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Accelerated and Premature Aging Characterizing Regional Cortical Volume Loss in Human Immunodeficiency Virus Infection: Contributions From Alcohol, Substance Use, and Hepatitis C Coinfection
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from Jules: consistent viral suppression less than 50 c/ml and normalized CD4 count may provide some benefit in holding off premature & accelerated brain aging. The CDC reports around 50% in the USA with diagnosed HIV-infection have detectable viral load, we can guess these individuals are at greater risk for brain affects, cognitive impairment, dementia etc. Another key reason why we need to pay more attention to the aging & HIV problem 2 fold: services for older aging HIV+ who need them & their clinics & clinicians and better funded research to broaden the research agenda and to include more patient focused research.
"Critically, significant HIV-age interactions in lobar and selective frontal and posterior parietal volumes endured in the subset of HIV-infected individuals free of substance dependence or HCV infection compared with control subjects, thereby supporting the premise that HIV infection itself confers a heightened risk of accelerated aging of the brain, notably in the frontal lobes.....Alcohol and drug dependence comorbidities and HCV coinfection exacerbated HIV-related volume deficits. ....Acceleration of volume deficits beyond normal aging was detectable in the superior frontal cortex in all three diagnostic groups. Brain regions showing accelerated aging unique to the HIV-only group were the middle and medial frontal and postcentral parietal cortices. Unique to the HIV + Alc group were deficits in midposterior cingulate and pallidal volumes. These cortical and subcortical regions are commonly affected in age-related dementing disorders, including mild cognitive impairment (52,53), Alzheimer's disease (54,55), and Parkinson's disease (56). Thus, we speculate that accelerated degeneration of this constellation of brain structures in currently non demented people living with HIV/ AIDS puts them at heightened risk for developing functional impairments that may mimic dementing disorders and ultimately interfere with activities of daily living. This is not to suggest that HIV-infected (55) individuals are at risk for developing Alzheimer's disease or other dementing diseases per se, but rather that the overlap of brain structures affected could potentially underlie selective functional declines characteristic of classical dementias (57).
- AUTHORS Conclusions -
The accelerated versus premature aging decline distinction required controlled longitudinal examination. The substantial proportion of the HIV-infected sample with a relatively late infection onset is at particular risk for either accelerated aging or premature aging brain volume deficits with compounded risk for frontal cortical involvement with alcohol-dependence comorbidity.
We speculate that treatment with antiretroviral medication may have mitigated acceleration of certain brain volume deficits; alternatively, incomplete treatment or viral suppression together with coinfection or alcohol or drug comorbidities may have contributed to brain volume deficits. Indirect support of this speculation derives from the correlation between higher VACS indices and smaller parietal volumes that may potentially reflect neuroinflammatory processes notable in HIV + HCV coinfection (64) or declining hepatic functioning in alcohol-dependent individuals.
In summary, the constellations of regional brain volume deficits detected in men and women living with HIV infection
were associated with markers of brain injury identified with either premature or accelerated aging. Also identified were contributing comorbidities to regional brain volume decline that may be arrested with treatment of the comorbid conditions. Similarly, functional ramifications for physiological fragility and cognitive and motor decline may be mitigated or reversed with tailored ART, enhancement of healthy living practices, and reduction in consumption of harmful amounts of alcohol and drugs."
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Accelerated and Premature Aging Characterizing Regional Cortical Volume Loss in Human Immunodeficiency Virus Infection: Contributions From Alcohol, Substance Use, and Hepatitis C Coinfection
July 2018 - Adolf Pfefferbaum, Natalie M. Zahr, Stephanie A. Sassoon, Dongjin Kwon, Kilian M. Pohl, and
Edith V. Sullivan https://doi.org/10.1016/j.bpsc.2018.06.006
Abstract
Background
Life expectancy of successfully treated human immunodeficiency virus (HIV)-infected individuals is approaching normal longevity (from Jules: no its NOT, its on average 8-10 years less & will worsen & mortality will worsen too). The growing HIV population ≥50 years of age is now at risk of developing HIV-associated neurocognitive disorder, acquiring coinfection with the hepatitis C virus (HCV), and engaging in hazardous drinking or drug consumption that can adversely affect trajectories of the healthy aging of brain structures.
