| 1. |
- Austin, Christine, et al.
(author)
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Elemental Dynamics in Hair Accurately Predict Future Autism Spectrum Disorder Diagnosis : An International Multi-Center Study
- 2022
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In: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 11:23
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Journal article (peer-reviewed)abstract
- Autism spectrum disorder (ASD) is a neurodevelopmental condition diagnosed in approximately 2% of children. Reliance on the emergence of clinically observable behavioral patterns only delays the mean age of diagnosis to approximately 4 years. However, neural pathways critical to language and social functions develop during infancy, and current diagnostic protocols miss the age when therapy would be most effective. We developed non-invasive ASD biomarkers using mass spectrometry analyses of elemental metabolism in single hair strands, coupled with machine learning. We undertook a national prospective study in Japan, where hair samples were collected at 1 month and clinical diagnosis was undertaken at 4 years. Next, we analyzed a national sample of Swedish twins and, in our third study, participants from a specialist ASD center in the US. In a blinded analysis, a predictive algorithm detected ASD risk as early as 1 month with 96.4% sensitivity, 75.4% specificity, and 81.4% accuracy (n = 486; 175 cases). These findings emphasize that the dynamics in elemental metabolism are systemically dysregulated in autism, and these signatures can be detected and leveraged in hair samples to predict the emergence of ASD as early as 1 month of age.
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| 2. |
- Curtin, Paul, et al.
(author)
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Associations between Elemental Metabolic Dynamics and Default Mode Network Functional Connectivity Are Altered in Autism.
- 2023
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In: Journal of clinical medicine. - : MDPI. - 2077-0383. ; 12:3
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Journal article (peer-reviewed)abstract
- Autism is a neurodevelopmental condition associated with atypical social communication, cognitive, and sensory faculties. Recent advances in exposure biology suggest that biomarkers of elemental uptake and metabolism measured in hair samples can yield an effective signal predictive of autism diagnosis. Here, we investigated if elemental biomarkers in hair were associated with functional connectivity in regions of the default mode network (DMN) previously linked to autism. In a study sample which included twin pairs with concordant and discordant diagnoses for autism, our analysis of hair samples and neuroimaging data supported two general findings. First, independent of autism diagnosis, we found a broad pattern of association between elemental biomarkers and functional connectivity in the DMN, which primarily involved dynamics in zinc metabolism. Second, we found that associations between the DMN and elemental biomarkers, particularly involving phosphorus, calcium, manganese, and magnesium, differed significantly in autistic participants from control participants. In sum, these findings suggest that functional dynamics in elemental metabolism relate broadly to persistent patterns of functional connectivity in the DMN, and that these associations are altered in the emergence of autism.
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| 3. |
- Dumitriu, Dani, et al.
(author)
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Deciduous tooth biomarkers reveal atypical fetal inflammatory regulation in autism spectrum disorder.
- 2023
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In: iScience. - : Cell Press. - 2589-0042. ; 26:3
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Journal article (peer-reviewed)abstract
- Atypical regulation of inflammation has been proposed in the etiology of autism spectrum disorder (ASD); however, measuring the temporal profile of fetal inflammation associated with future ASD diagnosis has not been possible. Here, we present a method to generate approximately daily profiles of prenatal and early childhood inflammation as measured by developmentally archived C-reactive protein (CRP) in incremental layers of deciduous tooth dentin. In our discovery population, a group of Swedish twins, we found heightened inflammation in the third trimester in children with future ASD diagnosis relative to controls (n = 66; 14 ASD cases; critical window: -90 to -50 days before birth). In our replication study, in the US, we observed a similar increase in CRP in ASD cases during the third trimester (n = 47; 23 ASD cases; -128 to -21 days before birth). Our results indicate that the third trimester is a critical period of atypical fetal inflammatory regulation in ASD.
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| 4. |
- Isaksson, Johan, et al.
(author)
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Nonshared environmental factors in the aetiology of autism and other neurodevelopmental conditions : a monozygotic co-twin control study.
