9 mm, pixel
bandwidth ⫽ 200 Hz/pix, iPAT ⫽ 2, and TA ⫽ 5 min.
Data Analysis
The statistical plan followed the aims of the study. First, we
investigated the neuropsychological data in order to investigate the
profile of possible cognitive abnormalities in HIV⫹ participants
(PCA and ANCOVA). Second, with the use of VBM we investi-
gated the effects of age, HIV, and the interaction effects on GM
M (SD) Range Median
6.1432 (5.39) .5–21 5
5.07 (5.03) .5–19 3
275.57 (126.57) 5–626 285
597.81 (172.89) 246–938 635
115,094 (128,133) 40–536,439 64,300
37.55 (9.58) 0–46 40
8.93 (2.29) 3–13 9
 BRAIN AND COGNITIVE CHANGES IN SUBJECTS WITH HIV 5

Table 2 only on the results of the control group. The analysis revealed that
HAND Status of HIV-Positive Participants (N ⫽ 53) five factors should be extracted (Table 3; Keyser-Meyer-Olkin of
sampling adequacy: (.728); Bartlett’s test of sphericity ⫽ (859.1),
HAND status N (%) df ⫽ 171, p ⬍ .001). The factor structure of the PCA of neuro-
No HAND 44 (83) psychological scores is presented in Table 3.
Asymptomatic HAND 5 (9) Factor 1 included tests measuring different dimensions of attention
Mild HAND 2 (4) and working memory: CTT, visual memory span, and digit span
Moderate HAND 1 (2) (hereafter, complex attention). The variables that loaded Factor 2 were
Data not provided 1 (2)
the results obtained in the CVLT; therefore, we interpreted this factor
as representing verbal learning and memory (hereafter, learning and
memory). The subtests of WCST and RUFF were loaded on Factor 3.
volume (regression analysis in VBM). Then, in order to elucidate We interpreted this factor as referring to executive functions (hereafter
the features that most accurately discriminate seropositive subjects executive functioning). Factor 4 included measurements sensitive to
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from healthy controls, we conducted an SVM analysis using as psychomotor speed (Grooved Pegboard and CTT; hereafter, psy-
This document is copyrighted by the American Psychological Association or one of its allied publishers.

inputs cognitive scores and brain structural measures generated by
automated segmentation implemented in FreeSurfer. Finally, a
regression analysis was performed on SVM outputs to further
investigate the effects of HIV, age and their possible interactions
on cognitive and structural variables elucidated by SVM analysis.
Analysis of Neuropsychological Data
SPSS for Windows V.23 I V.24 was used for data entry and
analysis. With respect to neuropsychological measurements, for
each participant, z-scores were calculated for each measure based
on the mean and standard deviation (SD) of the healthy controls
(HC) group. Then, a principal component analysis (PCA) was used
to identify the components out of the possibly correlated neuro-
psychological variables. The analysis was performed to reduce the
number of variables and to identify cognitive domains to be used
for further analysis (as SVM inputs and to test for HIV and age
interaction). The PCA with a Varimax rotation for components
with eigenvalues ⬎1.0 and a Kaiser-Meyer-Olkin test of sampling
adequacy was applied. Bartlett’s test of sphericity was done to
verify that the data set was suitable for PCA. To identify compo-
nents relevant for the healthy group, we performed the analysis
chomotor speed). Factor 5 included measurements sensitive to verbal
and nonverbal fluency (RUFF—total unique designs, verbal fluency,
WAIS-Vocabulary; hereafter, cognitive fluency). The five-factor
model explained 30% of the variance. The generated factor scores
were used for further analysis. Between-groups differences were
assessed by an analysis of covariance (ANCOVA). Covariates were
age and education (years of schooling).
VBM Analysis of GM Volume
Structural imaging analyses were carried out following the
standard analysis pipeline for whole-brain VBM. Initially, images
were visually inspected for artifacts and/or structural abnormalities
unrelated to HIV (e.g., tumors). Subsequently, group-related dif-
ferences were analyzed using VBM, implemented in SPM12
v.6906 (Wellcome Trust Centre for Neuroimaging) software run-
ning under MATLAB, 2016 (MathWorks, Natick, MA). During
VBM, preprocessed images of each patient were spatially normal-
ized to the Montreal Neurological Institute space. T1-weighted
images were segmented into GM, white matter, cerebrospinal fluid
(CSF), bone, fat, and air. GM images were modulated and
smoothed with a Gaussian kernel of 6 mm.

