Comparing Fractional Anisotropy in Patients With Childhood-Onset Schizophrenia, Their Healthy Siblings, and Normal Volunteers Through DTI

Moran, Marcel; Luscher, Z.; McAdams, Harrison; Hsu, John; Greenstein, Deanna; Clasen, Liv S.; Ludovici, Katharine; Lloyd, Jonae; Rapoport, Judith L.; Mori, Susumu; Gogtay, Nitin

doi:10.1093/schbul/sbu123

Cited by 22 publications

(20 citation statements)

References 44 publications

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“…Siblings carry increased risk for developing schizophrenia (25,38), and therefore, these findings suggest that the FA and KA factors may be potential endophenotypes associated with genetic or familial liability for schizophrenia. The DTI-FA finding replicates previous reports (39,40), but the findings from DKI and PDI in siblings are unique. The processing-speed deficit in the unaffected siblings of the patients is also nearly fully explained by the DTI and DWI factors, again ruling out antipsychotic medication as a primary cause for the finding.…”

Section: Regression Stepsupporting

confidence: 89%

Diffusion-weighted imaging uncovers likely sources of processing-speed deficits in schizophrenia

Kochunov

Rowland

Fieremans

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Schizophrenia, a devastating psychiatric illness with onset in the late teens to early 20s, is thought to involve disrupted brain connectivity. Functional and structural disconnections of cortical networks may underlie various cognitive deficits, including a substantial reduction in the speed of information processing in schizophrenia patients compared with controls. Myelinated white matter supports the speed of electrical signal transmission in the brain. To examine possible neuroanatomical sources of cognitive deficits, we used a comprehensive diffusion-weighted imaging (DWI) protocol and characterized the white matter diffusion signals using diffusion kurtosis imaging (DKI) and permeability-diffusivity imaging (PDI) in patients (n = 74), their nonill siblings (n = 41), and healthy controls (n = 113). Diffusion parameters that showed significant patient-control differences also explained the patient-control differences in processing speed. This association was also found for the nonill siblings of the patients. The association was specific to processing-speed abnormality but not specific to working memory abnormality or psychiatric symptoms. Our findings show that advanced diffusion MRI in white matter may capture microstructural connectivity patterns and mechanisms that govern the association between a core neurocognitive measureprocessing speed-and neurobiological deficits in schizophrenia that are detectable with in vivo brain scans. These non-Gaussian diffusion white matter metrics are promising surrogate imaging markers for modeling cognitive deficits and perhaps, guiding treatment development in schizophrenia.diffusion-weighted imaging | schizophrenia | processing speed | cognitive deficits | endophenotypes A lthough pharmaceutical interventions alleviate clinical symptoms, such as delusions and hallucinations, for some patients, schizophrenia remains a debilitating illness, often times leading to long-term disabilities and severe cognitive deficits (1). Discovering the underlying neurobiology behind these core cognitive deficits in schizophrenia patients may present a viable strategy to identify biomarkers for supporting pathophysiology and comprehensive treatment research. Two decades of research have implicated impaired brain connectivity as a source of functional disability in schizophrenia (1, 2). Delayed information processing is one of the most robust cognitive deficits (3, 4) and may contribute to other cognitive impairments in working memory and executive function (4-6).Myelinated axons in the brain's white matter (WM) support its functionality by propagating electric signal transmissions through saltatory conductance (7,8). Reports of WM abnormalities in patients with schizophrenia are common and include reduced fractional anisotropy (FA) of water diffusion measured by diffusion tensor imaging (DTI) MRI (9-11) as well as reduced axonal myelin levels and glial cell density in postmortem brain studies (12)(13)(14). Identifying the key WM microstructural properties that explain the patient-control...

