Assessment of Plasma Neurofilament Light as a Biomarker of Neuronal Injury in Young Adults with Perinatal HIV Infection

Assessment of Plasma Neurofilament Light as a Biomarker of Neuronal Injury in Young Adults with Perinatal HIV Infection | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Assessment of Plasma Neurofilament Light as a Biomarker of Neuronal Injury in Young Adults with Perinatal HIV Infection Beatriz Ruiz-Saez, Manuela Martín-Bejarano, Ana Martínez Aragon, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-787438/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Higher plasma concentration of neurofilament light (pNfL) is associated with neurodegeneration. However, to our knowledge, up to now, there are no data in HIV patients with infection due to vertical transmission. This is the first study to report pNfL in a cohort of HIV perinatally infected (PHIV) young adults compared with non-HIV (HIV-) controls. Methods: Thirty-three PHIV patients and 25 age-matched HIV- were recruited to this cross-sectional study. Plasma NfL concentrations were compared between both groups. In a subgroup of 48 participants (25 PHIV patients and 23 HIV-), brain volumes through magnetic resonance imaging (MRI) and neuropsychological testing (NT), were also conducted and compared with pNfL values. Plasma NfL concentration was measured using Single Molecule Array (Simoa) immunoassay. NT included fluid intelligence and processing speed through the WAIS-IV Coding subtest, and the Stroop Test. Results Fifty-eight participants were included, median age 20.7 years [IQR 17.8-23.4]. 100% of the patients were under antiretroviral treatment (cART) and 85% had viral load <50 copies/ml. Although no statistically significant differences were found between patients and controls regarding pNfL concentration, there was a trend towards higher levels in patients with viral load >50 copies/ml. With regard to brain volumes and NT, in the PHIV group, lower white matter volumes and lower score in the coding subtest were associated with higher pNfL values. Conclusions Most PHIV adolescents under cART have similar levels of pNfL than HIV-. As reported in adults, those with HIV-RNA >50 copies/ml showed higher values and lower white matter volumes that may imply an ongoing CNS injury. Plasma NfL could be a feasible biomarker of CNS injury in PHIV patients with unsuppressed viral load. Infectious Diseases Plasma NfL perinatal HIV neuroimaging neurocognitive cART Figures Figure 1 Figure 2 Background The incidence of HIV encephalopathy and severe neurological complications has been significantly reduced in perinatally HIV-infected patient since the introduction of combined antiretroviral therapy 1 . Nevertheless, in the PHIV population, CNS invasion of HIV occurs within the first 3 weeks of life, with a subsequent immune activation throughout the primary infection. This is among the most important reasons why research concerning the detection of persistent neurologic problems is essential 2 . This research could explain why less severe cognitive impairment often could persists in this population, especially in children who did not start treatment in early life 3 . To better understand how the development of brain injury and intrathecal immune activation and inflammation occur, several CSF biomarkers have been investigated, with CSF neurofilament light (NfL) being the most useful biomarker for the study of HIV-induced neuroaxonal injury 4 . This major structural component of myelinated axons is essential to maintain axonal calibre and to facilitate effective nerve conduction 5 . It is a sensitive, but disease-unspecific, biomarker for neuronal degeneration or acute neuronal damage 6 . Several studies performed in HIV-infected adults have shown increased CSF NfL levels in patients with HIV associated dementia but also in neuroasymptomatic subjects with low CD4 + T-cell counts 5 – 7 . Meanwhile, treated and virologically suppressed people living with HIV have lower CSF NfL levels, but this is still slightly higher than HIV-negative individuals 5 . Measuring CSF NfL uses the invasive procedure of lumbar puncture, so its use is limited. Therefore, a new technique has been developed using ultrasensitive (Simoa) immunoassay for measuring NfL in blood samples 8 . Results derived using this new method show that plasma NfL correlates strongly with CSF NfL levels at all stages of HIV infection 8 . To our knowledge, no study of plasma or CSF NfL has been performed in the perinatally HIV-infected population. It is worth stating, that in recent years, several neuroimaging studies have been performed in PHIV children and young adults demonstrating that, even in the cART era, there are alterations and lower volumes in brain structure 9 . As NfL CSF levels reflect leakage from injured or degenerating neurons, it correlates with white matter lesions and other injuries to subcortical brain regions 10 . To date, there are no studies correlating white matter brain volumes and pNfL values in perinatally HIV-infected patients. Therefore, the current study aimed to investigate, firstly, the pNfL levels in a group of PHIV population and compared them with a group of HIV-negative controls participating in the NeuroCoRISpe study. Secondly, a sub-study was performed to explore possible correlations between pNfL concentration and white matter volumes and processing speed performance in a group of participants. Methods Population and Study Design A multicentre cross-sectional study was carried out from 2016 to 2018 in a cohort of vertically HIV-infected adolescents and young adults followed at five public hospitals participating in the Madrid Cohort of HIV-Infected Children and Adolescents and in the Cohort of Spanish Pediatric HIV Network (CoRISpe) 11 . The HIV- were selected from voluntary recruitment through advertising. Thirty-three PHIV patients and 25 HIV- controls matched by age were recruited. For the study, all participants met the following inclusion criteria: (1) age 15 to 25 years old, (2) absence of neurological or psychiatric disorder other than history of older HIV encephalopathy, (3) HIV participants should be under cART treatment. Participants with current brain infection, neurological or psychiatric disorder, those who referred history of drug or alcohol abuse, or had any congenital abnormality, were excluded. The Institutional Review Boards (IRBs) of each research centre approved the study and written informed consent was obtained from all participants. Where participants were underage, an assent form was signed by themselves, with legal guardians providing the informed consent in accordance with the Helsinki Declaration. HIV-related measures In relation to the control of the infection the next parameters were collected: CDC classification, encephalopathy, suppressed viral load (defined as plasma HIV-RNA < 50 copies/ml), time of suppressed viral load, viral load in detectable patients, total numbers, and percentages of CD4 nadir, and current CD4, CD4 / CD8 ratio, cART history and adherence to treatment. These data were collected from clinical charts and the CoRISpe database. Plasma NfL measurements Whole blood was collected in EDTA tubes which were sent to the Spanish HIV HGM BioBank for centrifugation (2000 g) and aliquoted into cryo tubes in 1 mL portions and stored at − 80° for subsequent analysis 12 . Plasma NfL concentration was measured using a sensitive in-house sandwich immunoassay on the (Simoa) HD-1 Analyzer (Quanterix, Billerica, MA), as previously described in detail 8 . Neuropsychological and neuroimaging sub-study A subgroup of 48 participants (25 PHIV +, 23 HIV-) with no differences in sex, age, level of education and socioeconomic status between groups, underwent NT testing and MRI scan. These subjects participated previously in a neurocognitive and neuroimaging study (Ruiz-Saez et al, 2021) 13 and whole blood was collected at the same time and stored at the HIV HGM Biobank for subsequent pNfL analysis. The NT included fluid intelligence (FI) by the Kaufman Brief Intelligence Test 14 (K-BIT; Kaufman & Kaufman, 2000), and processing speed measured through two tests, the Digit Symbol-Coding subtest of the Wechsler Adult Intelligence Scale- 4th edition 15 (WAIS-IV, Weschler, 2012), and the first trial of the