HIV-associated Neurocognitive Disorders Research Articles

Evaluating Human Immunodeficiency Virus (HIV) Neuropathogenesis on HIV -Associated Neurocognitive Disorder (HAND): Role of Virology, Cellular and Immunology Aspects

Human Immunodeficiency Virus (HIV) became a worldwide pandemic with a global prevalence of 36.9 million in 2014. One of the neurological complications of HIV infection is HIV-associated neurocognitive disorder (HAND). The administration of antiretroviral (ARV) therapy to HIV patients in general contributed to lowering HIV mortality and morbidity. However, ARV therapy did not provide complete protection for neurons. The cumulative prevalence of severe HAND in the lifetime of HIV patients is estimated to be 15%. HAND is classified into three categories: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). HAND remains a significant cause of morbidity in HIV patients. Recent findings on research using animal models have shown new concept development, both viral and cellular-related, on HAND neuropathogenesis, including other clinical factors contributing to HAND progression. Factors contributing to HAND neuropathogenesis consist of the cellular aspect, shown by the role of macrophages and astrocytes, and the viral aspect, shown by the role of neurotoxic HIV proteins and inflammatory molecules. HAND progression comprised chronic neuroinflammation, postsynaptic density decrements, and neurogenesis impairment. A better understanding of HAND neuropathogenesis will increase the optimization of HAND therapy.

Clustering of cognitive domains among older persons with HIV.

Age and HIV are synergistic risk factors for conditions such as HIV-associated neurocognitive disorders (HAND). Yet, it is unclear whether older persons with HIV (OPWH) display different cognitive profiles for HAND. To describe the cognitive patterns of OPWH treated with combined antiretroviral therapy (cART). Cross-sectional study that included 330 participants with HIV, aged 50 years or older, cared for at a tertiary care hospital in Mexico City. A short neuropsychological test battery was used to assess a wide spectrum of cognitive functions. The optimal number of cognitive clusters was determined by the silhouette method and a minimization of the Bayesian information criterion. Participants' mean age was 58.8 years (standard deviation = 6.6), and 12.1% were women. A 3-cluster solution yielded stable Jaccard coefficients (p > 0.70). Cluster 1 showed more significant impairment in visual and verbal memory domains, whereas participants in cluster 3 showed significant impairment in language, and abstraction. Cluster 2 showed no predominance of any domain for alterations. There are different cognitive profiles among OAWH with HAND. These differences may be due to individual patterns of HIV-related and non-HIV-related factors.

Accelerated cognitive aging in chronically infected HIV-1 positive individuals despite effective long-term antiretroviral therapy.

People living with HIV (PLHIV) are known to be at a higher risk of developing an array of aging-related diseases despite well-adhered combined antiretroviral therapy (cART). The present study aimed to investigate the impact of chronic HIV infection on neurocognitive function in virally suppressed PLHIV. We enrolled HIV-positive individuals randomly from an ART Center in Chennai, South India. A similar number of HIV-uninfected individuals matched for age and gender with the HIV-infected individuals served as controls. All individuals provided a detailed clinical history and underwent neuropsychological assessment using the International HIV Dementia Scale (IHDS). Plasma proteome analysis was performed using the Proximity extension assay (PEA) with the Olink® neuroexploratory panel, and untargeted metabolomics was performed using Ultra-High-Performance Liquid Chromatography/Mass Spectrometry/Mass Spectrometry. Despite a median duration of 9years on first-line cART and suppressed viremia, a significant proportion of PLHIV registered significant levels of asymptomatic neurocognitive impairment, with 71% of these individuals scoring ≤ 10 in the IHDS test. We also observed significant alterations in a number of proteins and metabolites that are known to be associated with neuroinflammation, neurodegeneration, cognitive impairment, and gastrointestinal cancers, in the PLHIV group. Thus the study provides clinical as well as laboratory evidence to substantiate the presence of asymptomatic neurocognitive impairment in a large proportion of PLHIV, despite adequate cART and undetectable viremia, thereby supporting the view that HIV infection potentiates the risk for accelerated and accentuated neurological aging. This observation highlights the need to devise and implement appropriate intervention strategies for better long term management of HIV-infected persons.

