Bioenergetics and neuroimaging research: a neuropathophysiological linkage in the setting of cocaine use amongst persons with HIV

Despite innovations in antiretroviral therapy (ART) that have transformed HIV infection from an acute illness with high mortality risk into a chronic, largely manageable disease, the viral reservoir that persists in brain continues to pose a risk for neurocognitive impairment and other deleterious clinical outcomes. ART regimens can inhibit viral integration and suppress replication to nondetectable levels in plasma and cerebrospinal fluid (CSF) but do not eliminate viral reservoirs, including that in brain [1]. Moreover, HIV transcripts within CSF cells have been associated with brain injury despite suppressive ART [2]. Comorbid HIV and cocaine use exacerbates brain atrophy and neurocognitive decline despite viral suppression [3–5]. Intersecting factors disrupted by chronic cocaine use among people with HIV (PWH) contribute to HIV-associated neuropathology, including neurotransmitter signaling (particularly dopamine), neuroinflammation, blood–brain–barrier (BBB) integrity, and energy metabolism. Further, the neuropathological severity associated with HIV and cocaine is spatially heterogenous [6–8]. The healthy brain is energetically expensive and complex with region-specific, unique functional roles [9–11]. Further, compartmentalization of HIV infection in brain contributes to this heterogeneity [12]. Mechanistic links between HIV and cocaine require additional characterization to assess region-dependent contributions to develop therapeutic interventions for cocaine use disorder comorbid with HIV. Mamidi et al.[13] focused on associations between chronic cocaine use and HIV on glucose uptake. Using 18F-FDG PET/CT in a 2 × 2 experimental design with HIV (present/absent) and cocaine (present/absent) (N = 63), they showed the lowest uptake with both HIV and cocaine. One factor – HIV or cocaine – showed intermediate uptake, and neither factor showed the highest uptake. The pronounced impact of cocaine on HIV-associated neuropathology is, in part, due to disruption of dopaminergic neurotransmission. The dopamine system is linked to inflammation and immunological function. Brain regions with high basal dopamine levels, such as the striatum and substantia nigra, are amongst the most vulnerable to HIV [14]. Dopamine exposure to human macrophages results in elevated production of pro-inflammatory cytokines and chemokines [14]. Acutely, elevated dopamine concentrations due to cocaine use increase oxidative stress, exacerbated by Tat [15,16]. Chronically, cocaine use is associated with dopamine depletion, demonstrated by PET scanning research [17]. In addition, HIV itself is associated with dopamine depletion as well as neurocognitive impairment and depression [18] not investigated here. This constellation suggests a synergistic effect of HIV and cocaine on dopaminergic transmission. To the extent that dopaminergic neurotransmission impacts glucose uptake, only additive effects of HIV and cocaine were reported here. No interaction of HIV and cocaine was observed. A major hallmark of chronic HIV is elevated pro-inflammatory cytokine and chemokine production. Suppressed PWH still have elevated neuroinflammation in the parietal and occipital cortex and the globus pallidus. Neuroinflammation is associated with decreased neurocognitive performance and increased white matter damage supported by a PET study with [11C] PBR28 and neuropsychological testing [8]. Viral proteins, Tat and gp120, both facilitate the production of pro-inflammatory cytokine and chemokines that decrease BBB tight junction protein expression and are directly neurotoxic [19]. Loss of BBB integrity allows free virus and HIV-infected monocytes to enter brain, exacerbating neuronal damage [20]. Similarly, cocaine increases neuroinflammatory markers by activating microglial cells and disrupting BBB integrity – decreasing tight junction protein expression in human pericytes [21]. When measuring chronic cocaine-induced microglial activation in vivo, rhesus macaques displayed increased TSPO PET expression in dopamine-rich regions via [3H] PK-11195 [6,7]. However, humans with a history of chronic cocaine use assessed with TSPO PET via [11C] PBR28 displayed no significant changes [6,22]. Of note, increased TSPO expression using current tracers does not distinguish between microglial and astrocytic activation. Further, there are other limitations with the utility of both PK-11195 and PBR28 tracers. Hence, PET scanning studies are currently inconclusive, though studies using other methodologies support neuroinflammatory effects associated with cocaine. Cocaine has been linked with increased TNF-α expression and is well known to stimulate HIV replication through induction of NF-κB and activation of transcription through the HIV LTR. The increased expression of TNF-α induced by HIV might exacerbate that by cocaine. Pro-inflammatory cytokine production has been associated with dopamine depletion outside of HIV infection. This suggests an intrinsic link between chronic HIV despite suppression, ongoing neuroinflammation, and persistent dopamine depletion, which is associated with depression and neurocognitive symptoms. This linkage may also reflect the results reported here and suggests the possible clinical utility of TNF-α inhibitors and dopaminergic agonists for the treatment of depressive and neurocognitive symptoms in virally suppressed PWH, supporting normalization of brain glucose uptake. In adults, the brain\u27s immense energetic demands require roughly 20% of all glucose and constitute approximately the same proportion of total oxygen consumption during resting conditions [23,24]. Maintenance of brain metabolic homeostasis is particularly sensitive to metabolic coupling between types of brain cells that contribute to clinical disorders when disrupted [25–27]. Viral–host interactions after an infection like HIV shift bioenergetics for incompletely understood reasons. Changes in energetic metabolism have been reported to occur in vitro using cultured astrocytes, neurons, and microglia due to Tat and gp120 [28–30], cytokines and chemokines [31], oxidative stress [32], and ART [33]. In vivo, virally suppressed PWH display decreased glucose uptake in the frontal cortex and the anterior cingulate cortex via FDG-PET [34,35]. Altogether, these changes suggest a shift from metabolism of primarily glucose to other oxidative substrates. Moreover, in vitro, cocaine is associated with a similar metabolic shift [29]. As suggested above, energetic demands vary across brain regions. Recent studies suggest that the brain also uses other substrates, such as fatty acids, lactate, pyruvate, glutamate, glutamine, and ketone bodies, more frequently than previously considered [10,11,36]. The composition of substrates used may shift under various factors such as age, diet, brain activity or injury, cognitive reserve, and the presence of viral infections like HIV [26,37]. Hence, future studies should expand from the general study of glucose uptake as the primary substrate to other substrates and associated changes in oxidative stress and mitochondrial function. Clinical research suggests the importance of associated interacting comorbidities, such as cardiovascular disease, with HIV [38] and cocaine [39]. It should be noted that age, ethnicity, and education and concomitant opioid use were not able to be separately analyzed here. Of note, older age is also associated with dopamine depletion, suggesting a more prominent effect amongst older PWH. In addition to future studies examining other energy substrate outcome measures; improved control of extraneous factors; and integration of clinical outcomes of cocaine use among PWH, neuroimaging studies can be particularly helpful in examining spatial heterogeneity in energetic effects induced by toxic HIV protein and transcript burden as well as pro-inflammatory cytokine secretion associated with cocaine use. Yet, these methods incompletely capture metabolic changes in brain. It can be concluded that there remains much to explore as to how the bioenergetic shifts occurring due to HIV and cocaine may be mechanistically linked to clinical outcomes