Table 3
Factor Structure of Principal Component Analysis of Neuropsychological Scores

Factor loadings
Factor Test 1 2 3 4 5

Complex attention CTT-I .758

Visual Memory Span—backward .728
Visual Memory Span—forward .722
CTT-II .638 .457
WAIS—digit span backward .619
WAIS—digit span forward .580
Verbal learning and memory CVLT—short delay free recall .874
CVLT—long delay free recall .848
CVLT—List A Trials 1–5 .816
CVLT—semantic cluster .689
Executive functioning WCST—total perseverative errors .894
WCST—categories completed .848
WCST—nonperseverative errors .744
RFFT—total perseverations .609
Psychomotor speed Grooved Pegboard Test—dominant hand .838
Grooved Pegboard Test—nondominant hand .812
Cognitive fluency Verbal Fluency—total score .742
WCST—vocabulary .617
RFFT—total unique designs .431
 6 PLUTA ET AL.
To analyze the effects of age, HIV, and the interaction effects of
age and HIV on GM volume, we performed voxel-based regres-
sions using the SPM12 framework. We created a design matrix
which included two pairs of regressors (i.e., age and intercept), one
for each group (HC and HIV), in order to linearly regress age in
two groups independently. Additionally, the intracranial cavity
volume with ventricles and years of education were added as
covariates of no-interest for each group. Using this design allowed
us to test for a linear relationship between age and HIV status and
GM volume all over the brain as well as the potential difference in
slope for the two groups. The significance level was set at p ⬍ .05,
and voxel-based analyses were corrected for multiple comparisons
by the family wise error rate (FWE).
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FreeSurfer Analysis
FreeSurfer 5.3 (http://surfer.nmr.mgh.harvard.edu/; Fischl, 2012) was
used in order to derive morphometric measurements of individual
brain regions which were further used as inputs in SVM analysis. The
analysis was carried out with a standard (a) surface-based stream:
volume registration with the MNI305 (Collins, Neelin, Peters, &
Evans, 1994), intensity normalization, skull stripping, segmentation,
tessellation of the gray matter–white matter boundary, automated
topology correction, and surface deformation following intensity gra-
dients; and (b) a volume-based stream: volume registration with the
MNI305, initial volumetric labeling, intensity normalization, a high
dimensional nonlinear volumetric alignment to the MNI305, after the
preprocessing the volumes were labeled again. Image quality was
Figure 1. ROIs chosen as SVM inputs (including white matter and total gray matter volumes which are not
present in the picture). See the online article for the color version of this figure.
assessed by visual inspection to assure the results met quality assur-
ance standards for both cortical and subcortical segmentation. To
adjust for differences in brain volume, FreeSurfer volumetric mea-
surements for individual brain regions were divided by the intracranial
cavity volume with ventricles (the same metric as in the VBM
analysis).
As we investigated a very unique subpopulation of HIV patients, as
inputs for further SVM analysis we have chosen brain structures both
consistently and less frequently reported to be affected by HIV infec-
tion. The regions of interest (ROIs) included the following regions:
thalamus, caudate, putamen, globus pallidus, third ventricle, fourth
ventricle, lateral ventricles, hippocampus, amygdala, nucleus accum-
bens, anterior and posterior cingulate, inferior orbitofrontal gyri, in-
sula, supramarginal gyri, rectus gyri, subcollosal gyri, inferior tem-
poral gyri, temporal pole, intraparietal sulcus, as well as total cortical
gray matter volume and white matter thickness. All ROIs are pre-
sented in Figure 1.
Support Vector Machine Analysis
A linear SVM was used to find brain regions and cognitive
domains that best discriminated between HIV-positive subjects
and healthy controls. Inputs into the SVM were five neuropsycho-
logical factors determined by PCA and morphometric measures
derived from the FreeSurfer analysis, as presented in Figure 1. In
case of both neuropsychological factors and structural measure-
ments, we applied regression-based algorithms to adjust scores for
education. The LIBSVM-v.3.21 toolbox for MATLAB was used to
 BRAIN AND COGNITIVE CHANGES IN SUBJECTS WITH HIV 7

