Tracking brain development and dimensional psychiatric symptoms in children

__Objective:__ Psychiatric symptomatology during childhood predicts persistent mental illness later in life. While neuroimaging methodologies are routinely applied cross-sectionally to the study of child and adolescent psychopathology, the nature of the relationship between childhood symptoms and the underlying neurodevelopmental processes remains unclear. The authors used a prospective population-based cohort to delineate the longitudinal relationship between childhood psychiatric problems and brain development. __Methods:__ A total of 845 children participated in the study. Psychiatric symptoms were measured with the parent-rated Child Behavior Checklist at ages 6 and 10. MRI data were collected at ages 8 and 10. Cross-lagged panel models and linear mixed-effects models were used to determine the associations between psychiatric symptom ratings and quantitative anatomic and white matter microstructural measures over time. __Results:__ Higher ratings for externalizing and internalizing symptoms at baseline predicted smaller increases in both subcortical gray matter volume and global fractional anisotropy over time. The reverse relationship did not hold; thus, baseline measures of gray matter and white matter were not significantly related to changes in symptom ratings over time. __Conclusions:__ Children presenting with behavioral problems at an early age show differential subcortical and white matter development. Most neuroimaging models tend to explain brain differences observed in psychopathology as an underlying (causal) neurobiological substrate. However, the present work suggests that future neuroimaging studies showing effects that are pathogenic in nature should additionally explore the possibility of the downstream effects of psychopathology on the brain

Eye movement desensitization and reprocessing (EMDR) in children and adolescents with subthreshold PTSD after medically related trauma: design of a randomized controlled trial.

Background: Three in every 10 children and adolescents admitted to a hospital or undergoing medical treatment develop subthreshold symptoms of posttraumatic stress disorder (PTSD). When untreated, subthreshold PTSD can have a serious impact on psychosocial functioning, quality of life and long-term psychopathology. However, research investigating subthreshold PTSD and its treatment following paediatric medical interventions and/or hospitalization is scarce. Eye Movement Desensitization and Reprocessing (EMDR) is a fast and non-invasive psychosocial treatment for posttraumatic stress complaints. However, the effectiveness of EMDR in paediatric patients with subthreshold PTSD has not previously been systematically investigated. Objective: Describing the design of a randomized controlled trial (RCT) set up to evaluate the effectiveness of EMDR in children with subthreshold PTSD after hospitalization. Method: Children aged 4–15 years who have undergone a one-time (trauma type I) or repeated (trauma type II) hospitalization up to five years ago will be included. Participating children will be first screened with a standardized questionnaire for PTSD-symptoms. Subsequently, children with subthreshold PTSD will be randomly assigned to (1) approximately six sessions of standardized EMDR or (2) care as usual (CAU). Children with full diagnostic PTSD do not participate in the RCT, but are referred for direct treatment. Follow-up measurements will take place after eight weeks and eight months. Discussion: Considering the scarce evidence for the effectiveness of EMDR in children with medically related trauma, clinicans, researchers and children treated in hospitals can benefit from this study. Potential strengths and limitations of this study are discussed. Trial Registration: Netherlands Trial Register NTR580

Heterosexual HIV-1 infectiousness and antiretroviral use : systematic review of prospective studies of discordant couples