Methods
This cross-sectional/longitudinal study quantified regional brain volumes from 1101 magnetic resonance imaging scans collected over 14 years in 549 participants (25 to 75 years of age): 68 HIV-infected individuals without alcohol dependence, 60 HIV-infected individuals with alcohol dependence, 222 alcohol-dependent individuals, and 199 control subjects.
We tested 1) whether localized brain regions in HIV-infected individuals exhibited accelerated aging, or alternatively, nonaccelerated premature aging deficits; and 2) the extent to which alcohol or substance dependence or HCV coinfection altered brain aging trajectories.
Results
The HIV-infected cohort exhibited steeper declining volume trajectories than control subjects, consistently in the frontal cortex. Nonaccelerated volume deficits occurred in the temporal, parietal, insular, and cingulate regions of all three diagnostic groups. Alcohol and drug dependence comorbidities and HCV coinfection exacerbated HIV-related volume deficits. Accelerated age interactions in frontal and posterior parietal volumes endured in HIV-infected individuals free of alcohol or substance dependence and HCV infection comorbidities. Functionally, poorer HIV-associated neurocognitive disorder scores and Veterans Aging Cohort Study indices correlated with smaller regional brain volumes in the HIV-infected individuals without alcohol dependence and alcohol-dependent groups.
Conclusions
HIV infection itself may confer a heightened risk of accelerated brain aging, potentially exacerbated by HCV coinfection and substance dependency. Confirmation would require a prospective study with a preinfection baseline.
Before antiretroviral therapy (ART) was introduced in the mid-1990s, individuals infected with human immunodeficiency virus (HIV), whether young or old, lived for only 10 to 12 years after diagnosis. Currently, life expectancy estimates of ART-treated individuals, even when infected with HIV as young adults, are 64 years of age for men and 62 years of age for women, and are approaching longevity of the HIV-negative U.S. population-77 years of age for men and 82 years of age for women. Despite the effectiveness of ART, HIV infection continues to have major public health and clinical ramifications. In the United States, nearly half of the 1.2 million people living with HIV are 50 years of age and older (1). As many as 40% of HIV-infected individuals 55 years of age and older had late-stage infection at the time of diagnoses (2), are at highest risk for premature cognitive decline, and are more likely to delay treatment initiation, thereby jeopardizing optimal outcomes 3, 4. With advancing age, commonly acquired HIV comorbidities that can curtail life quality or expectancy include misuse of alcohol or other substances (occurring in approximately 75%) (5) or dependence on alcohol or other substances (∼33%) (6) and coinfection with hepatitis C virus (HCV) (7) [in ∼25%) (8)].
In HIV infection, cross-sectional studies report greater brain gray matter than white matter volume deficits accompanying advanced symptom stage (9). Gray matter volume in the frontal, parietal 10, 11, 12, cingulate, and motor cortices; thalamus; and hippocampi 13, 14 is smaller relative to control subjects and has been associated with low CD4 cell count 15, 16, even in virally suppressed HIV. That HIV infection can disrupt central nervous system integrity raises the likelihood that substance use comorbidities 17, 18, 19, 20 and HCV coinfection 15, 21 may compound central nervous system effects, increasing vulnerability to accelerated aging (22).
Mild to moderate cognitive deficits in HIV remain a problem, especially with extended longevity 23, 24, 25, 26, despite the declining prevalence of HIV-associated dementia with combination ART (27). HIV-associated neurocognitive disorder (HAND) indices, assessed using comprehensive neuropsychological batteries (28), allow for grading of functional impairment 29, 30, from asymptomatic neurocognitive impairment to HIV-associated dementia 31, 32. Although the profile of impairment is heterogeneous 33, 34, neuropsychological assessments of treatment-stabilized HIV patients often report a compromise in domains of attention, psychomotor speed, memory, and executive control 35, 36, likely related to central nervous system compromise.
Identifying HIV-related factors promoting premature aging or accelerated normal aging trajectory of regional brain integrity requires longitudinal investigation using quantitative methods across a broad age span. The few available longitudinal magnetic resonance imaging (MRI) studies of HIV infection report either no evidence for age interactions in middle-aged to older virologically suppressed HIV groups in 2- to 2.5-year follow-up studies 37, 38, 39, 40, or only modest evidence for HIV-age interactions targeting white matter 10, 41, 42. One of the longest controlled studies found accelerated volume decline over an average of 3.4 years in HIV-infected men 60 years of age and older in total cortical gray matter volume and in the frontal, caudate, cerebellar, and brain stem regions (43). In general, the length of follow-up has been relatively short, the sample sizes have been small, the age range has been restricted, and common comorbidities have more often been excluded or "controlled for" rather than examined directly.
