Journal of Neurodevelopmental Disorders最新文献

Objective: Hundreds of rare genetic variants associated with autism or intellectual disability have been identified, and many impact genes known to have a primary epigenetic/chromatin regulatory function. The objective of this study was to examine and compare behavioural profiles and longitudinal psychotropic treatment patterns in children with epigenetic/chromatin variants, other rare variants impacting neurodevelopment, or no known genetic condition.

Methods: Using electronic medical records from a pediatric psychopharmacology program for children with autism or intellectual disability, we compared clinical characteristics, longitudinal psychotropic medication profiles and side effects between those with and without a rare genetic variant, and by variant subtype [epigenetic/chromatin regulation or other variant].

Results: A total of 331 children attended 2724 unique medical visits between 2019 and 2022, with a mean of 8 follow-up visits over 3.4 years. Nine children (3%) had variants in epigenetic/chromatin regulatory genes (EC), twenty-three children (7%) had other rare genetic variants (OTH), and the rest had no reported variant (NR, n = 299, 90%). Those with a rare genetic variant (EC or OTH) were more likely to have an intellectual disability and had a greater number of co-occurring physical health conditions (p < 0.01). Overall, 66% of psychotropic medications were continued for ≥ 3 visits, while 26% were discontinued. Rates of psychotropic polypharmacy, medication patterns, behavioural challenges, and co-occurring developmental diagnoses were similar between genetic groups. Analyses uncorrected for multiple comparisons suggested those with genetic variants were more likely to experience drowsiness/sedation as a side effect (EC 33%, OTH 35%, NR 16%, p < 0.05); weight gain as a side effect was also higher in the epigenetic/chromatin group (EC 50% vs OTH 11%).

Conclusion: Genetic classification of neurodevelopmental disorders (NDDs) may help anticipate treatment tolerability; additional prescribing considerations may be needed for those with rare variants. Current psychotropic prescribing practices do not differ across rare genetic NDD subgroups.

It is well accepted that attention deficit hyperactivity disorder (ADHD) is in part driven by dysfunction in the monoaminergic neurotransmitter system, but both the extent of dysfunction and possible therapeutic avenues presented by serotonergic neurotransmission is frequently overlooked. As such, we present key evidence for dysfunction in serotonergic transmission, as seen from biochemical, genetic and pharmacological perspectives. An overall deficit in serotonin availability is a common theme throughout the literature, thus this review aims to explore possible dysfunctions in the serotonin synthesis pathway which result in this reduced bioavailability, and investigate whether such dysfunctions could be loci of change in ADHD. We have identified several steps in transmission, namely the conversion of tryptophan to 5-hydroxytryptophan and its use of cofactor tetrahydrobiopterin, which could present promising avenues for development of novel clinical interventions for ADHD.

Background: Adults with Down syndrome (DS) have a 90% lifetime risk for Alzheimer's disease (AD), with neurobiological pathology present decades prior to dementia onset. The profile and timing of cognitive decline in DS is well-documented. However, there is a small body of research on whether Behavioral and Psychological Symptoms of Dementia (BPSD) occur early on in the progression of AD in DS and are associated with early AD pathology (i.e., amyloid-beta [Aβ] and neurofibrillary tau tangles [NFT]).

Methods: Data were analyzed from 337 adults with DS (M = 45.13 years, SD = 9.53 years) enrolled in a large cohort study. The Reiss Screen for Maladaptive Behavior (RSMB) measured common behaviors reported in BPSD across up to four study cycles (spaced approximately 16 months apart). Linear mixed models estimated change in BPSD as predicted by baseline (a) dementia status (i.e., cognitively stable, mild cognitive impairment [MCI], or dementia), (b) Aβ positron emission tomography (PET) tracer [¹¹C] PiB, and (c) NFT PET tracer [¹⁸F]AV-1451. Models controlled for chronological age, sex, study site, premorbid intellectual disability level, APOE e4 allele carrier status, psychiatric diagnoses, and psychiatric medication use.

Results: Compared to cognitively stable participants, participants whose status was MCI or dementia, had significantly higher baseline RSMB subdomain scores. Increases in RSMB Depression-Behavioral, Depression-Physical, and Psychosis were observed for participants with MCI. Higher baseline Aβ and NFT were associated with higher RSMB Avoidant at baseline, and increases in RSMB Depression-Physical and Psychosis over time.

