HOARE Jacqueline, PHILLIPS Nicole, FOUCHE Jean- Paul, JOSKA John A, MYER Landon, ZAR Heather J STEIN Dan J

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1 Mental health, cognition and associated brain changes in perinatally infected young adolescents in the Cape Town Adolescent Antiretroviral Cohort (CTAAC) HOARE Jacqueline, PHILLIPS Nicole, FOUCHE Jean- Paul, JOSKA John A, MYER Landon, ZAR Heather J STEIN Dan J

2 No conflict of interest

3 Coping styles chronic illness may interfere with the developmental tasks of adolescents by making them more vulnerable to psychological and social problems Gortmaker, Walker, Weitzman, & Sobol, 1990; Lavigne & Faier-Routman, 1992). wide variation in the psychosocial functioning of adolescents well adjusted adolescents exhibited a higher percentage of active coping efforts (i.e. making decisions, seeking social support, and talking about problems with friends) Jorgensen and Dusek (1990)

4 Adolescents: why so complicated? Many health care professionals report that managing HIV in adolescents is more challenging than for other age groups The issues of adolescents infected with HIV could be linked to: 1) adolescence in general 2) the illness itself/neuroaids 3) mental health problems generated by the interaction between the illness, the adolescent and their environment

6 Adolescent decision making decision-making favors immediate rewards and discounts future outcomes. tangible immediate benefits of what I decide to do in my life now rather than the weaker reward of positive health in the distant future Biological underpinnings for this decision making pattern Maturation of prefrontal striatal connections, known to support top-down executive control of behavior occurs after adolescence Asato.Cereb. Cortex (2010)

8 Cape Town Adolescent Antiretroviral Cohort (CTAAC) CTAAC is to investigate markers of chronic disease processes and progression in perinatally HIVinfected adolescents Assessment of neurocognitive function, mental health and neuroimaging longitudinally over a three-year period. Baseline mental health and cognitive findings baseline neuroimaging analysis using DTI and structural MRI to determine white matter integrity, gray and white matter volumes

9 Background Impairment in cognition puts adolescents at risk of school failure and difficult transition to adult independence. lack of published data specific to the adolescent age group, particularly from SSA, which have the highest HIV prevalence effects on neurocognitive function and mental health in HIV+ve adolescents commenced on ART from an early age in resource-constrained settings remains unclear Compared to the adult population fewer neuroimaging studies have focused on adolescents infected with HIV since birth, and the outcomes are not consistent.

10 Larger cohorts Due to the complex nature of the developing adolescent brain, environmental influences and ART, there is an need for research in larger cohort studies on the trajectory of brain and cognitive development among adolescents perinatally infected with HIV, especially in high burden resource-constrained settings Longitudinal DTI findings support continued microstructural change in white matter during late adolescence in typically developing adolescents neuroimaging studies of early adolescence are needed to determine the impact of HIV on brain remodeling typically seen in later adolescence.

11 CTAAC neuro-substudy A study of DTI and structural brain MRI measures in a subgroup of perinatally infected adolescents enrolled in CTAAC (n=250) Adolescents were recruited from public sector health care service from across Cape Town inclusion criteria were aged 9-11 years perinatally infected ART for at least 6 months knew their HIV status and able to provide informed parental consent and participant assent Controls were HIV negative, age, sex and ethnicity matched All youth screened for the control cohort underwent rapid HIV testing prior to enrolment to confirm negative status. Participants were enrolled from August 2013 to April 2015 at the Research Centre for Adolescent and Children Health at Red Cross Children s Hospital, South Africa

12 Exclusion criteria Exclusion criteria for both groups were: an uncontrolled medical condition; an identified CNS condition (other than HIV), such as past or current TB meningitis or bacterial meningitis, documented cerebrovascular accident, lymphoma; a history of head injury with of loss of consciousness greater than 5 minutes, or any radiological evidence of skull fracture; a history of perinatal complications such as hypoxic ischemic encephalopathy or neonatal jaundice requiring exchange transfusion, or neurodevelopment disorder not attributed to HIV

13 Methods Baseline health and sociodemographic questionnaires were conducted to obtain general health information, past history and data on ancestry, language, education and treatment Recent CD4 and viral load results and ART regimen and date of initiation of ART were abstracted from care records.

