Parameter Space and Potential for Biomarker Development in 25 Years of fMRI Drug Cue Reactivity: A Systematic Review.

Importance: In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers. Objective: To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts. Evidence Review: The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders. Findings: There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes. Conclusions and Relevance: Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.

Causal factors in childhood and adolescence leading to anabolic-androgenic steroid use: A machine learning approach.

Background: Prior research has demonstrated associations between anabolic-androgenic steroid (AAS) use and features from several childhood and adolescent psychosocial domains including body image concerns, antisocial traits, and low levels of parental care. However, prior approaches have been limited by their focus on individual features and lack of consideration of the relevant causal structure. Methods: We re-analyzed data from a previous cross-sectional cohort study of 232 male weightlifters aged 18-40, of whom 101 had used AAS. These men completed retrospective measures of features from their childhood and early adolescence, including body image concerns, eating disorder psychopathology, antisocial traits, substance use, and family relationships. Using an approach informed by principles of causal inference, we applied four machine-learning methods - lasso regression, elastic net regression, random forests, and gradient boosting - to predict AAS use. Results: The four methods yielded similar receiver operating curves, mean area under the curve (range 0.66 to 0.72), and sets of highly important features. Features related to adolescent body image concerns (especially muscle dysmorphia symptoms) were the strongest predictors. Other important features were adolescent rebellious behaviors; adolescent feelings of ineffectiveness and lack of interoceptive awareness; and low levels of paternal care. Conclusions: Applying machine learning within a causally informed approach to re-analyze data from a prior study of weightlifters, we identified six factors (most prominently those related to adolescent body image concerns) as proposed causal factors for the development of AAS use. Compared with the prior analyses, this approach achieved greater methodologic rigor and yielded stronger and broader findings.

Effects of inhaled low-concentration xenon gas on naltrexone-precipitated withdrawal symptoms in morphine-dependent mice.

BACKGROUND: Opioid withdrawal symptoms (OWS) are highly aversive and prompt unprescribed opioid use, which increases morbidity, mortality, and, among individuals being treated for opioid use disorder (OUD), recurrence. OWS are driven by sympathetic nervous system (SNS) hyperactivity that occurs when blood opioid levels wane. We tested whether brief inhalation of xenon gas, which inhibits SNS activity and is used clinically for anesthesia and diagnostic imaging, attenuates naltrexone-precipitated withdrawal-like signs in morphine-dependent mice. METHODS: Adult CD-1 mice were implanted with morphine sulfate-loaded (60 mg/ml) minipumps and maintained for 6 days to establish morphine dependence. On day 7, mice were given subcutaneous naltrexone (0.3 mg/kg) and placed in a sealed exposure chamber containing either 21% oxygen/balance nitrogen (controls) or 21% oxygen/added xenon peaking at 30%/balance nitrogen. After 10 minutes, mice were transferred to observation chambers and videorecorded for 45 minutes. Videos were scored in a blind manner for morphine withdrawal behaviors. Data were analyzed using 2-way ANOVAs testing for treatment and sex effects. RESULTS AND CONCLUSIONS: Xenon-exposed mice exhibited fewer jumps (P = 0.010) and jumping suppression was detectible within the first 10-minute video segment, but no sex differences were detected. Brief inhalation of low concentration xenon rapidly and substantially attenuated naltrexone-precipitated jumping in morphine-dependent mice, suggesting that it can inhibit OWS. If xenon effects translate to humans with OUD, xenon inhalation may be effective for reducing OWS, unprescribed opioid use, and for easing OUD treatment initiation, which could help lower excess morbidity and mortality associated with OUD.

Age-related neuroendocrine, cognitive, and behavioral co-morbidities are promoted by HIV-1 Tat expression in male mice.

