Neuropsychological assessment of cognitive deficits in people living with HIV receiving antiretroviral therapy

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Despite these advances, HIV-associated neurocognitive alterations—collectively known as HIV-associated neurocognitive disorders (HAND)—continue to be observed even in individuals receiving effective treatment. The present study aimed to evaluate potential cognitive deficits in PLHIV undergoing ART and to characterize the clinical profile of neurocognitive manifestations. Thirty HIV-positive individuals aged between 18 and 40 years participated in the study. All participants had been receiving the antiretroviral regimen tenofovir, lamivudine, and dolutegravir (TDF/3TC + DTG) for at least one year. The assessment protocol included a sociodemographic questionnaire, the Instrumental Activities of Daily Living Scale (IADL), the International HIV Dementia Scale (IHDS), and the computerized Cambridge Neuropsychological Test Automated Battery (CANTAB), which evaluates psychomotor speed, sustained attention, visual memory, and emotion recognition. The results indicated that 66.7% of participants exhibited partial dependence in instrumental activities of daily living. Screening with the IHDS identified positive HAND screening in 96.7% of the sample. Performance on the CANTAB tasks revealed impairments primarily in memory, attention, and psychomotor speed, as well as difficulties in facial emotion recognition. Additionally, a significant association was observed between cognitive performance and functional capacity in everyday activities. These findings suggest that neurocognitive deficits remain prevalent among PLHIV even during antiretroviral therapy, highlighting the importance of systematic neuropsychological assessment in the clinical monitoring of this population. HIV HIV-associated neurocognitive disorders cognition CANTAB antiretroviral therapy Figures Figure 1 Figure 2 Introduction The advent of antiretroviral therapy (ART) has represented a major milestone in the clinical management of human immunodeficiency virus (HIV) infection, significantly reducing opportunistic infections and increasing the life expectancy of people living with HIV (PLHIV). As a result of these therapeutic advances, HIV infection is now widely considered a chronic and manageable condition. However, despite the effectiveness of ART in achieving viral suppression and reducing the incidence of severe neurological complications, neurocognitive manifestations associated with HIV infection remain an important clinical and scientific challenge. These alterations are currently grouped under the term HIV-associated neurocognitive disorders (HAND), which encompass a spectrum of cognitive impairments ranging from asymptomatic neurocognitive impairment to more severe forms such as HIV-associated dementia [ 1 , 2 ]. Epidemiological studies indicate that even among individuals receiving effective ART, between 30% and 50% of PLHIV may present some degree of neurocognitive impairment [ 3 , 4 ]. These deficits commonly involve domains such as attention, working memory, processing speed, executive functions, and psychomotor speed, and may also affect social cognition and functional capacity in activities of daily living [ 2 , 5 ]. From a pathophysiological perspective, HIV is believed to invade the central nervous system (CNS) early in the course of infection, establishing viral reservoirs in glial cells and triggering chronic inflammatory processes that may lead to progressive neuronal damage [ 6 , 7 ]. Even in individuals with systemic viral suppression, persistent neuroinflammation and the limited penetration of certain antiretroviral drugs into the CNS may contribute to the development and persistence of cognitive alterations over time [ 8 , 9 ]. In this context, the present study aimed to evaluate potential cognitive deficits in people living with HIV undergoing antiretroviral therapy and to characterize the clinical profile of neurocognitive manifestations using an integrated approach that combines clinical screening scales and computerized neuropsychological tests. This multifaceted approach allowed for a comprehensive and detailed assessment of cognitive functions, overcoming the limitations of isolated assessment methods and providing more accurate insights into the prevalence and characteristics of HAND in this population. Such methodology is particularly important because the diagnostic complexity of HAND and its diverse manifestations require thorough investigation to distinguish HIV-related neurocognitive impairment from other pre-existing neurobehavioral conditions [ 10 ]. In particular, deficits affecting two or more cognitive domains—such as executive function, memory, and information processing speed—are considered essential criteria for the diagnosis of HIV-associated neurocognitive disorder [ 11 ]. It is also important to note that, despite the introduction of ART, the prevalence of mild and moderate forms of HAND remains substantial, ranging from approximately 15% to 50%, and these conditions are associated with an increased risk of reduced treatment adherence and decreased quality of life [ 12 , 13 ]. Although combination antiretroviral therapy has reduced the occurrence of the most severe forms of HIV-associated dementia, milder cognitive deficits persist and may negatively impact the quality of life of patients and their families [ 14 ]. Furthermore, the aging of the population living with HIV—driven largely by the effectiveness of ART—introduces additional diagnostic and therapeutic challenges, as older HIV-positive individuals demonstrate up to a threefold increased risk of developing neurocognitive alterations, particularly involving attention, working memory, learning, memory, and executive functions [ 15 ]. Materials and Methods Study design This was an observational, cross-sectional, descriptive-analytical study conducted to evaluate the neurocognitive profile of people living with HIV (PLHIV) receiving antiretroviral therapy (ART). Participants A total of 30 individuals living with HIV, aged between 18 and 40 years, of both sexes, were recruited from the Center for Care of Acquired Infectious Diseases (CASA DIA) in the city of Belém, Pará, Brazil. Participants were eligible if they had been receiving antiretroviral therapy for at least one year using a regimen composed of tenofovir, lamivudine, and dolutegravir (TDF/3TC + DTG). Exclusion criteria included the current or previous diagnosis of psychiatric disorders, a history of central nervous system infection reported by the patient or documented in medical records, and illicit drug use within the previous 30 days. All participants who agreed to participate in the study signed two copies of the Informed Consent Form prior to the assessments. The study protocol was submitted to and approved by the Research Ethics Committee of the Federal University of Pará (UFPA) in accordance with Resolution No. 466/2012 of the Brazilian National Health Council (approval number 5.822.870). Data collection site All assessments were conducted at the Center for Care of Acquired Infectious Diseases (CASA DIA) in Belém, Pará, Brazil. The evaluations were carried out in a private room dedicated to test administration, ensuring adequate conditions of silence and comfort for participants. Procedures Participants were informed about the objectives and procedures of the study prior to the beginning of the assessments. After signing the informed consent form, participants underwent a neuropsychological evaluation. The evaluation protocol lasted approximately 120 minutes and was divided into three stages, with short intervals between assessments to minimize fatigue. Stage 1 – Sociodemographic questionnaire Initially, an adapted sociodemographic questionnaire was administered, consisting of ten questions addressing personal characteristics, educational level, socioeconomic status, medical history, and time since HIV diagnosis and treatment. Stage 2 – Functional assessment and cognitive screening At this stage, two instruments were administered: Instrumental Activities of Daily Living Scale (IADL) This scale was used to assess the level of functional independence in daily tasks such as financial management, medication use, shopping, and transportation. The scale consists of eight items, with a maximum score of 24 points. Functional classification was defined as follows: ≤ 8 points: total dependence 8 and < 24 points: partial dependence 24 points: independent International HIV Dementia Scale (IHDS) The IHDS was used as a screening instrument for HIV-associated neurocognitive impairment. The scale assesses three main cognitive domains: motor