Conclusions: BPSD are an important part of AD in DS, particularly during the prodromal stage. Elevated Aβ and NFT predict higher initial avoidance and change in physical depression behaviors and may indicate MCI in adults with DS. Broader increases in BPSD are observed as adults with DS progress from early to late-stage dementia. Clinicians should rule out other possible causes of BPSD when screening for AD, such as stressful life experiences or co-occurring medical conditions. Caregivers of adults with DS should have resources on BPSD management and self-care strategies.

Background: Changes in the brain structure of women with Triple X syndrome (karyotype 47,XXX) have been described in a few studies to date, including reduced total brain volume and regional reductions in gray substance in cortical and subcortical areas. However, the empirical evidence from adults is very limited and group comparison on a voxel-wise basis for gray matter volume and cortical thickness is still missing.

Methods: Using voxel-based morphometry (VBM) and surface-based morphometry (SBM), we investigated regional gray matter changes in a sample of n = 20 adult women (aged 18-49 years) with 47,XXX karyotype using T1-weighted 3T MRI scans.

Results: Compared to an age- and education-matched control group (and controlled for differences in total intracranial volume), the VBM revealed decreased regional gray matter volumes in the hippocampus, amygdala, parts of the basal ganglia, insula, prefrontal areas and cerebellum. To a lesser extent, we also noted specific reductions in cortical thickness in a smaller part of those regions.

Conclusion: The observed network is significantly involved in the processing of cognitive, affective, and social stimuli and might be a potential neuronal correlate of the autism-like social-cognitive problems described in 47,XXX in the literature.

Background: Despite the power and promise of early detection and treatment in autism spectrum disorder (ASD), early-life biomarkers are limited. An early-life risk biosignature would advance the field's understanding of ASD pathogenies and targets for early diagnosis and intervention. We therefore sought to add to the growing ASD biomarker literature and evaluate whether fetal metabolomics are altered in idiopathic ASD.

Methods: Banked cord blood plasma samples (N = 36 control, 16 ASD) were analyzed via gas chromatography and mass spectrometry (GC-MS). Samples were from babies later diagnosed with idiopathic ASD (non-familial, non-syndromic) or matched, neurotypical controls. Metabolite set enrichment analysis (MSEA) and biomarker prediction were performed (MetaboAnalyst).

Results: We detected 76 metabolites in all samples. Of these, 20 metabolites differed significantly between groups: 10 increased and 10 decreased in ASD samples relative to neurotypical controls (p < 0.05). MSEA revealed significant changes in metabolic pathways related to carbohydrate metabolism and glycemic control. Untargeted principle components analysis of all metabolites did not reveal group differences, while targeted biomarker assessment (using only Fructose 6-phosphate, D-Mannose, and D-Fructose) by a Random Forest algorithm generated an area under the curve (AUC) = 0.766 (95% CI: 0.612-0.896) for ASD prediction.

Conclusions: Despite a high and increasing prevalence, ASD has no definitive biomarkers or available treatments for its core symptoms. ASD's earliest developmental antecedents remain unclear. We find that fetal plasma metabolomics differ with child ASD status, in particular invoking altered carbohydrate metabolism. While prior clinical and preclinical work has linked carbohydrate metabolism to ASD, no prior fetal studies have reported these disruptions in neonates or fetuses who go on to be diagnosed with ASD. Future work will investigate concordance with maternal metabolomics to determine maternal-fetal mechanisms.

Background: Poor episodic autobiographical future thinking has recently been reported in 22q11.2 carriers. However, whether these impairments are due to poor language skills or indicate a true episodic autobiographical memory deficit remains unclear. Language impairments are the hallmark of the neuropsychological profile of young children with 22q11DS, but language outcomes in adolescence and young adulthood, especially high-level linguistic skills such as narrative, remain largely unexplored. The aims of this study are first to precisely characterize the narrative abilities of a group of adolescents and young adults with a 22q11DS and normal verbal intellectual functioning, in comparison to a control group. Second, to assess their (past) autobiographical episodic memory and their future episodic thinking abilities. Third, to examine the relationship between linguistic and autobiographical memory skills.