perform the classification. The classification procedure consisted
of two phases: training and testing. First, the algorithm found a
hyperplane that separated the examples in the input space based on
their class labels (HIV-positive/HC). The performance of the clas-
sifier was assessed using a leave-one-out cross-validation proce-
dure (Mourão-Miranda, Bokde, Born, Hampel, & Stetter, 2005).
The classifier was trained with all participants, except for one pair,
and subsequent testing was performed on the group membership
assigned to the excluded subjects. Then, to identify features with
the highest discriminative power, SVM recursive feature elimina-
tion was applied (De Martino et al., 2008). It is a backward-
elimination feature selection technique that iteratively ranked the
features and removed the least effective ones.
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
HIV-infected subjects showed smaller GM volumes in bilateral
caudate, insula, and inferior orbitofrontal cortex as well as the right
parahippocampus. Statistical results were thresholded at p ⬍ .05,
FWE corrected.
There was no significant effect of interaction between HIV and
age on GM volume when FWE correction was applied. However,
when a more lenient threshold (false discovery rate [FDRc]) was
used, an interaction effect was observed in four clusters: medial
cingulate gyrus, lateral globus pallidus, left putamen, and left
superior orbitofrontal cortex. As the results did not survive the
FWE threshold, we present them in the online supplementary
materials (Figure S1 and Table S2, respectively).

SVM Results
This document is copyrighted by the American Psychological Association or one of its allied publishers.

Regression Analysis on SVM Outputs

SVM provided a ranking of features associated with the most
Finally, neuropsychological scores (see above) and ROIs indi- discriminating structural and cognitive alterations related to HIV
cated by SVM to be most discriminative between groups were status. The highest classification accuracy was obtained using the
further analyzed via a series of linear regression models to estimate following measures: complex attention, psychomotor speed, total
the independent effects of HIV, age, and interaction effects of HIV cortical GM volume, white matter volume, third ventricle volume,
and age on selected variables. Age and group (HIV, control) were fourth ventricle volume, left amygdala volume, right lateral ven-
entered to the model in the first step, followed by Age ⫻ Group tricle volume, right caudate volume, and right putamen volume.
interaction. The interaction between age and group was of partic- The accuracy of SVM classification was 79.14%. According to
ular interest. In order to correct for multiple comparisons, we other studies applying SVM, classification accuracy is considered
applied the Bonferroni correction (0.05/n; n ⫽ 9). high when it is in the range of 70%–90% (Bi, Wang, Shu, Sun, &
Xu, 2018).
Results The structures showing the highest classification accuracy are
presented in Figure 2.
Performance on Neurocognitive Tasks
Table 4 shows the results of ANCOVA on five neurocognitive Results of Regression Analysis on SVM Outputs
domains (PCA factors) in the HIV and control group. Finally, multiple regression analyses estimated the contribution
The ANCOVA, with age and education covaried, showed that of HIV, age, and their interaction on variables indicated by SVM:
the HIV-positive subjects performed significantly worse than HIV- two cognitive domains and seven ROIs. No significant HIV by age
negative participants on complex attention and cognitive fluency. interaction effect was revealed for any neuropsychological scores
No significant differences were found in learning and memory, or ROIs. The overall regression models were significant for both
executive functioning, and psychomotor speed. cognitive variables and five ROIs. HIV and age were separately
In addition, the scores (unadjusted) obtained by each group in all significant predictors of the complex attention score. HIV was a
neuropsychological measurements are presented in Table S1 in the significant predictor of the fourth ventricle volume (but did not
online supplementary materials. survive Bonferroni correction, p ⫽ .028). Age was a significant
predictor of measures of total cortical GM, third ventricle, right
VBM Analysis of GM Volume lateral ventricle, and putamen (see Table 6 and Figure 3).
As shown in Figure 2 and Table 5, the volumetric between-
groups differences were observed in nine clusters. Specifically, Discussion
In the study we investigated the effect of HIV status, age, and
their possible interaction effect on MRI measures and cognitive
Table 4 domains in aviremic, high-functioning subjects with HIV. Taking
Analysis of Covariance of Cognitive Factors With Age into consideration very strict inclusion criteria regarding the med-
and Education ical and the socioeconomic status of the participants, the selected
subpopulation of seropositive patients is unique and therefore yet
HIV⫺ HIV⫹
ANCOVA not well examined. Thus, we applied exploratory (ANCOVAs,
Neuropsychological factors Mean SD Mean SD p-value VBM) and data-driven analysis (SVM and regression analysis on
Factor 1 complex attention .03 .49 ⫺.24 .44 ⬍.001
SVM outputs) to reinvestigate the pattern of abnormalities in brain
Factor 2 learning and memory .07 .67 ⫺.04 .72 ns structures and cognitive functions that are associated with HIV in
Factor 3 executing functioningⴱ ⫺.06 .59 ⫺.06 .56 ns high-functioning aviremic, seropositive individuals.
Factor 4 cognitive fluency .03 .41 ⫺.20 .51 ⬍.01 The key conclusions of our study are the following. Subjects
Factor 5 psychomotor speedⴱ ⫺.01 .56 .14 .57 ns with HIV demonstrated worse performance (in comparison with
ⴱ
The higher the score, the worse the performance. healthy controls) only in complex attention and cognitive fluency.
 8 PLUTA ET AL.
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
This document is copyrighted by the American Psychological Association or one of its allied publishers.