In the U.S. about half of the HIV-infected individuals are aged 50 and older. In men living with HIV, secondary hypogonadism is common and occurs earlier than in seronegative men, and its prevalence increases with age. While the mechanisms(s) are unknown, the HIV-1 trans-activator of transcription (Tat) protein disrupts neuroendocrine function in mice partly by dysregulating mitochondria and neurosteroidogenesis. We hypothesized that conditional Tat expression in middle-aged male transgenic mice [Tat(+)] would promote age-related comorbidities compared to age-matched controls [Tat(-)]. We expected Tat to alter steroid hormone milieu consistent with behavioral deficits. Middle-aged Tat(+) mice had lower circulating testosterone and progesterone than age-matched controls and greater circulating corticosterone and central allopregnanolone than other groups. Young Tat(+) mice had greater circulating progesterone and estradiol-to-testosterone ratios. Older age or Tat exposure increased anxiety-like behavior (open field; elevated plus-maze), increased cognitive errors (radial arm water maze), and reduced grip strength. Young Tat(+), or middle-aged Tat(-), males had higher mechanical nociceptive thresholds than age-matched counterparts. Steroid levels correlated with behaviors. Thus, Tat may contribute to HIV-accelerated aging.

Clathrin-nanoparticles deliver BDNF to hippocampus and enhance neurogenesis, synaptogenesis and cognition in HIV/neuroAIDS mouse model.

Brain derived neurotrophic factor (BDNF) promotes the growth, differentiation, maintenance and survival of neurons. These attributes make BDNF a potentially powerful therapeutic agent. However, its charge, instability in blood, and poor blood brain barrier (BBB) penetrability have impeded its development. Here, we show that engineered clathrin triskelia (CT) conjugated to BDNF (BDNF-CT) and delivered intranasally increased hippocampal BDNF concentrations 400-fold above that achieved previously with intranasal BDNF alone. We also show that BDNF-CT targeted Tropomyosin receptor kinase B (TrkB) and increased TrkB expression and downstream signaling in iTat mouse brains. Mice were induced to conditionally express neurotoxic HIV Transactivator-of-Transcription (Tat) protein that decreases BDNF. Down-regulation of BDNF is correlated with increased severity of HIV/neuroAIDS. BDNF-CT enhanced neurorestorative effects in the hippocampus including newborn cell proliferation and survival, granule cell neurogenesis, synaptogenesis and increased dendritic integrity. BDNF-CT exerted cognitive-enhancing effects by reducing Tat-induced learning and memory deficits. These results show that CT bionanoparticles efficiently deliver BDNF to the brain, making them potentially powerful tools in regenerative medicine.

A methodological checklist for fMRI drug cue reactivity studies: development and expert consensus.

Cue reactivity is one of the most frequently used paradigms in functional magnetic resonance imaging (fMRI) studies of substance use disorders (SUDs). Although there have been promising results elucidating the neurocognitive mechanisms of SUDs and SUD treatments, the interpretability and reproducibility of these studies is limited by incomplete reporting of participants' characteristics, task design, craving assessment, scanning preparation and analysis decisions in fMRI drug cue reactivity (FDCR) experiments. This hampers clinical translation, not least because systematic review and meta-analysis of published work are difficult. This consensus paper and Delphi study aims to outline the important methodological aspects of FDCR research, present structured recommendations for more comprehensive methods reporting and review the FDCR literature to assess the reporting of items that are deemed important. Forty-five FDCR scientists from around the world participated in this study. First, an initial checklist of items deemed important in FDCR studies was developed by several members of the Enhanced NeuroImaging Genetics through Meta-Analyses (ENIGMA) Addiction working group on the basis of a systematic review. Using a modified Delphi consensus method, all experts were asked to comment on, revise or add items to the initial checklist, and then to rate the importance of each item in subsequent rounds. The reporting status of the items in the final checklist was investigated in 108 recently published FDCR studies identified through a systematic review. By the final round, 38 items reached the consensus threshold and were classified under seven major categories: 'Participants' Characteristics', 'General fMRI Information', 'General Task Information', 'Cue Information', 'Craving Assessment Inside Scanner', 'Craving Assessment Outside Scanner' and 'Pre- and Post-Scanning Considerations'. The review of the 108 FDCR papers revealed significant gaps in the reporting of the items considered important by the experts. For instance, whereas items in the 'General fMRI Information' category were reported in 90.5% of the reviewed papers, items in the 'Pre- and Post-Scanning Considerations' category were reported by only 44.7% of reviewed FDCR studies. Considering the notable and sometimes unexpected gaps in the reporting of items deemed to be important by experts in any FDCR study, the protocols could benefit from the adoption of reporting standards. This checklist, a living document to be updated as the field and its methods advance, can help improve experimental design, reporting and the widespread understanding of the FDCR protocols. This checklist can also provide a sample for developing consensus statements for protocols in other areas of task-based fMRI.