Methods: Fifteen adolescents and young adults with 22q11DS were compared with 15 age- and sex-matched controls. Narrative ability was assessed with a storytelling task and included microstructural, macrostructural, and pragmatic linguistic measures. Episodic autobiographical memory was assessed using a paradigm involving recall of past personal memories and future thinking conditions.

Results: Adolescents and young adults with 22q11DS still struggled with high-level language skills such as storytelling tasks, and all linguistic levels were impaired, i.e., the microstructural, macrostructural, and pragmatic components of narrative. Second, 22q11DS carriers showed poor episodic autobiographical recall of their personal memories and reduced access to sensory details (visual, auditory…) compared to controls. Their poor autobiographical episodic memory skills were independent of language impairment, and there were no effects of age or intellectual level on their autobiographical (past) memories recollection. On the other hand, age and verbal intellectual functioning significantly contributed to their ability to produce episodic narratives in the future thinking condition, suggesting that the future thinking task relies on more complex and intricate factors than pure episodic memory ability.

Conclusions: Verbal narrative impairments did not account for poor recall of personal memories, suggesting dysfunctional episodic memory networks between hippocampi and posterior cortical areas in 22q11DS, where neuroanatomical and neurofunctional alterations have indeed been reported.

Background: Sensory reactivity differences are common across neurodevelopmental disorders (NDDs), however very few studies specifically examine tactile or pain responses in children with NNDs, especially those with communication challenges. The current study aimed to (a) replicate the feasibility of a modified quantitative sensory test (mQST) with a sample of children with NDDs, (b) assess validity evidence based on behavioral reactivity during mQST application and the corresponding behavioral measurement coding system, and (c) explore group differences in behavioral reactivity to mQST stimuli by demographic (sex), clinical (autism status), and behavioral pathology (self-injury) variables.

Methods: The mQST protocol was implemented and blindly coded across 47 participants aged 2-12 years (M age = 6.7 years, SD = 2.6; 70% male) with NDDs. Feasibility was measured by completion of the mQST protocol and interobserver agreement. Validity was assessed using paired t-tests investigating differences between behavioral reactivity to active stimuli compared to a sham trial. Boxplots were used to visually explore differences in group characteristics (sex, autism status, and self-injurious behavior), with two-sample t-tests used to further characterize differences in SIB group characteristics in behavioral reactivity to mQST stimuli.

Results: The mQST provided codable data across 91% of stimuli applications with high IOA (84.7% [76.7-95%]). Behavioral reactivity was significantly higher for active vs. sham stimuli. Children reported to engage in self-injurious behavior showed significantly more reactivity to the second half of the repeated von Frey stimulus application compared to children without caregiver-reported self-injurious behavior (M = 6.14, SD = 3.44), t (40)= -2.247, p =.04).

Conclusion: The mQST is a feasible approach to investigate tactile reactivity in children with NDDs and complex communication needs. The mQST may be useful in understanding sensory variables in relation to developmental and behavioral outcomes such as self-injurious behavior.

Background: The Autonomic Nervous System (ANS) regulates 'automatic' functions such as heart rate, and alterations may have significant impacts on health outcomes. Cardiovascular measures of autonomic function such as heart rate variability are of interest as biological markers in autism spectrum disorder (ASD). The interplay between the ANS and physical health establishes a need to examine cardiovascular autonomic functioning in youth with and without ASD over development. The current study aimed to identify change in autonomic function and balance across the parasympathetic and sympathetic branches over time as a function of diagnosis, age, pubertal development, and physical health status.

Methods: The study included 244 ASD (N = 140) or neurotypical (NT) (N = 104) youth, ages 10 to 13 years at enrollment and followed over four years. Resting state autonomic functioning was measured using respiratory sinus arrhythmia (RSA; parasympathetic) and pre-ejection period (PEP; sympathetic). Autonomic balance and regulation were also examined as outcomes. Linear mixed models tested between- and within-group differences in the primary autonomic outcomes as well as the influence of pubertal development, body weight, and medication use.