To address these shortcomings, the current longitudinal analysis quantified regional brain volumes from 1101 MRI scans collected in 549 participants included in one of four groups: 68 HIV-infected individuals (HIV only), 60 HIV-infected individuals with alcohol dependence (HIV + Alc), 222 alcohol-dependent individuals (Alc only), and 199 control subjects. At the final MRI, most HIV participants were 50 years of age or older (73.5% HIV group; 78.3% HIV + Alc group), thereby enhancing the opportunity to answer questions regarding aging with HIV. Accordingly, this study focused on three main areas. First, we tested whether localized brain regions in HIV-infected individuals exhibited accelerated aging, which would be revealed by group-by-age interactions, where brain tissue volume deficits in the diagnostic groups would show faster declining trajectories with aging than in control subjects; alternatively, volume differences would reflect premature aging deficits if they proceeded in parallel, rather than interacting with the aging trajectories of the control subjects (22). Second, we examined correlates of regional volume deficits, including age, sex, alcohol and substance dependence comorbidity, and HCV coinfection. Third, we explored relations between brain volumes and neuropsychological and physiological functions in the HIV-infected participants.
Methods and Materials
Participants
The participants were drawn from ongoing cross-sectional and longitudinal MRI brain structural studies [control subjects (44), HIV-only group (14), HIV + Alc group (45), and Alc-only group (46)]. From those studies, we accrued an adequate longitudinal dataset to address the current study aims; accordingly, the aggregate of the data described herein is novel. Research clinicians administered the Structured Clinical Interview for DSM-IV (47) to all participants, who provided written informed consent to join the study, which was approved by the institutional review boards of SRI International and Stanford University School of Medicine.
The age range of each group at study entry was limited to 25 to 75 years (Table 1).
Included were 1101 MRIs from men and women, most examined multiple times at 1-month to 8-year intervals: 417 acquired in 199 control subjects, 409 in 222 Alc individuals, 152 in 68 HIV-only individuals, and 123 in 60 HIV + Alc individuals. Of the 549 participants, 103 control subjects, 106 Alc individuals, 29 HIV-only individuals, and 22 HIV + Alc individuals had only one MRI; 96 control subjects, 116 Alc individuals, 39 HIV-only individuals, and 60 HIV + Alc individuals had two or more MRIs (Figure 1). Drug use history and serologically confirmed HCV status were determined in most participants.
MRI Acquisition and Analysis
Structural T1-weighted inversion-recovery prepared spoiled gradient recalled MRI data were acquired between April 11, 2003, and March 3, 2017, on a 3T whole-body MR system (GE Healthcare, Waukesha, WI). Detailed acquisition parameters and analysis methods appear in the Supplement(46).
Despite the 14-year span of data acquisition, all MRI data were processed at once using a common procedure. Parcellated maps of gray matter defined six lobar regions: the frontal, temporal, parietal, occipital, cingulate, and insular cortices (Figure 2). All but the insula were further divided: the precentral, superior, orbital, middle, inferior, supplemental motor, and medial frontal cortices; superior, middle, and inferior temporal cortices; postcentral, superior, inferior, supramarginal, precuneus, and paracentral parietal cortices; calcarine, cuneus, lingual, and lateral occipital cortices; and anterior and middle posterior cingulate cortices. Subcortical areas quantified included hippocampus, parahippocampus, amygdala, caudate, putamen, pallidum, and thalamus for 30 regions included for evaluation (Figure 3). To reduce the number of comparisons and because we had no hypotheses regarding structural laterality, gray matter volumes of bilateral hemispheres were summed for each region and used as the metric for analysis.
HAND and Composite Scores
HAND is a categorical rating based on deviations from the means of composite scores representing six functional domains [cf., 28, 30]: executive function, learning/memory, verbal/language, speed of information processing, motor skills, and quality of social functioning. Raw test scores included in each composite score were age corrected based on laboratory control participants, and expressed as standardized Z scores. The HAND categorical score ranged from 0 to 3, where 0 indicated normal performance. Descriptions of each test and derivation of the summary HAND score appear in the Supplement.
