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Dr Lucette Cysique

PUBLICATIONS

Atrophic brain signatures of mild forms of neurocognitive impairment in virally suppressed HIV infection.

Nichols MJ, Gates TM, Soares JR, Moffat KJ, Rae CD, Brew BJ, Cysique LA

There is a lack of evidence for the neurobiological underpinning of Asymptomatic Neurocognitive Impairment (ANI) and Mild Neurocognitive disorders (MND) in virally-suppressed HIV + persons. We hypothesized that such mild impairment would be associated with focal brain atrophy. ANI shows specific frontal WM atrophy to which HIV disease duration is a unique contributor. MND is characterised by more widespread subcortical atrophy.

Chronic Human Immunodeficiency Virus Infection With and Without Comorbidities Appears to Converge Toward Early Pathological Brain Aging.

Cysique LA

No neurocognitive advantage for immediate antiretroviral treatment in adults with greater than 500 CD4+ T-cell counts.

Wright EJ, Grund B, Robertson KR, Cysique L, Brew BJ, Collins GL, Poehlman-Roediger M, Vjecha MJ, Penalva de Oliveira AC, Standridge B, Carey C, Avihingsanon A, Florence E, Lundgren JD, Arenas-Pinto A, Mueller NJ, Winston A, Nsubuga MS, Lal L, Price RW,

To compare the effect of immediate versus deferred antiretroviral treatment (ART) on neuropsychological test performance in treatment-naive HIV-positive adults with more than 500 CD4 cells/μl. We observed substantial improvement in neurocognitive test performance during the first year in both study arms, underlining the importance of using a control group in studies assessing neurocognitive performance over time. Immediate ART neither benefitted nor harmed neurocognitive performance in individuals with CD4 cell counts above 500 cells/μl.

Utility of Using the Montreal Cognitive Assessment (MoCA) as a Screening Tool for HIV-Associated Neurocognitive Disorders (HAND) In Multi-Ethnic Malaysia.

Mukherjee T, Sakthivel R, Fong HY, McStea M, Chong ML, Omar SF, Chin AV, Kamaruzzaman S, Kamarulzaman A, Rajasuriar R, Cysique LA

HIV-Associated Neurocognitive Disorders: A Global Perspective.

Saloner R, Cysique LA

Covertly active and progressing neurochemical abnormalities in suppressed HIV infection.

Cysique LA, Jugé L, Gates T, Tobia M, Moffat K, Brew BJ, Rae C

To assess whether HIV-related brain injury is progressive in persons with suppressed HIV infection. Our study reveals covertly active or progressing HIV-related brain injury in the majority of this virally suppressed cohort, reflecting ongoing neuropathogenic processes that are only partially worsened by historical HAND and HIV duration. Longer-term studies will be important for determining the prognosis of these slowly evolving neurochemical abnormalities.

Utility of Using the Montreal Cognitive Assessment (MoCA) as a Screening Tool for HIV-Associated Neurocognitive Disorders (HAND) In Multi-Ethnic Malaysia.

Mukherjee T, Sakthivel R, Fong HY, McStea M, Chong ML, Omar SF, Chin AV, Kamaruzzaman S, Kamarulzaman A, Rajasuriar R, Cysique LA

This study determines the optimal cut-off scores for the Montreal Cognitive Assessment (MoCA) to detect HIV-associated neurocognitive disorders (HAND) in a multi-ethnic Malaysian HIV-positive cohort by developing demographically corrected normative standards among 283 HIV-negative community-based controls with overlapping demographic characteristics. The norms (corrected for age, sex, education, ethnicity) were applied to 342 HIV-positive virally suppressed individuals on cART. Impairment rates were classified using the Global Deficit Score (GDS ≥ .5) method. The MoCA was also scored according to the recommended cut-off of ≤ 26, and functional decline was applied to both impairment definitions to classify HAND per the Frascati criteria. The ≤ 26 cut-off considerably overestimated cognitive impairment in both samples (59.4% HIV-negative; 69.3% HIV-positive). In contrast, corrected scores yielded impairment rates consistent with what has been reported internationally in virally suppressed cohorts (23.4% with 83.3% mild impairment, 16.7% moderate impairment). A supplemental file allowing the computation of corrected MoCA scores and impairment status is included.