Results: Baseline models showed diagnostic differences, with lower parasympathetic regulation, in youth with ASD, but no differences were observed for the other three outcomes. Adding body mass index (BMI) percentile and medication use removed the statistically significant diagnostic effect, while both variables were significantly related to lower RSA and overall autonomic regulation. Parasympathetic function (RSA) was stable over age and pubertal stage, while a notable decrease in sympathetic control (increased PEP) was found for age and pubertal stage. BMI percentile at enrollment significantly predicted autonomic function, while change in BMI over time did not.

Conclusions: Minimal research to date has explored physical health (e.g., BMI) and autonomic outcomes in ASD. The current study observed few group differences yet demonstrates important effects of physical health on ANS function in both ASD and neurotypical youth. Findings further emphasize a need to focus on individual traits such as BMI and medication use to elucidate the extent to which autonomic differences are related to health status, irrespective of diagnostic category, across the lifespan.

Background: Sensory over-responsivity (SOR) is a heightened reaction to environmental stimuli commonly seen in autism spectrum disorder (ASD) which impacts daily functioning. Parent-reported and observed behavioral assessments are used to study SOR, but show limited associations with each other, possibly because they measure different aspects of SOR or because children inhibit their responses during standardized assessments. Physiological measures provide an objective measure of sensory reactivity, and atypical heart rate (HR) responses to aversive stimuli have been shown to be related to SOR in ASD youth. This study aimed to compare how reported and observed measures of SOR predict HR and to examine if the level of reported behavioral inhibition in ASD youth affects how observed SOR behaviors correlate with physiological reactivity.

Methods: Participants were 54 typically developing (TD) and 83 ASD youth, ages 8-17, who completed a standardized behavioral assessment of SOR while electrocardiogram recordings were collected. Participants' parents also reported on their child's SOR symptoms and behavioral inhibition.

Results: ASD youth showed lower inter-beat-intervals (IBI; higher HR) across all auditory and tactile stimuli. For ASD youth, parent-reported SOR interacted with observed SOR to predict HR changes across the stimulation periods, indicating that ASD participants whose parents reported they had high SOR in their daily life, and showed high observed SOR in the lab assessment, exhibited reduced HR deceleration (orienting) after the onset of the stimulus and subsequent increased HR acceleration. Finally, we found that ASD participants who had lower parent-reported behavioral inhibition had a stronger correlation between observed SOR behavior and atypical HR responses.

Conclusions: Results support prior findings that increased HR responses to aversive stimuli is related to both ASD and SOR. Furthermore, observed and parent-reported SOR interacted to predict HR, suggesting that a multi-method approach may best capture the extent of SOR for an individual. However, observed SOR measures may be most accurate for ASD youth who are less likely to inhibit their behavioral responses. This study illustrates the importance of integrating multiple measures of sensory reactivity to identify SOR. HR measures of sensory reactivity have the potential to serve as a biomarker of SOR across a diverse range of individuals.

Background: Neurofibromatosis Type 1 is a genetic condition diagnosed in infancy that substantially increases the likelihood of a child experiencing cognitive and developmental difficulties, including Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). Children with NF1 show clear differences in attention, but whether these differences emerge in early development and how they relate to broader difficulties with cognitive and learning skills is unclear. To address this question requires longitudinal prospective studies from infancy, where the relation between domains of visual attention (including exogenous and endogenous shifting) and cognitive development can be mapped over time.

Methods: We report data from 28 infants with NF1 tested longitudinally at 5, 10 and 14 months compared to cohorts of 29 typical likelihood infants (with no history of NF1 or ASD and/or ADHD), and 123 infants with a family history of ASD and/or ADHD. We used an eyetracking battery to measure both exogenous and endogenous control of visual attention.

Results: Infants with NF1 demonstrated intact social orienting, but slower development of endogenous visual foraging. This slower development presented as prolonged engagement with a salient stimulus in a static display relative to typically developing infants. In terms of exogenous attention shifting, NF1 infants showed faster saccadic reaction times than typical likelihood infants. However, the NF1 group demonstrated a slower developmental improvement from 5 to 14 months of age. Individual differences in foraging and saccade times were concurrently related to visual reception abilities within the full infant cohort (NF1, typical likelihood and those with a family history of ASD/ADHD).

Conclusions: Our results provide preliminary evidence that alterations in saccadic reaction time and visual foraging may contribute to learning difficulties in infants with NF1.