Stroop Test 16 (Golden, 2001). In this study, we focused on fluid intelligence to make sure abstract reasoning and problem solving in novel situations independently of experience was average in both groups. Processing speed was also evaluated, because is one of the main cognitive deficits in HIV patients 17 . Scores on all neuropsychological tests were converted into a Z-score relative to HCs. Scores on the Digit Symbol- Coding and Stroop-Card 1 were averaged into one PS composite Z-score. MRI data acquisition Different MRI scanner systems were used at each hospital study site. For specific details of the acquisition parameters see Supplementary material. Image quality was assessed in two independent processes. Radiologist checked for the presence of any brain pathology, such as tumour, cyst, or any other lesion. In addition, image quality and processing experts checked for motion artefacts, low contrasts, incomplete whole brain coverage, low SNR and low resolution. In a further analysis, all the acquisitions were correlated to determine the homogeneity of the image sample. Image processing The standard processing pipeline for volume based morphometry provided by The Computational Anatomy Toolbox (CAT12, http://dbm.neuro.uni-jena.de/cat/ version 1492), as an extension of SPM ( https://www.fil.ion.ucl.ac.uk/spm/software/spm12/ version 7487), was used for tissue segmentation and the extraction of tissue volumes. To measure regional brain volumes, native segmented images were parceled in regions of interest (ROI) according to the Hammers atlas 18 – 19 (Hammers et al. 2003; Gousias et al. 2008) and tissue volumes (mm 3 ) were estimated for each ROI and normalized by the total intracranial volume for each subject. Statistical analysis Categorical variables were summarized by using counts and proportions and continuous variables employing medians and interquartile ranges (IQR) or means and standard deviations (SD). Comparisons between patients and controls (NfL, age, Fluid Intelligence, Stroop, Coding and Composite z-score) were performed with the Student t test or the Mann–Whitney U test, if the variables did not follow a normal distribution. Comparisons between categorical variables were assessed using the Chi-square or the Fisher test. In the case of patients with and without undetectable viral load and controls, variables were analyzed with the Kruskal-Wallis test. Regarding the PHIV group, univariate analysis was performed to study associations between HIV variables and NfL. Spearman’s correlation test was used to assess association pNfL concentrations and white matter volumes. P values less than 0.05 were considered statistically significant. All analyses were performed using SPSS software ver. 22.0 (IBM, Armonk, NY, USA). Figure 2 was made using Stata Version 12 (STATA Corp, Texas, USA). Results Thirty-three young adults with perinatal HIV infection and 25 HIV-negative individuals were included. In the PHIV group, 54% were women and 73% were Caucasians. Median age was 20.7 years (IQR 17.8–23.4). In the HIV-negative group, median age was 21.3 years (IQR 19.7–23.1) and 60% were women. There were no significant differences between the two groups regarding these characteristics (p > 0.05). Regarding the PHIV group, 42% had a history of previous AIDS-defining diagnoses (21% with old and stable encephalopathy). At assessment, 100% were under cART for a median time of 16.42 years (IQR 12.99–18.70), and 85% had suppressed viral load (HIV RNA 50 copies/ml with a median of 69900 copies/ml (IQR 36774–267541). Those five patients had detectable viral load for a median of 5.75 years (IQR 5.03–16.75). Median CD4 was 738 cells/mm 3 (IQR 578–978) and median CD4 nadir 274 (IQR 104–382). (Table 1 ). Table 1 Clinical measures in 33 PHIV patients (n (%) or median [IQR]) No statistically significant differences were found between patients and controls regarding pNfL concentrations, but higher levels of pNfL were found in patients with increased viral load compared compared with undetectable patients and controls with a media pNfL of 9.19 pg/ml (SD 5.18) in patients with detectable viral load vs 6.6 pg/ml (SD 4.15) in undetectable patients and 5.29 pg/ml (SD 1.75) in the control group (p = 0.059) (Fig. 1 ). Furthermore, no correlations were found between pNfL levels and viral load, time to diagnosis, time on cART, CDC stage or presence of encephalopathy (p > 0.05 for all comparisons). In the correlation sub-study of pNfL with neuroimaging and neuropsychological evaluations, 25 PHIV + and 23 HIV-negative controls were evaluated. Sociodemographic characteristics are described in Table 2 . In relation to NT, we found that PHIV had significantly lower FI, but both groups had average results. Differences between groups in Stroop test performance were observed, but not in Coding. The mean PS composite z-score was lower in the PHIV group (Mean Z-score − 0.68 (SD 0.98)) compared to the HIV-negative group (Mean Z-score 0.00 (SD 1.00)) (p < 0.05) Table 2 Means (standard deviations) of demographic, psychosocial, neurocognitive and psychopathological characteristics. PHIV (n = 25) HIV- (n = 23) P value Sex (female) (%, n) 64 (16) 56,5 (13) 0.597 Age at assessment 21.0 (3.03) 20.9 (2.66) 0.522 Level of education (%, n) Low Medium High N = 24 62.5 (15) 16.7 (4) 20.8 (5) N = 21 76.2 (16) 0 (0) 23.8 (5) 0.146 Annual Income (%, n) Low Medium High N = 23 43.5 (10) 30.4 (7) 26.1 (6) N = 22 59.1 (13) 36.4 (8) 4.5 (1) 0.135 Caucasian (%, n) 72 (18) 56,5 (13) 0.263 Fluid Intelligence * -0.72 (1.13) 0.01 (0.98) 0.021 Stroop -0.84 (1.09) 0.00 (0.99) 0.009 Coding -0.31 (0.86) -0.12 (1.14) 0.512 Composite Processing Speed Z-score -0.68 (0.98) -0.00 (1.00) 0.025 Regarding brain volumes, the HIV infected group had significantly lower regional white matter volumes in left and right cerebellum (p = 0.030, p = 0.028), lateral occipital lobe (p = 0.020), left and right nucleus accumbens (p = 0.010, p < 0.001), left and right occipital lobe (p = 0.020, p = 0.042) and left postcentral gyrus (p = 0.022), but no significant differences were found in total white matter volumes. In the HIV group, Spearman’s correlation test revealed negative association between pNfL concentrations and different regional white matter volumes of left and right cerebellum (r -,440 p = 0.028; r -,0386, p = 0.056), left and right brainstem (r -,440 p = 0.028; r -,417 p = 0.038) and right nucleus accumbens ( r-,403, p = 0.046) Fig. (2), and also a negative correlation was found between pNfL concentration and Coding score (r -,425 p = 0.039). This association between NfL and brain volumes and coding score persisted when controlling for undetectable viral load. Discussion NfL is a neurofilament subunit particularly abundant in axons 20 . Plasma NfL concentration was recently reported as a potential prognostic biomarker of disease onset and progression in neurodegenerative diseases including HIV 4 – 8 . In this study, we have shown that treated and virologically suppressed PHIV people, presented pNfL concentrations similar of those found in HIV-negative individuals. In addition, even considering the limitation of the small sample, patients with detectable viral load had higher pNfL levels, showing that persistent viral replication may contribute to neuronal damage. This has been demonstrated similarly in the HIV adult population, in which the HIV-driven axonal degeneration can be halted by cART, which correlates to reduced CSF and pNfL concentrations over time after cART initiation 5,21−22 . These results emphasize the importance of an early and continuous antiretroviral therapy to avoid neuronal damage in children. In this exploratory study of PHIV adolescents and young adults, we found that higher pNfL concentration was significantly associated with lower regional brain volume and lower coding score. Similarly, Anderson et al . published that a higher pNfL was significantly associated with worse neuropsychological performance in the HIV adult population 23 . High concentration of NfL has been shown in multiple neurological diseases where processing speed is also one of the most affected cognitive processes, such as amyotrophic lateral sclerosis (ALS) 24 , 25 (Menke et al., 2015; Lu et al., 2015), Alzheimer’s disease 26 (Mattsson et al., 2017) and frontotemporal