No neurocognitive advantage for immediate antiretroviral treatment in adults with greater than 500 CD4+ T-cell counts.

Wright EJ, Grund B, Robertson KR, Cysique L, Brew BJ, Collins GL, Poehlman-Roediger M, Vjecha MJ, Penalva de Oliveira AC, Standridge B, Carey C, Avihingsanon A, Florence E, Lundgren JD, Arenas-Pinto A, Mueller NJ, Winston A, Nsubuga MS, Lal L, Price RW,

To compare the effect of immediate versus deferred antiretroviral treatment (ART) on neuropsychological test performance in treatment-naive HIV-positive adults with more than 500 CD4 cells/μl. We observed substantial improvement in neurocognitive test performance during the first year in both study arms, underlining the importance of using a control group in studies assessing neurocognitive performance over time. Immediate ART neither benefitted nor harmed neurocognitive performance in individuals with CD4 cell counts above 500 cells/μl.

HIV-Associated Neurocognitive Disorders: A Global Perspective.

Saloner R, Cysique LA

The present review on HIV-associated neurocognitive disorders (HAND) provides a worldwide overview of studies that have investigated the rate and neuropsychological (NP) profile of HAND research since the inception of the 2007 HAND diagnostic nomenclature. In the first part, the review highlights some of the current controversies around HAND prevalence rates. In the second part, the review critically assesses some solutions to move the field forward. In the third part, we present the cross-sectional NP profile in non-Western HIV+ cohorts and in relation to Western cohorts' findings. The adopted global perspective highlights the successful expansion of NP studies in HIV infection to culturally diverse low- to medium-income countries with high HIV burden. These studies have produced interestingly similar rates of HAND whether patients were naïve or treated and/or virally suppressed compared to the rich income countries where the NP research in NeuroHIV has originated. The perspective also demonstrates that globally, the group which is the most representative of the HIV epidemic, and thus at risk for HAND are persons with chronic HIV infection and survivors of past immunosuppression, while in relative terms, those who have been treated early with long-term viral suppression represent a minority. In the last part, we present a review of the naturalistic longitudinal NP global studies in HIV+cohorts, discuss the role of longitudinal design in solving issues around the question of asymptomatic neurocognitive impairment, and the question of biomarker discovery. Finally, we conclude by calling for greater methods and data harmonization at a global level. (JINS, 2017, 23, 860-869).

Monitoring HIV-Associated Neurocognitive Disorder Using Screenings: a Critical Review Including Guidelines for Clinical and Research Use.

Kamminga J, Lal L, Wright EJ, Bloch M, Brew BJ, Cysique LA

Screening tools to identify HIV-associated neurocognitive disorder (HAND) are primarily devised to detect cognitive impairment on a single occasion. With the chronicity of HIV infection and the risk of HAND developing or progressing despite viral control, it may be pertinent to repeat HAND screening at more than one time point. Despite this, there are limited data on longitudinal use of such screening tools, particularly with regard to the role of practice effects. Additionally, no guidelines currently exist on the timeframe between testing intervals, or recommendation of the magnitude of baseline impairment that warrants follow-up testing. The aim of the current paper was to review existing evidence for longitudinal validity of HAND screening tools. Only those HAND screening tools previously found to have high cross-sectional criterion validity were included. Preliminary recommendations for clinical use and future research are proposed including in international settings.

Concomitant medication polypharmacy, interactions and imperfect adherence are common in Australian adults on suppressive antiretroviral therapy.

