HIV-associated Neurocognitive Disorders Research Articles

The protective effects of apelin-13 in HIV-1 tat- induced macrophage infiltration and BBB impairment

ABSTRACT Impairment of the blood – brain barrier (BBB) and subsequent inflammatory responses contribute to the development of human immunodeficiency virus (HIV)-1-associated neurocognitive disorders (HAND). Apelin-13, the most abundant member of the apelin family, acts as the ligand of the angiotensin receptor-like 1 (APJ). However, its pharmacological function in HAND and its underlying mechanism are unknown. In the current study, we report that the presence of HIV-1 Tat reduced the levels of Apelin-13 and APJ in the cortex tissue of mice. Importantly, Apelin-13 preserved BBB integrity against HIV-1 Tat in mice by increasing the expression of the tight junction protein zonula occludens-1 (ZO-1) and occludin. Interestingly, increased macrophage infiltration, indicated by elevated CD68-positive staining was observed in the cortex after stimulation with HIV-1, which was mitigated by the administration of Apelin-13. Correspondingly, Apelin-13 reduced the expression of monocyte chemoattractant protein-1; (MCP-1). An in vitro two-chamber and two-cell trans-well assay demonstrated that HIV-1 Tat challenge significantly promoted macrophage migration, which was notably attenuated by the introduction of Apelin-13. Accordingly, treatment with Apelin-13 restored the HIV-1 Tat-induced reduction of occludin and ZO-1, while preventing the upregulation of MCP-1 in human brain microvascular endothelial cells (HBMVECs). Our results suggest that Apelin-13 may reduce macrophage infiltration into brain tissues and mitigate BBB dysfunction in patients with HAND.

Enhanced Cognition and Modulation of Brain Connectivity in Mild Neurocognitive Disorder: The Promise of Transcranial Pulse Stimulation.

Existing pharmacological treatments for mild neurocognitive disorder (NCD) offer limited effectiveness and adverse side effects. Transcranial pulse stimulation (TPS) utilizing ultrashort ultrasound pulses reaches deep brain regions and may circumvent conductivity issues associated with brain stimulation. This study addresses the gap in TPS research for mild NCD during a critical intervention period before irreversible cognitive degradation. Our objective was to explore the effectiveness and tolerability of TPS in older adults with mild NCD. In an open-label study, 17 older adults (including 10 females and 7 males) with mild NCD underwent TPS for two weeks with three sessions per week. Cognitive evaluations and fMRI scans were conducted pre- and post-intervention. The results indicated changes in functional connectivity in key brain regions, correlating with cognitive improvement at B = 0.087 (CI, 0.007-0.167; p = 0.038). However, cortical thickness measurements showed no significant differences. Here we show that TPS can enhance cognitive function within mild NCD. This proof-of-concept study suggests that TPS has potential as a non-invasive therapy used to attenuate cognitive decline, encouraging further investigation in larger randomized trials. The findings could influence clinical practice by introducing TPS as an adjunctive treatment option and potentially impact policy by promoting its inclusion in new treatment strategies for mild NCD.

B - 80 The Long-Term Memory Sign in Adults Referred for Neuropsychological Evaluation

Abstract Objective We investigated the clinical utility of the newly described long-term memory (LTM) sign in adults referred for neuropsychological evaluation. Individuals with dementia often report short-term episodic memory decline or no memory decline, but rarely report long-term episodic memory decline. The LTM sign refers to patient self-report of long-term episodic memory decline, that is equivalent to/or greater than, subjective short-term episodic memory decline. Method The LTM sign was endorsed on a pre-visit intake form and established during clinical interview in 568 patients (M age = 63, SD = 14.3) referred for neuropsychological evaluation at a large medical center in the Northwest United States. Results In our sample of 568 patients, 79 (14%) reported the LTM sign. In 79 patients with the LTM sign, 45 were diagnosed with a primary psychiatric disorder (57%), 23 were diagnosed with mild neurocognitive disorder (29%), seven had no cognitive or psychiatric diagnosis (9%), and four had dementia (5%). The LTM sign was most common in those with a history of trauma in childhood or adolescence (52/79, 66%) and substance use disorders (50/79, 63%). Conclusions The LTM sign was rare in dementia, but common in those with a current psychiatric diagnosis. These findings support the literature on episodic memory decline in dementia populations and suggests that encoding of early memories and/or retrieval of old memories is negatively impacted by a current psychiatric disorder, traumatic events in childhood and adolescence, and lifetime history of substance use disorder. The LTM sign is a valuable addition to the clinical interview of neuropsychological patients.