dementia 27 (Rohrer et al., 2016). Processing speed performance is considered to depend to a large extent on the properties of the white matter 28 – 30 (Posthuma et al, 2003; Borghesani et al., 2013; Jacobs et al., 2013). White matter includes myelinated axons in the brain, and the thickness of the myelin sheath is associated with nerve conduction velocity; therefore, its relation to processing speed and NfL seems consistent. Hence plasma NfL could be a feasible biomarker of milder neurocognitive alterations in the PHIV population. Likewise, increased NfL levels and reduced brain volume in cortical and subcortical grey matter and within the white matter has been found in patients with different neurodegenerative conditions 31 – 32 . However, research performed in the HIV adult population found that CSF neuronal damage biomarkers, including NfL, were not associated with imaging measures of brain structures 33 . It should be noted that NfL has the limitation that it is not a disease-specific biomarker. As we have mentioned, elevated NfL is observed in many other neurological disorders, including neurodegenerative diseases, peripheral neuropathy, and traumatic brain injuries 6 , 34 . Regarding brain volumes we found that the HIV group showed WM atrophy in selected brain regions despite being on cART for years. Some studies performed in adolescents living with PHIV has reported similar results showing lower white matter volumes when compared with HIV negative controls 35 , 36 . Limitations of this study include the small sample size and lack of longitudinal biomarker data. The small sample size has been partially compensated for by strict selection criteria for the control group. Moreover, other limitations of the study are that this age group is potentially more likely to be involved in sports with head trauma, and this group of population may have different stressors, that have not been measured. Number of adverse childhood events (ACEs) would be a useful marker but has not been used. These are potentially important considerations in the adolescent age group during a time of dynamic myelination. Finally, this current work was exploratory and therefore multiple statistical tests were performed, which might have resulted in type I errors. Strengths of our study are, the inclusion of young adults living with PHIV, who have not previously been examined regarding plasma NfL levels, and that we were able to correlate brain volumes and processing speed in this population. This research is representative of most young adults living with HIV vertically infected in developed healthcare systems. Moreover, thanks to the current great improvements in the diagnosis and treatment of HIV infection, this population that were born in the preTAR era making the study unique. Conclusions We can conclude that the ultrasensitive method to measure pNfL concentration provides an easily accessible biomarker in perinatally HIV infected patients avoiding lumbar puncture. Nevertheless, it remains unclear how pNfL varies in the PHIV population with virologic suppression or how its levels could be influenced in this population by the earlier initiation of effective antiretroviral therapy. Therefore, larger longitudinal studies are required in this group to further evaluate pNfL as a clinically useful biomarker of neurological deterioration. Declarations Ethics approval and consent to participate: The Institutional Review Boards (IRBs) of each research centre approved the study and written informed consent was obtained from all participants. Where participants were underage, an assent form was signed by themselves, with legal guardians providing the informed consent in accordance with the Helsinki Declaration. Consent for publication: We hereby verify that the manuscript has not been submitted or accepted elsewhere. All authors have given consent for its publication. Availability of data and material: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Competing interests: a) NeuroCoRISpe group declare no competing financial interest. b) The Sahlgrenska Academy at the University of Gothenburg group have no competing interests that could be construed as influencing the contents of this paper. However, the authors list the following general potential conflicts of interest: HZ has served on scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. MG reports personal fees (scientific advisory boards, lectures) from Gilead Sciences, GSK/ViiV, MSD, Biogen, Amgen, Novocure, Novo Nordic and research grants from Gilead Sciences, all outside the submitted work. Funding: a) NeuroCoRispe group and Spanish HIV HGM BioBank: This work was funded by the Instituto de Salud Carlos III, Acción Estratégica en Salud [FIS 15/00694] and Fondos FEDER of the UE. CoRISpe is integrated in the Spanish AIDS Research Network (RIS), supported by the Instituto de Salud Carlos III [RD16/0025/0017-ISCIII-FEDER,RD16/0025/0019-ISCIII-FEDER, RD16/0025/0024-ISCIII-FEDER and RIS -EPICLIN12/2012] ;BRS was funded by the Spanish Ministry of Science and Innovation- Instituto de Salud Carlos III (Contratos Rio Hortega CM 16/00224). This study takes part of the BRS PhD at Universidad de Alcalá (Madrid, Spain). b) Sahlgrenska Academy at the University of Gothenburg group : This work was supported by the Swedish state, under an agreement between the Swedish government and the county councils (ALF agreement ALFGBG-717531). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236). Authors' contributions: BRS, MMB, MGT, MM conceptualized and designed the study, participated in analysis and interpretation of the data, drafted the initial manuscript and contributed and approved the final manuscript as submitted. BRS, MMB, MG, HZ, KB, AMA, SOJ, SAL, MAM, HM, JTR, MLN, MIGT were involved in the provision of study subjects, reviewed the manuscript drafts, and approved the final manuscript as submitted. All authors read and approved the final manuscript Acknowledgments This study would not have been possible without the collaboration of all the participants, medical and nursing staff, and data managers who have taken part in Neurocorispe Project of The Pediatric National AIDS Research Network of Spain (CORISPE). This work has been performed in collaboration with Biobank Hospital Gregorio Marañon (HGM) and the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden References Patel K, Ming X, Williams PL, et al. Impact of HAART and CNS penetrating antiretroviral regimens on HIV encephalopathy among perinatally infected children and adolescents. AIDS. 2009;23:1893–1901. Cohen S, Caan MWA, Mutsaerts H-J, Scherpbier HJ, Kuijpers TW, Reiss P, et al. Cerebral injury in perinatally HIV-infected children compared to matched healthy controls. Neurology 2016; 86:19–27 Judd A, Le Prevost M, Melvin D, et al. 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Twin Research. 2003;6(02):131–9. Borghesani PR, Madhyastha TM, Aylward EH, Reiter MA, Swarny BR, Schaie KW, et al. The association between higher order abilities, processing speed, and age are variably mediated by white matter integrity during typical aging. Neuropsychologia. 2013;51(8):1435–44. pmid:23507612 Jacobs HIL, Leritz EC, Williams VJ, Van Boxtel MPJ, Elst Wvd, Jolles J, et al. Association between white matter microstructure, executive functions, and processing speed in older adults: the impact of vascular health. Human brain mapping. 2013;34(1):77–95. pmid:21954054 Eileanoir B Johnson 1 , Lauren M Byrne 1 , Sarah Gregory 1 , Filipe B Rodrigues 1 , Kaj Blennow 1 , Alexandra Durr 1 , Blair R Leavitt 1 , Raymund A Roos 1 , Henrik Zetterberg 1 , Sarah J Tabrizi 1 , Rachael I Scahill 1 , Edward J Wild 2 , TRACK-HD Study Group. Neurofilament light protein in blood predicts regional atrophy in Huntington disease. Neurology. 2018 Feb 20;90(8):e717-e723. Li QF, Dong Y, Yang L, Xie JJ, Ma Y, Du YC, Cheng HL, Ni W, Wu ZY. Neurofilament light chain is a promising serum biomarker in spinocerebellar ataxia type 3. Mol Neurodegener. 2019 Nov 4;14(1):39. Van Zoest R, Underwood J, De Francesco D, Sabin CA, Cole JH, Wit FW, et al. Structural Brain Abnormalities in Successfully Treated HIV Infection: Associations With Disease and Cerebrospinal Fluid Biomarkers. J Infect Dis 2017 Dec 27;217(1):69–81 doi: 10.1093/infdis/jix553 . Bridel C, van Wieringen WN, Zetterberg H, Tijms BM, Teunissen CE, Alvarez- Cermeno JC, et al. Diagnostic value of cerebrospinal fluid Neurofilament light protein in neurology: a systematic review and meta-analysis. JAMA Neurol. 