Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): an auditory evoked potential study of the duration-evoked mismatch negativity (MMN).

BACKGROUND: We interrogated auditory sensory memory capabilities in individuals with CLN3 disease (juvenile neuronal ceroid lipofuscinosis), specifically for the feature of "duration" processing. Given decrements in auditory processing abilities associated with later-stage CLN3 disease, we hypothesized that the duration-evoked mismatch negativity (MMN) of the event related potential (ERP) would be a marker of progressively atypical cortical processing in this population, with potential applicability as a brain-based biomarker in clinical trials. METHODS: We employed three stimulation rates (fast: 450 ms, medium: 900 ms, slow: 1800 ms), allowing for assessment of the sustainability of the auditory sensory memory trace. The robustness of MMN directly relates to the rate at which the regularly occurring stimulus stream is presented. As presentation rate slows, robustness of the sensory memory trace diminishes. By manipulating presentation rate, the strength of the sensory memory trace is parametrically varied, providing greater sensitivity to detect auditory cortical dysfunction. A secondary hypothesis was that duration-evoked MMN abnormalities in CLN3 disease would be more severe at slower presentation rates, resulting from greater demand on the sensory memory system. RESULTS: Data from individuals with CLN3 disease (N = 21; range 6-28 years of age) showed robust MMN responses (i.e., intact auditory sensory memory processes) at the medium stimulation rate. However, at the fastest rate, MMN was significantly reduced, and at the slowest rate, MMN was not detectable in CLN3 disease relative to neurotypical controls (N = 41; ages 6-26 years). CONCLUSIONS: Results reveal emerging insufficiencies in this critical auditory perceptual system in individuals with CLN3 disease.

Net effects explains the benefits to children from maternal fish consumption despite methylmercury in fish.

In 2001 the U.S. Food and Drug Administration (FDA) issued precautionary advice to pregnant women to limit fish consumption over concern that the methylmercury content might harm their children's neurodevelopment. This concern was based largely on results from an epidemiological study of mothers primarily exposed to methylmercury from consuming pilot whale. Subsequently, FDA and the World Health Organization/Food and Agriculture Organization (WHO/FAO) undertook independent assessments of fish consumption that considered net effects from both fish nutrients, primarily omega-3 fatty acids, as beneficial and methylmercury as harmful. Both assessments estimated that when mothers regularly consume fish during pregnancy, their children are likely to have improved neurodevelopment compared to children of non-fish eaters despite their exposure to methylmercury. These estimated improvements included gains of two to over five full scale IQ points from levels of maternal consumption that are achievable in most of the world. Consistent with those estimates, human research on fish consumption and child neurodevelopment from more than 200,000 mother-child pairs now collectively reports 51 beneficial associations with neurodevelopmental outcomes and three adverse associations, the latter with no discernable pattern. These associations include full scale IQ gains similar to, or somewhat higher than, those estimated by FDA and FAO/WHO. Also consistent with the FDA and FAO/WHO estimates, research has reported beneficial associations with fish consumption when pregnant women are exposed to methylmercury from fish in excess of the U.S. Environmental Protection Agency's (EPA) Reference Dose (RfD). Our analysis evaluates how the net effects approach as utilized by FDA and FAO/WHO provides a holistic explanation for these results with implications for public health policy. This concordance of net effects modeling and empirical scientific evidence supports a clarification of current public health recommendations to focus on greater fish consumption by pregnant women for their children's neurodevelopment.

Assessing the integrity of auditory sensory memory processing in CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease)): An auditory evoked potential study of the duration-evoked mismatch negativity (MMN).