- 2022
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In: Molecular autism. - : Springer Nature. - 2040-2392. ; 13:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: A significant proportion of variation in likelihood of neurodevelopmental conditions (NDCs) has been attributed to nonshared environmental (NSE) factors, although it remains unclear which NSE factors pose specific risks for certain NDCs.METHODS: A monozygotic co-twin design was applied in a sample of 224 twins (mean age = 17.70 years, SD = 6.28) controlling for confounders such as genes and shared environment. Generalized estimating equation models were fitted, using perinatal and postnatal indications of NSEs as exposure, operationalized both as separate risk factors and as cumulative risk loads. Categorical and dimensional operationalizations of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), intellectual disability and other NDCs were used as outcomes.RESULTS: Birth weight discordance was associated with dimensional autism and ADHD for the smaller twin, and medication during infancy was associated with dimensional autism. Among postnatal factors scarlet fever during early childhood was associated with lower IQ. Especially autism was associated with a greater cumulative perinatal or postnatal risk load.LIMITATIONS: When exploring the associations between each condition and specific NSEs the risk of being statistically underpowered increases. Hence, we limit the reported findings on specific indicators of NSEs to trait levels and present descriptive data for categorical NDCs.CONCLUSIONS: The findings support previous research by indicating an association between exposure to perinatal and postnatal risks and subsequent NDCs within twin pairs and suggest that autism may be especially linked to accumulative early environmental risks. The findings are potentially important for developmental outcomes prognoses and may inform targeted prevention and early interventions.
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| 5. |
- Lundin Remnélius, Karl, et al.
(author)
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Eating Problems in Autistic Females and Males : A Co-twin Control Study
- 2022
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In: Journal of autism and developmental disorders. - : Springer Nature. - 0162-3257 .- 1573-3432. ; 52:7, s. 3153-3168
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Journal article (peer-reviewed)abstract
- This study investigated the association between autism and self-reported eating problems and the influence of gender on the association, in a sample of adolescent and adult twins (N = 192). Autistic traits and autism diagnosis were associated with both total and specific eating problems, including selective eating and sensory sensitivity during mealtimes. Interaction effects indicated a stronger association between autistic traits and total eating problems in females, as well as more difficulties with eating in social contexts among autistic females. In within-pair analyses, where unmeasured confounders including genes and shared environment are implicitly controlled for, the association was lost within monozygotic pairs, which might further indicate a genetic influence on the relationship between autism and eating problems.
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| 6. |
- Lundin Remnélius, Karl
(author)
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Female autism phenotypes : sex/gender differences in functioning, camouflaging, and eating problems
- 2023
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Doctoral thesis (other academic/artistic)abstract
- Background: Autism is a neurodevelopmental condition defined by challenges in social interaction and communication and presence of repetitive patterns in behavior, interests, and activities alongside sensory processing alterations (RRBI). While a long-standing tenet of autism is a male predominance of the condition, recent research evidence indicate that autistic females are diagnosed late or even missed, limiting timely access to support, and potentially increasing the risk of mental health problems and reduced quality of life (QoL). Evidence also suggests elevated risks of other detrimental outcomes among autistic females, including suicide and internalizing mental health problems, although findings regarding the latter have been inconsistent. Research further characterizing female autism phenotypes and challenges in this group is warranted. Aims: The overarching aim of this thesis was to contribute to deeper insights into female autism phenotypes and associated risk factors for detrimental outcomes, via qualitative exploration of the perception of sex/gender differences in autism among professionals working with autistic people, and via quantitative investigations of eating problems and camouflaging. Methods: An expert survey exploring the perceptions of functional sex/gender differences in autism in a multi-disciplinary and international sample of professionals was conducted including descriptions of sex/gender-related characteristics pertaining to the individual as well as the environment. In addition, the link between dimensional and categorical operationalizations of autism and eating problems was evaluated including sex/gender moderation of the association, in a thoroughly phenotyped twin sample. Furthermore, a psychometric evaluation of a Swedish version of the Camouflaging Autistic Traits Questionnaire (CAT-Q) was performed, allowing further investigation of the construct. Finally, the hypothesized negative causal effect of camouflaging on QoL was tested using a co-twin control design and within-pair analyses controlling for familial confounding. Results: Professionals perceived autism manifestations in females as more difficult to recognize due to overall less salient challenges and increased use of behavioral strategies that camouflage autistic characteristics in this group. The investigation of eating problems indicate that problems such as selective eating and sensory issues in mealtimes are present among autistic adolescents and adults, but the association between autistic traits and overall eating problems was especially pronounced in females. Also, eating with others in social situations arose as a specific difficulty experienced by autistic females. The psychometric evaluation of the Swedish version of the CAT-Q (CAT-Q/SE) yielded partial support for the reliability and validity of the scale and indicated that camouflaging behaviors may decline with increasing age in non-autistic people while remaining at elevated levels among autistic people. Camouflaging was significantly associated with reduced QoL, also when controlling for familial factors within dizygotic (DZ) and monozygotic (MZ) twin pairs, consistent with a causal effect. Conclusions: This thesis found support for sex/gender moderation in areas that are potentially involved in shaping important outcomes among autistic females, including delayed diagnosis, low social participation, and QoL. The findings support that eating problems and camouflaging are prominent in female autism phenotypes and strengthen previous claims of camouflaging strategies having a negative impact on QoL. Addressing eating problems and camouflaging in health care services may facilitate functioning and QoL and could be of relevance among autistic females.