2019; Epub ahead of print. Cohen S, Caan MWA, Mutsaerts H-J, Scherpbier HJ, Kuijpers TW, Reiss P, et al. Cerebral injury in perinatally HIV-infected children compared to matched healthy controls. Neurology 2016; 86:19–27 Sarma, M. K., Nagarajan, R., Keller, M. A., Kumar, R., Nielsen-Saines, K., Michalik, D. E., et al (2014). Regional brain gray and white matter changes in perinatally HIV-infected adolescents. NeuroImage: Clinical , 4 , 29–34 Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial1.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-787438","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":45817093,"identity":"2678c601-4384-4e70-800b-2ba43348dbc9","order_by":0,"name":"Beatriz Ruiz-Saez","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAz0lEQVRIiWNgGAWjYBACAyA+AGaxN4C4FqRo4QFRBhLEaYEAiQQwSViLufQZw4M//tjJyc98fnXDjwIJBv727gS8Wiz7cgwOSLYlGzPOzim72QN0mMSZsxvwO+wMj8EBwwbmxGbpnLQbPEAtBhK5RGhJ+FNf3yZ5Ju3mH6K1HGA7nMAjwX7sNlG2WPawFRxsbDtuOIMnh+22jIEED0G/mPMwb/7440+1vHz78Wc33/yxkeNv78WvBQnwgOOIh1jlIMD+gBTVo2AUjIJRMIIAAMj+Rcs1MU6kAAAAAElFTkSuQmCC","orcid":"","institution":"Instituto de Investigación Sanitaria Gregorio Marañón (IisGM)","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Beatriz","middleName":"","lastName":"Ruiz-Saez","suffix":""},{"id":45817094,"identity":"49bbf9e3-92fb-4789-9e14-4e80ed234e56","order_by":1,"name":"Manuela Martín-Bejarano","email":"","orcid":"","institution":"Hospital Universitario 12 De Octubre","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Manuela","middleName":"","lastName":"Martín-Bejarano","suffix":""},{"id":45817095,"identity":"45ca8f2e-ad16-4d2e-9dd8-69327386a03a","order_by":2,"name":"Ana Martínez Aragon","email":"","orcid":"","institution":"Hospital Universitario 12 De Octubre","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ana","middleName":"Martínez","lastName":"Aragon","suffix":""},{"id":45817096,"identity":"5c92de7d-81db-4d3c-9a4e-3e22e31db9f8","order_by":3,"name":"Magnus Gisslen","email":"","orcid":"","institution":"the Sahlgrenska Academy at the University of Gothenburg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Magnus","middleName":"","lastName":"Gisslen","suffix":""},{"id":45817097,"identity":"2d0d7f3a-1f07-4909-b250-97b7e97b4707","order_by":4,"name":"Henrik Zetterberg","email":"","orcid":"","institution":"the Sahlgrenska Academy at the University of Gothenburg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Henrik","middleName":"","lastName":"Zetterberg","suffix":""},{"id":45817098,"identity":"cc98804a-c48d-4e8b-8622-179a32eaf399","order_by":5,"name":"Kaj Blennow","email":"","orcid":"","institution":"the Sahlgrenska Academy at the University of Gothenburg","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kaj","middleName":"","lastName":"Blennow","suffix":""},{"id":45817099,"identity":"9289962b-1a3e-424d-b88c-116a5fe998be","order_by":6,"name":"Santiago Jiménez de Ory","email":"","orcid":"","institution":"Hospital Universitario Gregorio Marañon. Madrid","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Santiago","middleName":"Jiménez","lastName":"de Ory","suffix":""},{"id":45817100,"identity":"c34f077c-8f36-4d9d-bf64-5f8cf2b2ae46","order_by":7,"name":"Susana Alvarez-Losada","email":"","orcid":"","institution":"Universidad Francisco de Vitoria","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Susana","middleName":"","lastName":"Alvarez-Losada","suffix":""},{"id":45817101,"identity":"f22c0996-a33d-4eb6-b777-71aa6d6cb548","order_by":8,"name":"Mª Angeles Muñoz-Fernández","email":"","orcid":"","institution":"Instituto de Investigación Sanitaria Gregorio Marañón (IisGM)","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mª","middleName":"Angeles","lastName":"Muñoz-Fernández","suffix":""},{"id":45817102,"identity":"58cb2389-941f-4850-8a06-50547f5e4c48","order_by":9,"name":"Helena Melero","email":"","orcid":"","institution":"Universidad Complutense de Madrid","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Helena","middleName":"","lastName":"Melero","suffix":""},{"id":45817103,"identity":"d0a74e8a-3070-4a0f-8978-5a83d7d284aa","order_by":10,"name":"Jose Tomás Ramos","email":"","orcid":"","institution":"Hospital Universitario Clínico San Carlos","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jose","middleName":"Tomás","lastName":"Ramos","suffix":""},{"id":45817104,"identity":"d9896ba8-e087-4601-a463-94e874b72a66","order_by":11,"name":"Maria Luisa Navarro","email":"","orcid":"","institution":"Hospital Universitario Gregorio Marañon. Madrid","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Luisa","lastName":"Navarro","suffix":""},{"id":45817105,"identity":"8dfebfca-22a0-4dc8-aafd-5875f7cfaf89","order_by":12,"name":"Maria Isabel González-Tomé","email":"","orcid":"","institution":"Hospital Universitario 12 De Octubre","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Isabel","lastName":"González-Tomé","suffix":""}],"badges":[],"createdAt":"2021-08-06 12:59:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-787438/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-787438/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":12506295,"identity":"c8657847-6a87-4856-93d8-ae58085f17ef","added_by":"auto","created_at":"2021-08-17 15:54:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":27511,"visible":true,"origin":"","legend":"Plasma NfL concentrations in 3 different groups: HIV-negative control group, PHIV patients with detectable VL, and PHIV patients with undetectable viral load","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-787438/v1/294f237fe42730620d68b6eb.png"},{"id":12506296,"identity":"a3b97f02-5e6a-4dbd-b067-12ac44a0a8a8","added_by":"auto","created_at":"2021-08-17 15:54:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":46735,"visible":true,"origin":"","legend":"Spearman correlations for cerebellum and brainstem volumetric measures and pNfL concentrations in HIV-infected patients","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-787438/v1/f2c41cc569157f1cb1d3b669.png"},{"id":15535632,"identity":"81801fe2-f7cd-427a-9516-9d575020e88f","added_by":"auto","created_at":"2021-11-15 09:14:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":574697,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-787438/v1/10b9d9a6-a07d-4a6a-badf-b6e528a5dbf9.pdf"},{"id":12506297,"identity":"84074dbd-93c6-45f0-9f56-03df3398182d","added_by":"auto","created_at":"2021-08-17 15:54:56","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16019,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial1.docx","url":"https://assets-eu.researchsquare.com/files/rs-787438/v1/c12c3cd012221b6def78cf8c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eAssessment of Plasma Neurofilament Light as a Biomarker of Neuronal Injury in Young Adults with Perinatal HIV Infection\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eThe incidence of HIV encephalopathy and severe neurological complications has been significantly reduced in perinatally HIV-infected patient since the introduction of combined antiretroviral therapy\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Nevertheless, in the PHIV population, CNS invasion of HIV occurs within the first 3 weeks of life, with a subsequent immune activation throughout the primary infection. This is among the most important reasons why research concerning the detection of persistent neurologic problems is essential\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. This research could explain why less severe cognitive impairment often could persists in this population, especially in children who did not start treatment in early life\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo better understand how the development of brain injury and intrathecal immune activation and inflammation occur, several CSF biomarkers have been investigated, with CSF neurofilament light (NfL) being the most useful biomarker for the study of HIV-induced neuroaxonal injury\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. This major structural component of myelinated axons is essential to maintain axonal