Background: We interrogated auditory sensory memory capabilities in individuals with CLN3 disease (juvenile neuronal ceroid lipofuscinosis), specifically for the feature of "duration" processing, a critical cue in speech perception. Given decrements in speech and language skills associated with later-stage CLN3 disease, we hypothesized that the duration-evoked mismatch negativity (MMN) of the event related potential (ERP) would be a marker of progressively atypical cortical processing in this population, with potential applicability as a brain-based biomarker in clinical trials. Methods: We employed three stimulation rates (fast: 450 ms, medium: 900 ms, slow: 1800 ms), allowing for assessment of the sustainability of the auditory sensory memory trace. The robustness of MMN directly relates to the rate at which the regularly occurring stimulus stream is presented. As presentation rate slows, robustness of the sensory memory trace diminishes. By manipulating presentation rate, the strength of the sensory memory trace is parametrically varied, providing greater sensitivity to detect auditory cortical dysfunction. A secondary hypothesis was that duration-evoked MMN abnormalities in CLN3 disease would be more severe at slower presentation rates, resulting from greater demand on the sensory memory system. Results: Data from individuals with CLN3 disease (N=21; range 6-28 years of age) showed robust MMN responses (i.e., intact auditory sensory memory processes) at the medium stimulation rate. However, at the fastest rate, MMN was significantly reduced, and at the slowest rate, MMN was not detectable in CLN3 disease relative to neurotypical controls (N=41; ages 6-26 years). Conclusions: Results reveal emerging insufficiencies in this critical auditory perceptual system in individuals with CLN3 disease.

Teacher Knowledge of Tourette Syndrome and Associated Factors.

BACKGROUND: Tourette syndrome (TS) is associated with learning disabilities and educational impairment. Teacher knowledge about TS may have a positive impact on students with TS, but factors associated with teacher knowledge of TS are not known. METHODS: In this cross-sectional study, teachers of youth with TS and of a community control group completed a Teacher Understanding of Tourette Syndrome Survey (TUTS), a pilot questionnaire enquiring about self-perceived understanding, teacher knowledge, and sources of information. We compared TUTS scores between TS and control groups and between those who did and did not use specific sources of information about TS using Wilcoxon rank-sum tests. Bivariate correlation analyses were used to evaluate associations between teacher knowledge and potential contributing factors. RESULTS: Data from 114 teachers of children with TS and 78 teachers of control subjects were included. Teachers of youth with TS had significantly more knowledge, had higher self-perceived understanding, and used more sources of information than teachers of the control group. Teachers who knew of the Tourette Association of America and who gathered information themselves had higher knowledge about TS than those who did not. CONCLUSION: Teachers of children with TS know more about TS and use more sources to learn about TS than teachers of children without TS.

Recommendations on the Selection, Development, and Modification of Performance Outcome Assessments: A Good Practices Report of an ISPOR Task Force.

In evaluating the clinical benefit of new therapeutic interventions, it is critical that the treatment outcomes assessed reflect aspects of health that are clinically important and meaningful to patients. Performance outcome (PerfO) assessments are measurements based on standardized tasks actively undertaken by a patient that reflect physical, cognitive, sensory, and other functional skills that bring meaning to people's lives. PerfO assessments can have substantial value as drug development tools when the concepts of interest being measured best suit task performance and in cases where patients may be limited in their capacity for self-report. In their development, selection, and modification, including the evaluation and documentation of validity, reliability, usability, and interpretability, the good practice recommendations established for other clinical outcome assessment types should continue to be followed, with concept elicitation as a critical foundation. In addition, the importance of standardization, and the need to ensure feasibility and safety, as well as their utility in patient groups, such as pediatric populations, or those with cognitive and psychiatric challenges, may enhance the need for structured pilot evaluations, additional cognitive interviewing, and evaluation of quantitative data, such as that which would support concept confirmation or provide ecological evidence and other forms of construct evidence within a unitary approach to validity. The opportunity for PerfO assessments to inform key areas of clinical benefit is substantial and establishing good practices in their selection or development, validation, and implementation, as well as how they reflect meaningful aspects of health is critical to ensuring high standards and in furthering patient-focused drug development.

Brief youth self-report screener for tics: Can a subscale of the Motor tic, Obsession and compulsion, and Vocal tic Evaluation Survey (MOVES) identify tic disorders in youth?

Tics are unwanted, repetitive movements and sounds that frequently present during childhood. They are typically brief and purposeless, but can create significant distress for individuals, and often co-occur with other neuropsychiatric conditions. Thus, early identification of tics is warranted. Unfortunately, tics are often misdiagnosed, and because tics may wax and wane, identification can be difficult, especially in the context of routine clinical visits. There are limited tools that can be used to reliably identify tics in clinical practice, especially in non-specialty settings. The purpose of the current study was to evaluate the performance of the Motor tic, Obsession and compulsion, and Vocal tic Evaluation Survey (MOVES), a self-report scale with some support as a screening tool. In addition, the performance of a subset of questions (the MOVES-6) was evaluated for rapid screening. Participants were recruited across two study sites and included children and adolescents diagnosed with Tourette syndrome (n = 151) or another persistent tic disorder (n = 10) and community controls (n = 74). Results suggest both the MOVES and the MOVES-6 have high sensitivity (90% and 88%, respectively) and at least acceptable specificity (77% and 86%, respectively) compared with expert assessment of tic disorders, suggesting that both versions can identify tic disorders without high proportions of false negatives. Both versions were highly sensitive with acceptable specificity regardless of sex, race/ethnicity, and age. The MOVES and MOVES-6 show promise as a screener for tics or tic disorders, but additional research is needed, particularly in a general population setting.