Redefining Aging in HIV Infection Using Phenotypes

Purpose of review: This article critically reviews the utility of “phenotypes” as behavioral descriptors in aging/HIV research that inform biological underpinnings and treatment development. We adopt a phenotypic redefinition of aging conceptualized within a broader context of HIV infection and of aging. Phenotypes are defined as dimensions of behavior, closely related to fundamental mechanisms, and, thus, may be more informative than chronological age. Primary emphasis in this review is given to comorbid aging and cognitive aging, though other phenotypes (i.e., disability, frailty, accelerated aging, successful aging) are also discussed in relation to comorbid aging and cognitive aging. Recent findings: The main findings that emerged from this review are as follows: (1) the phenotypes, comorbid aging and cognitive aging, are distinct from each other, yet overlapping; (2) associative relationships are the rule in HIV for comorbid and cognitive aging phenotypes; and (3) HIV behavioral interventions for both comorbid aging and cognitive aging have been limited. Summary: Three paths for research progress are identified for phenotype-defined aging/HIV research (i.e., clinical and behavioral specification, biological mechanisms, intervention targets), and some important research questions are suggested within each of these research paths

Normative Scores for a Brief Neuropsychological Battery for the Detection of HIV-Associated Neurocognitive Disorder (HAND) Among South Africans

There is an urgent need to more accurately diagnose HIV-associated neurocognitive disorder (HAND) in Africa. Rapid screening tests for HIV-associated dementia are of limited utility due to variable sensitivity and specificity. The use of selected neuropsychological tests is more appropriate, but norms for HIV seronegative people are not readily available for sub-Saharan African populations. We sought to derive normative scores for two commonly used neuropsychological tests that generate four test scores -- namely the Trail-Making Test (Parts A and B) and the Digit Span Test [Forward (DSF) and Backward (DSB)]. To assess memory and recall, we used the memory item of the International HIV Dementia Scale (IHDS)