speed psychomotor speed memory The maximum possible score is 12 points. Scores ≤ 11 were considered indicative of positive screening for HIV-associated neurocognitive disorders (HAND). Stage 3 – Computerized neuropsychological assessment To provide a more detailed evaluation of cognitive performance, the computerized Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered. This battery is widely used in neuropsychological research and includes standardized tests designed to evaluate multiple cognitive domains. Six tests known to be sensitive to cognitive alterations associated with HIV infection were selected: Motor Screening Task (MOT) Assesses possible sensorimotor difficulties or problems in understanding the task instructions. Reaction Time (RTI) Evaluates reaction speed and movement time, providing measures of motor and cognitive processing speed. Emotion Recognition Task (ERT) Assesses social cognition through the identification of facial emotional expressions, including happiness, sadness, fear, anger, disgust, and surprise. Rapid Visual Information Processing (RVP) Measures sustained attention and the ability to continuously monitor visual stimuli. Delayed Matching to Sample (DMS) Assesses short-term visual memory and visual matching ability. Pattern Recognition Memory (PRM) Evaluates visual recognition memory for abstract patterns. Statistical analysis Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software, version 20. Initially, descriptive analyses of sociodemographic, clinical, and neuropsychological variables were conducted. Results were presented as absolute and relative frequencies, means, and standard deviations, when appropriate. Scores obtained from the IHDS and IADL scales were used to characterize neurocognitive screening results and functional performance in daily activities, respectively. To investigate possible associations between cognitive domains assessed by the CANTAB tasks and the clinical measures obtained from the IHDS and IADL scales, Spearman’s correlation coefficient (ρ) was used. This method was chosen because it is a non-parametric analysis suitable for small sample sizes and for variables that may not follow a normal distribution. Correlations were analyzed between CANTAB performance variables (reaction time, number of correct and incorrect responses, and choice time) and scores obtained in the IHDS and IADL scales. The significance level adopted for all analyses was 5% (p ≤ 0.05), with a 95% confidence interval. Results Sample characterization The sample consisted of 30 people living with HIV undergoing clinical follow-up at the Center for Care of Acquired Infectious Diseases (CASA DIA) in Belém, Pará, Brazil. All participants were male and aged between 18 and 42 years. The predominant age group was between 26 and 36 years, corresponding to 66.67% of the sample (n = 20). Participants aged 18–25 years accounted for 23.33% (n = 7), while 10% (n = 3) were between 37 and 42 years old. All participants were literate and reported no current or previous history of psychiatric disorders, central nervous system infections, arterial hypertension, or diabetes mellitus. Regarding the duration of antiretroviral therapy, 50% of participants had been receiving treatment for more than five years, 43.33% between one and five years, and 6.67% for approximately one year. All participants were receiving the antiretroviral regimen composed of tenofovir, lamivudine, and dolutegravir (TDF/3TC + DTG). Only five participants (16.67%) reported the use of medications other than ART, mainly drugs for the treatment of gastritis. Functional evaluation (IADL) The functional evaluation using the Instrumental Activities of Daily Living (IADL) scale showed that none of the participants presented total dependence. Most participants (66.67%, n = 20) were classified as partially dependent, while 33.33% (n = 10) were considered independent. Regarding the specific tasks evaluated by the scale, 6.9% of participants reported being unable to manage their own finances, while 3.45% reported difficulties taking medications correctly, performing minor household repairs, or shopping. Conversely, 31.03% reported needing assistance for transportation, 27.59% for medication management, and 24.14% for performing small household repairs. Despite these difficulties, all participants reported being able to use the telephone without assistance, and most reported independence in shopping and meal preparation. The ability to manage finances and perform domestic activities independently was reported by 93.1% of participants. Screening for neurocognitive impairment (IHDS) Screening using the International HIV Dementia Scale (IHDS) indicated positive screening for HIV-associated neurocognitive disorders (HAND) in 96.67% of participants (n = 29), while only one participant (3.33%) scored above the cutoff point. In the analysis of the domains assessed by the scale, most participants scored between 3 and 4 points in the memory domain. In the motor speed domain, 48.28% obtained three points and 41.38% obtained two points. In the psychomotor speed domain, 72.41% obtained three points and 10.34% achieved the maximum score. In the memory domain, 3.45% of participants scored one point, 6.9% scored two points, 3.45% scored 2.5 points, 31.03% scored three points, 17.24% scored 3.5 points, and 37.93% obtained the maximum score of four points. All participants successfully completed the three tasks included in the scale and obtained at least the minimum score in each domain evaluated. Cognitive performance in the CANTAB battery In the Motor Screening Task (MOT), none of the participants presented significant difficulties in performing the task. All correctly selected the stimuli presented within the acceptable time limit (up to 6000 ms), suggesting the absence of significant sensorimotor impairment. In the Reaction Time (RTI) task, all participants successfully released the button and selected the stimulus within the expected time interval (100 to 5100 ms). The number of observed errors ranged from 0 to 15, which was considered within the acceptable range for this task. In the Emotion Recognition Task (ERT), the mean total number of errors was 20.88 responses across participants. The highest frequency of errors occurred in the identification of the emotion fear, followed by surprise. In contrast, the highest accuracy rates were observed for the emotions surprise and happiness. The mean response time for emotion recognition was 2388.44 ms, which is higher than the ideal response time for the task. In the Rapid Visual Information Processing (RVP) test, 83% of participants correctly detected between 1 and 27 target sequences, while approximately 90% presented errors in sequences between 28 and 54. Despite this, most participants demonstrated adequate sequence detection ability, with 73.33% showing performance values between 0.00 and 0.50 and 26.67% between 0.50 and 1.0, considering that 1.0 represents optimal performance. In the Delayed Matching to Sample (DMS) test, all participants correctly identified at least one pattern. The majority (83.33%) correctly matched between 11 and 20 patterns, while five participants presented performance between 1 and 5 correct responses. When considering only patterns presented after delay, 60% of participants correctly matched between 8 and 15 patterns. In the Pattern Recognition Memory (PRM) test, the mean accuracy rate before the pause was 61.67%, while after the pause it decreased to 55.86%. The mean pattern selection time before the pause was 8088.98 ms, decreasing to 1655.18 ms after the pause, although both values remained above the ideal response time for the task. Correlation between cognitive performance and functionality Spearman correlation analysis revealed significant associations between several CANTAB variables and the activities evaluated by the IADL scale. The results are summarized in Table 1 . A positive correlation was observed between the number of correct responses in the DMS test and the ability to perform domestic tasks, indicating that better visual memory performance was associated with greater autonomy in these activities. Table 1 Spearman correlations between CANTAB cognitive performance variables and the motor, psychomotor, and memory domains of the International HIV Dementia Scale (IHDS). Task Variable Correlation p -value Motor Button release time (RTI) -0.38 0.04 Choice time (ERT) -0.41 0.03 Total errors (RVP) -0.39 0.04 Incorrect with and without delay (DMS) -0.38 0.04 Incorrect with delay (DMS) -0.37 0.05 Psychomotor Selection time (RTI) -0.41 0.03 Incorrect happiness (ERT) -0.40 0.03 Incorrect fear (ERT) -0.38 0.04 Memory Correct surprise (ERT) 0.38 0.04 Correct with