Review Article: Anabolic-Androgenic Steroids, Violence, and Crime: Two Cases and Literature Review.

BACKGROUND AND OBJECTIVES: Anabolic-androgenic steroid (AAS) use has become a major worldwide substance use disorder, affecting tens of millions of individuals. Importantly, it is now increasingly recognized that some individuals develop uncharacteristically violent or criminal behaviors when using AAS. We sought to summarize available information on this topic. METHODS: We reviewed the published literature on AAS-induced behavioral effects and augmented this information with extensive observations from our clinical and forensic experience. RESULTS: It is now generally accepted that some AAS users develop uncharacteristically violent or criminal behaviors while taking these drugs. Although these behaviors may partially reflect premorbid psychopathology, sociocultural factors, or expectational effects, accumulating evidence suggests that they are also attributable to biological effects of AAS themselves. The mechanism of these effects remains speculative, but preliminary data suggest a possible role for brain regions involved in emotional reactivity, such as the amygdala and regions involved in cognitive control, including the frontal cortex. For unknown reasons, these effects appear idiosyncratic; most AAS users display few behavioral effects, but a minority develops severe effects. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Professionals encountering AAS users in clinical or forensic settings should be alert to the possibility of AAS-induced violence or criminality and should employ strategies to assess whether AAS is indeed a contributory factor in a given case. Further research is needed to elucidate the mechanism of AAS-induced violence and to explain why only a subset of AAS users appears vulnerable to these effects. (Am J Addict 2021;00:00-00).

In vivo proton magnetic resonance spectroscopy detection of metabolite abnormalities in aged Tat-transgenic mouse brain.

Most individuals living with HIV in the USA are over 45 years old and are vulnerable to the combined effects of HIV and aging. Antiretroviral therapies reduce HIV morbidity and mortality but do not prevent HIV trans-activator of transcription (Tat) protein expression or development of HIV-associated neurocognitive disorder (HAND), which may be caused by Tat. Tat-transgenic (Tat-tg) mice are used to study Tat's effects, typically after transgene induction with doxycycline. However, uninduced Tat-tg mice experience transgene leak and model aspects of HAND when aged, including neuroinflammation. We used in vivo 9.4-tesla proton magnetic resonance spectroscopy to compare neurochemistry in aged versus young female and male uninduced Tat-tg mice. Aged Tat-tg mice demonstrated measurable tat mRNA brain expression and had lower medial prefrontal cortex (MPFC) GABA, glutamate, and taurine levels and lower striatal GABA and taurine levels. Females had lower MPFC glutathione and taurine and lower striatal taurine levels. Brain testosterone levels were negatively correlated with age in aged males but not females. Aged mice had cortical abnormalities not previously reported in aged wild-type mice including lower MPFC GABA and taurine levels. As glutathione and taurine levels reflect inflammation and oxidative stress, our data suggest that Tat may exacerbate these processes in aged Tat-tg mice. However, additional studies in controls not expressing Tat are needed to confirm this point and to deconvolve individual effects of age and Tat expression. Sex steroid hormone supplements, which counter climacteric effects, increase taurine levels, and reduce inflammation and oxidative stress, could attenuate some of the brain abnormalities we identified in aged Tat-tg mice.