Behavioral Correlates for Quitting Opioids among Opioid-Dependent Pregnant and Non-Pregnant Women of Childbearing Age in Rural Appalachia

Background: The opioid epidemic is particularly worrisome in the pregnant population, wherein concerns are raised about the health of a mother and her child, resulting in an alarming incidence and prevalence of Neonatal Abstinence Syndrome (NAS). The 2016 National Survey on Drug Use and Health (NSDUH) show the rate of illicit psychoactive substance use among the females aged 12 or older was 15.5% in the past year. Among pregnant women aged 15 to 44, 6.3% were illicit psychoactive substance users. In Tennessee, the number of hospital discharged NAS cases from 2002 to 2013 increased from 1.50 to 16.6 cases per 1,000 live births. This number is triple the national incidence of NAS cases over the same time period. Between 2013 and 2016, at least 52.5% of children diagnosed with NAS in Tennessee have had exposure to one prescription drug, while 27.2% were exposed to a combination of prescribed medications and illicit substances. We examined the behavioral correlates that determine the wish to quit opioids or not to quit opioids among opioid-dependent pregnant and non-pregnant women in rural Appalachia. Methods: Ten women of childbearing age, whether pregnant or not, who were receiving prescribed opioids, were recruited to join the study. All the participating women were also receiving physician-managed Medication Assisted Treatment (MAT) therapy for the treatment of severe opioid use disorder, or are currently being prescribed an opioid medication. Study variables included age, Hamilton Depression Rating Scale (HAM-D), Visual Analogue Scale – Pain (VAS-P), the Modified Opiate Craving Scale (MOCS), the Visual Analog Commitment to Quit Opiates, the McGill Pain Index (MPI), prescriptions, tobacco and nicotine use, illicit substance use, the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES), and the Adverse Childhood Experience (ACE) questionnaire. The HAM-D, MOCS, MPI, and SOCRATES scores were log-transformed to approximate a normal distribution. Descriptive statistics and the Spearman’s rank correlation (with a 95% Confidence Interval) were conducted to examine significant behavioral correlates for quitting opioids. Results: Descriptive statistics show that women with higher HAM-D and MOCS scores are not likely to express willingness to quit opioids. There is a statistically significant strong positive correlation of 0.679 (pppp Conclusion: Women who recognize the need to quit opioids or are “taking steps” to quit are more likely to quit opioids. Women with high depression and pain scores are not likely to quit opioids. Non-opioid medications may reduce the number of opioid-dependent pregnant and non-pregnant women of childbearing age, and, in turn, lower the currently high incidence and prevalence rates of NAS

Practice Guideline for the treatment of patients with HIV-AIDS

This guideline addresses psychiatric issues in the care of people with HIV/AIDS. Originally published in November 2000. This guideline is more than 5 years old and has not yet been updated to ensure that it reflects current knowledge and practice. In accordance with national standards, including those of the Agency for Healthcare Research and Quality’s National Guideline Clearinghouse (http://www.guideline.gov/), this guideline can no longer be assumed to be current. The April 2006 Guideline Watch associated with this guideline provides additional information that has become available since publication of the guideline, but it is not a formal update of the guideline

Normative scores for a brief neuropsychological battery for the detection of HIV-associated neurocognitive disorder (HAND) among South Africans

<p>Abstract</p> <p>Background</p> <p>There is an urgent need to more accurately diagnose HIV-associated neurocognitive disorder (HAND) in Africa. Rapid screening tests for HIV-associated dementia are of limited utility due to variable sensitivity and specificity. The use of selected neuropsychological tests is more appropriate, but norms for HIV seronegative people are not readily available for sub-Saharan African populations. We sought to derive normative scores for two commonly used neuropsychological tests that generate four test scores -- namely the Trail-Making Test (Parts A and B) and the Digit Span Test [Forward (DSF) and Backward (DSB)]. To assess memory and recall, we used the memory item of the International HIV Dementia Scale (IHDS).</p> <p>Findings</p> <p>One hundred and ten HIV seronegative participants were assessed at McCord Hospital, Durban, South Africa between March 3^rdand October 31^st, 2008. We excluded people with major depressive disorder, substance use abuse and dependence and head injuries (with or without loss of consciousness). All the participants in this study were African and predominantly female with an average age of 28.5 years and 10 years of education. Age and gender influenced neuropsychological functioning, with older people performing worse. The effect of gender was not uniform across all the tests.</p> <p>Conclusion</p> <p>These two neuropsychological tests can be administered with the IHDS in busy antiretroviral clinics. Their performance can be measured against these norms to more accurately diagnose the spectrum and progression of HAND.</p

