White matter microstructural disturbance and its relationship with cognitive function in schizophrenia with comorbidity of metabolic syndrome_Journal of Biomedical Engineering

Authors：

ZHOU Jingyu ^1,2 , YU Kai ¹ , HAN Taisheng ¹ , HUANG Huan ¹ , DUAN Mingjun ¹ , María Luisa Bringas Vega ^3,4 ,  LUO Cheng ^1,2,3,5 ,  YAO Dezhong ^1,2,3,5

1. The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 611731, P. R. China;
2. Research Unit of NeuroInformation, Chinese Academy of Medical Sciences, 2019RU035, Chengdu 611731, P. R. China;
3. China-Cuba Belt and Road Joint Laboratory on Neurotechnology and Brain-Apparatus Communication, University of Electronic Science and Technology of China, Chengdu 610054, P. R. China;
4. Cuban Neuroscience Center, La Habana 10200, Cuba;
5. Department of Radiology, The Fourth People’s Hospital of Chengdu, Chengdu 611731, P. R. China;

Corresponding?author：

LUO Cheng, Email: chengluo@uestc.edu.cn; YAO Dezhong, Email: dyao@uestc.edu.cn

Keywords：

Schizophrenia; Metabolic syndrome; White matter; Cognitive function

DOI：

10.7507/1001-5515.202603015

Video：

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The mechanisms underlying the impact of metabolic syndrome on cognitive dysfunction in patients with schizophrenia remain unclear. The present study employed a two-factor factorial design to investigate the effects of metabolic syndrome on white matter microstructure in schizophrenia and its association with cognitive function. A total of 187 participants were included and classified into four groups based on the diagnoses of schizophrenia and metabolic syndrome: schizophrenia patients with metabolic syndrome (SZ-wMS), schizophrenia patients without metabolic syndrome, healthy controls with metabolic syndrome, and healthy controls without metabolic syndrome. Diffusion tensor imaging data were acquired. Using diffusion tensor model, fractional anisotropy (FA) was calculated to characterize the microstructural integrity of white matter. Peripheral metabolic indices and multiple domains of cognitive function were also assessed. The SZ-wMS group showed further reduced FA in the right sagittal stratum. Within the two-factor analytical framework, an interaction effect between metabolic syndrome and schizophrenia on FA in the right sagittal stratum was identified. Correlation analyses revealed that reduced FA in the right sagittal stratum was associated with impaired language function in patients with schizophrenia. Moreover, mediation analysis indicated that body mass index might indirectly affect language function by influencing FA in the right sagittal stratum. In summary, reduced integrity of white matter fibers in sagittal stratum may represent a potential neural mechanism underlying the comorbidity of schizophrenia and metabolic syndrome and may be associated with language dysfunction in schizophrenia.

Citation： ZHOU Jingyu, YU Kai, HAN Taisheng, HUANG Huan, DUAN Mingjun, María Luisa Bringas Vega, LUO Cheng, YAO Dezhong. White matter microstructural disturbance and its relationship with cognitive function in schizophrenia with comorbidity of metabolic syndrome. Journal of Biomedical Engineering, 2026, 43(3): 441-449. doi: 10.7507/1001-5515.202603015 Copy