Temporal patterns of suicide and circulatory system disease-related mortality are inversely correlated in several countries.

BACKGROUND: Nearly 800,000 suicides occur worldwide annually and suicide rates are increasing faster than population growth. Unfortunately, the pathophysiology of suicide remains poorly understood, which has hindered suicide prevention efforts. However, mechanistic clues may be found by studying effects of seasonality on suicide and other mortality causes. Suicides tend to peak in spring-summer periods and nadir in fall-winter periods while circulatory system disease-related mortality tends to exhibit the opposite temporal trends. This study aimed to determine for the first time whether monthly temporal cross-correlations exist between suicide and circulatory system disease-related mortality at the population level. If so and if common biological factors moderate risks for both mortality types, such factors may be discoverable and utilized to improve suicide prevention. METHODS: We conducted time series analyses of monthly mortality data from northern (England and Wales, South Korea, United States) and southern (Australia, Brazil) hemisphere countries during the period 2009-2018 (N = 41.8 million all-cause mortality cases). We used a Poisson regression variant of the standard cosinor model to determine peak months of mortality. We also estimated cross-correlations between monthly mortality counts from suicide and from circulatory system diseases. RESULTS: Suicide and circulatory disease-related mortality temporal patterns were negatively correlated in Australia (- 0.32), Brazil (- 0.57), South Korea (- 0.32), and in the United States (- 0.66), but no temporal correlation was discernable in England and Wales. CONCLUSIONS: The negative temporal cross-correlations between these mortality types we found in 4 of 5 countries studied suggest that seasonal factors broadly and inversely moderate risks for circulatory disease-related mortality and suicide, but not in all regions, indicating that the effect is not uniform. Since the seasonal factors of temperature and light exert opposite effects on suicide and circulatory disease-related mortality in several countries, we propose that physiologically-adaptive circulatory system responses to heat and light may increase risk for suicide and should be studied to determine whether they affect suicide risk. For example, heat and light increase production and release of the bioactive gas nitric oxide and reduce circulatory system disease by relaxing blood vessel tone, while elevated nitric oxide levels are associated with suicidal behavior, inverse effects that parallel the inverse temporal mortality patterns we detected.

HIV-1 Tat promotes age-related cognitive, anxiety-like, and antinociceptive impairments in female mice that are moderated by aging and endocrine status.

Hypogonadism is a common comorbidity associated with HIV-1 that is more prevalent among infected individuals over the age of 45. The underlying mechanisms are unknown, but both combined antiretroviral therapeutics and HIV-1 proteins, such as trans-activator of transcription protein (Tat), dysregulate steroid-synthetic mechanisms including lipid storage/synthesis and mitochondrial function. Thus, Tat expression may accelerate age-related comorbidities partly by impairing endocrine function. Few studies exist of Tat-mediated behavioral deficits in aged animals and effects of endocrine status have not been investigated. Accordingly, we tested whether conditional Tat expression in aged (~ 1.5 years old), female, Tat-transgenic [Tat(+)] mice increases anxiety-like behavior, impairs cognition, and augments mechanical allodynia, when compared to age-matched controls that do not express Tat protein [Tat(-)]. We further tested whether aged mice that maintained their endocrine status (pre-estropausal) were more resilient to Tat/age-related comorbidities than peri- or post-estropausal mice. Tat and endocrine aging status exerted separate and interacting effects that influenced anxiety-like and cognitive behaviors. Peri- and post-estropausal mice exhibited greater anxiety-like behavior in the elevated plus-maze and impaired learning in the radial arm water maze compared to pre-estropausal mice. Irrespective of estropause status, Tat(+) mice demonstrated impaired learning, reduced grip strength, and mechanical allodynia compared to Tat(-) mice. Tat exposure reduced circulating estradiol in post-estropausal mice and increased the estradiol-to-testosterone ratio in pre-estropausal mice. Changes in circulating estradiol, testosterone, and progesterone correlated with grip strength. Thus, endocrine status is an important factor in age-related anxiety, cognition, neuromuscular function, and allodynia that can be accelerated by HIV-1 Tat protein.

