Discriminant value of repetitive behaviors in families with autism spectrum disorder and obsessional compulsive disorder probands

International audienceRepetitive behaviors (RB) represent a wide spectrum of symptoms ranging from sensory-motor stereotypies to complex cognitive rituals, frequently dichotomized as low- and high-order sub-groups of symptoms. Even though these subgroups are considered as phenomenologically distinct in autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD), brain imaging and genetic studies suggest that they have common mechanisms and pathways. This discrepancy may be explained by the frequent intellectual disability reported in ASD, which blurs the RB expressivity. Given the high heritability of RB, that is, the diversity of symptoms expressed in the relatives are dependent on those expressed in their probands, we hypothesize that if RB expressed in ASD or OCD are two distinct entities, then the RB expressed in relatives will also reflect these two dimensions. We thus conduct a linear discriminant analysis on RB in both the relatives of probands with ASD and OCD and subjects from the general population (n = 1023). The discriminant analysis results in a classification of 81.1% of the controls (p < 10-4 ), but poorly differentiated the ASD and OCD relatives (≈46%). The stepwise analysis reveals that five symptoms attributed to high-order RB and two related to low-order RB (including hypersensitivity) are the most discriminant. Our results support the idea that the difference of RB patterns in the relatives is mild compared with the distribution of symptoms in controls. Our findings reinforce the evidence of a common biological pattern of RB both in ASD and OCD but with minor differences, specific to each of these two neuro-developmental disorders. LAY SUMMARY: Repetitive behaviors (RB), a key symptom in the classification of both OCD and ASD, are phenomenologically considered as distinct in the two disorders, which is in contrast with brain imaging studies describing a common neural circuit. Intellectual disability, which is frequently associated with ASD, makes RB in ASD more difficult to understand as it affects the expression of the RB symptoms. To avoid this bias, we propose to consider the familial aggregation in ASD and OCD by exploring RB in the first-degree relatives of ASD and OCD. Our results highlight the existence of RB expressed in relatives compared to the general population, with a common pattern of symptoms in relatives of both ASD and OCD but also minor differences, specific to each of these two neuro-developmental disorders

Persistence of dysfunctional natural killer cells in adults with high-functioning autism spectrum disorders: stigma/consequence of unresolved early infectious events?

International audienceBackground: Autism spectrum disorders (ASD) are characterized by abnormal neurodevelopment, genetic, and environmental risk factors, as well as immune dysfunctions. Several lines of evidence suggest alterations in innate immune responses in children with ASD. To address this question in adults with high-functioning ASD (hf-ASD), we sought to investigate the role of natural killer (NK) cells in the persistence of ASD.Methods: NK cells from 35 adults with hf-ASD were compared to that of 35 healthy controls (HC), selected for theabsence of any immune dysfunctions, at different time-points, and over a 2-year follow-up period for four patients.The phenotype and polyfunctional capacities of NK cells were explored according to infectious stigma and clinicalparameters (IQ, social, and communication scores).Results: As compared to HC, NK cells from patients with hf-ASD showed a high level of cell activation (p < 0.0001),spontaneous degranulation (p < 0.0001), and interferon-gamma production (p = 0.0004), whereas they were exhausted after in vitro stimulations (p = 0.0006). These data yielded a specific HLA-DR+KIR2DL1+NKG2C+ NK-cell signature. Significant overexpression of NKG2C in hf-ASD patients (p = 0.0005), indicative of viral infections, was inversely correlated with the NKp46 receptor level (r = − 0.67; p < 0.0001), regardless of the IgG status of tested pathogens. Multivariate linear regression analysis also revealed that expression of the late-activating HLA-DR marker was both associated with structural language (r = 0.48; p = 0.007) and social awareness (r = 0.60; p = 0.0007) scores in adult patients with hf-ASD, while KIR2DL1 expression correlated with IQ scores (p = 0.0083).Conclusions: This study demonstrates that adults with hf-ASD have specific NK-cell profile. Presence of NKG2Coverexpression together with high-level activation of NK cells suggest an association with underlying pathogens, ahypothesis warranting further exploration in future studie

Increased risk of ADHD in families with ASD

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Tackling hypo and hyper sensory processing heterogeneity in autism: From clinical stratification to genetic pathways