Siefried KJ, Mao L, Cysique LA, Rule J, Giles ML, Smith DE, McMahon J, Read TR, Ooi C, Tee BK, Bloch M, de Wit J, Carr A,

We quantified concomitant medication polypharmacy, pharmacokinetic and pharmacodynamic interactions, adverse effects and adherence in Australian adults on effective antiretroviral therapy. In a resource-rich setting with universal healthcare access, the majority of this sample took a concomitant medication. Over half had at least one of concomitant medication polypharmacy, pharmacokinetic or pharmacodynamic interaction. Concomitant medication use was associated with several adverse clinical outcomes.

Determining optimal impairment rating methodology for a new HIV-associated neurocognitive disorder screening procedure.

Kamminga J, Bloch M, Vincent T, Carberry A, Brew BJ, Cysique LA

The GDS is a relatively easy statistical method for computing impairment rate when using the CogState-based screen that yields adequate criterion validity compared to standard neuropsychological testing. Feasibility of standardized test administration and appropriate interpretation of results for this CogState-based screen in primary care was enhanced by the training and consultation provided by study neuropsychologists.

Covertly active and progressing neurochemical abnormalities in suppressed HIV infection.

Cysique LA, Jugé L, Gates T, Tobia M, Moffat K, Brew BJ, Rae C

To assess whether HIV-related brain injury is progressive in persons with suppressed HIV infection. Our study reveals covertly active or progressing HIV-related brain injury in the majority of this virally suppressed cohort, reflecting ongoing neuropathogenic processes that are only partially worsened by historical HAND and HIV duration. Longer-term studies will be important for determining the prognosis of these slowly evolving neurochemical abnormalities.

The high frequency of autoantibodies in HIV patients declines on antiretroviral therapy.

Bundell C, Brunt SJ, Cysique LA, Brusch A, Brew BJ, Price P

Autoantibodies have been described in samples from HIV positive patients, but the effects of antiretroviral therapy (ART) remain unclear. In a retrospective longitudinal study, we applied clinical assays for autoantibodies to sera collected from 13 HIV positive patients as they began ART with <210 CD4 T-cells/μL and over 2 years on treatment. Twelve of the 13 patients had at least one autoantibody. The frequency peaked before ART (21 from 156 assays) and declined to 8/143 positive reactions after 2 years. As anti-smooth muscle (ASM) antibodies remained common, these assays were applied to HIV patients (n = 67) who had <50 copies HIV RNA/mL plasma after 13 (2-17) years on ART, and healthy controls (n = 55). The frequency of ASM was high in these patients and correlated with levels of total IgG. Hence the high frequency of autoantibodies before ART declined, but did not disappear, with successful therapy. Autoantibody levels may reflect B-cell hyperactivity in patients stable on ART.

The Chronicity of HIV Infection Should Drive the Research Strategy of NeuroHIV Treatment Studies: A Critical Review.

Gates TM, Cysique LA

HIV infection has become a chronic illness when successfully treated with combined antiretroviral therapy (cART). The long-term health prognosis of aging with controlled HIV infection and HIV-associated neurocognitive disorder (HAND) remains unclear. In this review, we propose that, almost 20 years after the introduction of cART, a change in research focus is needed, with a greater emphasis on chronicity effects driving our research strategy. We argue that pre-emptive documentation of episodes of mild neurocognitive dysfunction is needed to determine their long-term prognosis. This strategy would also seek to optimally represent the entire HAND spectrum in therapeutic trials to assess positive and/or negative treatment effects on brain functions. In the first part of the paper, to improve the standard implementation of the Frascati HAND diagnostic criteria, we provide a brief review of relevant quantitative neuropsychology concepts to clarify their appropriate application for a non-neuropsychological audience working in HIV research and wanting to conduct randomized clinical trials on brain functions. The second part comprises a review of various antiretroviral drug classes and individual agents with respect to their effects on HAND, while also addressing the question of when cART should be initiated to potentially reduce HAND incidence. In each section, we use recent observational studies and randomized controlled trials to illustrate our perspective while also providing relevant statistical comments. We conclude with a discussion of the neuroimaging methods that could be combined with neuropsychological approaches to enhance the validity of HIV neurology (neuroHIV) treatment effect studies.