calibre and to facilitate effective nerve conduction\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. It is a sensitive, but disease-unspecific, biomarker for neuronal degeneration or acute neuronal damage\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSeveral studies performed in HIV-infected adults have shown increased CSF NfL levels in patients with HIV associated dementia but also in neuroasymptomatic subjects with low CD4\u0026thinsp;+\u0026thinsp;T-cell counts\u003csup\u003e\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Meanwhile, treated and virologically suppressed people living with HIV have lower CSF NfL levels, but this is still slightly higher than HIV-negative individuals \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMeasuring CSF NfL uses the invasive procedure of lumbar puncture, so its use is limited. Therefore, a new technique has been developed using ultrasensitive (Simoa) immunoassay for measuring NfL in blood samples\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Results derived using this new method show that plasma NfL correlates strongly with CSF NfL levels at all stages of HIV infection\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo our knowledge, no study of plasma or CSF NfL has been performed in the perinatally HIV-infected population.\u003c/p\u003e \u003cp\u003eIt is worth stating, that in recent years, several neuroimaging studies have been performed in PHIV children and young adults demonstrating that, even in the cART era, there are alterations and lower volumes in brain structure\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. As NfL CSF levels reflect leakage from injured or degenerating neurons, it correlates with white matter lesions and other injuries to subcortical brain regions\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. To date, there are no studies correlating white matter brain volumes and pNfL values in perinatally HIV-infected patients.\u003c/p\u003e \u003cp\u003eTherefore, the current study aimed to investigate, firstly, the pNfL levels in a group of PHIV population and compared them with a group of HIV-negative controls participating in the NeuroCoRISpe study. Secondly, a sub-study was performed to explore possible correlations between pNfL concentration and white matter volumes and processing speed performance in a group of participants.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePopulation and Study Design\u003c/h2\u003e \u003cp\u003eA multicentre cross-sectional study was carried out from 2016 to 2018 in a cohort of vertically HIV-infected adolescents and young adults followed at five public hospitals participating in the Madrid Cohort of HIV-Infected Children and Adolescents and in the Cohort of Spanish Pediatric HIV Network (CoRISpe) \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe HIV- were selected from voluntary recruitment through advertising.\u003c/p\u003e \u003cp\u003eThirty-three PHIV patients and 25 HIV- controls matched by age were recruited.\u003c/p\u003e \u003cp\u003eFor the study, all participants met the following inclusion criteria: (1) age 15 to 25 years old, (2) absence of neurological or psychiatric disorder other than history of older HIV encephalopathy, (3) HIV participants should be under cART treatment.\u003c/p\u003e \u003cp\u003eParticipants with current brain infection, neurological or psychiatric disorder, those who referred history of drug or alcohol abuse, or had any congenital abnormality, were excluded.\u003c/p\u003e \u003cp\u003e The Institutional Review Boards (IRBs) of each research centre approved the study and written informed consent was obtained from all participants. Where participants were underage, an assent form was signed by themselves, with legal guardians providing the informed consent in accordance with the Helsinki Declaration.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eHIV-related measures\u003c/h2\u003e \u003cp\u003eIn relation to the control of the infection the next parameters were collected: CDC classification, encephalopathy, suppressed viral load (defined as plasma HIV-RNA\u0026thinsp;\u0026lt;\u0026thinsp;50 copies/ml), time of suppressed viral load, viral load in detectable patients, total numbers, and percentages of CD4 nadir, and current CD4, CD4 / CD8 ratio, cART history and adherence to treatment. These data were collected from clinical charts and the CoRISpe database.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePlasma NfL measurements\u003c/h2\u003e \u003cp\u003eWhole blood was collected in EDTA tubes which were sent to the Spanish HIV HGM BioBank for centrifugation (2000 g) and aliquoted into cryo tubes in 1 mL portions and stored at \u0026minus;\u0026thinsp;80\u0026deg; for subsequent analysis\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Plasma NfL concentration was measured using a sensitive in-house sandwich immunoassay on the (Simoa) HD-1 Analyzer (Quanterix, Billerica, MA), as previously described in detail\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eNeuropsychological and neuroimaging sub-study\u003c/h2\u003e \u003cp\u003eA subgroup of 48 participants (25 PHIV +, 23 HIV-) with no differences in sex, age, level of education and socioeconomic status between groups, underwent NT testing and MRI scan. These subjects participated previously in a neurocognitive and neuroimaging study (Ruiz-Saez et al, 2021) \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e and whole blood was collected at the same time and stored at the HIV HGM Biobank for subsequent pNfL analysis.\u003c/p\u003e \u003cp\u003eThe NT included fluid intelligence (FI) by the Kaufman Brief Intelligence Test \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e (K-BIT; Kaufman \u0026amp; Kaufman, 2000), and processing speed measured through two tests, the Digit Symbol-Coding subtest of the Wechsler Adult Intelligence Scale- 4th edition\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e (WAIS-IV, Weschler, 2012), and the first trial of the Stroop Test\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e (Golden, 2001).\u003c/p\u003e \u003cp\u003eIn this study, we focused on fluid intelligence to make sure abstract reasoning and problem solving in novel situations independently of experience was average in both groups. Processing speed was also evaluated, because is one of the main cognitive deficits in HIV patients\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Scores on all neuropsychological tests were converted into a Z-score relative to HCs. Scores on the Digit Symbol- Coding and Stroop-Card 1 were averaged into one PS composite Z-score.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eMRI data acquisition\u003c/h2\u003e \u003cp\u003eDifferent MRI scanner systems were used at each hospital study site. For specific details of the acquisition parameters see Supplementary material.\u003c/p\u003e \u003cp\u003eImage quality was assessed in two independent processes. Radiologist checked for the presence of any brain pathology, such as tumour, cyst, or any other lesion.\u003c/p\u003e \u003cp\u003eIn addition, image quality and processing experts checked for motion artefacts, low contrasts, incomplete whole brain coverage, low SNR and low resolution. In a further analysis, all the acquisitions were correlated to determine the homogeneity of the image sample.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eImage processing\u003c/h2\u003e \u003cp\u003eThe standard processing pipeline for volume based morphometry provided by The Computational Anatomy Toolbox (CAT12, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dbm.neuro.uni-jena.de/cat/\u003c/span\u003e\u003c/span\u003e version 1492), as an extension of SPM (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.fil.ion.ucl.ac.uk/spm/software/spm12/\u003c/span\u003e\u003c/span\u003e version 7487), was used for tissue segmentation and the extraction of tissue volumes. To measure regional brain volumes, native segmented images were parceled in regions of interest (ROI) according to the Hammers atlas \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e(Hammers et al. 2003; Gousias et al. 2008) and tissue volumes (mm\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e) were estimated for each ROI and normalized by the total intracranial volume for each subject.