Statistical Analysis
Statistical analyses were performed with R (version 3.2.4) (48) and were based on linear or quadratic mixed effects models (lmer), which incorporated cross-sectional and longitudinal brain observations, to test primary variables of diagnosis, age, and sex (see Supplement for complete description).
To adjust for the magnitude of regional cortical gray matter volumes, which is highly correlated with supratentorial volume, the regression of regional volume on supratentorial volume was computed for control subjects with a general linear model (lm in R) and then applied to the data of all participants at each scan. Only control data at the initial MRI were used in the fitting function to ensure that the estimate of relation was not influenced by disease or by differences in numbers of MRI data per subject used in the fitting function. This procedure minimized sex effects. The effect of age on brain volumes was computed (lmer) for all control subjects for all observations. Similarly, the results of this function were then used to compute age-independent observations for all participants regardless of diagnosis over all observations, enabling tests to examine aging effects in diagnostic groups over and above those effects observed in control subjects. We also computed the R2 for the fixed (group) effects and fixed + random (group + individual variation) effects of the lmer for the main group differences between the control group and each diagnostic group and for group-by-age interactions and group-by-sex interactions (49) (Table 2 and Supplemental Table S1). R2 provides estimates of effect sizes, where R2 <.01 is trivial, >.01 to .09 is small to medium, >.09 to .25 is medium to large, and >.25 is large to very large.
Using the age- and sex-independent brain data for each diagnostic group separately, drug-dependent (cocaine, cannabis, amphetamine, opiates) and non-drug-dependent participants were tested against the 199 control subjects with a general linear model (lm) followed by analysis of variance (anova). The age- and sex-independent brain values were used to examine the influence of drinking, HIV, HCV, and neuropsychological variables with t tests for dichotomous variables and Pearson correlations for continuous variables.
Results
Diagnostic Groups and Regional Brain Volumes
Of the six major cortical volumes examined, five regions showed volume deficits in the combined group of 128 participants with HIV (i.e., HIV-only and HIV + Alc groups) relative to the control group; the exception was the occipital lobe. The same deficit pattern was present in the HIV-only (n = 68), HIV + Alc (n = 60), and Alc-only (n = 222) groups (Figure 2, Table 2).
Analysis of 30 regions revealed common volume deficits in all three diagnostic groups relative to the control group in seven regions: five frontal (precentral, superior, middle, inferior, and medial), postcentral parietal, and thalamus (false discovery rate corrected) (Figure 3). Volume deficits common and unique to the combined alcoholic groups (HIV + Alc and Alc only) were the superior parietal, precuneus, middle temporal, and hippocampal regions. Deficits unique to the HIV + Alc group were in the orbital frontal cortex (Figure 3, Supplemental Table S1).
Accelerated Aging: Age-by-Diagnosis Interactions
The effect of age was examined independently for each group. The control subjects showed significant aging effects in five of the six cortical regions (all but the insula). A search for diagnosis-by-age interactions over and above those measured in the control subjects revealed evidence for accelerated aging (diagnosis-by-age interaction) solely in the frontal cortex for the total HIV, the HIV-only, and Alc-only groups, but not for the HIV + Alc group (Table 2, Figure 4).
Examination of the 30 subregions revealed diagnosis-by-age interactions in the superior frontal cortex of the total HIV, HIV-only, HIV + Alc, and Alc-only groups (Figure 5; Supplemental Table S1, green cells; Supplemental Figures S1 and S2). Interactions unique to the HIV-only group were the middle and medial frontal and postcentral parietal cortices (Figure 5), whereas age interactions with the midposterior cingulate and pallidal volumes were unique to the HIV + Alc group. The supplementary motor cortex showed age interactions in the HIV-only and HIV + Alc groups, whereas the precentral cortex showed age interactions in the HIV-only and Alc-only groups (Supplemental Table S1, green cells).
Premature Aging Differences: Deficits Without Age-by-Diagnosis Interactions
For the lobar regions, only the HIV + Alc group exhibited the premature aging effect, having a frontal volume deficit but no age interaction. Additional volume deficits without age interactions were found in several of the 30 regions for each diagnostic group (Supplemental Table S1, orange cells). Specifically, all three groups had volume deficits without age interactions in the frontal inferior cortex and thalamus. The HIV + Alc and Alc-only groups also had nonaccelerated deficits in the medial frontal and postcentral, superior, and parietal cortices; precuneus; and hippocampus. The HIV-only and Alc-only groups had deficits in superior temporal, parietal inferior, and insular cortices. The Alc-only group had uniquely nonaccelerated deficits in the frontal inferior, paracentral parietal, and midposterior cingulate cortices and the pallidum.
