White matter abnormalities across the lifespan of schizophrenia: a harmonized multi-site diffusion MRI study

Cetin-Karayumak, Suheyla; Biase, Maria A Di; Chunga, Natalia; Reid, Benjamin; Somes, Nathaniel; Lyall, Amanda E.; Kelly, Sinéad; Solgun, Bengisu; Pasternak, Ofer; Vangel, Mark; Pearlson, Godfrey D.; Tamminga, Carol A.; Sweeney, John A.; Clementz, Brett A.; Schretlen, David; Viher, Petra; Stegmayer, Katharina; Walther, Sebastian; Lee, Jung Sun; Crow, T. J.; James, Anthony; Voineskos, Aristotle N.; Boyer, Robert; Szeszko, Philip R.; Malhotra, Anil K.; Hegde, Rachal; McCarley, Robert W.; Keshavan, Matcheri S.; Shenton, Martha E.; Rathi, Yogesh; Kubicki, Marek

doi:10.1038/s41380-019-0509-y

Cited by 117 publications

(121 citation statements)

References 53 publications

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“…This is the first brain age analysis in SZ that was focused on cerebral white matter. We demonstrated that Δage was significantly greater in patients than healthy controls thus supporting previous reports of accelerated white matter aging in this illness (Cetin-Karayumak et al, 2019;Kochunov et al, 2013b).…”

Section: Discussionsupporting

confidence: 90%

“…Previous studies demonstrated that the integrity of the cerebral white matter as measured by fractional anisotropy (FA) in diffusion weighted imaging (DTI), declined in SZ patients at nearly twice the aging rate of normal controls (Mori et al, 2007;Friedman et al, 2008;Kochunov et al, 2013aKochunov et al, , 2013bWright et al, 2014). An analysis of life-long trajectory of white matter integrity in 600 schizophrenia patients suggested that the peak of white matter integrity occurs earlier in SZ than healthy controls and the accelerated decline of the associative white matter tracts becomes evident in the 4 th decade of life and its slope shows a non-linear increase with age (Cetin-Karayumak et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Patients with schizophrenia (SZ) have a significantly higher risk (2-4 times) of experiencing an unfavorable aging trajectory that may increase their risk for cognitive decline and dementia (Ribe et al, 2015). The increased risk can be in part explained by the fact that the white matter integrity reaches its peak earlier in life for SZ than healthy controls (Cetin-Karayumak et al, 2019). Neuropathology of accelerated brain aging likely contributes to the severity of the cognitive deficits in patients that form the core of socioeconomic impairments in this illness (Kochunov et al, 2016b;Kelly et al, 2018;Kochunov et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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White matter brain aging In Relationship to Schizophrenia and Its Cognitive Deficit

Wang

Kochunov

Sampath

et al. 2020

Preprint

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We hypothesized that cerebral white matter deficits in schizophrenia (SZ) are driven in part by accelerated white matter aging and are associated with cognitive deficits. We used machine learning model to predict individual age from diffusion tensor imaging features and calculated the delta age (Δage) as the difference between predicted and chronological age. Through this approach, we translated multivariate white matter imaging features into an age-scaled metric and used it to test the temporal trends of accelerated aging-related white matter deficit in SZ and its association with the cognition. Followed feature selection, a machine learning model was trained with fractional anisotropy values in 34 of 43 tracts on a training set consisted of 107 healthy controls (HC). The brain age of 166 SZs and 107 HCs in the testing set were calculated using this model. Then, we examined the SZ-HC group effect on Δage and whether this effect was moderated by chronological age using the regression spline model. The results showed that Δage was significantly elevated in the age >30 group in patients (p < 0.001) but not in age ≤ 30 group (p = 0.364). Δage in patients was significantly and negatively associated with both working memory (β = -0.176, p = 0.007) and processing speed (β = -0.519, p = 0.035) while adjusting sex and chronological age. Overall, these findings indicate that the Δage is elevated in SZs and become significantly from middle life stage; the increase of Δage in SZs is associated with the decline neurocognitive performance.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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White matter brain aging In Relationship to Schizophrenia and Its Cognitive Deficit

Wang

Kochunov

Sampath

et al. 2020

Preprint

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“…Schizophrenia is associated with profound changes in brain structure, including altered cortical morphology (1)(2)(3)(4), subcortical volume loss (5) and white matter alterations (6)(7)(8)(9) leading to structural connectopathies (10)(11)(12)(13)(14)(15). Despite numerous cross-sectional and longitudinal investigations, the heterogeneity of schizophrenia has defied attempts to derive reproducible and definitive brain maps of the precise anatomical loci of these structural changes.…”