Association of Potentially Damaging De Novo Gene Variants With Neurologic Outcomes in Congenital Heart Disease.

Importance: Neurodevelopmental disabilities are commonly associated with congenital heart disease (CHD), but medical and sociodemographic factors explain only one-third of the variance in outcomes. Objective: To examine whether potentially damaging de novo variants (dDNVs) in genes not previously linked to neurodevelopmental disability are associated with neurologic outcomes in CHD and, post hoc, whether some dDNVs or rare putative loss-of-function variants (pLOFs) in specific gene categories are associated with outcomes. Design, Setting, and Participants: This cross-sectional study was conducted from September 2017 to June 2020 in 8 US centers. Inclusion criteria were CHD, age 8 years or older, and available exome sequencing data. Individuals with pathogenic gene variants in known CHD- or neurodevelopment-related genes were excluded. Cases and controls were frequency-matched for CHD class, age group, and sex. Exposures: Heterozygous for (cases) or lacking (controls) dDNVs in genes not previously associated with neurodevelopmental disability. Participants were separately stratified as heterozygous or not heterozygous for dDNVs and/or pLOFs in 4 gene categories: chromatin modifying, constrained, high level of brain expression, and neurodevelopmental risk. Main Outcomes and Measures: Main outcomes were neurodevelopmental assessments of academic achievement, intelligence, fine motor skills, executive function, attention, memory, social cognition, language, adaptive functioning, and anxiety and depression, as well as 7 structural, diffusion, and functional brain magnetic resonance imaging metrics. Results: The study cohort included 221 participants in the post hoc analysis and 219 in the case-control analysis (109 cases [49.8%] and 110 controls [50.2%]). Of those 219 participants (median age, 15.0 years [IQR, 10.0-21.2 years]), 120 (54.8%) were male. Cases and controls had similar primary outcomes (reading composite, spelling, and math computation on the Wide Range Achievement Test, Fourth Edition) and secondary outcomes. dDNVs and/or pLOFs in chromatin-modifying genes were associated with lower mean (SD) verbal comprehension index scores (91.4 [20.4] vs 103.4 [17.8]; P = .01), Social Responsiveness Scale, Second Edition, scores (57.3 [17.2] vs 49.4 [11.2]; P = .03), and Wechsler Adult Intelligence Scale, Fourth Edition, working memory scores (73.8 [16.4] vs 97.2 [15.7]; P = .03), as well as higher likelihood of autism spectrum disorder (28.6% vs 5.2%; P = .01). dDNVs and/or pLOFs in constrained genes were associated with lower mean (SD) scores on the Wide Range Assessment of Memory and Learning, Second Edition (immediate story memory: 9.7 [3.7] vs 10.7 [3.0]; P = .03; immediate picture memory: 7.8 [3.1] vs 9.0 [2.9]; P = .008). Adults with dDNVs and/or pLOFs in genes with a high level of brain expression had greater Conners adult attention-deficit hyperactivity disorder rating scale scores (mean [SD], 55.5 [15.4] vs 46.6 [12.3]; P = .007). Conclusions and Relevance: The study findings suggest neurodevelopmental outcomes are not associated with dDNVs as a group but may be worse in individuals with dDNVs and/or pLOFs in some gene sets, such as chromatin-modifying genes. Future studies should confirm the importance of specific gene variants to brain function and structure.

Approaches to the Assessment of Clinical Benefit of Treatments for Conditions That Have Heterogeneous Symptoms and Impacts: Potential Applications in Rare Disease.