14 Table I: Baseline demographic and clinical characteristics of CTAAC cohort HIV-infected Controls t p Variable (N = 204) (N = 44) Age in years: Mean (SD) (0.88) (1.09) Gender: Male/Female 100/104 20/ Ethnicity: Black 187/17 44/ African/Other Home language: 182/20 42/ isixhosa/ Other Education in years: 3.20 (1.13) 3.39 (1.35) Mean (SD) Repeated grades: 121/83 18/ * YES/NO Annual household income a 20.3% 27.3% 12/32/ Crowding b Ophanhood c 1.9 (3.11) 71 (35%).43 (3.79) 6 (14%) *.00* Anthropometry Weight in kg Height in cm Head circ in cm (7.26) (7.72) (2.14) (11.26) (8.76) (3.07) *.00*.08 Tanner s staging Breast develop. Pubic hair Testes growth 1.53 (.74) 1.29 (.58) 1.11 (.34) 1.87 (.61) 1.58 (.93) 1.15 (.37) * Caregiver depression 16.7 (12.44) (10.900) * ART regiment: First/Second/Third 112/56/14 Duration of ART: mean 7.18 (2.46) years (SD) Age of initiation: mean 3.41 (2.53) years (SD) Lifetime EFV treatment 142/59 Viral load mean (IU/mL) CD4 count mean (cells/mm 3)

15 Assessments 1. Mental health 2. Cognition 3. Imaging

16 1. Mental health

17 Depression/anxiety Beck Youth Inventories. This self-report scale has five inventories, which may be used to assess a child s experience of depression, anxiety, anger, disruptive behaviour, and selfconcept. The inventories are intended for use with children and adolescents between the ages of 7 18 years. The inventories are structured in line with DSM-IV-TR criteria.

18 Motivation Children s Motivation Scale (CMS). This 16-item instrument was used to measure the adolescent s motivation levels, or tendency toward apathy. For each item, the parent was asked to state how often his/her child engaged in self-motived activities. For example, if a statement read Starts playing (games, activities) on his/her own, the parent would select one of the following options: 0 (never or rarely occurs), 1 (1-3 times during a month), 2 (1-3 times per week), 3 (4-6 times per week), or 4 (1 or more times a day).

19 ADHD The Conner s Parent s Rating Scale (CPRS) is one of the three most popular rating scales used by professionals today for parent rating scales to diagnose ADHD. The CPRS addresses four factors: conduct problem, hyperactivity, inattentive-passive, and hyperactivity index.

20 Behaviour Child Behaviour Checklist (CBCL). This 113-item instrument is one of the most widely used and psychometrically sound measures for assessing child behavioural and emotional problems and psychopathology. It was used to measure internalizing and externalizing problems experienced by the child. It was also used to measure total problems experienced by the child, as well as the child s total competence. Parents were asked to rate items according to how much each given statement applied to their children: 0 (not true), 1 (somewhat or sometimes true), or 2 (very true or often true). Examples of some statements are: Acts too young for his/her age and Can t concentrate, can t pay attention for long.

21 Functioning Columbia Impairment Scale (CIS). The parent-rated version of this instrument (a 13-item Likert-type scale) was used to measure the child s global functioning level. It measures impairment within the following domains: interpersonal relationships, psychopathology, schoolwork, and use of leisure time. Parents were asked to rate, by responding to different statements, how much of a problem their child had within different areas of functioning. An example of one such statement is, How much of a problem would you say he/she has with: his/her behaviour at school. Parents were required to rate their child as having no problem, a very small problem, some problem, a moderate problem, or a very bad problem with each of the statements/scenarios given. Parents also had the option to answer not applicable or don t know.

22 Table II. CTAAC cohort baseline functional competence and mental health meassures, significant differences between means and clinical correlates. Outcome variable (N = 204) Controls (N = 44) HIVpositive Mann- Whitney U p (m) CBCL a total competence CBCL internalizing problems CBCL externalizing problems (7.75) (11.19) (10.94) CBCL total problems (11.31) BECK b self-concept (9.22) BECK anxiety (13.54) BECK depression (11.97) BECK anger (12.75) BECK disruptive behaviour (11.03) CMS c (7.69) (8.1) * (8.97) (9.95) (9.11) (7.37) (10.98) (8.46) (9.72) (7.98) (6.10) * * * CIS d 5.18 (6.62) 3.73 (4.79) Conner s ADHD (10.49) 8.52 (8.48) * NOTES: a: CBCL = Child Behaviours Checklist parent rated version. b: Beck Youth Inventory scale. c: CMS = Children s Motivation Scale. d: CIS = Columbia Impairment Scale. P (m) = the p-value related to the Mann-Whitney difference between groups. The Correlation coefficient is the bivariate correlation between the clinical variables and CD4 count for the HIV-positive group only. P (b) = the p-value related to the bivariate correlations to CD4 count. * indicates significance at the.05 level.