Sex-by-Diagnosis Interactions in Regional Brain Volumes
Testing for diagnosis-by-sex interactions yielded significant effects in only the HIV + Alc group. Three regional volumes indicated greater volume deficits in the male than in the female HIV + Alc participants (posterior central parietal [t = 2.048, p = .041], inferior parietal [t = 3.076, p = .002], and thalamus [t = 2.18, p = .029]). As with the lobar regions, age-sex effects were limited to the HIV + Alc group, which showed three modest interactions (postcentral parietal, inferior parietal, and thalamus volumes): while slightly faster in younger HIV + Alc women than in men, the overall rates of volume decline with aging were the same in HIV + Alc men and women.
Drug Dependence Comorbidity and Regional Brain Volumes
The effects of drug dependence on the Alc-only group appear elsewhere (46). Statistical testing for the effects of each drug of abuse separately was not possible in the HIV groups because of inadequate sample sizes. Thus, the primary diagnostic groups of HIV-only or HIV + Alc individuals were divided into drug-dependent (including any of one of the four drugs of abuse: cocaine, opiates, methamphetamine, or marijuana) and non-drug-dependent subgroups. Regardless of drug or alcohol history, the combined HIV group showed frontal volume deficits relative to control subjects. In addition, relative to the control group, the HIV-only drug-dependent group had volume deficits in parietal and temporal cortices, and the HIV + Alc drug-dependent group had volume deficits in the insular, cingulate, and parietal cortices (Table 3). Critically, the frontal volume deficit endured in the HIV group without a history of drug or alcohol dependence. Similarly, the frontal and parietal volume deficits endured in the HIV + Alc group without drug dependence (Table 3, Supplemental Figure S3).
HCV Coinfection and Regional Brain Volumes
We next examined the effects of HCV coinfection on volumes of the six lobar volumes in the combined HIV, HIV-only, and HIV + Alc groups against 89 control participants with known HCV serostatus (Table 4). HCV-positive versus HCV-negative status was also evaluated within each group. Participants in the combined HIV + HCV group had smaller volumes than control subjects in the frontal, temporal, parietal, insular, and cingulate cortices; however, volumes of these structures were not different between HCV-positive and HCV-negative HIV participants (Figure 5, Table 4). HIV-infected individuals, with or without HCV infection, exhibited frontal cortical volume deficits, although this deficit was at trend level in those without alcohol dependence or HCV infection. The most salient effect emerged in the HIV + Alc + HCV group, which had smaller frontal and temporal volumes than HIV + Alc individuals negative for HCV (Table 4, Supplemental Figure S4).
HIV Infection Absent Comorbidities and Regional Brain Volumes
This set of analyses examined whether regional volumes and age-HIV interactions endured in a subset of 24 HIV-infected participants with no history of drug or alcohol dependence or HCV infection. Significant volume deficits were detectable in the frontal superior cortex. Despite reduced power with the smaller sample size, HIV diagnosis-by-age interactions remained significant for the total frontal lobar volume and volumes of four frontal subregions (precentral, superior, middle, and medial) and the postcentral parietal cortex (Figure 6, Supplemental Table S2).
Exploratory Relations Between Clinical and Performance Indices and Brain Volumes
Analyses exploring relations between HIV-infection factors and regional brain volumes used data from the two HIV-infected groups combined. For lowest CD4 count known, the participants were divided into those with a count <200 and those that exceeded that limit. All MRI datasets with CD4 count data resulting in 265 data pairs were tested with t tests. Four of the six regions (frontal, cingulate, parietal, and temporal cortices) had small but significant correlations with CD4 count in the predicted direction (lower CD4 count with smaller volume) and met familywise one-tailed Bonferroni correction (p = .017). Then, defining acquired immunodeficiency syndrome (AIDS) as having had a CD4 count <200 or an HIV-related opportunistic infection anytime in a lifetime, we tested whether any of the six regional volumes related to history of an AIDS event (yes/no) or only a history of a CD4 count <200 (yes/no) using t tests and found no significant differences in brain volumes between groups with relative to those without such histories.