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Section: Regression Stepsupporting

confidence: 89%

Diffusion-weighted imaging uncovers likely sources of processing-speed deficits in schizophrenia

Kochunov

Rowland

Fieremans

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…12,29 Whereas the cause of these alterations is still unknown, there is significant evidence for heritability of WM integrity of specific brain regions in subjects with schizophrenia and their unaffected relatives. [16][17][18] These findings suggest that WM integrity measures may be useful endophenotypes for genetic studies of schizophrenia. 13 To date, none of the significant genome-wide genetic variations associated with schizophrenia have been found to explain the differences in WM integrity seen in schizophrenia patients.…”

Section: Discussionmentioning

confidence: 83%

“…15 It is unclear how WM integrity abnormalities relate to the underlying genetic architecture of Schizophrenia, nevertheless the endophenotypic importance of FA for schizophrenia is further supported by recent studies showing that many brain regions showing significant decrease in FA in subjects with schizophrenia (including childhood-onset schizophrenia) were also decreased similarly but with smaller effects in their relatives, with a continuous FA decrease from healthy subjects to relatives to subjects with schizophrenia. 16,17 Thus global WM integrity (as measured by FA) may provide a good biological endophenotype to explain genetic differences in the risk for schizophrenia. 18,19 In this study, we sought to investigate whether oligodendrocyte gene sets associated with schizophrenia are also associated with WM integrity.…”

Section: Introductionmentioning

confidence: 99%

Myelination-related genes are associated with decreased white matter integrity in schizophrenia

et al. 2015

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Disruptions in white matter (WM) tract structures have been implicated consistently in the pathophysiology of schizophrenia. Global WM integrity -as measured by fractional anisotropy (FA) -is highly heritable and may provide a good endophenotype for genetic studies of schizophrenia. WM abnormalities in schizophrenia are not localized to one specific brain region but instead reflect global low-level decreases in FA coupled with focal abnormalities. In this study, we sought to investigate whether functional gene sets associated with schizophrenia are also associated with WM integrity. We analyzed FA and genetic data from the Mind Research Network Clinical Imaging Consortium to study the effect of multiple oligodendrocyte gene sets on schizophrenia and WM integrity using a functional gene set analysis in 77 subjects with schizophrenia and 104 healthy controls. We found that a gene set involved in myelination was significantly associated with schizophrenia and FA. This gene set includes 17 genes that are expressed in oligodendrocytes and one neuronal gene (NRG1) that is known to regulate myelination. None of the genes within the gene set were associated with schizophrenia or FA individually, suggesting that no single gene was driving the association of the gene set. Our findings support the hypothesis that multiple genetic variants in myelination-related genes contribute to the observed correlation between schizophrenia and decreased WM integrity as measured by FA.

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“…Gogtay et al (2012) and Moran et al (2015) found a delayed white matter growth trajectory and decreased FA in adolescent COS siblings, Boos et al (2013) and Hoptman et al (2008), found increased FA in adult first-degree relatives of AOS, while others (Harms et al, 2015;Koivukangas et al, 2015) found no differences in AOS relatives compared to controls.…”

Section: Introductionmentioning

confidence: 94%

“…In addition, COS is a rare and more severe form of AOS and has a more pronounced genetic risk (Asarnow and Asarnow, 1994;Asarnow and Forsyth, 2013;Asarnow et al, 2001;Nicolson and Rapoport, 1999). There have been extremely few DTI studies in this population; Moran et al (2015) and Clark et al (2011) found decreased FA in COS patients, and Ashtari et al (2007) found decreased FA in early onset schizophrenia (defined as onset before the age of 18) patients.…”

Section: Introductionmentioning

confidence: 99%

DTI microstructural abnormalities in adolescent siblings of patients with childhood-onset schizophrenia

Waltzman

Knowlton

Cohen

et al. 2016

Psychiatry Research: Neuroimaging

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Comparing Fractional Anisotropy in Patients With Childhood-Onset Schizophrenia, Their Healthy Siblings, and Normal Volunteers Through DTI

Cited by 22 publications

References 44 publications

Diffusion-weighted imaging uncovers likely sources of processing-speed deficits in schizophrenia

Diffusion-weighted imaging uncovers likely sources of processing-speed deficits in schizophrenia

Myelination-related genes are associated with decreased white matter integrity in schizophrenia

DTI microstructural abnormalities in adolescent siblings of patients with childhood-onset schizophrenia

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