B - 145 CVLT-3 Forced Choice Recognition Failure Rate in a Mixed Clinical Population

Abstract Objective The CVLT-3 is a measure of verbal learning and memory used extensively in clinical and research settings that contains an embedded performance validity indicator, a forced choice recognition trial (CVLT-3-FCR). The CVLT-2-FCR was modified for the CVLT-3-FCR, replacing abstract with concrete distractor words. To date, no one has reported independent data on failure rates in clinical populations on the CVLT-3-FCR. Method Participants were 373 patients referred for clinical neuropsychological evaluation who completed the CVLT-3 (Standard form) as part of their evaluation. Mean age was 61.20 (SD = 14.30, range = 20–86), mean education was 15.00 years (SD = 2.87, range = 6–21), 53.1% were male, and 97.6% White. Failure was defined as CVLT-3-FCR score ≤ 14. Results 85.5% of our mixed clinical sample had CVLT-3-FCR score of 16/16, and 7.5% had 15/16. Only 7% (N = 26) scored ≤14, most common primary diagnoses being mild neurocognitive disorder (N = 9) and psychiatric (N = 7), while only four had dementia of any etiology. Those who failed tended to be a little older [pass = 60.82 years (SD = 14.44), fail = 66.38 years (SD = 11.28); p = 0.055) and scored lower for CVLT-3 Total Trials 1–5, short- and long-delay free recall, recognition hits, false positives, and discriminability (all p < 0.001). Conclusions Findings indicate CVLT-3-FCR ≤ 14 is extremely rare in a large mixed clinical sample of adults and older adults, even in subsamples for whom lower scores on PVTs have been suggested (e.g., dementia). While passing the CVLT-3-FCR does not in itself confirm adequate test engagement, failure should raise concern and the need for additional PVTs in one’s assessment.

One year analysis of Prospective Memory Clinics Registry in Qatar: A Critical Tool for Dementia Research and Policy Planning.

The Global Dementia Observatory (GDO) is a monitoring and accountability tool for the Global Action Plan on Public Response to Dementia 2017-25. Evidence from dementia registries may be utilized to better address WHO efforts in member countries, as well as to improve clinical practice and public health policy. The goal of this study was to analyze one-year data from a prospective memory clinic registry. This study was a baseline analysis of prospective memory clinics registry data of Qatar from January 1, 2023, through December 31, 2023. This study investigated the demographic, clinical, and lifestyle characteristics of 464 participants who were enrolled in memory clinics. Mild neurocognitive disorders were the most prevalent diagnoses in both sexes, affecting 61.5% of male patients and 63.7% of female patients. Dementia was slightly more common in men (19.8% vs. 18.9%), although delirium was more common in women (1.9% vs. 0%). In terms of risk factors, the analysis revealed that females were more likely to be obese (36.8% vs. 16.7% in males), while males had higher rates of diabetes (61.1% vs. 51.9% in females), hypertension (69.4% vs. 62.7% in females), and smoking (17.1% vs. 3.8% in females). The findings of this study highlight the differences in dementia risk factors between genders and races, highlighting the need for customized interventions. Furthermore, the registry is a great resource for policymakers and healthcare professionals, providing evidence-based suggestions to improve dementia care, increase the well-being of patients and caregivers, and maximize resource allocation.

Structural and Functional Dysregulation of the Brain Endothelium in HIV Infection and Substance Abuse.

Blood-brain barrier (BBB) injury and dysfunction following infection with the human immunodeficiency virus (HIV) enables viral entry into the brain, infection of resident brain cells, neuronal injury and subsequent neurodegeneration leading to HIV-associated neurocognitive disorders (HAND). Although combination antiretroviral therapy has significantly reduced the incidence and prevalence of acquired immunodeficiency syndrome and increased the life expectancy of people living with HIV, the prevalence of HAND remains high. With aging of people living with HIV associated with increased comorbidities, the prevalence of HIV-related central nervous system (CNS) complications is expected to remain high. Considering the principal role of the brain endothelium in HIV infection of the CNS and HAND, the purpose of this manuscript is to review the current literature on the pathobiology of the brain endothelium structural and functional dysregulation in HIV infection, including in the presence of HIV-1 and viral proteins (gp120, Tat, Nef, and Vpr). We summarize evidence from human and animal studies, in vitro studies, and associated mechanisms. We further summarize evidence of synergy or lack thereof between commonly abused substances (cocaine, methamphetamine, alcohol, tobacco, opioids, and cannabinoids) and HIV- or viral protein-induced BBB injury and dysfunction.