delay (DMS) 0.38 0.04 Correlations were also observed between performance in the RTI, RVP, and ERT tests and the ability to perform minor household repairs, manage medications correctly, and handle finances. In some cases, inverse correlations were identified, indicating that a higher number of errors in cognitive tests was associated with poorer performance in daily activities. Correlation between cognitive performance and HAND screening The analysis of correlations between CANTAB variables and the domains evaluated by the IHDS revealed significant associations between cognitive performance and motor, psychomotor, and memory domains. Inverse correlations were observed between response time in RTI, the number of errors in RVP and DMS, and scores in the motor and psychomotor domains of the IHDS. Conversely, positive correlations were observed between the number of correct responses in the DMS and ERT tests and the memory domain of the scale.These results suggest that cognitive performance alterations assessed through the CANTAB battery are associated with neurocognitive impairment detected by the IHDS. To explore these relationships more comprehensively, a correlation map was constructed integrating the variables obtained from the CANTAB tests with the clinical measures derived from the IHDS and IADL scales (Fig. 1 ). Positive correlations indicate a direct association between better cognitive performance and higher functional capacity, whereas negative correlations indicate associations between longer response times or higher error rates and poorer cognitive or functional performance. Overall, associations were observed between different cognitive domains and daily functional measures, suggesting that alterations in memory, attention, and psychomotor speed are related to variations in neurocognitive screening scores and levels of independence in instrumental activities of daily living. Finally, to facilitate visualization of the overall cognitive performance of the sample, a summarized cognitive profile was constructed considering the main domains assessed by the CANTAB battery (Fig. 2 ). Participants showed greater relative impairment in the psychomotor speed domain, while memory and attention domains appeared comparatively more preserved. Discussion The present study aimed to evaluate the neurocognitive profile of people living with HIV receiving antiretroviral therapy (ART) and to investigate the relationship between cognitive performance, screening for neurocognitive impairment, and functional capacity in instrumental activities of daily living. Overall, the results revealed a high frequency of positive screening for HIV-associated neurocognitive disorders (HAND), as well as impairments in cognitive domains related to memory, attention, and psychomotor speed, assessed through the computerized neuropsychological battery CANTAB. One of the most relevant findings of this study was the high proportion of participants with positive screening for HAND according to the International HIV Dementia Scale (IHDS). Although the introduction of combination antiretroviral therapy has significantly reduced the incidence of severe neurological complications, recent studies indicate that cognitive alterations associated with HIV remain frequent even among individuals with controlled viral load [ 2 , 4 , 16 ]. Current epidemiological estimates suggest that between 30% and 50% of people living with HIV present some degree of neurocognitive impairment, even in the era of modern antiretroviral therapy [ 17 ]. Recent meta-analyses report a global prevalence of approximately 42–46%, reinforcing that cognitive impairment remains one of the most relevant neurological complications of HIV infection [ 18 ]. The results obtained from the CANTAB battery also revealed impairments across different cognitive domains, particularly in tasks related to sustained attention, visual memory, and psychomotor speed. This pattern of impairment is consistent with the neuropsychological profile commonly described in patients with HAND, which is characterized by a predominantly subcortical pattern of cognitive dysfunction. This profile mainly involves psychomotor slowing, attentional deficits, and alterations in working memory and information processing speed [ 5 , 8 ]. Recent studies continue to demonstrate that deficits in processing speed, attention, and executive function are among the most frequently affected cognitive domains in individuals living with HIV [ 19 ]. Another relevant finding observed in this study was the presence of functional impairment among part of the evaluated participants. Although none of the individuals were classified as totally dependent in instrumental activities of daily living, the majority presented partial dependence in daily tasks. Evidence from the literature indicates that mild cognitive deficits in people living with HIV can impact complex daily activities such as medication management, financial organization, and mobility, even when individuals remain independent in basic activities [ 3 ]. Recent studies further suggest that cognitive alterations associated with HIV may compromise treatment adherence, occupational performance, and overall quality of life, particularly among individuals presenting mild forms of HAND [ 20 ]. Furthermore, the correlation analyses performed in this study demonstrated associations between cognitive test performance and functional measures assessed by the IADL scale. In general, better performance in tasks related to visual memory and attention was associated with greater functional independence, whereas longer response times or a higher number of errors in cognitive tests were associated with poorer performance in daily activities. These findings are consistent with evidence suggesting that subtle cognitive alterations may significantly affect daily functioning in people living with HIV, even in the early stages of neurocognitive impairment [ 2 , 3 ]. From a pathophysiological perspective, several mechanisms have been proposed to explain the persistence of cognitive alterations associated with HIV, even among individuals receiving ART. Evidence suggests that the virus may invade the central nervous system early during infection, establishing viral reservoirs in microglial cells and astrocytes and triggering chronic inflammatory processes that can result in progressive neuronal dysfunction [ 6 , 7 ]. Recent studies also highlight the role of persistent neuroinflammation, synaptic dysfunction, and alterations in neural connectivity as important factors in the pathophysiology of HAND [ 20 ]. In this context, the use of computerized neuropsychological batteries such as CANTAB represents a promising approach for the detailed assessment of cognitive functioning in people living with HIV. These instruments allow for the standardized and sensitive evaluation of multiple cognitive domains, enabling the early detection of cognitive alterations that may not be identified through simpler screening tools. The early identification of these alterations may contribute to improved clinical monitoring strategies and therapeutic interventions aimed at preserving cognitive function in people living with HIV. Study limitations Some limitations of the present study should be considered when interpreting the results. First, the relatively small sample size may limit the generalizability of the findings to broader populations of people living with HIV. Additionally, all participants in the present study were male, which prevents the analysis of potential sex-related differences in neurocognitive performance. Future studies including more diverse and larger samples may help clarify whether similar patterns of cognitive impairment occur across different demographic groups. Another limitation concerns the absence of a control group composed of HIV-negative individuals. The inclusion of a control group would allow a more precise comparison of cognitive performance and would strengthen the interpretation of the observed deficits as being specifically associated with HIV infection. Furthermore, the cross-sectional design of the study does not allow for the evaluation of longitudinal changes in cognitive functioning over time. Despite these limitations, the study provides valuable insights into the neurocognitive profile of people living with HIV receiving antiretroviral therapy and contributes to the growing body of literature investigating the persistence of neurocognitive alterations in the ART era. Clinical implications and future perspectives The findings of this study reinforce the importance of systematic neurocognitive evaluation in the clinical follow-up of people living with HIV. Even in the context