Figure 2. Brain regions showing significant differences in GM volume between HIV⫹ patients and healthy
controls (p ⬍ .05, FWE corrected, number of voxels ⬎25). See the online article for the color version of this
figure.

Exploratory analysis conducted with VBM revealed regions en-
compassing both cortical (orbitofrontal cortex, insula) and subcor-
tical structures (caudate, parahippocampus) in high-functioning
HIV-infected patients receiving cART as possibly affected by
HIV. Finally, SVM has partly replicated those findings. It has also
elucidated additional features that distinguish seropositive subjects
from HC. Consistent with the above analyses, scores in complex
attention and the volume of caudate were among variables show-
ing the highest discriminative accuracy. SVM indicated also psy-
chomotor speed; white matter; third, fourth, and lateral ventricles;
amygdala; and putamen. Taken together, those variables constitute
the optimal set of both structural and cognitive features which
seem to be most likely affected by HIV in aviremic subjects who
are otherwise healthy. Regression analysis has further strengthened
those results by showing variables predicted by HIV (complex
attention, fourth ventricle volume [the second variable did not
survive Bonferroni correction]) and age (complex attention, corti-
cal GM, third ventricle volume, right lateral ventricle volume, and
putamen). It has also corroborated VBM results showing no effect
of the HIV ⫻ Age interaction neither in selected structural ROIs
nor in cognitive scores. Below we discuss our findings in detail.
First, the fact that our results demonstrated mild cognitive
impairment in seropositive subjects on effective cART is consis-
tent with the current debate on HAND (Alfahad & Nath, 2013;
Tedaldi, Minniti, & Fischer, 2015). Although in the pre- or early
cART era researchers highlighted a “prototypical pattern” of neu-
ropsychological impairments in HIV patients encompassing cog-
nitive domains such as attention, memory, executive functions,
motor skills, learning, and processing speed (Dawes et al., 2008),
recent studies are contradictory in that matter (Underwood et al.,
2017) Heterogeneity in the pattern of cognitive impairments re-
ported by other authors may result from various comorbid condi-
tions (Nightingale et al., 2014), which our population was free
from. In the current study, the HIV-positive individuals showed

Table 5
Brain Regions Showing Significant Differences in the GM Volume Between HIV Patients and
Healthy Controls (p ⬍ .05, FWE Corrected)

Coordinates
Cluster size
x y z Region T-stats (number of voxels)

⫺6 8 ⫺8 Caudate_L 6.19 61
6 8 ⫺6 Caudate_R 5.92 100
23 ⫺6 ⫺20 Parahippocampus_R 5.81 142
⫺36 11 ⫺8 Insula_L 5.76 90
47 29 ⫺5 Frontal_Inf_Orb_R 5.71 43
44 18 3 Frontal_Inf_Tri_R 5.65 39
⫺33 20 5 Insula_L 5.64 38
26 15 ⫺20 Insula_R 5.37 72
⫺20 15 ⫺24 Frontal_Inf_Orb_L 5.36 27
 BRAIN AND COGNITIVE CHANGES IN SUBJECTS WITH HIV 9