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical variables were summarized by using counts and proportions and continuous variables employing medians and interquartile ranges (IQR) or means and standard deviations (SD). Comparisons between patients and controls (NfL, age, Fluid Intelligence, Stroop, Coding and Composite z-score) were performed with the Student t test or the Mann\u0026ndash;Whitney \u003cem\u003eU\u003c/em\u003e test, if the variables did not follow a normal distribution. Comparisons between categorical variables were assessed using the Chi-square or the Fisher test. In the case of patients with and without undetectable viral load and controls, variables were analyzed with the Kruskal-Wallis test. Regarding the PHIV group, univariate analysis was performed to study associations between HIV variables and NfL. Spearman\u0026rsquo;s correlation test was used to assess association pNfL concentrations and white matter volumes. P values less than 0.05 were considered statistically significant. All analyses were performed using SPSS software ver. 22.0 (IBM, Armonk, NY, USA). Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e was made using Stata Version 12 (STATA Corp, Texas, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThirty-three young adults with perinatal HIV infection and 25 HIV-negative individuals were included.\u003c/p\u003e\n\u003cp\u003eIn the PHIV group, 54% were women and 73% were Caucasians. Median age was 20.7 years (IQR 17.8\u0026ndash;23.4). In the HIV-negative group, median age was 21.3 years (IQR 19.7\u0026ndash;23.1) and 60% were women. There were no significant differences between the two groups regarding these characteristics (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003cp\u003eRegarding the PHIV group, 42% had a history of previous AIDS-defining diagnoses (21% with old and stable encephalopathy). At assessment, 100% were under cART for a median time of 16.42 years (IQR 12.99\u0026ndash;18.70), and 85% had suppressed viral load (HIV RNA\u0026thinsp;\u0026lt;\u0026thinsp;50 copies/ml); Only five patients had HIV-RNA\u0026thinsp;\u0026gt;\u0026thinsp;50 copies/ml with a median of 69900 copies/ml (IQR 36774\u0026ndash;267541). Those five patients had detectable viral load for a median of 5.75 years (IQR 5.03\u0026ndash;16.75). Median CD4 was 738 cells/mm\u003csup\u003e3\u003c/sup\u003e (IQR 578\u0026ndash;978) and median CD4 nadir 274 (IQR 104\u0026ndash;382). (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp style=\"text-align: center;\"\u003eTable 1\u003c/p\u003e\n\u003cp style=\"text-align: center;\"\u003e\u0026nbsp;Clinical measures in 33 PHIV patients (n (%) or median [IQR])\u003c/p\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cimg src=\"https://myfiles.space/user_files/58895_8739fc6c57c1c19a/58895_custom_files/img1629213868.png\"\u003e\u003c/p\u003e\n\u003cp\u003eNo statistically significant differences were found between patients and controls regarding pNfL concentrations, but higher levels of pNfL were found in patients with increased viral load compared compared with undetectable patients and controls with a media pNfL of 9.19 pg/ml (SD 5.18) in patients with detectable viral load vs 6.6 pg/ml (SD 4.15) in undetectable patients and 5.29 pg/ml (SD 1.75) in the control group (p\u0026thinsp;=\u0026thinsp;0.059) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eFurthermore, no correlations were found between pNfL levels and viral load, time to diagnosis, time on cART, CDC stage or presence of encephalopathy (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for all comparisons).\u003c/p\u003e\n\u003cp\u003eIn the correlation sub-study of pNfL with neuroimaging and neuropsychological evaluations, 25 PHIV\u0026thinsp;+\u0026thinsp;and 23 HIV-negative controls were evaluated. Sociodemographic characteristics are described in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. In relation to NT, we found that PHIV had significantly lower FI, but both groups had average results. Differences between groups in Stroop test performance were observed, but not in Coding. The mean PS composite z-score was lower in the PHIV group (Mean Z-score \u0026minus;\u0026thinsp;0.68 (SD 0.98)) compared to the HIV-negative group (Mean Z-score 0.00 (SD 1.00)) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05)\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMeans (standard deviations) of demographic, psychosocial, neurocognitive and psychopathological characteristics.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePHIV (n\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHIV- (n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex (female) (%, n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e56,5 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.597\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at assessment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21.0 (3.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.9 (2.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.522\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLevel of education (%, n)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLow\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMedium\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHigh\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e\n \u003cp\u003e62.5 (15)\u003c/p\u003e\n \u003cp\u003e16.7 (4)\u003c/p\u003e\n \u003cp\u003e20.8 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;21\u003c/p\u003e\n \u003cp\u003e76.2 (16)\u003c/p\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003cp\u003e23.8 (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.146\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnnual Income (%, n)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLow\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMedium\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHigh\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;23\u003c/p\u003e\n \u003cp\u003e43.5 (10)\u003c/p\u003e\n \u003cp\u003e30.4 (7)\u003c/p\u003e\n \u003cp\u003e26.1 (6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u0026thinsp;=\u0026thinsp;22\u003c/p\u003e\n \u003cp\u003e59.1 (13)\u003c/p\u003e\n \u003cp\u003e36.4 (8)\u003c/p\u003e\n \u003cp\u003e4.5 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.135\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCaucasian (%, n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e56,5 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.263\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFluid Intelligence *\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.72 (1.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01 (0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.021\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eStroop\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.84 (1.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.00 (0.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.009\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCoding\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.31 (0.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.12 (1.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.512\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eComposite Processing Speed Z-score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.68 (0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.00 (1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.025\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eRegarding brain volumes, the HIV infected group had significantly lower regional white matter volumes in left and right cerebellum (p\u0026thinsp;=\u0026thinsp;0.030, p\u0026thinsp;=\u0026thinsp;0.028), lateral occipital lobe (p\u0026thinsp;=\u0026thinsp;0.020), left and right nucleus accumbens (p\u0026thinsp;=\u0026thinsp;0.010, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001),\u003c/p\u003e\n\u003cp\u003eleft and right occipital lobe (p\u0026thinsp;=\u0026thinsp;0.020, p\u0026thinsp;=\u0026thinsp;0.042) and left postcentral gyrus (p\u0026thinsp;=\u0026thinsp;0.022), but no significant differences were found in total white matter volumes.