Section: Introductionmentioning

confidence: 99%

Individual deviations from normative models of brain structure in a large cross-sectional schizophrenia cohort

Biase

Cash

et al. 2020

Preprint

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Word count: 4000 Number of figures: 4 (supplementary: 7)Number of tables: 0 (supplementary: 1) Abstract Background: The heterogeneity of schizophrenia has defied efforts to derive reproducible and definitive anatomical maps of structural brain changes associated with the disorder. We aimed to map deviations from normative ranges of brain structure for individual patients and evaluate whether the loci of individual deviations recapitulated group-average brain maps of schizophrenia pathology. Methods:For each of 48 white matter tracts and 68 cortical regions, normative percentiles of variation in fractional anisotropy (FA) and cortical thickness (CT) were established using diffusionweighted and structural MRI from healthy adults (n=195). Individuals with schizophrenia (n=322) were classified as either within the normative range for healthy individuals of the same age and sex (5-95% percentiles), infra-normal (<5% percentile) or supra-normal (>95% percentile).Repeating this classification for each tract and region yielded a deviation map for each individual.Results: Compared to the healthy comparison group, the schizophrenia group showed widespread reductions in FA and CT, involving virtually all white matter tracts and cortical regions.Paradoxically, however, no more than 15-20% of patients deviated from the normative range for any single tract or region, whereas 79% of patients showed infra-normal deviations for at least one locus (healthy individuals: 59±2%, p<0.001). Higher polygenic risk for schizophrenia associated with a greater number of regions with infra-normal deviations in CT (r=-0.17, p=0.006). Conclusions: Anatomical loci of schizophrenia-related changes are highly heterogeneous across individuals to the extent that group-consensus pathological maps are not representative of most individual patients. Normative modeling can aid in parsing schizophrenia heterogeneity and guiding personalized interventions.

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“…Thus, the significant correlation suggested that VF and brief visuospatial memory tests scores have important clinical significance. As suggested in previous studies, it is also closely associated with the degeneration of the brain in schizophrenia patients (Zhang et al, 2012(Zhang et al, , 2014Cetin-Karayumak et al, 2019). Further, recent research mentioned that words and visuospatial memory information are conveyed across aforesaid regions via the excitatory projections of glutamatergic pyramidal neurons (Hoftman et al, 2017;Nikolova et al, 2017).…”

Section: Main Effect Of Rs3813296 On Causality Connectivity In the Frmentioning

confidence: 66%

Modulation on Glutamic Pathway of Frontal-Striatum-Thalamus by rs11146020 and rs3813296 Gene Polymorphism in First-Episode Negative Schizophrenia

Cai

Huang

et al. 2020

Front. Neurosci.

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Objectives: The frontal-striatum-thalamus pathway is important in the glutamic neural circuit. The hypofunction of GRIN1 and GRIA2 subunits from glutamic receptors has been hypothesized as the primary process in the etiology of schizophrenia. Identified gene polymorphism involved in the pathogenesis of schizophrenia may uncover relevant mechanism pathways. Methods: We selected two loci of rs11146020 and rs3813296 distributed in GRIN1 and GRIA2 genes and tested their main and interaction effects on causality connections and structural characteristics in the frontal-striatum-thalamus pathway in 55 Han Chinese first-episode negative schizophrenia patients.Results: We found that: (1) rs11146020 has a significant main effect on the causality connections between the bilateral dorsolateral prefrontal cortex, and rs3813296 mainly influences those of the descending pathway from the prefrontal cortex to the striatum;(2) interaction effect of rs11146020 and rs3813296 on causality connections are located in the ascending pathway from the pallidum to the dorsolateral prefrontal cortex; and (3) the two loci have effects on the volumes of several regions of this pathway. Conclusion:Our results suggested there is modulation on glutamic frontal-striatumthalamus pathway by rs11146020 and rs3813296 gene polymorphism. Patients with different genotypes have different neuroimaging characteristics, which indirectly reminded clinicians those patients should receive different clinical interventions.

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White matter abnormalities across the lifespan of schizophrenia: a harmonized multi-site diffusion MRI study

Cited by 117 publications

References 53 publications

White matter brain aging In Relationship to Schizophrenia and Its Cognitive Deficit

White matter brain aging In Relationship to Schizophrenia and Its Cognitive Deficit

Individual deviations from normative models of brain structure in a large cross-sectional schizophrenia cohort

Modulation on Glutamic Pathway of Frontal-Striatum-Thalamus by rs11146020 and rs3813296 Gene Polymorphism in First-Episode Negative Schizophrenia

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