The prefrontal cortex, but not the medial temporal lobe, is associated with episodic memory in middle-aged persons with HIV.

Identifying persons with HIV (PWH) at increased risk for Alzheimer's disease (AD) is complicated because memory deficits are common in HIV-associated neurocognitive disorders (HAND) and a defining feature of amnestic mild cognitive impairment (aMCI; a precursor to AD). Recognition memory deficits may be useful in differentiating these etiologies. Therefore, neuroimaging correlates of different memory deficits (i.e., recall, recognition) and their longitudinal trajectories in PWH were examined. We examined 92 PWH from the CHARTER Program, ages 45-68, without severe comorbid conditions, who received baseline structural MRI and baseline and longitudinal neuropsychological testing. Linear and logistic regression examined neuroanatomical correlates (i.e., cortical thickness and volumes of regions associated with HAND and/or AD) of memory performance at baseline and multilevel modeling examined neuroanatomical correlates of memory decline (average follow-up = 6.5 years). At baseline, thinner pars opercularis cortex was associated with impaired recognition (p = 0.012; p = 0.060 after correcting for multiple comparisons). Worse delayed recall was associated with thinner pars opercularis (p = 0.001) and thinner rostral middle frontal cortex (p = 0.006) cross sectionally even after correcting for multiple comparisons. Delayed recall and recognition were not associated with medial temporal lobe (MTL), basal ganglia, or other prefrontal structures. Recognition impairment was variable over time, and there was little decline in delayed recall. Baseline MTL and prefrontal structures were not associated with delayed recall. Episodic memory was associated with prefrontal structures, and MTL and prefrontal structures did not predict memory decline. There was relative stability in memory over time. Findings suggest that episodic memory is more related to frontal structures, rather than encroaching AD pathology, in middle-aged PWH. Additional research should clarify if recognition is useful clinically to differentiate aMCI and HAND.

Linguistic Markers of Subtle Cognitive Impairment in Connected Speech: A Systematic Review.

This systematic review covers the current stage of research on subtle cognitive impairment with connected speech. It aims at surveying the linguistic features in use to single out those that can best identify patients with mild neurocognitive disorders (mNCDs), whose cognitive changes remain underdiagnosed. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and proposed a full definition of features for the analysis of speech features. Fifty-one studies met the inclusion criteria. Most of them focused on age-related progressive diseases and included fewer than 30 subjects. A total of 384 features labeled with 335 different names was retrieved, yielding various results in discriminating individuals with mNCDs from controls. This finding highlights the need for harmonized labels to further investigate mNCDs with linguistic markers. We suggest two different ways of assessing a feature's reliability. We also point out potential methodological issues that remain to be resolved, along with recommendations for reproducible research in the field.

Effect of different durations of preoperative computerised cognitive training on postoperative delirium in older patients undergoing cardiac surgery: a study protocol for a prospective, randomised controlled trial

IntroductionPostoperative delirium (POD) is a common neurological complication after surgery among older patients, characterised by acute disturbances in consciousness, attention and cognition, usually occurring within 24–72 hours after surgery. POD...

Nef mediates neuroimmune response, myelin impairment, and neuronal injury in EcoHIV-infected mice.

The introduction of antiretroviral therapy has markedly improved the management of HIV-associated neurocognitive disorders (HAND). However, HAND still affects nearly half of HIV-infected individuals, presenting significant challenges to their well-being. This highlights the critical need for a deeper understanding of HAND mechanisms. Among HIV viral proteins, Nef is notable for its multifaceted role in HIV pathogenesis, though its specific involvement in HAND remains unclear. To investigate this, we used a murine model infected with Nef-expressing (EcoHIV) and Nef-deficient (EcoHIVΔNef) murine HIV. Comparative analyses revealed increased neuroinflammation and reduced myelin and neuronal integrity in EcoHIV-infected brains compared with those with EcoHIVΔNef. Both viruses induced astrogliosis, with stronger GFAP activation in Nef-deficient infections. These findings suggest that Nef contributes to neuroinflammation, primarily through microglial targeting and demyelination, although other factors may regulate astrogliosis. Our results indicate that Nef may significantly contribute to neuronal injury in EcoHIV-infected mice, offering insights into Nef-induced neuropathology in HAND and guiding future research.