Contribution of a Tablet-Based Tests to the Diagnosis of Neurocognitive Disorders in Older Adults: A Feasibility Study.

Neurocognitive diseases are diagnosed in specialized centers such as memory clinics, where the waiting time can be long. The reference assessment involves a battery of tests carried out by a specialized team. Facilitating screening in primary care using new technologies could make it possible to appropriately direct care pathways towards specialist care. This work aimed to set up a battery of questionnaires, cognitive and manual dexterity tests on a digital tablet to screen people with cognitive impairment. Three groups of people are recruited from a memory consultation: people with major neurocognitive disorders, people with mild neurocognitive disorders and people with no cognitive impairment. Initial results in geriatric settings show that the digital tablet assessment test is feasible and well accepted, but that manual dexterity assessment needs to be adapted to the bodily particularities of the very old.

A Digital Clock Drawing Test on Tablet for the Diagnosis of Neurocognitive Disorders in Older Adults.

The diagnosis of neurocognitive diseases is an important health issue for patients, families and healthcare professionals. The need to develop rapid, high-performance screening tools would improve access to care. The Clock Drawing Test (CDT) is widely used and validated with the older adults, and its digital version is becoming increasingly widespread. We propose to confirm its validity in a population of old patients hospitalized in a geriatric unit, and secondly to verify its performance in comparison with the reference diagnosis made by a specialized team in a memory consultation. CDTs were collected from older hospitalized patients, both in paper form and digitally on a touchscreen tablet. The results show good agreement between the paper and digital versions (kappa coefficient = 0.81). Sensitivity and specificity of the digital CDT were 0.84 and 0.59 respectively for the diagnosis of major cognitive disorders. The corresponding values were 0.72 and 0.59 for the diagnosis of mild neurocognitive disorders. User questionnaires indicate that older participants find the digital tablet easy to use. However, they prefer to use paper, even if they are open to learning how to use the tablet.

AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.

Neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing.

The magnitude of neurocognitive disorders and associated factors among people living with HIV AIDS facilities in Bahir Dar City Ethiopia

Neurocognitive disorders are mental health conditions that are caused by medical illnesses and can lead to several acquired cognitive deficits, which represent a decline from a previously attained level of functioning. The principal domains of cognitive functions include complex attention, executive function, learning and memory, language, perceptual–motor function, and social cognition. Studies have shown that people living with human immunodeficiency virus (HIV) are at a heightened risk of experiencing cognitive challenges across multiple domains. Given that, a substantial number of people live in Amhara region, assessing cognitive domains to estimate the current magnitude and factors associated with neurocognitive disorders among HIV/AIDS patients is crucial. An institutional-based cross-sectional study was conducted among 569 participants adults living with HIV attending the city’s selected health facilities from March 20 to April 30, 2023. A multistage sampling technique was used. The International HIV Dementia Scale (IHDS) was used to measure the outcome of interest. The data were collected using a structured questionnaire and document review. The data were analyzed using STATA version 14. Multiple binary logistic regressions were used as the final model. A total of 501 individuals, with a response rate of 88.04% participated in the study. The overall proportion of HIV patients with neurocognitive impairment was 54.7% (95% CI 50.62–58.77). Factors associated with the neurocognitive impairment were: being widowed AOR = 3.05 (95% CI 1.47–6.31), divorced AOR = 1.95 (1.16–3.28), rural residence AOR = 2.28 (95% CI 1.02–5.09), CD4 count below 500 cells/dl AOR = 1.61 (95% CI 1.03–2.50), history of opportunistic infection AOR = 2.21 (95% CI 1.42–3.41), being in first-line drug regimen AOR = 2.92 (95% CI 1.22–7.00), being in a first-line regimen with Efavirenz AOR = 4.36 (95% CI 1.07–17.73), and impairment in daily living AOR = 2.64 (95% CI 1.39–4.99). In this study, the proportion of neurocognitive impairment was greater than that in most previous studies conducted in Ethiopia. The factors associated with the disorder were: being widowed or divorced, living in a rural area, having low CD4, having a history of opportunistic infection, receiving a first-line drug regimen, receiving efavirenz-containing drugs, and having impaired daily living. Hence, routine neuropsychological screenings should be integrated into comprehensive ART care by the regional health bureau and implemented by hospitals and health centers.