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| 7. |
- Mastropasqua, Francesca, et al.
(author)
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Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis.
- 2023
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In: Biology open. - : The Company of Biologists. - 2046-6390. ; 12:10
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Journal article (peer-reviewed)abstract
- Genetic variants affecting Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) have been identified in several neurodevelopmental disorders (NDDs). HNRNPU is widely expressed in the human brain and shows the highest postnatal expression in the cerebellum. Recent studies have investigated the role of HNRNPU in cerebral cortical development, but the effects of HNRNPU deficiency on cerebellar development remain unknown. Here, we describe the molecular and cellular outcomes of HNRNPU locus deficiency during in vitro neural differentiation of patient-derived and isogenic neuroepithelial stem cells with a hindbrain profile. We demonstrate that HNRNPU deficiency leads to chromatin remodeling of A/B compartments, and transcriptional rewiring, partly by impacting exon inclusion during mRNA processing. Genomic regions affected by the chromatin restructuring and host genes of exon usage differences show a strong enrichment for genes implicated in epilepsies, intellectual disability, and autism. Lastly, we show that at the cellular level HNRNPU downregulation leads to an increased fraction of neural progenitors in the maturing neuronal population. We conclude that the HNRNPU locus is involved in delayed commitment of neural progenitors to differentiate in cell types with hindbrain profile.
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| 8. |
- Neufeld, Janina, et al.
(author)
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A co-twin-control study of altered sensory processing in autism
- 2021
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In: Autism. - : Sage Publications. - 1362-3613 .- 1461-7005. ; 25:5, s. 1422-1432
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Journal article (peer-reviewed)abstract
- Autism spectrum disorder is associated with sensory processing alterations, such as sensory hyper- and hypo-responsiveness. Twin studies are scarce in this field, but they are necessary in order to disentangle the genetic and environmental contributions to this association. Furthermore, it is unclear how different neurodevelopmental/psychiatric conditions contribute to altering sensory processing. We investigated the association between autistic traits/autism spectrum disorder diagnosis and sensory processing alterations in twins (N = 269), using the adult/adolescent sensory profile, which differentiates four sub-domains: Low Registration, Sensation Seeking, Sensory Sensitivity, and Sensation Avoiding. While the associations between autistic traits and Low Registration and Sensation Avoiding persisted within monozygotic (genetically identical) twins, Sensory Sensitivity was only associated with autistic traits within dizygotic twins. In multivariate analyses with different neurodevelopmental/psychiatric diagnoses as predictor variables, autism spectrum disorder and attention deficit hyperactivity disorder were the strongest predictors for two adult/adolescent sensory profile sub-domains each. The results suggest that the association between autistic traits and Sensory Sensitivity is influenced by genetics while non-shared environmental factors influence the associations between autistic traits and Low Registration and Sensation Avoiding. They further indicate that altered sensory processing is not specific to autism spectrum disorder, while autism spectrum disorder is a strong predictor of certain sensory processing alterations, even when controlling for other (comorbid) neurodevelopmental/psychiatric conditions.
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| 9. |
- Neufeld, Janina, et al.
(author)
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The impact of atypical sensory processing on adaptive functioning within and beyond autism : The role of familial factors
- 2021
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In: Autism. - : Sage Publications. - 1362-3613 .- 1461-7005. ; 25:8, s. 2341-2355
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Journal article (peer-reviewed)abstract
- Atypical sensory processing is prevalent across neurodevelopmental conditions and a key diagnostic criterion of autism spectrum disorder. It may have cascading effects on the development of adaptive functions. However, its unique contribution to adaptive functioning and the genetic/environmental influences on this link are unclear. In a clinically enriched twin sample (n = 289, 60 diagnosed with autism spectrum disorder), we investigated the associations between the quadrants of the Adult/Adolescent Sensory Profile (low registration, sensory sensitivity, sensation seeking, and sensation avoiding) and adaptive functioning. Associations were modeled across the cohort accounting for the effects of clinical diagnosis, IQ, sex and age, and within-twin pairs, additionally implicitly adjusting for familial factors. Furthermore, we explored interaction effects between atypical sensory processing and autism spectrum disorder diagnosis. Sensory sensitivity and sensation avoiding were associated with reduced adaptive functioning across individuals, but not within-twin pairs. An interaction effect was found between sensation seeking and autism spectrum disorder diagnosis, showing a negative association between sensation seeking and adaptive functioning only in individuals diagnosed with autism spectrum disorder. The results suggest that atypical sensory processing is associated with reduced adaptive functioning and that familial factors influence this link. In addition, sensation seeking behaviors might interfere with adaptive functioning specifically in individuals with autism spectrum disorder.
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