OBJECTIVES: Evaluating the clinical benefit of interventions for conditions with heterogeneous symptom and impact presentations is challenging. The same condition can present differently across and within individuals over time. This occurs frequently in rare diseases. The purpose of this review was to identify (1) assessment approaches used in clinical trials to address heterogeneous manifestations that could be relevant in rare disease research and (2) US Food and Drug Administration (FDA)-approved labeling claims that used these approaches. METHODS: A targeted literature review was conducted examining peer-reviewed publications and FDA-approved labeling claims from January 2002 to July 2020, focusing on claims incorporating clinical outcome assessments. Approaches were then assessed for their potential application in rare diseases. RESULTS: A total of 6 assessment approaches were identified: composite or other multicomponent endpoints, multidomain responder index, most bothersome symptom (MBS), goal attainment scaling, sliding dichotomy, and adequate relief. A total of 59 FDA-approved labeling claims associated with these approaches were identified: composite or other multicomponent endpoints (n=49), MBS (n=9), and adequate relief (n=1). A total of 10 FDA-approved labeling claims, all using multicomponent endpoints, were identified for rare diseases. CONCLUSIONS: Multicomponent, MBS, and adequate relief have been included in FDA-approved labeling claims. Multicomponent endpoints, including composite endpoints, were the most frequent way to address heterogeneous manifestations of both common and rare diseases. MBS may be acceptable to regulators, whereas multidomain responder index is unlikely to be. The goal attainment scaling and adequate relief approaches may have potential utility in rare disease trials, assuming the theoretical and statistical challenges inherent in each approach are managed.

Longitudinal Cognitive Outcomes in Children With HIV in Zambia: 2-Year Outcomes From the HIV-Associated Neurocognitive Disorders in Zambia (HANDZ) Study.

OBJECTIVE: To describe longitudinal outcomes and predictors of cognitive outcomes in children with HIV in Zambia. BACKGROUND: Multiple studies have shown that children with HIV are at risk for impaired cognition. However, there are limited data on longitudinal cognitive outcomes in children with HIV. METHODS: We conducted a prospective cohort study of 208 perinatally infected children with HIV ages 8-17 years, all treated with antiretroviral therapy, and 208 HIV-exposed uninfected controls. Participants were followed for 2 years. Cognition was assessed with a custom NIH Toolbox Cognition Battery, and tests were combined to generate a Summary Cognition Score (SCS). The contribution of potential risk factors to outcomes was explored using regression models and group-based trajectory modeling. RESULTS: HIV was strongly associated with lower SCS at baseline [ß-14, 95% confidence interval (CI): -20 to -7, P < 0.001]. Change scores over time were similar between groups, but poorer average performance in children with HIV persisted at the 2-year follow-up visit (adjusted ß = -11, 95% CI: -22 to -0.3, P = 0.04). Other than HIV, the strongest predictors of baseline SCS included socioeconomic status index (ß =3, 95% CI: 1, 5, P = 0.004), history of growth stunting (ß=-14, 95% CI: -23 to -6, P = 0.001), history of CD4 count below 200 (ß = -19, 95% CI: -35 to -2, P = 0.02), and history of World Health Organization stage 4 disease (ß = -10, 95% CI: -19 to -0.2, P = 0.04). In the group-based trajectory model, HIV+ status predicted membership in the lowest performing trajectory group (odds ratio 2.5, 95% CI: 1.2 to 5.1, P = 0.01). CONCLUSIONS: Children with HIV are at risk of poor cognitive outcomes, despite chronic treatment with antiretroviral therapy.

Validation of the National Institute of Health Toolbox Cognition Battery (NIHTB-CB) in Children and Adolescents with and without HIV Infection in Lusaka, Zambia.

The objective of this study was to validate the NIH Toolbox Cognition Battery (NIHTB-CB) in Zambian children with and without HIV-infection. Children living with HIV and HIV-exposed, uninfected (HEU) children completed traditional neuropsychological and NIHTB-CB tasks. Using pairwise correlation and a linear regression model we measured associations between traditional measure composite scores and parental ratings of children's abilities, and NIHTB-CB scores. A Receiver Operating Characteristic (ROC) curve was developed to identify participants with impairment. 389 children, 8-17 years old participated. NIHTB-CB and traditional measures converged well as a whole and when comparing analogous individual tests across the two batteries. The NIHTB-CB composite score discriminated between the groups and was positively associated with external criteria for cognitive function: parental ratings of intelligence and school performance. Some English vocabulary and/or an unfamiliar cultural context presented challenges. NIHTB-CB was associated with children's everyday cognitive abilities, though future use may require linguistic and cultural adaptation.