of effective antiretroviral therapy and viral suppression, cognitive alterations may persist and affect daily functioning and treatment adherence. The use of computerized neuropsychological tools such as CANTAB may represent an important strategy for improving the detection of subtle cognitive deficits that are not always identified through traditional screening instruments. Early identification of cognitive impairment may allow the implementation of targeted interventions, including cognitive rehabilitation programs, improved clinical monitoring, and strategies aimed at optimizing adherence to antiretroviral therapy. Future research should aim to investigate larger and more heterogeneous samples, incorporate longitudinal designs, and explore potential biological markers associated with HAND. Additionally, studies integrating neuropsychological evaluation with neuroimaging and neurophysiological approaches may contribute to a more comprehensive understanding of the mechanisms underlying HIV-associated neurocognitive impairment. Conclusion The present study demonstrated a high frequency of neurocognitive alterations in people living with HIV receiving antiretroviral therapy, with impairments primarily observed in domains related to psychomotor speed, attention, and memory. These findings reinforce that HIV-associated neurocognitive disorders remain prevalent even in the era of effective antiretroviral treatment. Furthermore, the observed associations between cognitive performance and functional capacity highlight the potential impact of subtle cognitive deficits on daily activities. The use of integrated assessment approaches combining clinical screening scales and computerized neuropsychological batteries may improve the identification of cognitive impairment in this population. Overall, these results emphasize the importance of incorporating routine neurocognitive assessment into the clinical management of people living with HIV. Declarations Conflict of interest The authors declare that they have no financial or non-financial conflicts of interest related to this study. Ethical approval This study was approved by the Research Ethics Committee of the Federal University of Pará (UFPA) under approval number 5.822.870, in accordance with Resolution No. 466/2012 of the Brazilian National Health Council. Consent to participate All participants provided written informed consent prior to participation in the study. Funding Samilly Palheta Gonçalves received financial support through a scholarship granted by the Coordination for the Improvement of Higher Education Personnel (CAPES). Author Contribution Author 1: study conception, data collection, and manuscript drafting.Author 2: study conception, statistical analysis, manuscript revision, and final approval. Acknowledgement The authors thank the Center for Care of Acquired Infectious Diseases (CASA DIA) for its support during data collection and the study participants for their voluntary contribution to this research. 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Front Immunol 3 de fevereiro de 16:1478187. 10.3389/fimmu.2025.1478187 Zhou Z, Wang W, Li H, Shi Y, Zhao L, Lu Y et al (2025) Decoding HIV-associated neurocognitive disorders: a new perspective from multimodal connectomics. Front Neurol 29 de janeiro de 16:1467175. 10.3389/fneur.2025.1467175 Clifford DB (2017) HIV-associated neurocognitive disorder. Curr Opin Infect Dis fevereiro de 30(1):117–122. 101097/QCO.0000000000000328 PubMed PMID: 27798498; PubMed Central PMCID: PMC5382956 Hu A, Zaongo SD, Harypursat V, Wang X, Ouyang J, Chen Y (2024) HIV-associated neurocognitive disorder: key implications of the microbiota-gut-brain axis. Front Microbiol 2 de agosto de 15:1428239. 10.3389/fmicb.2024.1428239 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9227316","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":615237362,"identity":"30819df3-c426-403c-9e24-e70f64fcfc44","order_by":0,"name":"Samilly Palheta Gonçalves","email":"","orcid":"","institution":"Federal University of Pará (UFPA)","correspondingAuthor":false,"prefix":"","firstName":"Samilly","middleName":"Palheta","lastName":"Gonçalves","suffix":""},{"id":615237364,"identity":"4584b54d-1d52-4fc0-840d-6f68a5b0aba0","order_by":1,"name":"Fernando Rocha","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAqklEQVRIiWNgGAWjYHACNgYGGxsG9gYGBmYStKSlMfAcIFHLYRK0mLc3P3vwI+F8Yo908wPmwj1EaJE5c8zcsCfhdmKPzDED5hnPiNAiIZHDJsH743bifokEA2aQ64jSIvkn4Vxij0T6B+K1SPMkHABqySHWFp5jZtIyCcnGPTJnCg7PIEoLe/MzyTcJdrI90u0bHxcQowVJMwMDaRrAWkbBKBgFo2AUYAUAZD4y3j7lXGAAAAAASUVORK5CYII=","orcid":"","institution":"Federal University of Pará (UFPA)","correspondingAuthor":true,"prefix":"","firstName":"Fernando","middleName":"","lastName":"Rocha","suffix":""}],"badges":[],"createdAt":"2026-03-25 22:23:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9227316/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9227316/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106096109,"identity":"dde79f26-3f53-4797-83da-11a81f0c93d4","added_by":"auto","created_at":"2026-04-03 11:52:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":222911,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation map between cognitive variables assessed by the CANTAB battery and clinical measures obtained from the IHDS and IADL scales.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9227316/v1/f7d80567108cf0c41a151cac.png"},{"id":106096116,"identity":"4c2a4f6f-9fec-4548-92a6-bba55faff66e","added_by":"auto","created_at":"2026-04-03 11:52:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":68398,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCognitive profile of participants evaluated using the Cambridge Neuropsychological Test Automated Battery (CANTAB). The graph illustrates the relative performance across the main cognitive domains assessed in the study: sustained attention (RVP), visual memory (DMS/PRM), psychomotor speed (RTI), and social cognition (ERT).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9227316/v1/8970e43f33d3e458aaa4383a.png"},{"id":108491558,"identity":"309e1840-b471-4992-92e7-a14f60fad92a","added_by":"auto","created_at":"2026-05-05 09:54:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":517178,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9227316/v1/6d7dfc7f-d843-42a5-8565-9f28ae5d9ccb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Neuropsychological assessment of cognitive deficits in people living with HIV receiving antiretroviral therapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe advent of antiretroviral therapy (ART) has represented a major milestone in the clinical management of human immunodeficiency virus (HIV) infection, significantly reducing opportunistic infections and increasing the life expectancy of people living with HIV (PLHIV). As a result of these therapeutic advances, HIV infection is now widely considered a chronic and manageable condition. However, despite the effectiveness of ART in achieving viral suppression and reducing the incidence of severe neurological complications, neurocognitive manifestations associated with HIV infection remain an important clinical and scientific challenge.\u003c/p\u003e \u003cp\u003eThese alterations are currently grouped under the term HIV-associated neurocognitive disorders (HAND), which encompass a spectrum of cognitive impairments ranging from asymptomatic neurocognitive impairment to more severe forms such as HIV-associated dementia [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Epidemiological studies indicate that even among individuals receiving effective ART, between 30% and 50% of PLHIV may present some degree of neurocognitive impairment [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. These deficits commonly involve domains such as attention, working memory, processing speed, executive functions, and psychomotor speed, and may also affect social cognition and functional capacity in activities of daily living [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFrom a pathophysiological perspective, HIV is believed to invade the central nervous system (CNS) early in the course of infection, establishing viral reservoirs in glial cells and triggering chronic inflammatory processes that may lead to progressive neuronal damage [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Even in individuals with systemic viral suppression, persistent neuroinflammation and the limited penetration of certain antiretroviral drugs into the CNS may contribute to the development and persistence of cognitive alterations over time [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this context, the present study aimed to evaluate potential cognitive deficits