International audienceAs an integral part of autism spectrum symptoms, sensory processing issues including both hypo and hyper sensory sensitivities. These sensory specificities may result from an excitation/inhibition imbalance with a poorly understood of their level of convergence with genetic alterations in GABA-ergic and glutamatergic pathways. In our study, we aimed to characterize the hypo/hyper-sensory profile among autistic individuals. We then explored its link with the burden of deleterious mutations in a subset of individuals with available whole-genome sequencing data. To characterize the hypo/hyper-sensory profile, the differential Short Sensory Profile (dSSP) was defined as a normalized and centralized hypo/hypersensitivity ratio from the Short Sensory Profile (SSP). Including 1136 participants (533 autistic individuals, 210 first-degree relatives, and 267 controls) from two independent study samples (PARIS and LEAP), we observed a statistically significant dSSP mean difference between autistic individuals and controls, driven mostly by a high dSSP variability, with an intermediated profile represented by relatives. Our genetic analysis tended to associate the dSSP and the hyposensitivity with mutations of the GABAergic pathway. The major limitation was the dSSP difficulty to discriminate subjects with a similar quantum of hypo- and hyper-sensory symptoms to those with no such symptoms, resulting both in a similar ratio score of 0. However, the dSSP could be a relevant clinical score, and combined with additional sensory descriptions, genetics and endophenotypic substrates, will improve the exploration of the underlying neurobiological mechanisms of sensory processing differences in autism spectrum

Exploring the multidimensional nature of repetitive and restricted behaviors and interests (RRBI) in autism: neuroanatomical correlates and clinical implications

International audienceBackgroundRepetitive and restricted behaviors and interests (RRBI) are core symptoms of autism with a complex entity and are commonly categorized into ‘motor-driven’ and ‘cognitively driven’. RRBI symptomatology depends on the individual’s clinical environment limiting the understanding of RRBI physiology, particularly their associated neuroanatomical structures. The complex RRBI heterogeneity needs to explore the whole RRBI spectrum by integrating the clinical context [autistic individuals, their relatives and typical developing (TD) individuals]. We hypothesized that different RRBI dimensions would emerge by exploring the whole spectrum of RRBI and that these dimensions are associated with neuroanatomical signatures—involving cortical and subcortical areas.MethodA sample of 792 individuals composed of 267 autistic subjects, their 370 first-degree relatives and 155 TD individuals was enrolled in the study. We assessed the whole patterns of RRBI in each individual by using the Repetitive Behavior Scale-Revised and the Yale-Brown Obsessive Compulsive Scale. We estimated brain volumes using MRI scanner for a subsample of the subjects (n = 152, 42 ASD, 89 relatives and 13 TD). We first investigated the dimensionality of RRBI by performing a principal component analysis on all items of these scales and included all the sampling population. We then explored the relationship between RRBI-derived factors with brain volumes using linear regression models.ResultsWe identified 3 main factors (with 30.3% of the RRBI cumulative variance): Factor 1 (FA1, 12.7%) reflected mainly the ‘motor-driven’ RRBI symptoms; Factor 2 and 3 (respectively, 8.8% and 7.9%) gathered mainly Y-BOCS related items and represented the ‘cognitively driven’ RRBI symptoms. These three factors were significantly associated with the right/left putamen volumes but with opposite effects: FA1 was negatively associated with an increased volume of the right/left putamen conversely to FA2 and FA3 (all uncorrected p < 0.05). FA1 was negatively associated with the left amygdala (uncorrected p < 0.05), and FA2 was positively associated with the left parietal structure (uncorrected p = 0.001).ConclusionOur results suggested 3 coherent RRBI dimensions involving the putamen commonly and other structures according to the RRBI dimension. The exploration of the putamen’s integrative role in RSBI needs to be strengthened in further studies

Tackling hypo and hyper sensory processing heterogeneity in autism: From clinical stratification to genetic pathways

International audienceAs an integral part of autism spectrum symptoms, sensory processing issues including both hypo and hyper sensory sensitivities. These sensory specificities may result from an excitation/inhibition imbalance with a poorly understood of their level of convergence with genetic alterations in GABA-ergic and glutamatergic pathways. In our study, we aimed to characterize the hypo/hyper-sensory profile among autistic individuals. We then explored its link with the burden of deleterious mutations in a subset of individuals with available whole-genome sequencing data. To characterize the hypo/hyper-sensory profile, the differential Short Sensory Profile (dSSP) was defined as a normalized and centralized hypo/hypersensitivity ratio from the Short Sensory Profile (SSP). Including 1136 participants (533 autistic individuals, 210 first-degree relatives, and 267 controls) from two independent study samples (PARIS and LEAP), we observed a statistically significant dSSP mean difference between autistic individuals and controls, driven mostly by a high dSSP variability, with an intermediated profile represented by relatives. Our genetic analysis tended to associate the dSSP and the hyposensitivity with mutations of the GABAergic pathway. The major limitation was the dSSP difficulty to discriminate subjects with a similar quantum of hypo- and hyper-sensory symptoms to those with no such symptoms, resulting both in a similar ratio score of 0. However, the dSSP could be a relevant clinical score, and combined with additional sensory descriptions, genetics and endophenotypic substrates, will improve the exploration of the underlying neurobiological mechanisms of sensory processing differences in autism spectrum

Preserved Navigation abilities and Spatio-Temporal Memory in individuals with Autism Spectrum Disorder