Magnetic resonance spectroscopy studies of substance use disorders: Current landscape and potential future directions.

Over 200 in vivo magnetic resonance spectroscopy (MRS) studies of substance use and related disorders (SUD) were published this past decade. The large majority of this work used proton (1H)-MRS to characterize effects of acute and chronic exposures to drugs of abuse on human brain metabolites including N-acetylaspartate, choline-containing metabolites, creatine plus phosphocreatine, glutamate, and GABA. Some studies used phosphorus (31P)-MRS to quantify biomarkers of cerebral metabolism including phosphocreatine and adenosine triphosphate. A few studies used carbon (13C)-MRS to quantify intermediary metabolism. This Mini-review discusses select studies that illustrate how MRS can complement neurocircuitry research including by use of multimodal imaging strategies that combine MRS with functional MRI (fMRI) and/or diffusion tensor imaging (DTI). Additionally, magnetic resonance spectroscopic imaging (MRSI), which enables simultaneous multivoxel MRS acquisitions, can be used to better understand and interpret whole-brain functional or structural connectivity data. The review discusses some limitations in MRS methodology and then highlights important knowledge gaps and areas for potential future investigation, including the use of 1H- and 31P-MRS to quantify cerebral metabolism, oxidative stress, inflammation, and brain temperature, all of which are associated with SUD and all of which can influence neurocircuitry and behavior.

Effects of long-term cocaine self-administration on brain resting-state functional connectivity in nonhuman primates.

Long-term cocaine use is associated with a variety of neural and behavioral deficits that impact daily function. This study was conducted to examine the effects of chronic cocaine self-administration on resting-state functional connectivity of the dorsal anterior cingulate (dACC) and putamen-two brain regions involved in cognitive function and motoric behavior-identified in a whole brain analysis. Six adult male squirrel monkeys self-administered cocaine (0.32 mg/kg/inj) over 140 sessions. Six additional monkeys that had not received any drug treatment for ~1.5 years served as drug-free controls. Resting-state fMRI imaging sessions at 9.4 Tesla were conducted under isoflurane anesthesia. Functional connectivity maps were derived using seed regions placed in the left dACC or putamen. Results show that cocaine maintained robust self-administration with an average total intake of 367 mg/kg (range: 299-424 mg/kg). In the cocaine group, functional connectivity between the dACC seed and regions primarily involved in motoric behavior was weaker, whereas connectivity between the dACC seed and areas implicated in reward and cognitive processing was stronger. In the putamen seed, weaker widespread connectivity was found between the putamen and other motor regions as well as with prefrontal areas that regulate higher-order executive function; stronger connectivity was found with reward-related regions. dACC connectivity was associated with total cocaine intake. These data indicate that functional connectivity between regions involved in motor, reward, and cognitive processing differed between subjects with recent histories of cocaine self-administration and controls; in dACC, connectivity appears to be related to cumulative cocaine dosage during chronic exposure.

Experimental Traumatic Brain Injury during Adolescence Enhances Cocaine Rewarding Efficacy and Dysregulates Dopamine and Neuroimmune Systems in Brain Reward Substrates.