in people living with HIV undergoing antiretroviral therapy and to characterize the clinical profile of neurocognitive manifestations using an integrated approach that combines clinical screening scales and computerized neuropsychological tests. This multifaceted approach allowed for a comprehensive and detailed assessment of cognitive functions, overcoming the limitations of isolated assessment methods and providing more accurate insights into the prevalence and characteristics of HAND in this population. Such methodology is particularly important because the diagnostic complexity of HAND and its diverse manifestations require thorough investigation to distinguish HIV-related neurocognitive impairment from other pre-existing neurobehavioral conditions [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In particular, deficits affecting two or more cognitive domains\u0026mdash;such as executive function, memory, and information processing speed\u0026mdash;are considered essential criteria for the diagnosis of HIV-associated neurocognitive disorder [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIt is also important to note that, despite the introduction of ART, the prevalence of mild and moderate forms of HAND remains substantial, ranging from approximately 15% to 50%, and these conditions are associated with an increased risk of reduced treatment adherence and decreased quality of life [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Although combination antiretroviral therapy has reduced the occurrence of the most severe forms of HIV-associated dementia, milder cognitive deficits persist and may negatively impact the quality of life of patients and their families [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Furthermore, the aging of the population living with HIV\u0026mdash;driven largely by the effectiveness of ART\u0026mdash;introduces additional diagnostic and therapeutic challenges, as older HIV-positive individuals demonstrate up to a threefold increased risk of developing neurocognitive alterations, particularly involving attention, working memory, learning, memory, and executive functions [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis was an observational, cross-sectional, descriptive-analytical study conducted to evaluate the neurocognitive profile of people living with HIV (PLHIV) receiving antiretroviral therapy (ART).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eA total of 30 individuals living with HIV, aged between 18 and 40 years, of both sexes, were recruited from the Center for Care of Acquired Infectious Diseases (CASA DIA) in the city of Bel\u0026eacute;m, Par\u0026aacute;, Brazil.\u003c/p\u003e \u003cp\u003eParticipants were eligible if they had been receiving antiretroviral therapy for at least one year using a regimen composed of tenofovir, lamivudine, and dolutegravir (TDF/3TC\u0026thinsp;+\u0026thinsp;DTG). Exclusion criteria included the current or previous diagnosis of psychiatric disorders, a history of central nervous system infection reported by the patient or documented in medical records, and illicit drug use within the previous 30 days. All participants who agreed to participate in the study signed two copies of the Informed Consent Form prior to the assessments. The study protocol was submitted to and approved by the Research Ethics Committee of the Federal University of Par\u0026aacute; (UFPA) in accordance with Resolution No. 466/2012 of the Brazilian National Health Council (approval number 5.822.870).\u003c/p\u003e\n\u003ch3\u003eData collection site\u003c/h3\u003e\n\u003cp\u003eAll assessments were conducted at the Center for Care of Acquired Infectious Diseases (CASA DIA) in Bel\u0026eacute;m, Par\u0026aacute;, Brazil. The evaluations were carried out in a private room dedicated to test administration, ensuring adequate conditions of silence and comfort for participants.\u003c/p\u003e\n\u003ch3\u003eProcedures\u003c/h3\u003e\n\u003cp\u003eParticipants were informed about the objectives and procedures of the study prior to the beginning of the assessments. After signing the informed consent form, participants underwent a neuropsychological evaluation. The evaluation protocol lasted approximately 120 minutes and was divided into three stages, with short intervals between assessments to minimize fatigue.\u003c/p\u003e\n\u003ch3\u003eStage 1 – Sociodemographic questionnaire\u003c/h3\u003e\n\u003cp\u003eInitially, an adapted sociodemographic questionnaire was administered, consisting of ten questions addressing personal characteristics, educational level, socioeconomic status, medical history, and time since HIV diagnosis and treatment.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStage 2 \u0026ndash; Functional assessment and cognitive screening\u003c/h2\u003e \u003cp\u003eAt this stage, two instruments were administered:\u003c/p\u003e \u003cp\u003eInstrumental Activities of Daily Living Scale (IADL)\u003c/p\u003e \u003cp\u003eThis scale was used to assess the level of functional independence in daily tasks such as financial management, medication use, shopping, and transportation. The scale consists of eight items, with a maximum score of 24 points. Functional classification was defined as follows:\u003c/p\u003e \u003cp\u003e\u0026le;\u0026thinsp;8 points: total dependence\u003c/p\u003e \u003cp\u003e8 and \u0026lt;\u0026thinsp;24 points: partial dependence\u003c/p\u003e \u003cp\u003e24 points: independent\u003c/p\u003e \u003cp\u003eInternational HIV Dementia Scale (IHDS)\u003c/p\u003e \u003cp\u003eThe IHDS was used as a screening instrument for HIV-associated neurocognitive impairment. The scale assesses three main cognitive domains:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003emotor speed\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003epsychomotor speed\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ememory\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eThe maximum possible score is 12 points. Scores\u0026thinsp;\u0026le;\u0026thinsp;11 were considered indicative of positive screening for HIV-associated neurocognitive disorders (HAND).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStage 3 – Computerized neuropsychological assessment\u003c/h3\u003e\n\u003cp\u003eTo provide a more detailed evaluation of cognitive performance, the computerized Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered. This battery is widely used in neuropsychological research and includes standardized tests designed to evaluate multiple cognitive domains.\u003c/p\u003e \u003cp\u003eSix tests known to be sensitive to cognitive alterations associated with HIV infection were selected:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eMotor Screening Task (MOT)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAssesses possible sensorimotor difficulties or problems in understanding the task instructions.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eReaction Time (RTI)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eEvaluates reaction speed and movement time, providing measures of motor and cognitive processing speed.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eEmotion Recognition Task (ERT)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAssesses social cognition through the identification of facial emotional expressions, including happiness, sadness, fear, anger, disgust, and surprise.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eRapid Visual Information Processing (RVP)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eMeasures sustained attention and the ability to continuously monitor visual stimuli.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eDelayed Matching to Sample (DMS)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAssesses short-term visual memory and visual matching ability.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ePattern Recognition Memory (PRM)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eEvaluates visual recognition memory for abstract patterns.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software, version 20. Initially, descriptive analyses of sociodemographic, clinical, and neuropsychological variables were conducted. Results were presented as absolute and relative frequencies, means, and standard deviations, when appropriate. Scores obtained from the IHDS and IADL scales were used to characterize neurocognitive screening results and functional performance in daily activities, respectively.\u003c/p\u003e \u003cp\u003eTo investigate possible associations between cognitive domains assessed by the CANTAB tasks and the clinical measures obtained from the IHDS and IADL scales, Spearman\u0026rsquo;s correlation coefficient (ρ) was used. This method was chosen because it is a non-parametric analysis suitable for small sample sizes and for variables that may not follow a normal distribution.