A Machine Learning-Based Linguistic Battery for Diagnosing Mild Cognitive Impairment Due to Alzheimer\u27s Disease

This is an open access article distributedunder the terms of the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproductionin any medium,provided the original author and source are credited. There is a limited evaluation of an independent linguistic battery for early diagnosis of Mild Cognitive Impairment due to Alzheimer\u27s disease (MCI-AD). We hypothesized that an independent linguistic battery comprising of only the language components or subtests of popular test batteries could give a better clinical diagnosis for MCI-AD compared to using an exhaustive battery of tests. As such, we combined multiple clinical datasets and performed Exploratory Factor Analysis (EFA) to extract the underlying linguistic constructs from a combination of the Consortium to Establish a Registry for Alzheimer\u27s disease (CERAD), Wechsler Memory Scale (WMS) Logical Memory (LM) I and II, and the Boston Naming Test. Furthermore, we trained a machine-learning algorithm that validates the clinical relevance of the independent linguistic battery for differentiating between patients with MCI-AD and cognitive healthy control individuals. Our EFA identified ten linguistic variables with distinct underlying linguistic constructs that show Cronbach\u27s alpha of 0.74 on the MCI-AD group and 0.87 on the healthy control group. Our machine learning evaluation showed a robust AUC of 0.97 when controlled for age, sex, race, and education, and a clinically reliable AUC of 0.88 without controlling for age, sex, race, and education. Overall, the linguistic battery showed a better diagnostic result compared to the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale (CDR), and a combination of MMSE and CDR

The comorbidity of depression and neurocognitive disorder in persons with HIV infection: call for investigation and treatment

Depression and neurocognitive disorder continue to be the major neuropsychiatric disorders affecting persons with HIV (PWH). The prevalence of major depressive disorder is two to fourfold higher among PWH than the general population (∼6.7%). Prevalence estimates of neurocognitive disorder among PWH range from 25 to over 47% – depending upon the definition used (which is currently evolving), the size of the test battery employed, and the demographic and HIV disease characteristics of the participants included, such as age range and sex distribution. Both major depressive disorder and neurocognitive disorder also result in substantial morbidity and premature mortality. However, though anticipated to be relatively common, the comorbidity of these two disorders in PWH has not been formally studied. This is partly due to the clinical overlap of the neurocognitive symptoms of these two disorders. Both also share neurobehavioral aspects — particularly apathy — as well as an increased risk for non-adherence to antiretroviral therapy. Shared pathophysiological mechanisms potentially explain these intersecting phenotypes, including neuroinflammatory, vascular, and microbiomic, as well as neuroendocrine/neurotransmitter dynamic mechanisms. Treatment of either disorder affects the other with respect to symptom reduction as well as medication toxicity. We present a unified model for the comorbidity based upon deficits in dopaminergic transmission that occur in both major depressive disorder and HIV-associated neurocognitive disorder. Specific treatments for the comorbidity that decrease neuroinflammation and/or restore associated deficits in dopaminergic transmission may be indicated and merit study

The comorbidity of depression and neurocognitive disorder in persons with HIV infection: call for investigation and treatment

Depression and neurocognitive disorder continue to be the major neuropsychiatric disorders affecting persons with HIV (PWH). The prevalence of major depressive disorder is two to fourfold higher among PWH than the general population (∼6.7%). Prevalence estimates of neurocognitive disorder among PWH range from 25 to over 47% – depending upon the definition used (which is currently evolving), the size of the test battery employed, and the demographic and HIV disease characteristics of the participants included, such as age range and sex distribution. Both major depressive disorder and neurocognitive disorder also result in substantial morbidity and premature mortality. However, though anticipated to be relatively common, the comorbidity of these two disorders in PWH has not been formally studied. This is partly due to the clinical overlap of the neurocognitive symptoms of these two disorders. Both also share neurobehavioral aspects — particularly apathy — as well as an increased risk for non-adherence to antiretroviral therapy. Shared pathophysiological mechanisms potentially explain these intersecting phenotypes, including neuroinflammatory, vascular, and microbiomic, as well as neuroendocrine/neurotransmitter dynamic mechanisms. Treatment of either disorder affects the other with respect to symptom reduction as well as medication toxicity. We present a unified model for the comorbidity based upon deficits in dopaminergic transmission that occur in both major depressive disorder and HIV-associated neurocognitive disorder. Specific treatments for the comorbidity that decrease neuroinflammation and/or restore associated deficits in dopaminergic transmission may be indicated and merit study