\u003c/p\u003e\n\u003cp\u003eIn the HIV group, Spearman\u0026rsquo;s correlation test revealed negative association between pNfL concentrations and different regional white matter volumes of left and right cerebellum (r -,440 p\u0026thinsp;=\u0026thinsp;0.028; r -,0386, p\u0026thinsp;=\u0026thinsp;0.056), left and right brainstem (r -,440 p\u0026thinsp;=\u0026thinsp;0.028; r -,417 p\u0026thinsp;=\u0026thinsp;0.038) and right nucleus accumbens ( r-,403, p\u0026thinsp;=\u0026thinsp;0.046) Fig. (2), and also a negative correlation was found between pNfL concentration and Coding score (r -,425 p\u0026thinsp;=\u0026thinsp;0.039). This association between NfL and brain volumes and coding score persisted when controlling for undetectable viral load.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eNfL is a neurofilament subunit particularly abundant in axons\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Plasma NfL concentration was recently reported as a potential prognostic biomarker of disease onset and progression in neurodegenerative diseases including HIV\u003csup\u003e\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn this study, we have shown that treated and virologically suppressed PHIV people, presented pNfL concentrations similar of those found in HIV-negative individuals. In addition, even considering the limitation of the small sample, patients with detectable viral load had higher pNfL levels, showing that persistent viral replication may contribute to neuronal damage.\u003c/p\u003e \u003cp\u003eThis has been demonstrated similarly in the HIV adult population, in which the HIV-driven axonal degeneration can be halted by cART, which correlates to reduced CSF and pNfL concentrations over time after cART initiation\u003csup\u003e5,21\u0026minus;22\u003c/sup\u003e. These results emphasize the importance of an early and continuous antiretroviral therapy to avoid neuronal damage in children.\u003c/p\u003e \u003cp\u003eIn this exploratory study of PHIV adolescents and young adults, we found that higher pNfL concentration was significantly associated with lower regional brain volume and lower coding score. Similarly, Anderson \u003cem\u003eet al\u003c/em\u003e. published that a higher pNfL was significantly associated with worse neuropsychological performance in the HIV adult population\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHigh concentration of NfL has been shown in multiple neurological diseases where processing speed is also one of the most affected cognitive processes, such as amyotrophic lateral sclerosis (ALS) \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e (Menke et al., 2015; Lu et al., 2015), Alzheimer\u0026rsquo;s disease\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e (Mattsson et al., 2017) and frontotemporal dementia\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e (Rohrer et al., 2016). Processing speed performance is considered to depend to a large extent on the properties of the white matter\u003csup\u003e\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e(Posthuma et al, 2003; Borghesani et al., 2013; Jacobs et al., 2013). White matter includes myelinated axons in the brain, and the thickness of the myelin sheath is associated with nerve conduction velocity; therefore, its relation to processing speed and NfL seems consistent. Hence plasma NfL could be a feasible biomarker of milder neurocognitive alterations in the PHIV population.\u003c/p\u003e \u003cp\u003eLikewise, increased NfL levels and reduced brain volume in cortical and subcortical grey matter and within the white matter has been found in patients with different neurodegenerative conditions\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. However, research performed in the HIV adult population found that CSF neuronal damage biomarkers, including NfL, were not associated with imaging measures of brain structures\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIt should be noted that NfL has the limitation that it is not a disease-specific biomarker. As we have mentioned, elevated NfL is observed in many other neurological disorders, including neurodegenerative diseases, peripheral neuropathy, and traumatic brain injuries\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRegarding brain volumes we found that the HIV group showed WM atrophy in selected brain regions despite being on cART for years. Some studies performed in adolescents living with PHIV has reported similar results showing lower white matter volumes when compared with HIV negative controls\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eLimitations of this study include the small sample size and lack of longitudinal biomarker data. The small sample size has been partially compensated for by strict selection criteria for the control group. Moreover, other limitations of the study are that this age group is potentially more likely to be involved in sports with head trauma, and this group of population may have different stressors, that have not been measured. Number of adverse childhood events (ACEs) would be a useful marker but has not been used. These are potentially important considerations in the adolescent age group during a time of dynamic myelination.\u003c/p\u003e \u003cp\u003eFinally, this current work was exploratory and therefore multiple statistical tests were performed, which might have resulted in type I errors.\u003c/p\u003e \u003cp\u003eStrengths of our study are, the inclusion of young adults living with PHIV, who have not previously been examined regarding plasma NfL levels, and that we were able to correlate brain volumes and processing speed in this population.\u003c/p\u003e \u003cp\u003eThis research is representative of most young adults living with HIV vertically infected in developed healthcare systems. Moreover, thanks to the current great improvements in the diagnosis and treatment of HIV infection, this population that were born in the preTAR era making the study unique.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWe can conclude that the ultrasensitive method to measure pNfL concentration provides an easily accessible biomarker in perinatally HIV infected patients avoiding lumbar puncture. Nevertheless, it remains unclear how pNfL varies in the PHIV population with virologic suppression or how its levels could be influenced in this population by the earlier initiation of effective antiretroviral therapy. Therefore, larger longitudinal studies are required in this group to further evaluate pNfL as a clinically useful biomarker of neurological deterioration.\u003c/p\u003e "},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThe Institutional Review Boards (IRBs) of each research centre approved the study and written informed consent was obtained from all participants. Where participants were underage, an assent form was signed by themselves, with legal guardians providing the informed consent in accordance with the Helsinki Declaration.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eConsent for publication:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eWe hereby verify that the manuscript has not been submitted or accepted elsewhere. All authors have given consent for its publication.\u003c/p\u003e\n\u003ch2\u003eAvailability of data and material:\u003c/h2\u003e\n\u003cp\u003eThe authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.\u003c/p\u003e\n\u003ch2\u003eCompeting interests:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003ea) NeuroCoRISpe group declare no competing financial interest.\u003c/p\u003e\n\u003cp\u003eb) The Sahlgrenska Academy at the University of Gothenburg group have no\u003c/p\u003e\n\u003cp\u003ecompeting interests that could be construed as influencing the contents of this paper. However, the authors list the following general potential conflicts of interest:\u003c/p\u003e\n\u003cp\u003eHZ has served on scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work).\u003c/p\u003e\n\u003cp\u003eKB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program.\u003c/p\u003e\n\u003cp\u003eMG reports personal fees (scientific advisory boards, lectures) from Gilead Sciences, GSK/ViiV, MSD, Biogen, Amgen, Novocure, Novo Nordic and research grants from Gilead Sciences, all outside the submitted work.