\u003c/p\u003e \u003cp\u003eCorrelations were analyzed between CANTAB performance variables (reaction time, number of correct and incorrect responses, and choice time) and scores obtained in the IHDS and IADL scales. The significance level adopted for all analyses was 5% (p\u0026thinsp;\u0026le;\u0026thinsp;0.05), with a 95% confidence interval.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSample characterization\u003c/h2\u003e \u003cp\u003eThe sample consisted of 30 people living with HIV undergoing clinical follow-up at the Center for Care of Acquired Infectious Diseases (CASA DIA) in Bel\u0026eacute;m, Par\u0026aacute;, Brazil. All participants were male and aged between 18 and 42 years. The predominant age group was between 26 and 36 years, corresponding to 66.67% of the sample (n\u0026thinsp;=\u0026thinsp;20). Participants aged 18\u0026ndash;25 years accounted for 23.33% (n\u0026thinsp;=\u0026thinsp;7), while 10% (n\u0026thinsp;=\u0026thinsp;3) were between 37 and 42 years old. All participants were literate and reported no current or previous history of psychiatric disorders, central nervous system infections, arterial hypertension, or diabetes mellitus.\u003c/p\u003e \u003cp\u003eRegarding the duration of antiretroviral therapy, 50% of participants had been receiving treatment for more than five years, 43.33% between one and five years, and 6.67% for approximately one year. All participants were receiving the antiretroviral regimen composed of tenofovir, lamivudine, and dolutegravir (TDF/3TC\u0026thinsp;+\u0026thinsp;DTG). Only five participants (16.67%) reported the use of medications other than ART, mainly drugs for the treatment of gastritis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eFunctional evaluation (IADL)\u003c/h2\u003e \u003cp\u003eThe functional evaluation using the Instrumental Activities of Daily Living (IADL) scale showed that none of the participants presented total dependence. Most participants (66.67%, n\u0026thinsp;=\u0026thinsp;20) were classified as partially dependent, while 33.33% (n\u0026thinsp;=\u0026thinsp;10) were considered independent. Regarding the specific tasks evaluated by the scale, 6.9% of participants reported being unable to manage their own finances, while 3.45% reported difficulties taking medications correctly, performing minor household repairs, or shopping. Conversely, 31.03% reported needing assistance for transportation, 27.59% for medication management, and 24.14% for performing small household repairs.\u003c/p\u003e \u003cp\u003e Despite these difficulties, all participants reported being able to use the telephone without assistance, and most reported independence in shopping and meal preparation. The ability to manage finances and perform domestic activities independently was reported by 93.1% of participants.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eScreening for neurocognitive impairment (IHDS)\u003c/h2\u003e \u003cp\u003eScreening using the International HIV Dementia Scale (IHDS) indicated positive screening for HIV-associated neurocognitive disorders (HAND) in 96.67% of participants (n\u0026thinsp;=\u0026thinsp;29), while only one participant (3.33%) scored above the cutoff point.\u003c/p\u003e \u003cp\u003eIn the analysis of the domains assessed by the scale, most participants scored between 3 and 4 points in the memory domain. In the motor speed domain, 48.28% obtained three points and 41.38% obtained two points. In the psychomotor speed domain, 72.41% obtained three points and 10.34% achieved the maximum score. In the memory domain, 3.45% of participants scored one point, 6.9% scored two points, 3.45% scored 2.5 points, 31.03% scored three points, 17.24% scored 3.5 points, and 37.93% obtained the maximum score of four points.\u003c/p\u003e \u003cp\u003eAll participants successfully completed the three tasks included in the scale and obtained at least the minimum score in each domain evaluated.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eCognitive performance in the CANTAB battery\u003c/h2\u003e \u003cp\u003eIn the Motor Screening Task (MOT), none of the participants presented significant difficulties in performing the task. All correctly selected the stimuli presented within the acceptable time limit (up to 6000 ms), suggesting the absence of significant sensorimotor impairment. In the Reaction Time (RTI) task, all participants successfully released the button and selected the stimulus within the expected time interval (100 to 5100 ms). The number of observed errors ranged from 0 to 15, which was considered within the acceptable range for this task. In the Emotion Recognition Task (ERT), the mean total number of errors was 20.88 responses across participants. The highest frequency of errors occurred in the identification of the emotion fear, followed by surprise. In contrast, the highest accuracy rates were observed for the emotions surprise and happiness. The mean response time for emotion recognition was 2388.44 ms, which is higher than the ideal response time for the task. In the Rapid Visual Information Processing (RVP) test, 83% of participants correctly detected between 1 and 27 target sequences, while approximately 90% presented errors in sequences between 28 and 54. Despite this, most participants demonstrated adequate sequence detection ability, with 73.33% showing performance values between 0.00 and 0.50 and 26.67% between 0.50 and 1.0, considering that 1.0 represents optimal performance.\u003c/p\u003e \u003cp\u003eIn the Delayed Matching to Sample (DMS) test, all participants correctly identified at least one pattern. The majority (83.33%) correctly matched between 11 and 20 patterns, while five participants presented performance between 1 and 5 correct responses. When considering only patterns presented after delay, 60% of participants correctly matched between 8 and 15 patterns. In the Pattern Recognition Memory (PRM) test, the mean accuracy rate before the pause was 61.67%, while after the pause it decreased to 55.86%. The mean pattern selection time before the pause was 8088.98 ms, decreasing to 1655.18 ms after the pause, although both values remained above the ideal response time for the task.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation between cognitive performance and functionality\u003c/h2\u003e \u003cp\u003eSpearman correlation analysis revealed significant associations between several CANTAB variables and the activities evaluated by the IADL scale. The results are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. A positive correlation was observed between the number of correct responses in the DMS test and the ability to perform domestic tasks, indicating that better visual memory performance was associated with greater autonomy in these activities.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSpearman correlations between CANTAB cognitive performance variables and the motor, psychomotor, and memory domains of the International HIV Dementia Scale (IHDS).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTask\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCorrelation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMotor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eButton release time (RTI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.38\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChoice time (ERT)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.41\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eTotal errors (RVP)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-0.39\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eIncorrect with and without delay (DMS)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-0.38\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eIncorrect with delay (DMS)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-0.37\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.05\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePsychomotor\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eSelection time (RTI)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-0.41\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.03\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eIncorrect happiness (ERT)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-0.40\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.03\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eIncorrect fear (ERT)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e-0.38\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMemory\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eCorrect surprise (ERT)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.38\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eCorrect with delay (DMS)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.38\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.04\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCorrelations were also observed between performance in the RTI, RVP, and ERT tests and the ability to perform minor household repairs, manage medications correctly, and handle finances. In some cases, inverse correlations were identified, indicating that a higher number of errors in cognitive tests was associated with poorer performance in daily activities.