Clustering of cognitive domains among older adults with HIV

Age and HIV are synergistic risk factors for conditions such as HIV-associated neurocognitive disorders (HAND). Yet, it is unclear whether OAWH display different cognitive profiles for HAND. To describe the cognitive patterns of OAWH 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 (SD = 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.

HIV transcription persists in the brain of virally suppressed people with HIV.

HIV persistence in the brain is a barrier to cure, and potentially contributes to HIV-associated neurocognitive disorders. Whether HIV transcription persists in the brain despite viral suppression with antiretroviral therapy (ART) and is subject to the same blocks to transcription seen in other tissues and blood, is unclear. Here, we quantified the level of HIV transcripts in frontal cortex tissue from virally suppressed or non-virally suppressed people with HIV (PWH). HIV transcriptional profiling of frontal cortex brain tissue (and PBMCs where available) from virally suppressed (n = 11) and non-virally suppressed PWH (n = 13) was performed using digital polymerase chain reaction assays (dPCR). CD68+ myeloid cells or CD3+ T cells expressing HIV p24 protein present in frontal cortex tissue was detected using multiplex immunofluorescence imaging. Frontal cortex brain tissue from PWH had HIV TAR (n = 23/24) and Long-LTR (n = 20/24) transcripts. Completion of HIV transcription was evident in brain tissue from 12/13 non-virally suppressed PWH and from 5/11 virally suppressed PWH, with HIV p24+CD68+ cells detected in these individuals. While a block to proximal elongation was present in frontal cortex tissue from both PWH groups, this block was more extensive in virally suppressed PWH. These findings suggest that the brain is a transcriptionally active HIV reservoir in a subset of virally suppressed PWH.

Combination antiretroviral therapy prevents SIV- induced aging in the hippocampus and neurodegeneration throughout the brain.

Virus-induced accelerated aging has been proposed as a potential mechanism underlying the persistence of HIV-associated neurocognitive disorders (HAND) despite advances in access and adherence to combination antiretroviral therapies (cART). While some studies have demonstrated evidence of accelerated aging in PLWH, studies examining acute infection, and cART intervention are limited, with most studies being in vitro or utilizing small animal models. Here, we utilized FFPE tissues from Simian immunodeficiency virus (SIV) infected rhesus macaques to assess the levels of two proteins commonly associated with aging - the cellular senescence marker p16INK4a (p16) and the NAD-dependent deacetylase sirtuin 1 (SIRT1). Our central hypothesis was that SIV infection induces accelerated aging phenotypes in the brain characterized by increased expression of p16 and altered expression of SIRT1 that correlate with increased neurodegeneration, and that cART inhibits this process. We found that SIV infection induced increased GFAP, p16, SIRT1, and neurodegeneration in multiple brain regions, and treatment with cART reduced GFAP expression in SIV-infected animals and thus likely decreases inflammation in the brain. Importantly, cART reversed SIV-induced accelerated aging (p16 and SIRT1) and neurodegeneration in the frontal lobe and hippocampus. Combined, these data suggest that cART is both safe and effective in reducing neuroinflammation and age-associated alterations in astrocytes that contribute to neurodegeneration, providing possible therapeutic targets in the treatment of HAND.

Levetiracetam Prevents Neurophysiological Changes and Preserves Cognitive Function in the Human Immunodeficiency Virus (HIV)-1 Transactivator of Transcription Transgenic Mouse Model of HIV-Associated Neurocognitive Disorder.

Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) affects nearly half of the 39 million people living with HIV. HAND symptoms range from subclinical cognitive impairment to dementia; the mechanisms that underlie HAND remain unclear and there is no treatment. The HIV protein transactivator of transcription (TAT) is thought to contribute to HAND because it persists in the central nervous system and elicits neurotoxicity in animal models. Network hyperexcitability is associated with accelerated cognitive decline in neurodegenerative disorders. Here we show that the antiepileptic drug levetiracetam (LEV) attenuated aberrant excitatory synaptic transmission, protected synaptic plasticity, reduced seizure susceptibility, and preserved cognition in inducible TAT (iTAT) transgenic male mice. iTAT mice had an increased frequency of spontaneous excitatory postsynaptic currents in hippocampal slice recordings and impaired long-term potentiation, a form of synaptic plasticity that underlies learning and memory. Two-week administration of LEV by osmotic minipump prevented both impairments. Kainic acid administered to iTAT mice induced a higher maximum behavioral seizure score, longer seizure duration, and shorter latency to first seizure, consistent with a lower seizure threshold. LEV treatment prevented these in vivo signs of hyperexcitability. Lastly, in the Barnes maze, iTAT mice required more time to reach the goal, committed more errors, and received lower cognitive scores relative to iTAT mice treated with LEV. Thus, TAT expression drives functional deficits, suggesting a causative role in HAND. As LEV not only prevented aberrant synaptic activity in iTAT mice but also prevented cognitive dysfunction, it may provide a promising pharmacological approach to the treatment of HAND. SIGNIFICANCE STATEMENT: Approximately half of people living with human immunodeficiency virus (HIV) also suffer from HIV-associated neurocognitive disorder (HAND), for which there is no treatment. The HIV protein transactivator of transcription (TAT) causes toxicity that is thought to contribute to HAND. Here, the antiepileptic drug levetiracetam (LEV) prevented synaptic and cognitive impairments in a TAT-expressing mouse. LEV is widely used to treat seizures and is well-tolerated in humans, including those with HIV. This study supports further investigation of LEV-mediated neuroprotection in HAND.

The Role of Functional Deficits, Depression, and Cognitive Symptoms in the Perceived Loneliness of Older Adults in Mexico City.

The world is aging and experiencing loneliness. Functional impairment in instrumental activities of daily living (IADL) in older people (OP) with mild neurocognitive disorder (MNCD) predicts loneliness. After the pandemic, there was an increase in perceived loneliness. We explored the association between loneliness, depression, deficits in IADL, and cognitive symptoms among OP. From February to December 2023, using a cross-sectional design, we interviewed probable cases with mild cognitive impairment and caregivers in two public facilities. We administered the UCLA Loneliness Scale v3, Lawton IADL Scale, Mini-Mental State Examination (MMSE), and Yesavage's Geriatric Depression Scale. Samples were matched: 85 per group, 82.4% were women, married (52.95%), and mean age of 69.17 (±6.93) years. In our study, 30% displayed moderate to high levels of perceived loneliness. Multivariate analysis showed loneliness was associated with depression, low levels of IADL, and older age, but not with cognitive symptoms, which explained 22% of the total variance (F 165) = 16.99, (p < 0.001). Targeting symptoms and behaviors that could be modified (i.e., depression and functionality) can improve feelings of perceived loneliness and have an impact on morbidity and mortality with which it is associated.

Efficacy and Safety of Exogenous Ketones in People with Mild Neurocognitive Disorder and Alzheimer's Disease: A Systematic Literature Review.

Mild neurocognitive disorder (NCD), formally known as mild cognitive impairment, is usually the clinical stage preceding the development of Alzheimer's disease (AD), the most prevalent major NCD, and other causes of dementia. Glucose is a major source of energy for human brain metabolism and the uptake of glucose is reduced in patients with mild NCD, AD, and other NCDs. Unlike glucose, the uptake of ketones remains normal in people with mild NCD and AD, suggesting that the use of ketone bodies may compensate for glucose energy deficiency in patients with mild NCD and AD. The aim of this systematic review was to summarize the efficacy and safety of exogenic ketones, including medium chain triglycerides (MCTs), on cognitive function in patients with mild NCD and AD. The Embase, MEDLINE, MEDLINE In-Process, PubMed Ahead-of-Print, Cochrane Central Register of Controlled Trials, Europe PMC databases were searched from inception to April 2022. Studies reporting cognitive function efficacy and safety outcomes from randomized controlled trials of exogenic ketones in patients with mild NCD and AD were included. Data were extracted by 1 reviewer and checked by a second reviewer. Risk of bias was assessed using the Cochrane risk of bias tool, version 2. This review identified 13 individual trials investigating the efficacy and safety of MCT or coconut oil for patients with mild NCD or with AD. Because of the heterogeneity of the studies, a narrative synthesis was used. Overall, improvements associated with exogenic ketones were observed in multiple aspects of cognitive abilities, although the large heterogeneity between the included studies makes it difficult to draw firm conclusions from the current literature. Although some studies investigated the impact of the apolipoprotein E ε4 allele status on treatment efficacy, the current data are insufficient to conclude whether such an effect is present. PROSPERO registration No. CRD42022336664.