Risk Behaviors in Youth With and Without Tourette Syndrome.

BACKGROUND: Specific health-risk behaviors are present in older adolescents and young adults wtih Tourette syndrome (TS), but little is known about health-risk behaviors in youth with TS. METHODS: We compared responses on the Youth Risk Behavior Surveillance System (YRBS) in youth with TS with those in a concurrent community control group. The YRBS evaluates risk behaviors most closely associated with morbidity and mortality in young people. Tic severity, presence of comorbid attention-deficit/hyperactivity disorder (ADHD), measures of ADHD symptom severity, and whether or not the individual had been bullied in school were also compared between the groups. RESULTS: Data from 52 youth with TS and 48 control youth were included. We did not detect any differences between control youth and youth with TS in the reporting of risky behaviors. Tic severity was not significantly associated with high-risk behavior. However, ADHD was significantly more common in youth with TS (P < 0.0002), and youth with TS who identified themselves as victims of bullying had significantly higher ADHD symptom severity scores (P = 0.04) compared with those who were not bullied. CONCLUSIONS: Risk behaviors are not reliably or clinically different in youth with TS compared with control youth. ADHD severity, but not tic severity, was associated with being bullied in youth with TS.

Socioeconomic Status and Cognitive Function in Children With HIV: Evidence From the HIV-Associated Neurocognitive Disorders in Zambia (HANDZ) Study.

BACKGROUND: Multiple previous studies have identified a detrimental effect of pediatric HIV on cognitive function. Socioeconomic status (SES) is one of the strongest predictors of cognitive performance and may affect the relationship between HIV and cognition. METHODS: As part of the ongoing HIV-Associated Neurocognitive Disorders in Zambia (HANDZ) study, a prospective cohort study, we recruited 208 participants with HIV and 208 HIV-exposed uninfected controls, all aged 8-17 years. A standardized questionnaire was administered to assess SES, and all participants had comprehensive neuropsychological testing. An NPZ8 score was derived as a summary measure of cognitive function. Logistic regression and linear regression were used to model the relationship between SES and cognitive function, and mediation analysis was used to identify specific pathways by which SES may affect cognition. RESULTS: Children with HIV performed significantly worse on a composite measure of cognitive function (NPZ8 score -0.19 vs. 0.22, P < 0.001) and were more likely to have cognitive impairment (33% vs. 19%, P = 0.001). Higher SES was associated with reduced risk of cognitive impairment (odds ratio 0.8, 95% confidence interval: 0.75-0.92, P < 0.001) in both groups, with similar effects in children with HIV and HIV-exposed uninfected groups. SES was more strongly correlated with NPZ8 score in children with HIV than in uninfected controls (Pearson's R 0.39 vs. 0.28), but predicted NPZ8 in both groups. Mediation analysis suggested that the effect of SES on cognition was most strongly mediated through malnutrition. CONCLUSIONS: Cognitive function is strongly correlated with SES in children with HIV, suggesting a synergistic effect of HIV and poverty on cognitive function.

Neighborhood-Based Socioeconomic Determinants of Cognitive Impairment in Zambian Children With HIV: A Quantitative Geographic Information Systems Approach.

BACKGROUND: Place-based inequalities, such as exposure to violence and access to nutritious food and clean water, may contribute to human immunodeficiency virus (HIV)-associated cognitive impairment. In this study, we investigated neighborhood effects on cognition in children and adolescents with HIV in Lusaka, Zambia. METHODS: We conducted a prospective cohort study of 208 children with perinatally acquired HIV (ages 8-17) and 208 HIV-exposed uninfected controls. Participants underwent neuropsychological testing and interviews assessing socioeconomic status. Geographic regions with clusters of participants with HIV and cognitive impairment were identified using quantitative geographic information systems (QGIS) and SaTScan. Associations between location of residence and cognitive function were evaluated in bivariable and multivariable regression models. Mediation analysis was performed to assess direct and indirect effects of location of the residence on cognitive impairment. RESULTS: Residence in Chawama, one of the poorest neighborhoods in Lusaka, was significantly associated with cognitive impairment in participants with HIV (odds ratio 2.9; P = .005) and remained significant in a multivariable regression model controlling for potential confounders. Mediation analysis found that 46% of the cognitive effects of residence in Chawama were explained by higher rates of malnutrition, lower school attendance, and poorer self-reported health. CONCLUSIONS: Place-based socioeconomic inequality contributes to cognitive impairment in Zambian children and adolescents with HIV. Neighborhood effects may be mediated by concentrated poverty, malnutrition, limited access to education and health care, and other yet unknown environmental factors that may be potentially modifiable.