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation between cognitive performance and HAND screening\u003c/h2\u003e \u003cp\u003eThe analysis of correlations between CANTAB variables and the domains evaluated by the IHDS revealed significant associations between cognitive performance and motor, psychomotor, and memory domains. Inverse correlations were observed between response time in RTI, the number of errors in RVP and DMS, and scores in the motor and psychomotor domains of the IHDS. Conversely, positive correlations were observed between the number of correct responses in the DMS and ERT tests and the memory domain of the scale.These results suggest that cognitive performance alterations assessed through the CANTAB battery are associated with neurocognitive impairment detected by the IHDS.\u003c/p\u003e \u003cp\u003eTo explore these relationships more comprehensively, a correlation map was constructed integrating the variables obtained from the CANTAB tests with the clinical measures derived from the IHDS and IADL scales (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePositive correlations indicate a direct association between better cognitive performance and higher functional capacity, whereas negative correlations indicate associations between longer response times or higher error rates and poorer cognitive or functional performance. Overall, associations were observed between different cognitive domains and daily functional measures, suggesting that alterations in memory, attention, and psychomotor speed are related to variations in neurocognitive screening scores and levels of independence in instrumental activities of daily living.\u003c/p\u003e \u003cp\u003eFinally, to facilitate visualization of the overall cognitive performance of the sample, a summarized cognitive profile was constructed considering the main domains assessed by the CANTAB battery (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Participants showed greater relative impairment in the psychomotor speed domain, while memory and attention domains appeared comparatively more preserved.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study aimed to evaluate the neurocognitive profile of people living with HIV receiving antiretroviral therapy (ART) and to investigate the relationship between cognitive performance, screening for neurocognitive impairment, and functional capacity in instrumental activities of daily living. Overall, the results revealed a high frequency of positive screening for HIV-associated neurocognitive disorders (HAND), as well as impairments in cognitive domains related to memory, attention, and psychomotor speed, assessed through the computerized neuropsychological battery CANTAB.\u003c/p\u003e \u003cp\u003eOne of the most relevant findings of this study was the high proportion of participants with positive screening for HAND according to the International HIV Dementia Scale (IHDS). Although the introduction of combination antiretroviral therapy has significantly reduced the incidence of severe neurological complications, recent studies indicate that cognitive alterations associated with HIV remain frequent even among individuals with controlled viral load [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Current epidemiological estimates suggest that between 30% and 50% of people living with HIV present some degree of neurocognitive impairment, even in the era of modern antiretroviral therapy [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Recent meta-analyses report a global prevalence of approximately 42\u0026ndash;46%, reinforcing that cognitive impairment remains one of the most relevant neurological complications of HIV infection [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe results obtained from the CANTAB battery also revealed impairments across different cognitive domains, particularly in tasks related to sustained attention, visual memory, and psychomotor speed. This pattern of impairment is consistent with the neuropsychological profile commonly described in patients with HAND, which is characterized by a predominantly subcortical pattern of cognitive dysfunction. This profile mainly involves psychomotor slowing, attentional deficits, and alterations in working memory and information processing speed [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Recent studies continue to demonstrate that deficits in processing speed, attention, and executive function are among the most frequently affected cognitive domains in individuals living with HIV [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnother relevant finding observed in this study was the presence of functional impairment among part of the evaluated participants. Although none of the individuals were classified as totally dependent in instrumental activities of daily living, the majority presented partial dependence in daily tasks. Evidence from the literature indicates that mild cognitive deficits in people living with HIV can impact complex daily activities such as medication management, financial organization, and mobility, even when individuals remain independent in basic activities [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Recent studies further suggest that cognitive alterations associated with HIV may compromise treatment adherence, occupational performance, and overall quality of life, particularly among individuals presenting mild forms of HAND [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, the correlation analyses performed in this study demonstrated associations between cognitive test performance and functional measures assessed by the IADL scale. In general, better performance in tasks related to visual memory and attention was associated with greater functional independence, whereas longer response times or a higher number of errors in cognitive tests were associated with poorer performance in daily activities. These findings are consistent with evidence suggesting that subtle cognitive alterations may significantly affect daily functioning in people living with HIV, even in the early stages of neurocognitive impairment [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFrom a pathophysiological perspective, several mechanisms have been proposed to explain the persistence of cognitive alterations associated with HIV, even among individuals receiving ART. Evidence suggests that the virus may invade the central nervous system early during infection, establishing viral reservoirs in microglial cells and astrocytes and triggering chronic inflammatory processes that can result in progressive neuronal dysfunction [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Recent studies also highlight the role of persistent neuroinflammation, synaptic dysfunction, and alterations in neural connectivity as important factors in the pathophysiology of HAND [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this context, the use of computerized neuropsychological batteries such as CANTAB represents a promising approach for the detailed assessment of cognitive functioning in people living with HIV. These instruments allow for the standardized and sensitive evaluation of multiple cognitive domains, enabling the early detection of cognitive alterations that may not be identified through simpler screening tools. The early identification of these alterations may contribute to improved clinical monitoring strategies and therapeutic interventions aimed at preserving cognitive function in people living with HIV.