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Neuroimaging Insight Into Fragile X-Associated Neuropsychiatric Disorders: Literature Review

ABSTRACT: FMR1 premutation is defined by 55–200 CGG repeats in the Fragile X Mental Retardation 1 (FMR1) gene. FMR1 premutation carriers are at risk of developing a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI) in adulthood. In the last years an increasingly board spectrum of clinical manifestations including psychiatric disorders have been described as occurring at a greater frequency among FMR1 premutation carriers. Herein, we reviewed the neuroimaging findings reported in relation with psychiatric symptomatology in adult FMR1 premutation carriers. A structured electronic literature search was conducted on FMR1 premutation and neuroimaging yielding a total of 3,229 articles examined. Of these, 7 articles were analyzed and are included in this review. The results showed that the main radiological findings among adult FMR1 premutation carriers presenting neuropsychiatric disorders were found on the amygdala and hippocampus, being the functional abnormalities more consistent and the volumetric changes more inconsistent among studies. From a molecular perspective, CGG repeat size, FMR1 mRNA and FMRP levels have been investigated in relation with the neuroimaging findings. Based on the published results, FMRP might play a key role in the pathophysiology of the psychiatric symptoms described among FMR1 premutation carriers. However, additional studies including further probes of brain function and a broader scope of psychiatric symptom measurement are required in order to obtain a comprehensive landscape of the neuropsychiatric phenotype associated with the FMR1 premutation.

SUBMITTER: Elias-Mas A

PROVIDER: S-EPMC8554234 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) is an umbrella term for the behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations of TSC. Although TAND affects 90% of individuals with TSC during their lifetime, these manifestations are relatively under-assessed, under-treated and under-researched. We performed a comprehensive scoping review of all TAND research to date (a) to describe the existing TAND research landscape and (b) to identify knowledge gaps to guide future TAND research.MethodsThe study was conducted in accordance with stages outlined within the Arksey and O'Malley scoping review framework. Ten research questions relating to study characteristics, research design and research content of TAND levels and clusters were examined.ResultsOf the 2841 returned searches, 230 articles published between 1987 and 2020 were included (animal studies = 30, case studies = 47, cohort studies = 153), with more than half published since the term TAND was coined in 2012 (118/230; 51%). Cohort studies largely involved children and/or adolescents (63%) as opposed to older adults (16%). Studies were represented across 341 individual research sites from 45 countries, the majority from the USA (89/341; 26%) and the UK (50/341; 15%). Only 48 research sites (14%) were within low-middle income countries (LMICs). Animal studies and case studies were of relatively high/high quality, but cohort studies showed significant variability. Of the 153 cohort studies, only 16 (10%) included interventions. None of these were non-pharmacological, and only 13 employed remote methodologies (e.g. telephone interviews, online surveys). Of all TAND clusters, the autism spectrum disorder-like cluster was the most widely researched (138/230; 60%) and the scholastic cluster the least (53/200; 27%).ConclusionsDespite the recent increase in TAND research, studies that represent participants across the lifespan, LMIC research sites and non-pharmacological interventions were identified as future priorities. The quality of cohort studies requires improvement, to which the use of standardised direct behavioural assessments may contribute. In human studies, the academic level in particular warrants further investigation. Remote technologies could help to address many of the TAND knowledge gaps identified.

Project description:IntroductionCore psychopathy is characterized by grandiosity, callousness, manipulativeness, and lack of remorse, empathy, and guilt. It is often comorbid with conduct disorder and antisocial personality disorder (ASPD). Psychopathy is present in forensic as well as prison and general populations. In recent years, an increasing amount of neuroimaging studies has been conducted in order to elucidate the obscure neurobiological etiology of psychopathy. The studies have yielded heterogenous results, and no consensus has been reached.AimsThis study systematically reviewed and qualitatively summarized functional and structural neuroimaging studies conducted on individuals with psychopathic traits. Furthermore, this study aimed to evaluate whether the findings from different MRI modalities could be reconciled from a neuroanatomical perspective.Materials and methodsAfter the search and auditing processes, 118 neuroimaging studies were included in this systematic literature review. The studies consisted of structural, functional, and diffusion tensor MRI studies.ResultsPsychopathy was associated with numerous neuroanatomical abnormalities. Structurally, gray matter anomalies were seen in frontotemporal, cerebellar, limbic, and paralimbic regions. Associated gray matter volume (GMV) reductions were most pronounced particularly in most of the prefrontal cortex, and temporal gyri including the fusiform gyrus. Also decreased GMV of the amygdalae and hippocampi as well the cingulate and insular cortices were associated with psychopathy, as well as abnormal morphology of the hippocampi, amygdala, and nucleus accumbens. Functionally, psychopathy was associated with dysfunction of the default mode network, which was also linked to poor moral judgment as well as deficient metacognitive and introspective abilities. Second, reduced white matter integrity in the uncinate fasciculus and dorsal cingulum were associated with core psychopathy. Third, emotional detachment was associated with dysfunction of the posterior cerebellum, the human mirror neuron system and the Theory of Mind denoting lack of empathy and persistent failure in integrating affective information into cognition.ConclusionsStructural and functional aberrancies involving the limbic and paralimbic systems including reduced integrity of the uncinate fasciculus appear to be associated with core psychopathic features. Furthermore, this review points towards the idea that ASPD and psychopathy might stem from divergent biological processes.

Project description:OBJECTIVE:Neurodevelopmental disorders presumably involve events that occur during brain development. The authors hypothesized that neuropsychiatric disorders considered to be developmental in etiology are associated with susceptibility genes that are relatively upregulated during fetal life (i.e., differentially expressed). METHOD:The authors investigated the presence of prenatal expression enrichment of susceptibility genes systematically, as composite gene sets associated with six neuropsychiatric disorders in the microarray-based "BrainCloud" dorsolateral prefrontal cortex transcriptome. RESULTS:Using a fetal/postnatal log2-fold change threshold of 0.5, genes associated with syndromic neurodevelopmental disorders (N=31 genes, p=3.37×10-3), intellectual disability (N=88 genes, p=5.53×10-3), and autism spectrum disorder (N=242 genes, p=3.45×10-4) were relatively enriched in prenatal transcript abundance, compared with the overall transcriptome. Genes associated with schizophrenia by genome-wide association studies were not preferentially fetally expressed (N=106 genes, p=0.46), nor were genes associated with schizophrenia by exome sequencing (N=212 genes, p=0.21), but specific genes within copy-number variant regions associated with schizophrenia were relatively enriched in prenatal transcript abundance, and genes associated with schizophrenia by meta-analysis were functionally enriched for some neurodevelopmental processes. In contrast, genes associated with neurodegenerative disorders were significantly underexpressed during fetal life (N=46 genes, p=1.67×10-3). CONCLUSIONS:The authors found evidence for relative prenatal enrichment of putative susceptibility genes for syndromic neurodevelopmental disorders, intellectual disability, and autism spectrum disorder. Future transcriptome-level association studies should evaluate regions other than the dorsolateral prefrontal cortex, at other time points, and incorporate further RNA sequencing analyses.

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Neuroimaging Insight Into Fragile X-Associated Neuropsychiatric Disorders: Literature Review

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