Background: Recent studies have estimated the reduction in HIV-1 infectiousness with antiretroviral therapy (ART), but high-quality studies such as randomized controlled trials, accompanied by rigorous adherence counseling, are likely to overestimate the effectiveness of treatment-as-prevention in real-life settings. Methods: We attempted to summarize the effect of ART on HIV transmission by undertaking a systematic review and meta-analysis of HIV-1 infectiousness per heterosexual partnership (incidence rate and cumulative incidence over study follow-up) estimated from prospective studies of discordant couples. We used random-effects Poisson regression models to obtain summary estimates. When possible, the analyses were further stratified by direction of transmission (man-to-woman or woman-to-man) and economic setting (high- or low-income countries). Potential causes of heterogeneity of estimates were explored through subgroup analyses. Results: Fifty publications were included. Nine allowed comparison between ART and non-ART users within studies (ART-stratified studies), in which summary incidence rates were 3.6/100 person-years (95% confidence interval = 2.0-6.5) and 0.2/100 person-years (0.07-0.7) for non-ART- and ART-using couples, respectively (P < 0.001), constituting a 91% (79-96%) reduction in per-partner HIV-1 incidence rate with ART use. The 41 studies that did not stratify by ART use provided estimates with high levels of heterogeneity (I2 statistic) and few reported levels of ART use, making interpretation difficult. Nevertheless, estimates tended to be lower with ART use. Infectiousness tended to be higher for low-income than high-income settings, but there was no clear pattern by direction of transmission (man-to-woman and woman-to-man). Conclusions: ART substantially reduces HIV-1 infectiousness within discordant couples, based on observational studies, and could play a major part in HIV-1 prevention efforts. However, the non-zero risk from partners receiving ART demonstrates that appropriate counseling and other risk-reduction strategies for discordant couples are still required. Additional estimates of ART effectiveness by adherence level from real-life settings will be important, especially for persons starting treatment early without symptoms

Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study

Neuroinflammation is emerging as an important pathological process in frontotemporal dementia (FTD), but biomarkers are lacking. We aimed to determine the value of complement proteins, which are key components of innate immunity, as biomarkers in cerebrospinal fluid (CSF) and plasma of presymptomatic and symptomatic genetic FTD mutation carriers.We measured the complement proteins C1q and C3b in CSF by ELISAs in 224 presymptomatic and symptomatic GRN, C9orf72 or MAPT mutation carriers and non-carriers participating in the Genetic Frontotemporal Dementia Initiative (GENFI), a multicentre cohort study. Next, we used multiplex immunoassays to measure a panel of 14 complement proteins in plasma of 431 GENFI participants. We correlated complement protein levels with corresponding clinical and neuroimaging data, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP).CSF C1q and C3b, as well as plasma C2 and C3, were elevated in symptomatic mutation carriers compared to presymptomatic carriers and non-carriers. In genetic subgroup analyses, these differences remained statistically significant for C9orf72 mutation carriers. In presymptomatic carriers, several complement proteins correlated negatively with grey matter volume of FTD-related regions and positively with NfL and GFAP. In symptomatic carriers, correlations were additionally observed with disease duration and with Mini Mental State Examination and Clinical Dementia Rating scale® plus NACC Frontotemporal lobar degeneration sum of boxes scores.Elevated levels of CSF C1q and C3b, as well as plasma C2 and C3, demonstrate the presence of complement activation in the symptomatic stage of genetic FTD. Intriguingly, correlations with several disease measures in presymptomatic carriers suggest that complement protein levels might increase before symptom onset. Although the overlap between groups precludes their use as diagnostic markers, further research is needed to determine their potential to monitor dysregulation of the complement system in FTD.© 2022. The Author(s)

Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort

Coinvestigators are listed at https://links.lww.com/WNL/B988.Copyright © 2022 The Author(s). Background and Objectives: Disease-modifying therapeutic trials for genetic frontotemporal dementia (FTD) are underway, but sensitive cognitive outcome measures are lacking. The aim of this study was to identify such cognitive tests in early stage FTD by investigating cognitive decline in a large cohort of genetic FTD pathogenic variant carriers and by investigating whether gene-specific differences are moderated by disease stage (asymptomatic, prodromal, and symptomatic). Methods: C9orf72, GRN, and MAPT pathogenic variant carriers as well as controls underwent a yearly neuropsychological assessment covering 8 cognitive domains as part of the Genetic FTD Initiative, a prospective multicenter cohort study. Pathogenic variant carriers were stratified according to disease stage using the global Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center (NACC) FTLD score (0, 0.5, or ≥1). Linear mixed-effects models were used to investigate differences between genetic groups and disease stages as well as the 3-way interaction between time, genetic group, and disease stage. Results: A total of 207 C9orf72, 206 GRN, and 86 MAPT pathogenic variant carriers and 255 controls were included. C9orf72 pathogenic variant carriers performed lower on attention, executive function, and verbal fluency from CDR plus NACC FTLD 0 onwards, with relatively minimal decline over time regardless of the CDR plus NACC FTLD score (i.e., disease progression). The cognitive profile in MAPT pathogenic variant carriers was characterized by lower memory performance at CDR plus NACC FTLD 0.5, with decline over time in language from the CDR plus NACC FTLD 0.5 stage onwards, and executive dysfunction rapidly developing at CDR plus NACC FTLD ≥1. GRN pathogenic variant carriers declined on verbal fluency and visuoconstruction in the CDR plus NACC FTLD 0.5 stage, with progressive decline in other cognitive domains starting at CDR plus NACC FTLD ≥1. Discussion: We confirmed cognitive decline in the asymptomatic and prodromal stage of genetic FTD. Specifically, tests for attention, executive function, language, and memory showed clear differences between genetic groups and controls at baseline, but the speed of change over time differed depending on genetic group and disease stage. This confirms the value of neuropsychological assessment in tracking clinical onset and progression and could inform clinical trials in selecting sensitive end points for measuring treatment effects as well as characterizing the best time window for starting treatment.European Reference Network for Rare Neurological Diseases 739510; Miriam Marks Brain Research UK Senior Fellowship; UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MR/M008525/1; NIHR Rare Disease Translational Research Collaboration BRC149/NS/MH; UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MR/M023664/1; JPND GENFIPROX grant 2019-02248; Bluefield Project; Dioraphte Foundation 09-02-00; Association for Frontotemporal Dementias Research Grant 2009; Netherlands Organization for Scientific Research (NWO) HCMI 056-13-018; ZonMw Memorabel (Deltaplan Dementie) 733 050 103 and 733 050 813; JPND PreFrontAls consortium 733051042; Alzheimer Nederland WE.15-2019.02; Tau Consortium; Instituto de Salud Carlos IIIPI20/00448; United States Department of Health & Human Services National Institutes of Health (NIH) - USA; Swedish Research Council European Commission; JPND grant GENFI-PROX 201902248; JPND grant PrefrontALS 2015-02926; Swedish Research Council European Commission 2018-02754; Schorling Foundation; Swedish FTD Initiative; Swedish Alzheimer Foundation; Swedish Brain Foundation; Region StockholmALF project; Karolinska Institutet; Swedish Dementia Foundation; National Institute for Health Research (NIHR); UK Research & Innovation (UKRI) Medical Research Council UK (MRC) BRC-1215-20014 and SUAG/051 G101400; Canadian Institutes of Health Research (CIHR); Physician's Services Incorporated Foundation

Impairment of episodic memory in genetic frontotemporal dementia: A GENFI study

Introduction We aimed to assess episodic memory in genetic frontotemporal dementia (FTD) with the Free and Cued Selective Reminding Test (FCSRT). Methods The FCSRT was administered in 417 presymptomatic and symptomatic mutation carriers (181 chromosome 9 open reading frame 72 [C9orf72], 163 progranulin [GRN], and 73 microtubule-associated protein tau [MAPT]) and 290 controls. Group differences and correlations with other neuropsychological tests were examined. We performed voxel-based morphometry to investigate the underlying neural substrates of the FCSRT. Results All symptomatic mutation carrier groups and presymptomatic MAPT mutation carriers performed significantly worse on all FCSRT scores compared to controls. In the presymptomatic C9orf72 group, deficits were found on all scores except for the delayed total recall task, while no deficits were found in presymptomatic GRN mutation carriers. Performance on the FCSRT correlated with executive function, particularly in C9orf72 mutation carriers, but also with memory and naming tasks in the MAPT group. FCSRT performance also correlated with gray matter volumes of frontal, temporal, and subcortical regions in C9orf72 and GRN, but mainly temporal areas in MAPT mutation carriers. Discussion The FCSRT detects presymptomatic deficits in C9orf72- and MAPT-associated FTD and provides important insight into the underlying cause of memory impairment in different forms of FTD