23 Table III. Clinical cut-off range distribution within the CTAAC cohort and differences between the groups regarding clinical cut-offs. Outcome variable CBCL a total competence CBCL internalizing problems CBCL externalizing problems HIV-positive (N = 204) Controls (N = 44) 81 (39.7) 11 (25) * 62 (30.4) 8 (18.2) (15.7) 4 (9.1) CBCL total problems 46 (22.5) 4 (9.1) * BECK b self-concept 46 (22.5) 4 (9.1) * BECK anxiety 24 (11.8) 4 (9.1) BECK depression 13 (6.4) 1 (2.3) * BECK anger 13 (6.4) 1 (2.3) * BECK disruptive behaviour 8 (3.9) 0 (0) * NOTE: For the HIV-positive and Controls columns the number of clinical range cases are presented as a whole number and the percentage of the sample in parentheses. a: CBCL = Child Behaviours Checklist parent rated version. b: Beck Youth Inventory scale. t p

24 2. Cognition

25 Comprehensive neuropsychological test battery All neuro sub-study participants completed a comprehensive neuropsychological test battery as previously described (Hoare et al., 2012). The battery measures cognitive performance within the following cognitive domains: general intellectual function, attention, working memory, verbal memory, visual memory, visual spatial ability, language, motor coordination, processing speed and executive function.

26 The measures include the following tests: TEA-Ch (version B) sky, score, creature counting, sky DT, opposite world Grooved pegboard CAT-Rapid Digit Span forward, backward Colour Trails 1, 2 BNT Coding (version B) RCF copy RCF 3 minute recall Nepsy Inhibition Shapes: naming, inhibition, switching Nepsy Inhibition Arrows: naming, inhibition, switching WISC Symbol Search (version B) HVLT 1, 2, 3 RCF 30 min delayed HVLT 5 minute delayed, recognition NEPSY FTT IHDS WASI vocab, block, sim, matrix VFLU phonemic, category

27 10 domains We created ten separate composite cognitive domains: general intellectual functioning, attention, working memory, visual memory, verbal memory, language, visual spatial ability, motor coordination, processing speed and executive function. To determine the statistical strength of each cognitive domain, we conducted Cronbach s alpha tests on various combinations of neuropsychological tests to determine which neuropsychological tests had strong inter-relatedness (or internal consistency) within a specific domain.

29 Variable HIV-infected Controls t p (N = 203) (N = 44) Cognitive domains: means (SD) General intellectual function -.54 (.78).00 (.79) ** Attention -.39 (.92).00 (.92) ** Motor coordination.02 (.99).00 (.91) Visual memory -.49 (.87) -.00 (.98) ** Verbal memory -.56 (.67) -.00 (.68) ** Working memory -.35 (.89).00 (1.00) ** Language -.38 (1.02) -.00 (1.00) ** Visual spatial ability -.52 (1.26).00 (.84) ** Processing speed -.56 (.67) -.00 (.68) ** Executive function -.48 (.67).01 (.60) **

30 Major and minor NCD Using the cognitive data we applied the youth neurocognitive disorders criteria (Hoare et. el., 2017) to determine how many of the HIVinfected participants meet the criteria for having a major neurocognitive disorder or a minor neurocognitive disorder.

32 3. Neuroimaging

33 DTI and MRI Structural and Diffusion weighted imaging was performed at the Cape Universities Brain Imaging Centre on a 3T Siemens Allegra Cortical morphometry was performed using FreeSurfer software analysis Diffusion weighted images were corrected for eddy current distortion within FSL and imported into MATLAB R2013b for processing.

35 DTI results Whole brain mean FA was significantly reduced in the HIV infected group (p=. 031) no significant difference was found for whole brain mean MD.