Although clinical studies identify traumatic brain injury (TBI) as a risk factor for the development of substance use disorder, much remains unknown about the possible underlying pathogenesis and age-specific effects. Thus, the aim of this study is to test the hypothesis that at an age of ongoing maturation, adolescent TBI alters elements of the reward pathway, resulting in increased sensitivity to the rewarding effects of a subthreshold dose of cocaine that does not induce significant behavioral changes in naïve, non-injured mice. Specifically, these results were derived from the combination of the controlled cortical impact model of TBI, performed on either adolescent (6 weeks) or young adult (8 weeks) mice, followed by the cocaine-induced conditioned place preference assay 2 weeks later. Using three-dimensional isosurface rendering and volumetric image analysis, TBI was found to induce neuromorphological changes such as decreased dendritic complexity and reduced spine density in brain regions essential for reward perception and processing of drug-induced euphoria. Further, we demonstrated that these neuronal changes may affect the differential expression of dopamine-associated genes. Our analysis also provided evidence for age-related differences in immune response and the distinct involvement of augmented microglial phagocytic activity in the remodeling of neuronal structures in the adolescent TBI brain. Our studies suggest that TBI during adolescence, a period associated with ongoing maturation of dopaminergic systems, may subsequently enhance the abuse liability of cocaine in adulthood.

Targeted Treatment of Individuals With Psychosis Carrying a Copy Number Variant Containing a Genomic Triplication of the Glycine Decarboxylase Gene.

BACKGROUND: The increased mutational burden for rare structural genomic variants in schizophrenia and other neurodevelopmental disorders has so far not yielded therapies targeting the biological effects of specific mutations. We identified two carriers (mother and son) of a triplication of the gene encoding glycine decarboxylase, GLDC, presumably resulting in reduced availability of the N-methyl-D-aspartate receptor coagonists glycine and D-serine and N-methyl-D-aspartate receptor hypofunction. Both carriers had a diagnosis of a psychotic disorder. METHODS: We carried out two double-blind, placebo-controlled clinical trials of N-methyl-D-aspartate receptor augmentation of psychotropic drug treatment in these two individuals. Glycine was used in the first clinical trial, and D-cycloserine was used in the second one. RESULTS: Glycine or D-cycloserine augmentation of psychotropic drug treatment each improved psychotic and mood symptoms in placebo-controlled trials. CONCLUSIONS: These results provide two independent proof-of-principle demonstrations of symptom relief by targeting a specific genotype and explicitly link an individual mutation to the pathophysiology of psychosis and treatment response.

Effects of chronic cocaine self-administration and N-acetylcysteine on learning, cognitive flexibility, and reinstatement in nonhuman primates.

RATIONALE: Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine's deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotransmission in CUD and drugs that normalize glutamatergic homeostasis (e.g., N-acetylcysteine [NAC]) may attenuate CUD-related relapse behavior. OBJECTIVES: The present studies examined the impact of chronic cocaine exposure on touchscreen-based models of learning (repeated acquisition) and cognitive flexibility (discrimination reversal) and, also, the ability of NAC to modulate cocaine self-administration and its capacity to reinstate drug-seeking behavior. METHODS: First, stable repeated acquisition and discrimination reversal performance was established. Next, high levels of cocaine-taking behavior (2.13-3.03 mg/kg/session) were maintained for 150 sessions during which repeated acquisition and discrimination reversal performance was probed periodically. Finally, the effects of NAC treatment were examined on cocaine self-administration and, subsequently, extinction and reinstatement. RESULTS: Cocaine self-administration significantly impaired performance under both cognitive tasks; however, discrimination reversal was disrupted considerably more than acquisition. Performance eventually approximated baseline levels during chronic exposure. NAC treatment did not perturb ongoing self-administration behavior but was associated with significantly quicker extinction of drug-lever responding. Cocaine-primed reinstatement did not significantly differ between groups. CONCLUSIONS: The disruptive effects of cocaine on learning and cognitive flexibility are profound but performance recovered during chronic exposure. Although the effects of NAC on models of drug-taking and drug-seeking behavior in monkeys are less robust than reported in rodents, they nevertheless suggest a role for glutamatergic modulators in CUD treatment programs.

Supraphysiologic-dose anabolic-androgenic steroid use: A risk factor for dementia?