Measuring the effects of ketogenic diet on neuropsychiatric disorder: A scoping review.

This scoping review aims to examine the available literature on the ketogenic diet's (KD) efficiency as a potential therapeutic intervention for various neuropsychiatric disorders. The KD is a high-fat, low-carbohydrate diet that has been studied for its potential benefits in managing neuropsychiatric disorders. However, the extent of its effectiveness across a spectrum of these conditions remains unclear. The study designs considered eligible encompassed randomized and non-randomized controlled trials, retrospective and prospective observational studies, and comparative effectiveness assessments. The criteria for including each study were specifically related to neuropsychiatric disorders, referring to the DSM-5 coding guidelines. A systemic search was performed by an experienced reference librarian across multiple databases to pinpoint studies relevant to the influence of the ketogenic diet on neuropsychiatric disorders. All relevant articles were included that ranged over the last thirteen years. All relevant records identified were compiled into the Covidence systematic review software. A total of 30 studies were reviewed, which reported effects of the KD on neuropsychiatric disorders, including improvements in Global Developmental Delay, Childhood Autism, Attention Deficit/Hyperactivity Disorder (ADHD) symptoms, psychotic symptoms, Bipolar and Related Disorders, Depressive Disorder symptoms, anxiety symptoms, eating disorders, Substance-Related and Addictive Disorders, Major and Mild Neurocognitive Disorders, and Seizure Disorders. The KD may serve as a promising therapeutic intervention for various neuropsychiatric disorders. However, the evidence is heterogeneous, and further rigorous research is needed to establish the KD as a standard treatment for these disorders and to understand the underlying mechanisms of its effects. This review underscores the need for healthcare professionals to consider the potential benefits and limitations of the KD when managing patients with neuropsychiatric disorders. It also highlights the importance of individualized treatment plans based on the specific needs and responses of each patient.

Association between a lower T-CD4+ /CD8+ lymphocyte ratio and cognitive impairment in older persons with HIV.

To ascertain the association between the LT-CD4 + /CD8 + ratio and cognitive impairment in older people living with HIV. A cross-sectional study was conducted, including 207 adults aged > 50years with HIV, receiving care at a tertiary-care hospital in Mexico City. Participants underwent a standardized geriatric and neuropsychological assessment to establish the presence of HIV-associated neurocognitive disorder according to the validated Antinori criteria. Multivariate logistic regression models were performed to determine the association between T-CD4 + /CD8 + lymphocyte ratio tercile values (0.57-0.91, and < 0.56; with > 0.91 being the reference category) and cognitive impairment. Participants' median age was 56 (IQR 53-62)years and 173 (83.6%) were men. The prevalence of any kind of cognitive impairment according to the Antinori criteria was 66.2% (n = 137), the highest proportion being asymptomatic neurocognitive impairment (n = 114, 83.2%). Adjusted logistic regression analyses showed that the lowest LT-CD4 + /CD8 + ratio tercile values (< 0.56) were independently associated with the presence of cognitive impairment (OR 3.16; 95% CI 1.22-8.16, p = 0.017). Lower LT-CD4 + /CD8 + ratios are independently associated with cognitively impaired older persons with HIV, which represents another factor that could be addressed to identify individuals at risk and focus on cognitive screening as well as correction of other modifiable risk factors.

The impacts of tobacco and nicotine on HIV-1 infection, inflammation, and the blood-brain barrier in the central nervous system.