Targeting monocytic Occludin impairs transendothelial migration and HIV neuroinvasion

Transmigration of circulating monocytes from the bloodstream to tissues represents an early hallmark of inflammation. This process plays a pivotal role during viral neuroinvasion, encephalitis, and HIV-associated neurocognitive disorders. How monocytes locally unzip endothelial tight junction-associated proteins (TJAPs), without perturbing impermeability, to reach the central nervous system remains poorly understood. Here, we show that human circulating monocytes express the TJAP Occludin (OCLN) to promote transmigration through endothelial cells. We found that human monocytic OCLN (hmOCLN) clusters at monocyte-endothelium interface, while modulation of hmOCLN expression significantly impacts monocyte transmigration. Furthermore, we designed OCLN-derived peptides targeting its extracellular loops (EL) and show that transmigration of treated monocytes is inhibited in vitro and in zebrafish embryos, while preserving vascular integrity. Monocyte transmigration toward the brain is an important process for HIV neuroinvasion and we found that the OCLN-derived peptides significantly inhibit HIV dissemination to cerebral organoids. In conclusion, our study identifies an important role for monocytic OCLN during transmigration and provides a proof-of-concept for the development of mitigation strategies to prevent monocyte infiltration and viral neuroinvasion.

Diagnostic accuracy, reliability, and construct validity of the German quick mild cognitive impairment screen

BackgroundEarly detection of cognitive impairment is among the top research priorities aimed at reducing the global burden of dementia. Currently used screening tools have high sensitivity but lack specificity at their original cut-off, while decreasing the cut-off was repeatedly shown to improve specificity, but at the cost of lower sensitivity. In 2012, a new screening tool was introduced that aims to overcome these limitations – the Quick mild cognitive impairment screen (Qmci). The original English Qmci has been rigorously validated and demonstrated high diagnostic accuracy with both good sensitivity and specificity. We aimed to determine the optimal cut-off value for the German Qmci, and evaluate its diagnostic accuracy, reliability (internal consistency) and construct validity.MethodsWe retrospectively analyzed data from healthy older adults (HOA; n = 43) and individuals who have a clinical diagnosis of ‘mild neurocognitive disorder’ (mNCD; n = 37) with a biomarker supported characterization of the etiology of mNCD of three studies of the ‘Brain-IT’ project. Using Youden’s Index, we calculated the optimal cut-off score to distinguish between HOA and mNCD. Receiver operating characteristic (ROC) curve analysis was performed to evaluate diagnostic accuracy based on the area under the curve (AUC). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Reliability (internal consistency) was analyzed by calculating Cronbach’s α. Construct validity was assessed by analyzing convergent validity between Qmci-G subdomain scores and reference assessments measuring the same neurocognitive domain.ResultsThe optimal cut-off score for the Qmci-G was ≤ 67 (AUC = 0.96). This provided a sensitivity of 91.9% and a specificity of 90.7%. The PPV and NPV were 89.5% and 92.9%, respectively. Cronbach’s α of the Qmci-G was 0.71 (CI95% [0.65 to 0.78]). The Qmci-G demonstrated good construct validity for subtests measuring learning and memory. Subtests that measure executive functioning and/or visuo-spatial skills showed mixed findings and/or did not correlate as strongly as expected with reference assessments.ConclusionOur findings corroborate the existing evidence of the Qmci’s good diagnostic accuracy, reliability, and construct validity. Additionally, the Qmci shows potential in resolving the limitations of commonly used screening tools, such as the Montreal Cognitive Assessment. To verify these findings for the Qmci-G, testing in clinical environments and/or primary health care and direct comparisons with standard screening tools utilized in these settings are warranted.