Maraviroc-intensified combined antiretroviral therapy improves cognition in virally suppressed HIV-associated neurocognitive disorder.

Gates TM, Cysique LA, Siefried KJ, Chaganti J, Moffat KJ, Brew BJ

To investigate whether intensification of combined antiretroviral therapy (cART) with the CC chemokine receptor type 5 (CCR5) entry inhibitor maraviroc leads to improvement in global neurocognitive functioning in virally suppressed men with HIV-associated neurocognitive disorder (HAND). This pilot study provides feasibility, tolerability, proof-of-concept and preliminary evidence for clinically relevant neurocognitive improvement in cART enhancement with maraviroc in virally suppressed HAND patients. Lack of concomitant brain metabolite and biomarker change may be related to complex dynamics of brain repair.

Short Communication: Do Cytomegalovirus Antibody Levels Associate with Age-Related Syndromes in HIV Patients Stable on Antiretroviral Therapy?

Brunt SJ, Cysique LA, Lee S, Burrows S, Brew BJ, Price P

HIV(+) persons stable on antiretroviral therapy (ART) face early onset of age-related diseases. This may arise from a high burden of cytomegalovirus (CMV). To address the role of CMV, we investigated univariate and multivariate associations between markers of systemic and endothelial inflammation, vascular damage, insulin resistance (IR), neurocognitive decline, and antibodies reactive with CMV. In this study, HIV(+) participants (n = 91) aged >45 years with <50 copies HIV RNA/ml plasma after >2 years on ART were assessed for cardiovascular risk (the D:A:D algorithm), type II diabetes (the HOMA-IR index), and neurocognitive performance. Blood samples were assayed for lipids, T cells, insulin, glucose, C-reactive protein, CX3CL1, sTNF-R1, total immunoglobulin G (IgG), and antibodies reactive with CMV lysate, glycoprotein B, or immediate-early-1. Levels of antibodies detected with the three antigens were tightly correlated. Levels of CMV lysate antibody were higher in patients than in age-matched healthy controls and reflected their nadir CD4 T-cell count (p = .001), total IgG (p = .02), and age (p = .08). Levels of CMV lysate antibody correlated with D:A:D score (p = .04), neurocognitive performance (p = .045), and fasting insulin (p = .02). In multivariable analyses, some associations reflected the effect of age, but CMV lysate antibody and CD8 T-cell counts were significant predictors of the HOMA-IR index (R(2) = 0.09, p = .01) independent of age. We conclude that associations between levels of CMV antibodies, cardiovascular risk, and neurocognitive health in HIV(+) patients stable on ART are moderated by age-associated increases in response to CMV, while CMV antibodies may be independently linked with IR.

Identifying Neurocognitive Decline at 36 Months among HIV-Positive Participants in the CHARTER Cohort Using Group-Based Trajectory Analysis.

Brouillette MJ, Yuen T, Fellows LK, Cysique LA, Heaton RK, Mayo NE

To estimate the magnitude and pattern of neurocognitive change over the first 3 years of follow-up using Group-Based Trajectory Analysis (GBTA) applied to participants in the longitudinal arm of the CHARTER cohort. The present study identified heterogeneous trajectories over 3 years across 15 NP raw test scores using GBTA. Cognitive decline was observed in only a small subset of this study cohort. Decliners had demographics and HIV characteristics that have been previously associated with cognitive decline, suggesting clinical validity for the method.

A Screening Strategy for HIV-Associated Neurocognitive Disorders That Accurately Identifies Patients Requiring Neurological Review.

Bloch M, Kamminga J, Jayewardene A, Bailey M, Carberry A, Vincent T, Quan D, Maruff P, Brew B, Cysique LA

Symptomatic HAND warranting neurological review was accurately predicted using a CogState-based screening procedure.

Cognitive change trajectories in virally suppressed HIV-infected individuals indicate high prevalence of disease activity.