Human immunodeficiency virus (HIV-1) remains a persistent global health crisis. Even while successfully virologically suppressed, people with HIV (PWH) experience a higher risk for inflammatory disorders such as HIV-associated neurocognitive disorder (HAND). Tobacco use puts PWH at higher risk for neurocognitive symptoms resulting from HIV-associated neuroinflammation. The NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome has been implicated as a driver of HIV-associated inflammation, including HAND. Nicotine, the psychoactive component of tobacco smoke, has also been shown to signal through the NLRP3 inflammasome and modulate inflammatory signaling in the CNS. Here, we explore the impacts of nicotine and tobacco on the complex neurobiology of HAND, including effects on cognition, inflammation, viral latency, and blood-brain barrier integrity. We outline nicotine's role in the establishment of active and latent infection in the brain and posit the NLRP3 inflammasome as a common pathway by which HIV-1 and nicotine promote neuroinflammation in PWH.

Brain-Derived Neurotrophic Factor (BDNF) is Associated with Self-Reported Cognitive Function in Adults with HIV.

Background: People with HIV (PWH) are at risk of developing HIV-associated neurocognitive disorder (HAND) despite receiving combination antiretroviral therapy. Brain-derived neurotrophic factor (BDNF) has been implicated in cognitive function and neuroplasticity, but its role in HIV-related neuroinflammation remains understudied. Methods: This study analyzed data from the CHAMPS study, assessing BDNF serum levels and cognitive function in 140 adults with HIV at baseline. Cognitive function was evaluated using the PROMIS Applied Cognition-Abilities 8-item questionnaire. BDNF levels (pg/ml) were measured using high sensitivity Enzyme-Linked Immunoassay (ELISA) kits. Linear regression analyses were conducted to explore the associations between BDNF levels, cognitive function, and AIDS diagnosis, adjusting for demographic variables. Results: A significant positive association was found between BDNF levels and cognitive function scores in PWH (p = .03). Additionally, PWH with a history of AIDS diagnosis showed significantly lower BDNF levels (p = .02). Other demographic factors did not significantly impact cognitive function or BDNF levels in this cohort. Conclusions: Our results highlight the potential of BDNF as a biomarker for cognitive decline in PWH and suggest its relevance in understanding HAND pathophysiology. Further research is warranted to explore the multifaceted interactions influencing cognitive outcomes in this population and to develop targeted interventions for improving cognitive health in PWH.

Impact of switching from EFV/F/TDF to B/F/TAF on psychiatric symptoms and neurocognition.

The aim was to investigate whether switching from EFV/F/TDF to B/F/TAF may improve neuropsychiatrc symptoms and neurocognition. Pilot, single-arm, prospective study of persons with HIV (PWH) on the efficacy and safety of switching from EFV/F/TDF to B/F/TAF. Participants underwent neuropsychological assessment (NPA) at switch (T0) and after 48 weeks (T1). NPA was carried out through a standardized battery of 12 tests. Neurocognitive impairment (NCI) was defined by a score ≥1 standard deviation (SD) below the normal mean on at least 2 tests or ≥2 SD below on 1 test. Individual z-scores were determined, NPZ-12 was calculated as the average of 12 test z-scores and change of NPZ-12 was the outcome. HIV-associated Neurocognitive Disorder (HAND) was classified by Frascati's criteria. Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI-II), and Pittsburgh Sleep Quality Index (PSQI) were administered. Paired-Wilcoxon and McNemar tests were used for comparisons, and logistic regression for associations with NCI changes. Out of 126 participants, BAI, BDI-II, and PSQI questionnaires revealed an improvement at T1. NPA revealed NCI in 40.5% of persons at T0 and 42.1% at T1 (p = 0.746). Specifically, at T0, among participants with NCI, 35% improved; among those without, 26% worsened at T1; NPZ-12 score worsened at T1. 5.6% of ANI was observed at T0 and 7.9% at T1. No factor associated with these changes was found. Our results suggest switching from EFV/F/TDF to B/F/TAF significantly improves psychiatric symptoms and sleep quality. Neurocognitive performance remained stable, although a decline in NPZ-12 and in specific domains was observed.

HIV-Associated Neurocognitive Disorder (HAND) and Alzheimer's Disease Pathogenesis: Future Directions for Diagnosis and Treatment.

