White matter abnormalities in 22q11.2 deletion syndrome patients showing cognitive decline

Nuninga, Jasper O.; Bohlken, Marc M.; Koops, Sanne; Fiksinski, Ania; Mandl, René C.W.; Breetvelt, Elemi J.; Duijff, Sasja N.; Kahn, René S.; Sommer, Iris E.; Vorstman, Jacob

doi:10.1017/s0033291717003142

Cited by 13 publications

(9 citation statements)

References 65 publications

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“…These microstructural changes were not seen in those without cognitive decline. 50 Microstructural white matter changes in individuals with 22q11.2 deletion syndrome were associated with lower axonal integrity, whereas in individuals without deletion at ultra-high risk for psychosis, such changes were suggestive of abnormal myelination. 49 Together, these data provide strong evidence that the 22q11.2 deletion has profound effects on brain structure in children and adults.…”

Section: Imaging Studiesmentioning

confidence: 98%

“…Some diffusion tensor imaging studies that have been done in individuals with 22q11.2 deletion syndrome found evidence for altered myelin and axon integrity in multiple tracts, some of which have been implicated in neuropsychiatric disorders. [48][49][50] Studies using rs-fMRI reported a global decrease in functional connectivity. 51,52 Preliminary results from the ENIGMA-22q working group, who collected the largest data set on 22q11.2 deletion syndrome to date, suggest lower diffusivity in individuals with 22q11.2 deletion syndrome than in healthy controls, possibly because of smaller axonal diameter.…”

Section: Imaging Studiesmentioning

confidence: 99%

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Neurobiological perspective of 22q11.2 deletion syndrome

Zinkstok

Boot

Bassett

et al. 2019

The Lancet Psychiatry

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22q11.2 deletion syndrome is characterised by a well defined microdeletion that is associated with a high risk of neuropsychiatric disorders, including intellectual disability, schizophrenia, attentiondeficit hyperactivity disorder, autism spectrum disorder, anxiety disorders, seizures and epilepsy, and early-onset Parkinson's disease. Preclinical and clinical data reveal substantial variability of the neuropsychiatric phenotype despite the shared underlying deletion in this genetic model. Factors that might explain this variability include genetic background effects, additional rare pathogenic variants, and potential regulatory functions of some genes in the 22q11.2 deletion region. These factors might also be relevant to the pathophysiology of these neuropsychiatric disorders in the general population. We review studies that might provide insight into pathophysiological mechanisms underlying the expression of neuropsychiatric disorders in 22q11.2 deletion syndrome, and potential implications for these common disorders in the general (non-deleted) population. The recurrent hemizygous 22q11.2 deletion, associated with 22q11.2 deletion syndrome, has attracted attention as a genetic model for common neuropsychiatric disorders because of its association with substantially increased risk of such disorders. 1 Studying such a model has many advantages. First, 22q11.2 deletion has been genetically well characterised. 2 Second, most genes present in the region typically deleted at the 22q11.2 locus are expressed in the brain. 3-5 Third, genetic diagnosis might be made early in life, long before recognisable neuropsychiatric disorders have emerged. Thus, this genetic condition offers a unique opportunity for early intervention, and monitoring individuals with 22q11.2 deletion syndrome throughout life could provide important information on factors contributing to disease risk and protection. Despite the commonly deleted region being shared by about 90% of individuals with 22q11.2 deletion syndrome, neuropsychiatric outcomes are highly variable between individuals and across the lifespan. A clear link remains to be established between genotype and phenotype. 3,5 In this Review, we summarise preclinical and clinical studies investigating biological mechanisms in 22q11.2 deletion syndrome, with a focus on those that might provide insight into mechanisms underlying neuropsychiatric disorders in 22q11.2 deletion syndrome and in the general population. Neuropsychiatric phenotype in 22q11.2 deletion syndrome Many psychiatrists will encounter a patient with 22q11.2 deletion syndrome during their career because of the recurrent nature of the associated deletion and high prevalence of psychopathology in this population. However, such an encounter might often occur unknowingly because of ongoing under-recognition of the syndrome. Schizophrenia and related psychotic disorders in 22q11.2 deletion syndrome have been the most widely studied. Lifetime prevalence of schizophrenia in 22q11.2 deletion syndrome is estimated to be about 25%. 1...