\u003c/p\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eStudy limitations\u003c/h2\u003e \u003cp\u003eSome limitations of the present study should be considered when interpreting the results. First, the relatively small sample size may limit the generalizability of the findings to broader populations of people living with HIV. Additionally, all participants in the present study were male, which prevents the analysis of potential sex-related differences in neurocognitive performance. Future studies including more diverse and larger samples may help clarify whether similar patterns of cognitive impairment occur across different demographic groups. Another limitation concerns the absence of a control group composed of HIV-negative individuals. The inclusion of a control group would allow a more precise comparison of cognitive performance and would strengthen the interpretation of the observed deficits as being specifically associated with HIV infection. Furthermore, the cross-sectional design of the study does not allow for the evaluation of longitudinal changes in cognitive functioning over time. Despite these limitations, the study provides valuable insights into the neurocognitive profile of people living with HIV receiving antiretroviral therapy and contributes to the growing body of literature investigating the persistence of neurocognitive alterations in the ART era.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eClinical implications and future perspectives\u003c/h2\u003e \u003cp\u003eThe findings of this study reinforce the importance of systematic neurocognitive evaluation in the clinical follow-up of people living with HIV. Even in the context of effective antiretroviral therapy and viral suppression, cognitive alterations may persist and affect daily functioning and treatment adherence. The use of computerized neuropsychological tools such as CANTAB may represent an important strategy for improving the detection of subtle cognitive deficits that are not always identified through traditional screening instruments. Early identification of cognitive impairment may allow the implementation of targeted interventions, including cognitive rehabilitation programs, improved clinical monitoring, and strategies aimed at optimizing adherence to antiretroviral therapy. Future research should aim to investigate larger and more heterogeneous samples, incorporate longitudinal designs, and explore potential biological markers associated with HAND. Additionally, studies integrating neuropsychological evaluation with neuroimaging and neurophysiological approaches may contribute to a more comprehensive understanding of the mechanisms underlying HIV-associated neurocognitive impairment.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe present study demonstrated a high frequency of neurocognitive alterations in people living with HIV receiving antiretroviral therapy, with impairments primarily observed in domains related to psychomotor speed, attention, and memory. These findings reinforce that HIV-associated neurocognitive disorders remain prevalent even in the era of effective antiretroviral treatment. Furthermore, the observed associations between cognitive performance and functional capacity highlight the potential impact of subtle cognitive deficits on daily activities. The use of integrated assessment approaches combining clinical screening scales and computerized neuropsychological batteries may improve the identification of cognitive impairment in this population. Overall, these results emphasize the importance of incorporating routine neurocognitive assessment into the clinical management of people living with HIV.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflict of interest\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no financial or non-financial conflicts of interest related to this study.\u003c/p\u003e\n\u003ch2\u003eEthical approval\u003c/h2\u003e \u003cp\u003e This study was approved by the Research Ethics Committee of the Federal University of Par\u0026aacute; (UFPA) under approval number 5.822.870, in accordance with Resolution No. 466/2012 of the Brazilian National Health Council.\u003c/p\u003e \u003ch2\u003eConsent to participate\u003c/h2\u003e \u003cp\u003e All participants provided written informed consent prior to participation in the study.\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eSamilly Palheta Gon\u0026ccedil;alves received financial support through a scholarship granted by the Coordination for the Improvement of Higher Education Personnel (CAPES).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor 1: study conception, data collection, and manuscript drafting.Author 2: study conception, statistical analysis, manuscript revision, and final approval.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003e The authors thank the Center for Care of Acquired Infectious Diseases (CASA DIA) for its support during data collection and the study participants for their voluntary contribution to this research.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAntinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M et al (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurol 30 de outubro de 69(18):1789\u0026ndash;1799. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1212/01.WNL.0000287431.88658.8b\u003c/span\u003e\u003cspan address=\"10.1212/01.WNL.0000287431.88658.8b\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaylor D, Dickens AM, Sacktor N, Haughey N, Slusher B, Pletnikov M et al (2016) HIV-associated neurocognitive disorder \u0026mdash; pathogenesis and prospects for treatment. 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Curr Opin Infect Dis fevereiro de 30(1):117\u0026ndash;122. 101097/QCO.0000000000000328 PubMed PMID: 27798498; PubMed Central PMCID: PMC5382956\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu A, Zaongo SD, Harypursat V, Wang X, Ouyang J, Chen Y (2024) HIV-associated neurocognitive disorder: key implications of the microbiota-gut-brain axis. Front Microbiol 2 de agosto de 15:1428239. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fmicb.2024.1428239\u003c/span\u003e\u003cspan address=\"10.3389/fmicb.2024.1428239\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"HIV, HIV-associated neurocognitive disorders, cognition, CANTAB, antiretroviral therapy","lastPublishedDoi":"10.21203/rs.3.rs-9227316/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9227316/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe introduction of antiretroviral therapy (ART) has substantially reduced opportunistic infections and significantly increased the life expectancy of people living with HIV (PLHIV). Despite these advances, HIV-associated neurocognitive alterations\u0026mdash;collectively known as HIV-associated neurocognitive disorders (HAND)\u0026mdash;continue to be observed even in individuals receiving effective treatment. The present study aimed to evaluate potential cognitive deficits in PLHIV undergoing ART and to characterize the clinical profile of neurocognitive manifestations. Thirty HIV-positive individuals aged between 18 and 40 years participated in the study. All participants had been receiving the antiretroviral regimen tenofovir, lamivudine, and dolutegravir (TDF/3TC\u0026thinsp;+\u0026thinsp;DTG) for at least one year. The assessment protocol included a sociodemographic questionnaire, the Instrumental Activities of Daily Living Scale (IADL), the International HIV Dementia Scale (IHDS), and the computerized Cambridge Neuropsychological Test Automated Battery (CANTAB), which evaluates psychomotor speed, sustained attention, visual memory, and emotion recognition. The results indicated that 66.7% of participants exhibited partial dependence in instrumental activities of daily living. Screening with the IHDS identified positive HAND screening in 96.7% of the sample. Performance on the CANTAB tasks revealed impairments primarily in memory, attention, and psychomotor speed, as well as difficulties in facial emotion recognition. Additionally, a significant association was observed between cognitive performance and functional capacity in everyday activities. These findings suggest that neurocognitive deficits remain prevalent among PLHIV even during antiretroviral therapy, highlighting the importance of systematic neuropsychological assessment in the clinical monitoring of this population.\u003c/p\u003e","manuscriptTitle":"Neuropsychological assessment of cognitive deficits in people living with HIV receiving antiretroviral therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-03 11:25:11","doi":"10.21203/rs.3.rs-9227316/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3f0d1b3e-27d6-4c5f-ad3d-e6c50239fec6","owner":[],"postedDate":"April 3rd, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-04-30T20:18:39+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-30T20:24:19+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-03 11:25:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9227316","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9227316","identity":"rs-9227316","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}