HIV-associated neurocognitive disorder (HAND) and Alzheimer's disease (AD) are two neurocognitive disorders with overlapping clinical presentations and pathophysiology. The two have been thought to be two separate entities. However, the introduction and widespread use of antiretroviral therapy (ART) has altered the clinical manifestations of HAND, shifting from a pattern of subcortical dementia to one more akin to cortical dementia, resembling AD. Thus, the line between the two disease entities is not clear-cut. In this review, we discuss the concept of Alzheimer's disease-like dementia (ADLD) in HIV, which describes this phenomenon. While the mechanisms of HIV-associated ADLD remain to be elucidated, potential mechanisms include HIV-specific pathways, including epigenetic imprinting from initial viral infection, persistent and low viral load (which can only be detected by ultra-sensitive PCR), HIV-related inflammation, and putative pathways underlying traditional AD risk factors. Importantly, we have shown that HIV-specific microRNAs (miRs) encapsulated in extracellular vesicles (EV-miRs) play an important role in mediating the detrimental effects in the cardiovascular system. A useful preclinical model to study ADLD would be to expose AD mice to HIV-positive EVs to identify candidate EV-miRs that mediate the HIV-specific effects underlying ADLD. Characterization of the candidate EV-miRs may provide novel therapeutic armamentaria for ADLD.

Role of Meaningful Social Participation and Technology Use in Mitigating Loneliness and Cognitive Decline Among Older Adults.

Community social participation aids dementia prevention and alleviates loneliness among older adults. Incorporating occupational therapy using information and communications technology (ICT) could potentially delay dementia onset and reduce loneliness. To quantify how meaningful social participation, participation frequency, ICT use, and expanded social networks influence cognitive function and loneliness among socially active older Japanese adults. Cross-sectional exploratory study using structural equation modeling. Meetings organized by older adults at seven community gathering places in Osaka Prefecture, Japan. One hundred thirteen healthy older adult cohort members. Cognitive function assessed via Mini-Cog; loneliness assessed via the condensed UCLA Loneliness Scale. The final model demonstrated excellent fit, χ2(23) = 28.291, p = .205 (root mean square error of approximation = .045, 90% confidence interval [.000, .094]; confirmatory factor index = .995; Tucker-Lewis Index = .993). ICT use directly affected social networks (β = 0.472), which directly influenced participation frequency (β = 0.324) and meaningful social participation (β = 0.381). The indirect effect of meaningful participation significantly improved cognitive function (β = 0.237). The only indirect effect of meaningful interpersonal participation was a reduction in loneliness (β = -0.235). ICT use contributes to the expansion of social networks among elderly people. Furthermore, the frequency of social participation and the meaningfulness of such participation are related to reduction in loneliness and maintenance of cognitive function. Although the frequency of social participation was not directly related to these outcomes, the results suggest that meaningful social participation may play an important role in reducing loneliness and maintaining cognitive function. Plain-Language Summary: The promotion of social participation among older people is a global phenomenon, driven by the recognition of its positive relationship with cognitive function and the alleviation of loneliness. Nevertheless, older people's social participation is constrained by a combination of physical and social factors. To address this issue, there has been a push to promote social participation based on information and communications technology (ICT). However, no specific study has been conducted on occupational therapists' perspective in capturing social participation and the use of ICT. The findings of this study show that using ICT has the potential to enhance opportunities for social interaction for older adults, thereby improving the quality and quantity of social participation. The quality of social participation was identified as the sole factor that had a positive impact on cognitive function and loneliness. This study suggests the need for occupational therapists to consider means of facilitating the use of ICTs among older adults as well as interventions that use occupational therapy theory to enhance the meaningfulness of existing social participation opportunities.

Assessment of prevalence, risk factors, and neuropsychiatric symptoms of mild neurocognitive disorder among elderly in Suez Canal Area