A diagnostic confidence scheme for CLN3 disease.

Over the past 20 years, diagnostic testing for genetic diseases has evolved, leading to variable diagnostic certainty for individuals included in long-term natural history studies. Using genotype and phenotype data from an ongoing natural history study of CLN3 disease, we developed a hierarchical diagnostic confidence scheme with three major classes: Definite, Probable, or Possible CLN3 disease. An additional level, CLN3 Disease PLUS, includes individuals with CLN3 disease plus an additional disorder with a separate etiology that substantially affects the phenotype. Within the Definite and Probable CLN3 disease classes, we further divided individuals into subclasses based on phenotype. After assigning participants to classes, we performed a blinded reclassification to assess the reliability of this scheme. A total of 134 individuals with suspected CLN3 disease were classified: 100 as Definite, 21 as Probable, and 7 as Possible. Six individuals were classified as CLN3-PLUS. Phenotypes included the classical juvenile-onset syndromic phenotype, a "vision loss only" phenotype, and an atypical syndromic phenotype. Some individuals were too young to fully classify phenotype. Test-retest reliability showed 96% agreement. We created a reliable diagnostic confidence scheme for CLN3 disease that has excellent face validity. This scheme has implications for clinical research in CLN3 and other rare genetic neurodegenerative disorders.

Management of CLN1 Disease: International Clinical Consensus.

BACKGROUND: CLN1 disease (neuronal ceroid lipofuscinosis type 1) is a rare, genetic, neurodegenerative lysosomal storage disorder caused by palmitoyl-protein thioesterase 1 (PPT1) enzyme deficiency. Clinical features include developmental delay, psychomotor regression, seizures, ataxia, movement disorders, visual impairment, and early death. In general, the later the age at symptom onset, the more protracted the disease course. We sought to evaluate current evidence and to develop expert practice consensus to support clinicians who have not previously encountered patients with this rare disease. METHODS: We searched the literature for guidelines and evidence to support clinical practice recommendations. We surveyed CLN1 disease experts and caregivers regarding their experiences and recommendations, and a meeting of experts was conducted to ascertain points of consensus and clinical practice differences. RESULTS: We found a limited evidence base for treatment and no clinical management guidelines specific to CLN1 disease. Fifteen CLN1 disease experts and 39 caregivers responded to the surveys, and 14 experts met to develop consensus-based recommendations. The resulting management recommendations are uniquely informed by family perspectives, due to the inclusion of caregiver and advocate perspectives. A family-centered approach is supported, and individualized, multidisciplinary care is emphasized in the recommendations. Ascertainment of the specific CLN1 disease phenotype (infantile-, late infantile-, juvenile-, or adult-onset) is of key importance in informing the anticipated clinical course, prognosis, and care needs. Goals and strategies should be periodically reevaluated and adapted to patients' current needs, with a primary aim of optimizing patient and family quality of life.

Evaluating the Relationship Between Depression and Cognitive Function Among Children and Adolescents with HIV in Zambia.

Depression is common among people living with HIV. Multiple studies demonstrate a link between depression and cognitive dysfunction in adults with HIV, but the association has been minimally investigated in children and adolescents with HIV in Africa. We conducted a cross-sectional analysis as part of the HIV-associated Neurocognitive Disorders in Zambia study, a prospective cohort study in Lusaka, Zambia. We included 208 perinatally-infected children with HIV ages 8-17 taking antiretroviral therapy and 208 HIV-exposed uninfected (HEU) controls. Cognition was assessed with a comprehensive neuropsychological battery. Depressive symptoms were evaluated using self-report and parent-report versions of the NIH Toolbox Sadness module and the Patient Health Questionnaire-9 (PHQ-9). Risk factors for depression and associations between depressive symptoms and cognition were evaluated in bivariable and multivariable regression models. Participants with HIV demonstrated higher levels of depressive symptoms than controls (mean NIH Toolbox Sadness T-Score 50 vs. 44, p < 0.01; mean PHQ-9 score 2.0 vs. 1.5, p = 0.03), and were more likely to have cognitive impairment (30% vs. 13%, p < 0.001). Risk factors for depressed mood included self-reported poor health (OR 7.8, p < 0.001) and negative life events (OR 1.3, p = 0.004) Depressed mood was associated with cognitive impairment in participants with HIV (OR = 2.9, 95% CI 1.2-7.2, p = 0.02) but not in HEU participants (OR 1.7, 95% CI 0.18-15.7, p = 0.6). In conclusion, depressed mood is common among youth with HIV in Zambia, and is associated with cognitive impairment. Depression may be a result of HIV-related stress and stigma, or may be part of the spectrum of HIV-associated neurocognitive disorders. The causal relationship between depressed mood and cognitive impairment is unclear and should be evaluated in future longitudinal studies.