Supraphysiologic-dose anabolic-androgenic steroid (AAS) use is associated with physiologic, cognitive, and brain abnormalities similar to those found in people at risk for developing Alzheimer's Disease and its related dementias (AD/ADRD), which are associated with high brain ß-amyloid (Aß) and hyperphosphorylated tau (tau-P) protein levels. Supraphysiologic-dose AAS induces androgen abnormalities and excess oxidative stress, which have been linked to increased and decreased expression or activity of proteins that synthesize and eliminate, respectively, Aß and tau-P. Aß and tau-P accumulation may begin soon after initiating supraphysiologic-dose AAS use, which typically occurs in the early 20s, and their accumulation may be accelerated by other psychoactive substance use, which is common among non-medical AAS users. Accordingly, the widespread use of supraphysiologic-dose AAS may increase the numbers of people who develop dementia. Early diagnosis and correction of sex-steroid level abnormalities and excess oxidative stress could attenuate risk for developing AD/ADRD in supraphysiologic-dose AAS users, in people with other substance use disorders, and in people with low sex-steroid levels or excess oxidative stress associated with aging.

Simian immunodeficiency virus transiently increases brain temperature in rhesus monkeys: detection with magnetic resonance spectroscopy thermometry.

PURPOSE: To evaluate brain temperature effects of early simian immunodeficiency virus (SIV) infection in rhesus macaques using proton magnetic resonance spectroscopy (MRS) thermometry (MRSt) and to determine whether temperature correlates with brain choline or myo-inositol levels. METHODS: Brain temperature was retrospectively determined in serial MRS scans that had been acquired at baseline and at 2 and 4 weeks post-SIV infection (wpi) in 16 monkeys by calculating the chemical shift difference between N-acetylaspartate (NAA) and water peaks in sequentially acquired water-suppressed and unsuppressed point-resolved spectroscopy (PRESS) spectra. Frontal and parietal cortex, basal ganglia, and white matter spectra were analyzed. RESULTS: At 2 wpi, brain and rectal temperatures increased relative to baseline and normalized at 4 wpi. Brain temperatures correlated with choline levels in several brain areas, but not with myo-inositol levels. CONCLUSION: These data indicate that SIV transiently increases brain temperature soon after infection and that temperature is correlated with transient changes in choline levels. Given that choline levels are associated with brain inflammation in SIV-infected monkeys, our findings suggest that the SIV-induced temperature increase reflects brain inflammation. We conclude that MRSt may be informative in human immunodeficiency virus models and may be useful for assessing effects of treatments that reduce inflammation. This study also illustrates that existing MRS data sets containing unsuppressed water spectra can be used to measure tissue temperature, an important physiological parameter.

Public health impact of androgens.

PURPOSE OF REVIEW: To summarize recent findings regarding the public health impact of androgen abuse. RECENT FINDINGS: Abuse of androgens (also called 'anabolic-androgenic steroids') has grown into a major worldwide substance abuse problem involving tens of millions of individuals, of whom about 98% are men. Most androgen abusers are still under age 50 today, and thus, the long-term effects of these drugs are only beginning to be understood. Recent studies confirm that long-term supraphysiologic androgen exposure produces cardiovascular toxicity, characterized especially by cardiomyopathy and atherosclerotic disease. Withdrawal from androgens after long-term use may produce prolonged and sometimes irreversible hypogonadism in men. Supraphysiologic androgen levels may sometimes cause irritability, aggressiveness, and violence, whereas androgen withdrawal may cause depression. However, these psychiatric effects are idiosyncratic, affecting only a minority of users. Emerging evidence now also suggests that long-term androgen exposure may cause neurotoxicity, raising the possibility that aging androgen abusers may be at increased risk for dementia. Several recent studies have also described androgen-induced hepatotoxicity, nephrotoxicity, and adverse musculoskeletal effects. SUMMARY: Recent studies have demonstrated marked adverse effects of long-term androgen abuse. As increasing numbers of androgen abusers reach middle age, these effects will likely represent an emerging public health problem.