Abstract Background Mild neurocognitive disorder is mild reduction in cognitive abilities than a previous level, requiring compensatory strategies that help maintain independence, and is associated with behavioral and psychiatric symptoms. This cross-sectional comparative study aimed to evaluate prevalence of mild neurocognitive disorder, its risk factors, and associated neuropsychiatric symptoms. It included a sample of 156 elderly people ≥ 60 years old in Suez Canal Area from geriatric homes and primary health care centers. Study tools included a semi-structured clinical interview to assess sociodemographic, clinical, and lifestyle risk factors, DSM-5 criteria for diagnosis of neurocognitive disorders, the Montreal Cognitive Assessment Scale, and the Neuropsychiatric Inventory Questionnaire. Results Prevalence of mild neurocognitive disorder was 37.2% in total sample with mean total score of 22.7 ± 6.1 by Montreal Cognitive Assessment Scale. The most common subtype was amnestic multiple domain subtype (72.4%). Its predicting factors included advanced age, lower education, physical work, non-adherence to treatment, less physical activity, bone and joint disorders, and family history of cognitive impairment. The neuropsychiatric symptoms with highest scores were sleep/nighttime behavior, depression, irritability, and eating/appetite, respectively. Among the two study groups, geriatric home residents had highly significant lower cognitive scores (p &lt; 0.001) and higher Neuropsychiatric Inventory Questionnaire scores. Conclusion Mild neurocognitive disorder is common among elderly people and is associated with neuropsychiatric symptoms that need screening and management. Modifiable risk factors should be identified to provide interventions.

Modulating Immune Responses: The Double-Edged Sword of Platelet CD40L.

The CD40-CD40L receptor ligand pair plays a fundamental role in the modulation of the innate as well as the adaptive immune response, regulating monocyte, T and B cell activation, and antibody isotype switching. Although the expression and function of the CD40-CD40L dyad is mainly attributed to the classical immune cells, the majority of CD40L is expressed by activated platelets, either in a membrane-bound form or shed as soluble molecules in the circulation. Platelet-derived CD40L is involved in the communication with different immune cell subpopulations and regulates their functions effectively. Thus, platelet CD40L contributes to the containment and clearance of bacterial and viral infections, and additionally guides leukocytes to sites of infection. However, platelet CD40L promotes inflammatory cellular responses also in a pathophysiological context. For example, in HIV infections, platelet CD40L is supportive of neuronal inflammation, damage, and finally HIV-related dementia. In sepsis, platelet CD40L can induce extensive endothelial and epithelial damage resulting in barrier dysfunction of the gut, whereby the translocation of microbiota into the circulation further aggravates the uncontrolled systemic inflammation. Nevertheless, a distinct platelet subpopulation expressing CD40L under septic conditions can attenuate systemic inflammation and reduce mortality in mice. This review focuses on recent findings in the field of platelet CD40L biology and its physiological and pathophysiological implications, and thereby highlights platelets as vital immune cells that are essential for a proper immune surveillance. In this context, platelet CD40L proves to be an interesting target for various inflammatory diseases. However, either an agonism or a blockade of CD40L needs to be well balanced since both the approaches can cause severe adverse events, ranging from hyperinflammation to immune deficiency. Thus, an interference in CD40L activities should be likely done in a context-dependent and timely restricted manner.

Examining the effects of the HIV-1 protein Tat and morphine on antiretroviral accumulation and distribution within the brain.

Despite combination antiretroviral therapy effectively suppressing HIV within the periphery, neuro-acquired HIV (neuroHIV) remains a significant problem and approximately half of people living with HIV will experience HIV-associated neurocognitive disorders (HAND). Concurrent opioid use exacerbates neuroHIV by promoting neuroinflammation, neuronal injury and synaptodendritic culling, viral replication, and potentially altering antiretroviral concentrations within the brain. The present study examined the effects of HIV and morphine co-exposure on the accumulation and spatial distribution of antiretroviral drugs across multiple regions within the brain in an HIV-1 Tat transgenic mouse model by using infrared-matrix-assisted laser desorption electrospray ionization mass spectrometry imaging (IR-MALDESI MSI). Morphine exposure uniquely decreased antiretroviral concentrations in anterior cerebral (primary motor and somatosensory) cortices, corpus collosum (anterior forceps), caudoputamen, nucleus accumbens, and posterior regions including the hippocampus, corpus callosum (main body), cerebral cortex (somatosensory and auditory cortices), thalamus, and hypothalamus. Interestingly, male mice experienced greater morphine-associated decreases in antiretroviral concentrations than females. The study also assessed whether changes in antiretroviral concentrations were linked with inflammation in astroglia, assessed through the measurement of astroglial activation using glial fibrillary acidic protein (GFAP) as a marker. Alterations in antiretroviral concentrations co-registering with areas of astroglial activation exhibited sex-specific treatment differences. This study highlights the intricate interplay between HIV, opioids, and antiretroviral drugs within the CNS, elucidating distinct regional and sex variations in responsiveness. Our findings emphasize the identification of vulnerabilities within the neural landscape and underscore the necessity of carefully monitoring opioid use to maintain the efficacy of antiretroviral therapies.