Anxiety Symptoms Differ in Youth With and Without Tic Disorders.

We compared anxiety symptoms in youth with and without tic disorders by comparing scores on the Multidimensional Anxiety Scale for Children (MASC) in youth with tic disorders to those in a concurrent community control group and in a group of treatment-seeking anxious youth from the Child/Adolescent Anxiety Multimodal Study (CAMS). Data from 176 youth with tic disorders, 93 control subjects, and 488 CAMS participants were included. Compared to youth with tic disorders, controls had lower total MASC scores (p < 0.0001) and CAMS participants had similar total MASC scores (p = 0.13). Separation Anxiety (p = 0.0003) and Physical Symptom (p < 0.0001) subscale scores were higher in youth with tic disorders than in CAMS participants. We conclude that the anxiety symptom profile differs in youth with and without tic disorders, which may have important implications for targeting treatment of anxiety in youth with tic disorders.

Cerebrovascular Disease in Children Perinatally Infected With Human Immunodeficiency Virus in Zambia.

BACKGROUND: High rates of cerebrovascular disease (CVD) have previously been described in pediatric human immunodeficiency virus (HIV). However, little is known about pediatric CVD in the era of antiretroviral therapy or about the contribution of CVD to HIV-associated neurocognitive disorders. METHODS: We completed a neuroimaging substudy of the HIV-Associated Neurocognitive Disorders in Zambia study, a prospective cohort study of neurocognitive complications of pediatric HIV. Brain magnetic resonance imaging (1.5 T) was acquired for 34 HIV+ children on antiretroviral therapy and 17 HIV-exposed uninfected children (aged eight to 17 years). Demographics, medical history, neurological examination, and neuropsychologic testing results were collected. Two neuroradiologists, unaware of HIV status and clinical course, read the scans. RESULTS: CVD was identified in seven of 34 children with HIV (HIV+ CVD+) and no HIV-exposed uninfected children (21% vs 0%, P = 0.05). Three participants had white matter changes suggestive of small vessel disease, four had infarcts, and two had evidence of intracranial artery stenosis. Age of antiretroviral therapy initiation and exposure to protease inhibitors or efavirenz was not significantly different between children with and without CVD. HIV+ CVD+ children had significantly worse scores on a summary measure of cognition than the HIV+ CVD- group (NPZ8 score -0.57 vs 0.33, P = 0.04). CONCLUSIONS: This study demonstrates high rates of CVD in children with HIV despite antiretroviral therapy, and worse cognitive performance in children with CVD. Longitudinal studies are necessary to determine the mechanisms and incidence of new-onset CVD in children with HIV.

Therapy development for the mucopolysaccharidoses: Updated consensus recommendations for neuropsychological endpoints.

Neurological dysfunction represents a significant clinical component of many of the mucopolysaccharidoses (also known as MPS disorders). The accurate and consistent assessment of neuropsychological function is essential to gain a greater understanding of the precise natural history of these conditions and to design effective clinical trials to evaluate the impact of therapies on the brain. In 2017, an International MPS Consensus Panel published recommendations for best practice in the design and conduct of clinical studies investigating the effects of therapies on cognitive function and adaptive behavior in patients with neuronopathic mucopolysaccharidoses. Based on an International MPS Consensus Conference held in February 2020, this article provides updated consensus recommendations and expands the objectives to include approaches for assessing behavioral and social-emotional state, caregiver burden and quality of life in patients with all mucopolysaccharidoses.