International audienceCerebellar abnormalities have been reported in autism spectrum disorder (ASD). Beyond its role in hallmark features of ASD, the cerebellum and its connectivity with forebrain structures also play a role in navigation. However, the current understanding of navigation abilities in ASD is equivocal, as is the impact of the disorder on the functional anatomy of the cerebellum. In the present study, we investigated the navigation behavior of a population of ASD and typically developing (TD) adults related to their brain anatomy as assessed by structural and functional MRI at rest. We used the Starmaze task, which permits assessing and distinguishing two complex navigation behaviors, one based on allocentric and the other on egocentric learning of a route with multiple decision points. Compared to TD controls, individuals with ASD showed similar exploration, learning, and strategy performance and preference. In addition, there was no difference in the structural or functional anatomy of the cerebellar circuits involved in navigation between the two groups. The findings of our work suggest that navigation abilities, spatio-temporal memory, and their underlying circuits are preserved in individuals with ASD

Preserved Navigation abilities and Spatio-Temporal Memory in individuals with Autism Spectrum Disorder

International audienceCerebellar abnormalities have been reported in autism spectrum disorder (ASD). Beyond its role in hallmark features of ASD, the cerebellum and its connectivity with forebrain structures also play a role in navigation. However, the current understanding of navigation abilities in ASD is equivocal, as is the impact of the disorder on the functional anatomy of the cerebellum. In the present study, we investigated the navigation behavior of a population of ASD and typically developing (TD) adults related to their brain anatomy as assessed by structural and functional MRI at rest. We used the Starmaze task, which permits assessing and distinguishing two complex navigation behaviors, one based on allocentric and the other on egocentric learning of a route with multiple decision points. Compared to TD controls, individuals with ASD showed similar exploration, learning, and strategy performance and preference. In addition, there was no difference in the structural or functional anatomy of the cerebellar circuits involved in navigation between the two groups. The findings of our work suggest that navigation abilities, spatio-temporal memory, and their underlying circuits are preserved in individuals with ASD

Natural history of Type 2 and 3 spinal muscular atrophy: 2-year NatHis-SMA study.

OBJECTIVE: To characterize the natural history of spinal muscular atrophy (SMA) over 24 months using innovative measures such as wearable devices, and to provide evidence for the sensitivity of these measures to determine their suitability as endpoints in clinical trials. METHODS: Patients with Type 2 and 3 SMA (N = 81) with varied functional abilities (sitters, nonsitters, nonambulant, and ambulant) who were not receiving disease-modifying treatment were assessed over 24 months: motor function (Motor Function Measure [MFM]), upper limb strength (MyoGrip, MyoPinch), upper limb activity (ActiMyo(®) ), quantitative magnetic resonance imaging (fat fraction [FF(T2) ] mapping and contractile cross-sectional area [C-CSA]), pulmonary function (forced vital capacity [FVC], peak cough flow, maximum expiratory pressure, maximum inspiratory pressure, and sniff nasal inspiratory pressure), and survival of motor neuron (SMN) protein levels. RESULTS: MFM32 scores declined significantly over 24 months, but not 12 months. Changes in upper limb activity could be detected over 6 months and continued to decrease significantly over 12 months, but not 24 months. Upper limb strength decreased significantly over 12 and 24 months. FVC declined significantly over 12 months, but not 24 months. FF(T2) increased over 12 and 24 months, although not with statistical significance. A significant increase in C-CSA was observed at 12 but not 24 months. Blood SMN protein levels were stable over 12 and 24 months. INTERPRETATION: These data demonstrate that the MFM32, MyoGrip, MyoPinch, and ActiMyo(®) enable the detection of a significant decline in patients with Type 2 and 3 SMA over 12 or 24 months

Patients with autism spectrum disorders display reproducible functional connectivity alterations

Despite the high clinical burden, little is known about pathophysiology underlying autism spectrum disorder(ASD). Recent resting-state functional magnetic resonance imaging (rs-fMRI) studies have found atypical synchro-nization of brain activity in ASD. However, no consensus has been reached on the nature and clinical relevance ofthese alterations. Here, we addressed these questions in four large ASD cohorts. Using rs-fMRI, we identified func-tional connectivity alterations associated with ASD. We tested for associations of these imaging phenotypes withclinical and demographic factors such as age, sex, medication status, and clinical symptom severity. Our resultsshowed reproducible patterns of ASD-associated functional hyper- and hypoconnectivity. Hypoconnectivity wasprimarily restricted to sensory-motor regions, whereas hyperconnectivity hubs were predominately located inprefrontal and parietal cortices. Shifts in cortico-cortical between-network connectivity from outside to withinthe identified regions were shown to be a key driver of these abnormalities. This reproducible pathophysiologicalphenotype was partially associated with core ASD symptoms related to communication and daily living skills andwas not affected by age, sex, or medication status. Although the large effect sizes in standardized cohorts areencouraging with respect to potential application as a treatment and for patient stratification, the moderate linkto clinical symptoms and the large overlap with healthy controls currently limit the usability of identified altera-tions as diagnostic or efficacy readout