Table 6
Multiple Regression: Effects of HIV and Aging on Selected Cognitive Domains and Regions of Interest

HIV Age F; p HIV and Age interaction

Variable B SE B ß t p B SE B ß t p F(2.11) ns

Complex attention ⫺.59 .16 ⫺.29 ⫺3.5 ⬍.001 ⫺.04 .01 ⫺.43 ⫺5.20 ⬍.001 18.75; ⬍.001 ns
Psychomotor speed ns ⫺.04 .01 ⫺.48 ⫺5.89 ⬍.001 18.78; ⬍.001 ns
Cortical GM volume ns ⫺.03 .01 ⫺.41 ⫺4.81 ⬍.000 11.90; ⬍.001 ns
Third ventricle volume ns .05 .01 .54 6.66 ⬍.000 22.45; ⬍.001 ns
Fourth ventricle volume .54 .24 .20 2.29 .028ⴱ ns 3.39; .039 ns
Right lateral ventricle
volume ns .047 .007 .518 6.374 ⬍.000 20.78; ⬍.001 ns
Right Putamen volume ns ⫺.04 .01 ⫺.46 ⫺5.41 ⬍.000 14.75; ⬍.001 ns
Note. B ⫽ unstandardized Beta coefficient; SE B ⫽ standard error of a B coefficient; ß ⫽ standardized Beta.
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.

ⴱ
Did not survive Bonferroni correction.
This document is copyrighted by the American Psychological Association or one of its allied publishers.

slightly worse performance in tasks of complex attention and
cognitive fluency, as compared with healthy controls. While at-
tention deficits are still widely reported in seropositive subjects
(e.g., Underwood et al., 2017), fluency impairments were more
typical in the pre- or early cART era (Heaton et al., 2011) and
verbal fluency impairments are especially common in HAND
(Woods et al., 2004). In our study worse performance was mainly
observed in tests of fluency which were sensitive to time con-
strains (e.g., the verbal fluency and Ruff subtests). Therefore, it is
possible that the increased cognitive load due to time constraints
introduced by the task resulted in worse scores. It should be
stressed that the very mild cognitive impairment in HIV-positive
subjects demonstrated in the current study did not affect the daily
activities of subjects, as there were no significant group differences
detected in the PAOFI questionnaire. In comparison with other
studies, here subjects with HIV had a higher socioeconomic status
(at least secondary education, the majority of them were em-
ployed) which might have mobilized positive neuroplasticity and
the cognitive reserve (Brayne et al., 2010; Tedaldi et al., 2015).
Very strict inclusion criteria enabled us to disentangle the role of
HIV from other factors influencing cognition. Therefore, we sug-
gest that a slight cognitive impediment is likely to result from
neurotoxicity of HIV (Gannon, Khan, & Kolson, 2011; Saylor et
al., 2016). However, we cannot rule out an alternative hypothesis
related to the possible neurotoxicity of cART (Tovar-y-Romo et
al., 2012). Deciding between the two would, however, require
investigating HIV-infected subjects who are not using any treat-
ment. This would be hard (if not impossible) in Poland, due to the
advanced medical services available for people with HIV or AIDS.
Antiretroviral drugs are free of charge and they are universally
available in all major Polish cities.
The pattern of structural brain abnormalities elucidated in our
study is partly in line with other work (Kuper et al., 2011). Apart
from some differences in locations, our results support the recent
study of Underwood et al. (2017), who showed widespread struc-
tural abnormalities in successfully treated HIV-infected subjects.
Using two different analysis, VBM and SVM, we found regions
which were reported to be affected by HIV in previous studies