Exploration of Risk Factors for Mild and Major Neurocognitive Disorders in A Sample of Elderly Population

Exploration of Risk Factors for Mild and Major Neurocognitive Disorders in A Sample of Elderly Population

Reevaluating ADHD and its First-Line Treatment: Insights from DSM-5-TR and Modern Approaches.

Is Attention Deficit Hyperactivity Disorder (ADHD) a "brain disorder"? Should it be managed regularly with stimulant drugs? This article critically examines the evolving biomedical discourse surrounding these questions through a close inspection of the latest edition of the influential psychiatric manual - the DSM-5-TR - as well as additional authoritative sources (e.g., previous DSM editions, consensus statements, FDA communications). The DSM-5-TR acknowledges that "no biological marker is diagnostic for ADHD" and that "meta-analyses of all neuroimaging studies do not show differences between individuals with ADHD and control subjects." The authors of the DSM-5-TR, therefore, conclude that "until these issues are resolved, no form of neuroimaging can be used for diagnosis of ADHD." These statements, along with biases in the neuroimaging literature and additional empirical evidence presented in the article, challenge popular myths about the neurobiological basis of ADHD. Similarly, common beliefs about the first-line treatment of ADHD with stimulant drugs are being increasingly questioned today. For instance, the DSM-5-TR's section on Stimulant-Related Disorders introduces a new diagnostic entity named: Stimulant-Induced Mild Neurocognitive Disorder. This addition aligns with a recent FDA Drug Safety Communication for "all prescription stimulants," which highlights longstanding concerns regarding the safety of medications prescribed to millions of diagnosed individuals, primarily children. The FDA now mandates that "the Boxed Warning, FDA's most prominent warning, will describe the risks of misuse, abuse, addiction, and overdose," emphasizing that such "misuse and abuse of prescription stimulants can result in overdose and death." In light of these challenges to the biomedical discourse, this article offers a neurodiversity-oriented alternative. Using evolutionary principles and historical context, it argues that most cases of ADHD fall under the DSM's socio-philosophical category of "conflicts that are primarily between the individual and society" (similar to homosexuality, which was removed from the DSM in 1973), and are therefore "not mental disorders".

Changes in cerebrospinal fluid proteins across the spectrum of untreated and treated chronic HIV-1 infection.

Using the Olink Explore 1536 platform, we measured 1,463 unique proteins in 303 cerebrospinal fluid (CSF) specimens from four clinical centers contributed by uninfected controls and 12 groups of people living with HIV-1 infection representing the spectrum of progressive untreated and treated chronic infection. We present three initial analyses of these measurements: an overview of the CSF protein features of the sample; correlations of the CSF proteins with CSF HIV-1 RNA and neurofilament light chain protein (NfL) concentrations; and comparison of CSF proteins in HIV-associated dementia (HAD) and neurosymptomatic CSF escape (NSE). These reveal a complex but coherent picture of CSF protein changes with highest concentrations of many proteins during CNS injury in the HAD and NSE groups and variable protein changes across the course of systemic HIV-1 progression that included two common patterns, designated as lymphoid and myeloid patterns, related to principal involvement of their underlying inflammatory cell lineages. Antiretroviral therapy reduced CSF protein perturbations, though not always to control levels. The dataset of these CSF protein measurements, along with background clinical information, is posted online. Extended studies of this unique dataset will supplement this report to provide more detailed characterization of the dynamic impact of HIV-1 infection on the CSF proteome across the spectrum of HIV-1 infection, advancing the mechanistic understanding of HIV-1-related CNS pathobiology.