36 Table 2: Comparison between HIV+ adolescents and controls on measures of FA and MD Anatomy MNI coordinates Cluster size (mm 3 ) P-value Decreased FA in HIV+ children compared to controls Left superior -6; -29; cerebellar peduncle Right anterior limb 15; 3; of internal capsule Left anterior limb of -13; 3; internal capsule Left posterior limb -18; -6; of internal capsule Right retrolenticular 29; -25; part of internal capsule Right superior 27; -17; corona radiata Left sagittal stratum -41; -29; Left superior -39; -21; longitudinal fasciculus Right superior fronto-occipital fasciculus 21; -5 ; Increased MD in HIV+ children compared to controls Left anterior limb of -19; 7; internal capsule Left posterior limb of internal capsule -22; -14;

37 CTAAC DTI results (results superimposed on an MNI brain template) Decreased FA in HIV+ children P A R L R L Increased MD in HIV+ children P A R L R L

38 FreeSurfer: Cortical (surface-based) Analysis. FreeSurfer: Volume analysis Cortex White Matter Lateral Ventricle Thalamus Caudate Pallidum Hippocampus Putamen Amygdala

39 Structural MRI results No significant differences were found for total brain WM or GM volume no significant differences in cortical thickness or white matter volumes between the two groups.

40 Table 3: Comparison between HIV+ adolescents and controls on Freesurfer morphometric measures Gray matter region Talaraich coordinates (x,y,z) Cluster size (mm 2 ) Local maxima z- value P-value Decreased gray matter volume in HIV+ children compared to controls Left postcentral gyrus -55.7, -9.9, Decreased cortical surface area in HIV+ children compared to controls Left precentral -45.6, -7.3, < gyrus Left pericalcarine gyrus -12.2, -65.2, Decreased gyrification in HIV+ children compared to controls Left inferior -49.4, -61.4, temporal gyrus Right lateral occipital gyrus 31.8, -79.4,

gyrus of HIV+ children (bar represents the Z-value) LH Decreased

41 CTAAC Freesurfer results (results are shown on an inflated brain surface for ease of view) Decreased volume in left postcentral gyrus of HIV+ children (bar represents the Z-value) LH Decreased cortical surface area in left precentral gyrus of HIV+ children LH

42 Decreased gyrification in left inferior temporal and right lateral occipital gyrus of HIV+ children LH RH

43 Table 4: Clinical variables that displayed a significant association with brain imaging measurements within HIV+ children Whole Brain Clinical variable Pearson P-value structure measurement correlation Gray matter WASI IQ volume White matter WASI IQ volume Beck Self-Concept Inventory for Youth Cortical thickness Viral load Fractional Beck Anger Inventory for anisotropy Youth Beck Disruptive Behavior Inventory for Youth Mean diffusivity CBCL total competence EFV treatment status Children s Motivation Scale

44 Limitations cross sectional design of the study but longitudinal followup is underway to better understand the impact of HIV on brain remodeling typically seen in later adolescence The control group is small in comparison to the participant group There are limitations associated with DTI as a quantitative imaging technique. Although other congenital infections and incidental CNS abnormalities were excluded as far as possible on history, clinical examination and on clinical review of the MRI scans, it remains a possibility that there may be some overlapping effects of undiagnosed conditions such as congenital CMV.

45 Conclusion The pattern of neurocognitive impairment, damaged neuronal microstructure, smaller gray matter volumes, reduced cortical surface area and decreased gyrification, suggests abnormal neurodevelopment in perinatally infected younger adolescents Empathy, patience, serious respect!!!

Source of Funding: This research was supported by NICHD under grant R01HD074051 Acknowledgments: The authors would like to thank

46 Source of Funding: This research was supported by NICHD under grant R01HD Acknowledgments: The authors would like to thank the adolescents and their caregivers who participated in this study, as well as the study staff for their support of this research.

47 FOUCHE Jean-Paul PHILLIPS Nicole JOSKA John A MYER Landon ZAR Heather J STEIN Dan J Research staff Study participants Thank you

Imaging in Pediatric `neurohiv Dr Jackie Hoare Head of Liaison Psychiatry Groote Schuur Hospital, UCT

Imaging in Pediatric `neurohiv Dr Jackie Hoare Head of Liaison Psychiatry Groote Schuur Hospital, UCT ? Spectrum of Neurocognitive disorders The adult literature on HIV related CNS damage supports a spectrum