Figure 3. Brain structures showing the best classification accuracy in SVM analysis. See the online article for
the color version of this figure.
 10 PLUTA ET AL.
(caudate, parahippocampal gyrus, putamen, third ventricle, fourth
ventricle) as well as some less consistently reported (orbitofrontal
cortex, insula, amygdala). It is well known that those regions are
implicated in extensive cognitive function which might be affected
by HIV. All—the caudate, putamen, parahippocampal cortex, or-
bitofrontal cortex and insula (although functionally heterotopic)—
are implicated in general attention, executive functions, learning,
and memory (see Aminoff, Kveraga, & Bar, 2013; Menon, Uddin,
2010). Ventricular enlargements have also been reported to be
associated with general cognitive dysfunction (Cavedo, Galluzzi,
Pievani, Boccardi, & Frisoni, 2012). Therefore, smaller volume
and thickness in above mentioned regions as well as ventricular
enlargements may contribute to the impaired neuropsychological
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
profile observed in seropositive subjects.
This document is copyrighted by the American Psychological Association or one of its allied publishers.
The applied classification approach enabled us to indicate patterns
of cognitive and structural alternations specific to HIV infection in
high-functioning subjects on stable treatment. The abovementioned
cognitive domains and brain structures have been indicated separately
to be significantly affected by HIV by many researchers (e.g., Tow-
good et al., 2013). Our study shows that although, if investigated
separately (in regression analysis using inputs produced by SVM), not
all tested regions show to be affected by HIV, their combination
proves to be the most discriminative for HIV.
Finally, our results are in line with studies showing that both HIV
and aging independently affect structural measurements (Becker et al.,
2012; Kuhn et al., 2017; Underwood et al., 2017) and neuropsycho-
logical performance (Valcour et al., 2011).
The VBM analysis revealed an effect of HIV and age interaction
on structural brain measured when lenient thresholds were applied.
Therefore, it should be interpreted with caution. However, as the
observed regions (putamen, lateral globus pallidus, medial cingu-
late gyrus, and frontal superior orbitofrontal cortex) corroborate
other findings on aging (Nunnemann et al., 2009; Pardo et al.,
2007) we claim that our results might show a trend of increased
brain aging in HIV infection. It is possible that we examined a
population that was too young (mean age ⫽ 42.4 years) to verify
exacerbated age-related neurodegeneration in well-educated HIV-
positive subjects using successful treatment. Longitudinal studies
are needed to further investigate HIV by age interactions in high
functioning seropositive subjects on effective cART.
Several limitations to this work need to be considered. First, the
HIV-positive participants were all well-educated men with the
infection transmitted sexually and mostly without comorbidities
typical for an HIV infection. The restrictive inclusion criteria may
have significantly diminished the representativeness of the sample.
The inclusion criteria have been chosen according to the most
recent HIV/AIDS epidemiological data in Poland, where every
year approximately 85% of the newly infected are males, among
whom above 60% are MSM (Niedźwiedzka-Stadnik, Pielacha, &
Rosińska, 2016). Taken together, our sample well represents an
important part of the HIV-positive population in Poland. Second,
although the range of the subjects’ age was wide (24 –75), only 14
participants were above 60 (six in the HIV-positive group). The
median age was 40 in the HIV-positive group and 43 in healthy
controls, which means that the samples were relatively young.
Future research on the effect of age in the HIV-positive population
should include older participants. Third, it has been suggested that
particular cART therapies may be neurotoxic and, thus, affect not
only cognition but also brain aging (Ances, Roc, Korczykowski,
Wolf, & Kolson, 2008; Robertson et al., 2010; Schweinsburg et al.,
2005). In the present study, such adverse effects of cART could
not have been analyzed because all HIV-positive participants were
receiving antiretroviral treatment. Therapy using cART is strongly
recommended by the World Health Organization (WHO, 2015),
European AIDS Clinical Society (EACS, 2016), and the Polish
AIDS Society (Horban et al., 2016) in all adults with HIV. Thus,
the question of effects of cART on brain aging remains open.
Future analyses should address this issue.
Overall, patients with HIV on effective cART demonstrate
smaller volumetric measures relative to seronegative individuals.
Despite it, a comprehensive battery of neurocognitive tests to
capture even discrete cognitive deficits demonstrated impediments
only in complex attention and cognitive fluency, whereas other
skills remained (relatively) unaffected in HIV-infected patients.
Additionally, we showed that SVMs can be a powerful tool for
HIV classification and of potential use in the clinic.
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Received September 15, 2017
Revision received August 21, 2018
Accepted August 21, 2018 䡲