Gott C, Gates T, Dermody N, Brew BJ, Cysique LA

Despite long-term viral suppression, we found mostly subclinical levels of decline in psychomotor speed and executive functioning (mental flexibility and cognitive inhibition); well-established markers of HAND progression. Moreover, 57% of our cohort is undergoing slow evolution of their disease, challenging the notion of prevalent neurocognitive stability in virally suppressed HIV infection.

White matter measures are near normal in controlled HIV infection except in those with cognitive impairment and longer HIV duration.

Cysique LA, Soares JR, Geng G, Scarpetta M, Moffat K, Green M, Brew BJ, Henry RG, Rae C

The objective of the current study was to quantify the degree of white matter (WM) abnormalities in chronic and virally suppressed HIV-infected (HIV+) persons while carefully taking into account demographic and disease factors. Diffusion tensor imaging (DTI) was conducted in 40 HIV- and 82 HIV+ men with comparable demographics and life style factors. The HIV+ sample was clinically stable with successful viral control. Diffusion was measured across 32 non-colinear directions with a b-value of 1000 s/mm; fractional anisotropy (FA) and mean diffusivity (MD) maps were quantified with Itrack IDL. Using the ENIGMA DTI protocol, FA and MD values were extracted for each participant and in 11 skeleton regions of interest (SROI) from standard labels in the JHU ICBM-81 atlas covering major striato-frontal and parietal tracks. We found no major differences in FA and MD values across the 11 SROI between study groups. Within the HIV+ sample, we found that a higher CNS penetrating antiretroviral treatment, higher current CD4+ T cell count, and immune recovery from the nadir CD4+ T cell count were associated with increased FA and decreased MD (p < 0.05-0.006), while HIV duration, symptomatic, and asymptomatic cognitive impairment were associated with decreased FA and increased MD (p < 0.01-0.004). Stability of HIV treatment and antiretroviral CNS penetration efficiency in addition to current and historical immune recovery were related to higher FA and lower MD (p = 0.04-p < 0.01). In conclusion, WM DTI measures are near normal except for patients with neurocognitive impairment and longer HIV disease duration.

Socioeconomic factors explain suboptimal adherence to antiretroviral therapy among HIV-infected Australian adults with viral suppression.

Siefried KJ, Mao L, Kerr S, Cysique LA, Gates TM, McAllister J, Maynard A, de Wit J, Carr A,

In this population, 15% reported recent suboptimal ART adherence at levels associated in prospective studies with subsequent virological failure, despite all having an undetectable viral load. Associations were with social/economic/cultural/patient engagement factors, but not ART regimen/clinical factors. These associations may help identify those at higher risk of future virological failure and guide patient education and support.

The Chronicity of HIV Infection Should Drive the Research Strategy of NeuroHIV Treatment Studies: A Critical Review.

Gates TM, Cysique LA

HIV infection has become a chronic illness when successfully treated with combined antiretroviral therapy (cART). The long-term health prognosis of aging with controlled HIV infection and HIV-associated neurocognitive disorder (HAND) remains unclear. In this review, we propose that, almost 20 years after the introduction of cART, a change in research focus is needed, with a greater emphasis on chronicity effects driving our research strategy. We argue that pre-emptive documentation of episodes of mild neurocognitive dysfunction is needed to determine their long-term prognosis. This strategy would also seek to optimally represent the entire HAND spectrum in therapeutic trials to assess positive and/or negative treatment effects on brain functions. In the first part of the paper, to improve the standard implementation of the Frascati HAND diagnostic criteria, we provide a brief review of relevant quantitative neuropsychology concepts to clarify their appropriate application for a non-neuropsychological audience working in HIV research and wanting to conduct randomized clinical trials on brain functions. The second part comprises a review of various antiretroviral drug classes and individual agents with respect to their effects on HAND, while also addressing the question of when cART should be initiated to potentially reduce HAND incidence. In each section, we use recent observational studies and randomized controlled trials to illustrate our perspective while also providing relevant statistical comments. We conclude with a discussion of the neuroimaging methods that could be combined with neuropsychological approaches to enhance the validity of HIV neurology (neuroHIV) treatment effect studies.