In the combined HIV groups, older age at final MRI correlated with length of infection (r = .388, p = .00001) and older age at HIV infection (r = .570, p = .00001). Despite these relations, only older age at MRI was predictive of frontal cortical volume deficits. Also in the combined HIV groups, a higher (worse) Veterans Aging Cohort Study (VACS) score correlated with smaller parietal volumes (Supplemental Figure S5, Table 5). A higher HAND category, indicating greater impairment, also correlated with smaller parietal volumes. Lower scores on four of the six composite measures correlated with smaller regional brain volumes: executive function with the parietal cortex; learning/memory and speed of information processing with the insular, parietal, and temporal cortices; and motor skills with the temporal cortex (Table 5).
In the Alc-only group, a higher VACS index correlated with smaller frontal volumes, and a higher HAND category correlated with smaller insular volumes (Supplemental Figure S5). In addition, lower scores on three performance composite measures correlated with smaller regional volumes: verbal/language and executive function with the temporal cortex, and speed of information processing with the frontal and temporal cortices (Table 5).
Discussion
A central theme of this longitudinal study conducted over 14 years in patients and control subjects spanning the same age range of 25 to 75 years at study entry was to test whether HIV-infected individuals were subject to premature aging, nonaccelerated differences, or accelerated regional brain volume declines in excess of aging trajectories measured in uninfected counterparts. Compared with control subjects, the HIV-infected cohort exhibited steeper declining volume trajectories, most consistently in the frontal cortex, despite ART (50). Nonaccelerated volume deficits were detected in the temporal, parietal, insular, and cingulate lobar regions of all three diagnostic groups. Sex differences were minimal, likely given that all regional brain volumes were corrected for supratentorial volume (51). Also identified were contributions to group differences in brain volumes from alcohol and drug dependence comorbidities and from HCV coinfection. Critically, significant HIV-age interactions in lobar and selective frontal and posterior parietal volumes endured in the subset of HIV-infected individuals free of substance dependence or HCV infection compared with control subjects, thereby supporting the premise that HIV infection itself confers a heightened risk of accelerated aging of the brain, notably in the frontal lobes.
Regional Volume Deficits and Accelerated Versus Premature Aging in HIV Infection
Acceleration of volume deficits beyond normal aging was detectable in the superior frontal cortex in all three diagnostic groups. Brain regions showing accelerated aging unique to the HIV-only group were the middle and medial frontal and postcentral parietal cortices. Unique to the HIV + Alc group were deficits in midposterior cingulate and pallidal volumes. These cortical and subcortical regions are commonly affected in age-related dementing disorders, including mild cognitive impairment 52, 53, Alzheimer's disease 54, 55, and Parkinson's disease (56). Thus, we speculate that accelerated degeneration of this constellation of brain structures in currently nondemented people living with HIV/AIDS puts them at heightened risk for developing functional impairments that may mimic dementing disorders and ultimately interfere with activities of daily living. This is not to suggest that HIV-infected (55) individuals are at risk for developing Alzheimer's disease or other dementing diseases per se, but rather that the overlap of brain structures affected could potentially underlie selective functional declines characteristic of classical dementias (57). Further, neither length of HIV infection nor older age at infection was a significant correlate of regional brain volumes or accelerated volume decline. Rather, only age itself correlated with declining brain volumes, thereby contributing to acceleration. This uncoupling of the HIV factors, age, and brain volumes was surprising, given that individuals who are older when first infected commonly seek treatment later than individuals with younger onset do 3, 4. Perhaps with further follow-up such relations will emerge.
Brain regions showing nonaccelerated volume deficits despite age correction were considered to reflect premature aging differences. We interpret these static differences as resulting from the initial infection insult without progression or improvement. Regions subject to premature aging differences were volumes of the inferior frontal and thalamus identified in all three diagnostic groups (HIV only, HIV + Alc, and Alc only). Specific to the two alcoholic groups (Alc and HIV + Alc only) were nonaccelerated volume deficits in the middle and medial frontal and postcentral, superior, and parietal cortices; precuneus; and hippocampus. These regional deficits are largely consistent with published findings 43, 58 and may represent structures that are especially vulnerable to insult from HIV infection with or without exacerbation from comorbid experience with alcohol or drugs or from coinfection from HCV.