Study of Clinical Spectrum of Neurological Manifestations in HIV/AIDS Seen at Tertiary Referral Hospital in India

Objectives: The pandemic caused by human immunodeficiency virus (HIV) is one of the fastest growing health problems in the world today. Neurological manifestations of HIV infection and acquired immunodeficiency syndrome (AIDS) are being seen in a frequency that is parallel to the increasing number of new cases seen the world over. The World Health Organisation (WHO) estimates that 36.7 million people in the world are infected with HIV. Neurological manifestations of HIV disease can be seen in 20% of outpatients in HIV clinics and almost half of HIV patients being treated as in-patients. Of the various subtypes of HIV, subtype C is responsible for more than 50% of HIV1 infections causing rapidly growing epidemics in India. The objectives of this study were as follows: (1) To evaluate the prevalence of neurological manifestation in HIV-positive patients admitted to a tertiary referral Hospital in India. (2) To describe the neurological manifestations documented. (3) To find the possible predictors of neurological manifestations. Material and Methods: This study was a single centre prospective cross-sectional study in which out of 200 HIV/AIDS patients, 40 patients with neurological manifestations were analysed over a period of 18 months. They were interviewed and evaluated with particular reference to neurological manifestations, and were classified using the WHO staging system. Results: Amongst the studied population of 40 patients, 16 patients (40%) manifested as tuberculous meningitis (TBM) with or without brain tuberculomas, followed by seven patients (18%) presented with peripheral neuropathy and six patients (15%) presented with central nervous system (CNS) vasculitic or multi-infarct state. Cryptococcal meningitis was seen in five patients (12%), efavirenz-induced psychosis/seizure seen in one patient, while HIV-induced polymyositis, progressive multifocal leukoencephalopathy progressive multifocal leukoencephalopathy, acute inflammatory demylinating polyradiculoneuropathy, AIDS dementia complex and CNS toxoplasmosis were seen in one patient each respectively. One patient presented with dual opportunistic infection with coexistence of cryptococcal and tuberculous meningitis. Conclusion: Headache with or without vomiting, seizures and altered sensorium were the most common neurological symptoms. Fundus abnormalities, meningeal signs, gait abnormalities, cranial nerve dysfunction and hemiplegia were the most common neurological signs. New-onset headache was a significant predictor of the occurrence of neurological complications. Opportunistic infections such as TBM and Cryptococcal meningitis were most commonly observed.

Prevalence of neurocognitive disorders 5 years after elective orthopaedic surgery.

Peri-operative neurocognitive disorders are one of the most common complications affecting older adults after anaesthesia and surgery. It is not clear how exposure to surgery and anaesthesia contributes to the prevalence of long-term neurocognitive disorders. This study aimed to report the prevalence of neurocognitive disorders, and explore pre-operative factors associated with neurocognitive disorders 5 years after elective orthopaedic surgery. A prospective, 5-year longitudinal, cohort study was performed recruiting patients (aged ≥ 60 y) undergoing elective orthopaedic surgery and a contemporaneous non-surgical control group. Neurocognitive disorder was evaluated and classified at baseline and 5-year review incorporating: self- and informant-reported cognition; functional participation; and performance on neuropsychological tests. Recruitment at 5-year follow-up included 195 patients and 21 control participants. In the patient cohort the prevalence of neurocognitive disorder was 38.1% (n = 75), with 61 (30.1%) meeting the criteria for mild neurocognitive disorder and 14 (7.1%) for major neurocognitive disorder. At 5-year follow-up, 121 (61.4%) patients were classified with a neurocognitive disorder, with 88 (44.7%) characterised with mild neurocognitive disorder and 33 (16.8%) with major neurocognitive disorder. Age (odds ratio (95%CI) 1.07 (1.02-1.13); p = 0.01) and baseline cognitive impairment (odds ratio (95%CI) 2.1 (1.06-4.15); p = 0.03) were significant predictors of neurocognitive disorder 5 years after surgery. More than half of older adult patients had some form of neurocognitive disorder 5 years after elective orthopaedic surgery. Surgery and anaesthesia may be associated with the trajectory of cognitive decline in at-risk older adults, including those with pre-operative cognitive impairment. Cognitive screening should be factored into pre-operative assessments of older adults to inform subsequent care.