\u003c/p\u003e\n\u003ch2\u003eFunding:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003e\u003cu\u003ea) NeuroCoRispe group and Spanish HIV HGM BioBank:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThis work was funded by the Instituto de Salud Carlos III, Acci\u0026oacute;n Estrat\u0026eacute;gica en Salud [FIS 15/00694] and Fondos FEDER of the UE. CoRISpe is integrated in the Spanish AIDS Research Network (RIS), supported by the Instituto de Salud Carlos III\u0026nbsp;[RD16/0025/0017-ISCIII-FEDER,RD16/0025/0019-ISCIII-FEDER, RD16/0025/0024-ISCIII-FEDER and RIS -EPICLIN12/2012]\u0026nbsp;;BRS was funded by the Spanish Ministry of Science and Innovation- Instituto de\u0026nbsp;Salud Carlos III (Contratos Rio Hortega CM 16/00224). This study takes part of the BRS PhD at Universidad de Alcal\u0026aacute; (Madrid, Spain).\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eb) Sahlgrenska Academy at the University of Gothenburg group\u003c/u\u003e\u003cu\u003e:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Swedish state, under an agreement between the Swedish government and the county councils (ALF agreement ALFGBG-717531).\u003c/p\u003e\n\u003cp\u003eHZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer\u0026apos;s Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen f\u0026ouml;r Gamla Tj\u0026auml;narinnor, Hj\u0026auml;rnfonden, Sweden (#FO2019-0228), the European Union\u0026rsquo;s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL.\u003c/p\u003e\n\u003cp\u003eKB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hj\u0026auml;rnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), and European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236).\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026apos; contributions:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eBRS, MMB, MGT, MM conceptualized and designed the study, participated in analysis and interpretation of the data, drafted the initial manuscript and contributed and approved the final manuscript as submitted. BRS, MMB, MG, HZ, KB, AMA, SOJ, SAL, MAM, HM, JTR, MLN, MIGT were involved in the provision of study subjects, reviewed the manuscript drafts, and approved the final manuscript as submitted. All authors read and approved the final manuscript\u003c/p\u003e\n\u003ch2\u003e\u0026nbsp;Acknowledgments\u003c/h2\u003e\n\u003cp\u003e\u003cem\u003eThis study would not have been possible without the collaboration of all the participants, medical and nursing staff, and data managers who have taken part in\u0026nbsp;\u003c/em\u003e\u003cem\u003eNeurocorispe Project of The Pediatric National AIDS Research Network of Spain (CORISPE).\u0026nbsp;\u003c/em\u003eThis work has been performed in collaboration with Biobank Hospital Gregorio Mara\u0026ntilde;on (HGM) and the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePatel K, Ming X, Williams PL, et al. 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HIV-Associated Cognitive Impairment in Perinatally Infected Children: A Meta-analysis. Pediatrics. 2016 Nov;138(5):e20160893\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHammers A, Allom R, Koepp MJ, Free SL, Myers R, Lemieux L, Mitchell TN, Brooks DJ, Duncan JS. Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe. Hum Brain Mapp 2003, 19: 224\u0026ndash;247.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGousias IS, Rueckert D, Heckemann RA, Dyet LE, Boardman JP, Edwards AD, Hammers A. Automatic segmentation of brain MRIs of 2-year-olds into 83 regions of interest. 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Neurology. 2018 Feb 20;90(8):e717-e723.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi QF, Dong Y, Yang L, Xie JJ, Ma Y, Du YC, Cheng HL, Ni W, Wu ZY. Neurofilament light chain is a promising serum biomarker in spinocerebellar ataxia type 3. Mol Neurodegener. 2019 Nov 4;14(1):39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan Zoest R, Underwood J, De Francesco D, Sabin CA, Cole JH, Wit FW, et al. Structural Brain Abnormalities in Successfully Treated HIV Infection: Associations With Disease and Cerebrospinal Fluid Biomarkers. J Infect Dis 2017 Dec 27;217(1):69\u0026ndash;81 doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/infdis/jix553\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBridel C, van Wieringen WN, Zetterberg H, Tijms BM, Teunissen CE, Alvarez- Cermeno JC, et al. Diagnostic value of cerebrospinal fluid Neurofilament light protein in neurology: a systematic review and meta-analysis. JAMA Neurol. 2019; Epub ahead of print.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCohen S, Caan MWA, Mutsaerts H-J, Scherpbier HJ, Kuijpers TW, Reiss P, \u003cem\u003eet al.\u003c/em\u003e Cerebral injury in perinatally HIV-infected children compared to matched healthy controls. \u003cem\u003eNeurology\u003c/em\u003e 2016; 86:19\u0026ndash;27\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSarma, M. K., Nagarajan, R., Keller, M. A., Kumar, R., Nielsen-Saines, K., Michalik, D. E., et al (2014). Regional brain gray and white matter changes in perinatally HIV-infected adolescents. \u003cem\u003eNeuroImage: Clinical\u003c/em\u003e, \u003cem\u003e4\u003c/em\u003e, 29\u0026ndash;34\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"Plasma NfL, perinatal HIV, neuroimaging, neurocognitive, cART","lastPublishedDoi":"10.21203/rs.3.rs-787438/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-787438/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eHigher plasma concentration of neurofilament light (pNfL) is associated with neurodegeneration. However, to our knowledge, up to now, there are no data in HIV patients with infection due to vertical transmission. This is the first study to report pNfL in a cohort of HIV perinatally infected (PHIV) young adults compared with non-HIV (HIV-) controls.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThirty-three PHIV patients and 25 age-matched HIV- were recruited to this cross-sectional study. Plasma NfL concentrations were compared between both groups. In a subgroup of 48 participants (25 PHIV patients and 23 HIV-), brain volumes through magnetic resonance imaging (MRI) and neuropsychological testing (NT), were also conducted and compared with pNfL values.\u003c/p\u003e\u003cp\u003ePlasma NfL concentration was measured using Single Molecule Array (Simoa) immunoassay.\u003c/p\u003e\u003cp\u003eNT included fluid intelligence and processing speed through the WAIS-IV Coding subtest, and the Stroop Test.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eFifty-eight participants were included, median age 20.7 years [IQR 17.8-23.4]. \u0026nbsp;100% of the patients were under antiretroviral treatment (cART) and 85% had viral load \u0026lt;50 copies/ml.\u003c/p\u003e\u003cp\u003eAlthough no statistically significant differences were found between patients and controls regarding pNfL concentration, there was a trend towards higher levels in patients with viral load \u0026gt;50 copies/ml.\u003c/p\u003e\u003cp\u003eWith regard to brain volumes and NT, in the PHIV group, lower white matter volumes and lower score in the coding subtest were associated with higher pNfL values. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eMost PHIV adolescents under cART have similar levels of pNfL than HIV-. As reported in adults, those with HIV-RNA \u0026gt;50 copies/ml showed higher values and lower white matter volumes that may imply an ongoing CNS injury. Plasma NfL could be a feasible biomarker of CNS injury in PHIV patients with unsuppressed viral load.\u003c/p\u003e","manuscriptTitle":"Assessment of Plasma Neurofilament Light as a Biomarker of Neuronal Injury in Young Adults with Perinatal HIV Infection","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-08-17 15:54:54","doi":"10.21203/rs.3.rs-787438/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":"a1780bc9-85c9-4dd5-abf8-253c0cf71ed6","owner":[],"postedDate":"August 17th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":6514388,"name":"Infectious Diseases"}],"tags":[],"updatedAt":"2021-11-15T09:14:12+00:00","versionOfRecord":[],"versionCreatedAt":"2021-08-17 15:54:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-787438","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-787438","identity":"rs-787438","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}