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Section: Imaging Studiesmentioning

confidence: 98%

Section: Imaging Studiesmentioning

confidence: 99%

Neurobiological perspective of 22q11.2 deletion syndrome

Zinkstok

Boot

Bassett

et al. 2019

The Lancet Psychiatry

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“…Importantly, multivariate modeling revealed very consistent and widespread patterns of brain alterations, in line with recent evidence indicating that white matter alterations of first-episode and chronic stages of schizophrenia are very diffuse and affect the brain on a global level 9,38,39 . While studies have also demonstrated an involvement of white matter alterations in preclinical high-risk stages of psychosis in the general population 8 and in patients with 22q11.2DS presenting psychotic symptoms 19,[34][35][36] or a cognitive decline 37 , results were heterogeneous and prevented the identification of a reliable biomarker, likely because of the variability and small magnitude of premorbid anomalies. Current evidence suggests that, on the other hand, a multivariate assessment of brain structure can effectively identify early, more subtle patterns of alterations.…”

Section: Discussionmentioning

confidence: 99%

“…Apart from univariate studies that investigated white matter microstructure in patients with 22q11.2DS presenting psychotic symptoms 19,[34][35][36] or a cognitive decline 37 , the impact of the above-mentioned risk factors on white matter maturation remains largely unknown. Evidence increasingly shows that white matter alterations associated with psychosis are widespread and subtle 38,39 , suggesting that multivariate approaches may be better suited to capture the complex nature of brain alterations related to premorbid stages.…”

Section: Introductionmentioning

confidence: 99%

Identifying neurodevelopmental anomalies of white matter microstructure associated with high risk for psychosis in 22q11.2DS

et al. 2020

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Disruptions of white matter microstructure have been widely reported in schizophrenia. However, the emergence of these alterations during preclinical stages remains poorly understood. 22q11.2 Deletion Syndrome (22q11.2DS) represents a unique model to study the interplay of different risk factors that may impact neurodevelopment in premorbid psychosis. To identify the impact of genetic predisposition for psychosis on white matter development, we acquired longitudinal MRI data in 201 individuals (22q11.2DS = 101; controls = 100) aged 5–35 years with 1–3 time points and reconstructed 18 white matter tracts using TRACULA. Mixed model regression was used to characterize developmental trajectories of four diffusion measures—fractional anisotropy (FA), axial (AD), radial (RD), and mean diffusivity (MD) in each tract. To disentangle the impact of additional environmental and developmental risk factors on white matter maturation, we used a multivariate approach (partial least squares (PLS) correlation) in a subset of 39 individuals with 22q11.2DS. Results revealed no divergent white matter developmental trajectories in patients with 22q11.2DS compared to controls. However, 22q11.2DS showed consistently increased FA and reduced AD, RD, and MD in most white matter tracts. PLS correlation further revealed a significant white matter-clinical risk factors relationship. These results indicate that while age-related changes are preserved in 22q11.2DS, white matter microstructure is widely disrupted, suggesting that genetic high risk for psychosis involves early occurring neurodevelopmental insults. In addition, multivariate modeling showed that clinical risk factors further impact white matter development. Together, these findings suggest that genetic, developmental, and environmental risk factors may play a cumulative role in altering normative white matter development during premorbid stages of psychosis.

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“…The presence of supernumerary neurons within the white matter of the subcortical region is a commonly observed anomaly of ASD. Additionally, white matter integrity as measured by fractional anisotropy seems to be altered in 22q11.2 deletion patients [97] and 16p11.2 deletion is also associated with decreased myelination in the subcortical region of the brain [98]. A recent animal study of Cyfip1 function in the corpus callosum showed that its deletion decreases the myelinating potential of oligodendrocytes [99].…”

Section: White Matter Alterationsmentioning

confidence: 99%

Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD

et al. 2020

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Patients diagnosed with chromosome microdeletions or duplications, known as copy number variants (CNVs), present a unique opportunity to investigate the relationship between patient genotype and cell phenotype. CNVs have high genetic penetrance and give a good correlation between gene locus and patient clinical phenotype. This is especially effective for the study of patients with neurodevelopmental disorders (NDD), including those falling within the autism spectrum disorders (ASD). A key question is whether this correlation between genetics and clinical presentation at the level of the patient can be translated to the cell phenotypes arising from the neurodevelopment of patient induced pluripotent stem cells (iPSCs). Here, we examine how iPSCs derived from ASD patients with an associated CNV inform our understanding of the genetic and biological mechanisms underlying the aetiology of ASD. We consider selection of genetically characterised patient iPSCs; use of appropriate control lines; aspects of human neurocellular biology that can capture in vitro the patient clinical phenotype; and current limitations of patient iPSC-based studies. Finally, we consider how future research may be enhanced to maximise the utility of CNV patients for research of pathological mechanisms or therapeutic targets.

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White matter abnormalities in 22q11.2 deletion syndrome patients showing cognitive decline

Cited by 13 publications

References 65 publications

Neurobiological perspective of 22q11.2 deletion syndrome

Neurobiological perspective of 22q11.2 deletion syndrome

Identifying neurodevelopmental anomalies of white matter microstructure associated with high risk for psychosis in 22q11.2DS

Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD

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