Influence of Alcohol and Drug Dependence on Brain Volume Differences and Trajectories
Alcohol and drug abuse and dependence are frequent concomitants of HIV infection 59, 60, 61. Rather than excluding users, we directly tested the effects on brain structural volumes of these common HIV comorbidities. The alcohol and drug dependence subgroups had volume deficits in the temporal, parietal, insular, and cingulate cortices compared with control subjects, but not in excess of the drug- and alcohol-free HIV subgroups. Nonetheless, the frontal volume deficit persisted in the alcohol- and drug-free HIV-infected subgroup. Further, the two Alc groups (HIV + Alc and Alc only) had volume deficits in the superior parietal cortex, precuneus, and hippocampus, which were beyond those observed in HIV infection alone and in regions commonly affected in Alzheimer's disease (52). The question remains, however, whether these focal volume deficits present a selective liability for functional compromise to the HIV + Alc group, especially the midposterior cingulum and pallidum, which showed accelerated volumetric decline.
Contribution of HCV Coinfection to Brain Volume Differences and Trajectories
HCV coinfection is prevalent in the HIV community (62). The combined HIV groups (HIV only and HIV + Alc) coinfected with HCV had smaller volumes of the insular, cingulate, parietal, and temporal cortices relative to their HCV-seronegative counterparts and control subjects. Thus, HCV coinfection extended the number of brain regions affected in HIV infection.
Relevance of HIV-Related Variables to Brain Volume Deficits
The VACS index predicts all-cause mortality, cause-specific mortality, and other outcomes in those living with HIV infection (63). This physiological indicator of fragility was found elsewhere to correlate with peripherally circulating levels of cytokines (monocyte chemoattractant protein 1, interferon gamma-induced protein 10, tumor necrosis factor alpha) in HIV + HCV coinfection (64). Herein, a high VACS score in the combined HIV groups correlated with smaller parietal volumes, which may be the first report of a specific brain correlate of the VACS index. Also novel is the correlation between VACS scores and frontal volumes in the Alc-only group, which could reflect declining hepatic function.
Exploratory correlations revealed that higher HAND scores, reflecting greater functional impairment, were associated with smaller parietal volumes in the total HIV group. This relation between higher HAND and VACS scores and smaller parietal volumes suggests a physiological substrate, potentially involving hepatic dysfunction, of this functional decline. We speculate that reduction or abstinence from alcohol and drug misuse and HCV treatment may have the potential to enhance physiological functioning, thereby improving affected cortical and cognitive systems. Thus, unlike classical dementias, HIV-related dysfunction, detectable in the six domains examined as part of the HAND assessment, may be reversible.
Limitations
Despite its extensive longitudinal data, this study has limitations. As a clinical investigation, we did not have access to study participants before infection onset, thereby limiting conclusions about HIV infection as the cause of identified brain volume deficits. Further, although the observations included 1101 MRI sessions and spanned upwards of 8 years per participant, the session intervals may have been too irregular to capture the dynamic progression of the infection with variation in and response to treatment. Finally, a study goal was to examine the effect of substance-dependence comorbidity and HCV coinfection on regional brain volume differences and trajectories in HIV infection rather than simply controlling or excluding for them. Although this goal was achieved, the sample sizes of resulting drug-type subsamples precluded questioning effects of specific illicit drug dependence on regional brain volumes.
Conclusions
The accelerated versus premature aging decline distinction required controlled longitudinal examination. The substantial proportion of the HIV-infected sample with a relatively late infection onset is at particular risk for either accelerated aging or premature aging brain volume deficits with compounded risk for frontal cortical involvement with alcohol-dependence comorbidity. We speculate that treatment with antiretroviral medication may have mitigated acceleration of certain brain volume deficits; alternatively, incomplete treatment or viral suppression together with coinfection or alcohol or drug comorbidities may have contributed to brain volume deficits. Indirect support of this speculation derives from the correlation between higher VACS indices and smaller parietal volumes that may potentially reflect neuroinflammatory processes notable in HIV + HCV coinfection (64) or declining hepatic functioning in alcohol-dependent individuals. In summary, the constellations of regional brain volume deficits detected in men and women living with HIV infection were associated with markers of brain injury identified with either premature or accelerated aging. Also identified were contributing comorbidities to regional brain volume decline that may be arrested with treatment of the comorbid conditions. Similarly, functional ramifications for physiological fragility and cognitive and motor decline may be mitigated or reversed with tailored ART, enhancement of healthy living practices, and reduction in consumption of harmful amounts of alcohol and drugs.
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