Advancing research in NeuroAIDS using collaboration and public data sharing.

Cysique LA

In this issue of BMC Medical Genomics Griffin et al. present a user-friendly and freely accessible HIV-associated neurocognitive disorder (HAND) genomic database that compiles viral (HIV-1) genetic sequences and other relevant clinical and treatment data. We discuss the benefits and caveats of public data sharing in NeuroAIDS research, while emphasizing the importance of such novel initiatives for advancing knowledge.

The role of depression chronicity and recurrence on neurocognitive dysfunctions in HIV-infected adults.

Cysique LA, Dermody N, Carr A, Brew BJ, Teesson M

Research assessing whether major depressive disorders (MDD) impacts neurocognitive functions in HIV+ persons has yielded inconsistent results. However, none have considered the role of MDD remission, chronicity, and stability on treatment. Ninety-five HIV+ adults clinically stable on combined antiretroviral treatment completed a psychiatric interview, a depression scale, a neuropsychological, daily living, and cognitive complaints assessments at baseline and 18 months. Participants were screened for current (within 12 months of study entry) alcohol and/or substance use disorder. History of alcohol and/or substance abuse disorder prior to the 12 months entry screen and MDD treatments were recorded. Participants were grouped into two psychiatric nomenclatures: (1) lifetime: no MD episode (MDE), single MDE life-event treated and fully remitted, chronic MDD treated and stable, chronic MDD treated and unstable, and baseline untreated MDE; (2) recent: last 2 years MDE (yes or no). We found that lifetime and recent psychiatric history were more strongly associated with decreased in independence in daily living and cognitive complaints than with baseline neuropsychological performance. However, lack of full remission, instability on treatment in chronic MDD, and severity of symptoms in current MDE were factors in whether MDD impacted baseline neuropsychological performance. Depressive symptoms improved at follow-up in those with baseline moderate-severe symptoms, and MDD was not associated with neurocognitive change at 18 months. A history of alcohol and/or substance abuse disorder was significantly more frequent in those with treated and unstable chronic MDD but it was not associated with neuropsychological performance. MDD recurrence, chronicity profiles, and associated comorbidities are keys factors to understand any potential impact on neurocognitive abilities in HIV infection. More comprehensive consideration of these complex effects could serve at constructively updating the HAND diagnostic criteria.

Peripheral blood mononuclear cells HIV DNA levels impact intermittently on neurocognition.

Cysique LA, Hey-Cunningham WJ, Dermody N, Chan P, Brew BJ, Koelsch KK

To determine the contribution of peripheral blood mononuclear cells' (PBMCs) HIV DNA levels to HIV-associated dementia (HAD) and non-demented HIV-associated neurocognitive disorders (HAND) in chronically HIV-infected adults with long-term viral suppression on combined antiretroviral treatment (cART). PBMC HIV DNA plays a role in HAD pathogenesis, and this is moderated by pre-morbid cognitive ability in the context of long-term viral suppression. While the HIV DNA levels in PBMC are not associated with current non-demented HAND, increasing HIV DNA levels were associated with a decline in neurocognitive functions associated with HAND progression.

APOE ε4 moderates abnormal CSF-abeta-42 levels, while neurocognitive impairment is associated with abnormal CSF tau levels in HIV+ individuals - a cross-sectional observational study.

Cysique LA, Hewitt T, Croitoru-Lamoury J, Taddei K, Martins RN, Chew CS, Davies NN, Price P, Brew BJ

Similarly to larger studies, APOE ε4 genotype was not directly associated with HAND, but moderated CSF levels of Aβ1-42 in a minority of participants. In the majority of participants, increased CSF p-tau levels were associated with current neurocognitive impairment. Combined CSF biomarker risk for AD in the current HIV+ sample is more than 10 times greater than in the Australian population of the same age. Larger prospective studies are warranted.