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2.	McCutcheon R A, Keefe R S E, Mcguire P K. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Mol Psychiatry, 2023, 28(5): 1902-1918.
3.	Hagi K, Nosaka T, Dickinson D, et al. Association between cardiovascular risk factors and cognitive impairment in people with schizophrenia: a systematic review and meta-analysis. JAMA Psychiatry, 2021, 78(5): 510-518.
4.	Arango C, Dragioti E, Solmi M, et al. Risk and protective factors for mental disorders beyond genetics: an evidence-based atlas. World Psychiatry, 2021, 20(3): 417-436.
5.	Mitchell A J, Vancampfort D, Sweers K, et al. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders--a systematic review and meta-analysis. Schizophr Bull, 2013, 39(2): 306-318.
6.	De Nijs J, Schnack H G, Koevoets M G J C, et al. Reward-related brain structures are smaller in patients with schizophrenia and comorbid metabolic syndrome. Acta Psychiatr Scand, 2018, 138(6): 581-590.
7.	Boyer L, Testart J, Michel P, et al. Neurophysiological correlates of metabolic syndrome and cognitive impairment in schizophrenia: a structural equation modeling approach. Psychoneuroendocrinology, 2014, 50: 95-105.
8.	Kelly S, Jahanshad N, Zalesky A, et al. Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group. Mol Psychiatry, 2017, 23(5): 1261-1269.
9.	Spangaro M, Mazza E, Poletti S, et al. Obesity influences white matter integrity in schizophrenia. Psychoneuroendocrinology, 2018, 97: 135-142.
10.	Hidese S, Ota M, Matsuo J, et al. Association of obesity with cognitive function and brain structure in patients with major depressive disorder. J Affect Disord, 2018, 225: 188-194.
11.	田慧, 楊明慧, 李亮, 等. 磁共振擴散張量成像對青少年單純性肥胖胼胝體微結構的研究初探. 新疆醫科大學學報, 2017, 40(11): 1410-1412.
12.	Zhang X, Yang M, Du X, et al. Glucose disturbances, cognitive deficits and white matter abnormalities in first-episode drug-naive schizophrenia. Mol Psychiatry, 2020, 25(12): 3220-3230.
13.	翁深宏, 王高華, 徐順生, 等. 首發精神分裂癥腦白質微結構異常與臨床癥狀、認知損害及早期轉歸的關系. 中華行為醫學與腦科學雜志, 2021, 30(11): 997-1004.
14.	Wu X, Chen X, Liao K, et al. Characterization of the white matter networks in schizophrenia patients with metabolic syndrome undergoing risperidone or clozapine treatment. Front Neurosci, 2025, 19: 1579810.
15.	Alberti K G Z P, Shaw J. Metabolic syndrome--a new world-wide definition: a consensus statement from the International Diabetes Federation. Diabet Med, 2006, 23(5): 469-480.
16.	Bastiani M, Cottaar M, Fitzgibbon S P, et al. Automated quality control for within and between studies diffusion MRI data using a non-parametric framework for movement and distortion correction. Neuroimage, 2019, 184: 801-812.
17.	Hayes A F. Introduction to mediation, moderation, and conditional process analysis: a regression-based approach. New York: Guilford Press, 2013.
18.	Di Carlo D T, Benedetto N, Duffau H, et al. Microsurgical anatomy of the sagittal stratum. Acta Neurochir (Wien), 2019, 161(11): 2319-2327.
19.	Catani M, Jones D K, Donato R, et al. Occipito-temporal connections in the human brain. Brain, 2003, 126(9): 2093-2107.
20.	Spieker E A, Kochunov P, Rowland L M, et al. Shared genetic variance between obesity and white matter integrity in Mexican Americans. Front Genet, 2015, 6: 26.
21.	Shimoji K, Abe O, Uka T, et al. White matter alteration in metabolic syndrome: diffusion tensor analysis. Diabetes Care, 2013, 36(6): 696-700.
22.	Papageorgiou I, Astrakas L G, Xydis V, et al. Abnormalities of brain neural circuits related to obesity: a diffusion tensor imaging study. Magn Reson Imaging, 2017, 37: 116-121.
23.	Repple J, Opel N, Meinert S, et al. Elevated body-mass index is associated with reduced white matter integrity in two large independent cohorts. Psychoneuroendocrinology, 2018, 91: 179-185.
24.	Jensen D E A, Ebmeier K P, Akbaraly T, et al. Association of diet and waist-to-hip ratio with brain connectivity and memory in aging. JAMA Netw Open, 2025, 8(3): e250171.
25.	Andica C, Kamagata K, Uchida W, et al. White matter fiber-specific degeneration in older adults with metabolic syndrome. Mol Metab, 2022, 62: 101527.
26.	Asmal L, Kilian S, Du Plessis S, et al. Childhood trauma associated white matter abnormalities in first-episode schizophrenia. Schizophr Bull, 2019, 45(2): 369-376.
27.	O’Hanlon E, Leemans A, Kelleher I, et al. White matter differences among adolescents reporting psychotic experiences: a population-based diffusion magnetic resonance imaging study. JAMA Psychiatry, 2015, 72(7): 668-677.
28.	Barth C, Kelly S, Nerland S, et al. In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis. Mol Psychiatry, 2023, 28(3): 1159-1169.
29.	Surbeck W, Hanggi J, Scholtes F, et al. Anatomical integrity within the inferior fronto-occipital fasciculus and semantic processing deficits in schizophrenia spectrum disorders. Schizophr Res, 2020, 218: 267-275.
30.	Matrone M, Kotzalidis G D, Romano A, et al. Treatment-resistant schizophrenia: addressing white matter integrity, intracortical glutamate levels, clinical and cognitive profiles between early- and adult-onset patients. Prog Neuropsychopharmacol Biol Psychiatry, 2022, 114: 110493.
31.	Luckhoff H K, Du Plessis S, Scheffler F, et al. Fronto-limbic white matter fractional anisotropy and body mass index in first-episode schizophrenia spectrum disorder patients compared to healthy controls. Psychiatry Res Neuroimaging, 2020, 305: 111173.
32.	Minichino A, Ando A, Francesconi M, et al. Investigating the link between drug-naive first episode psychoses (FEPs), weight gain abnormalities and brain structural damages: relevance and implications for therapy. Prog Neuropsychopharmacol Biol Psychiatry, 2017, 77: 9-22.
33.	付桂, 張文靜, 劉杰克, 等. 精神分裂癥患者腦白質微結構改變與外周血白細胞介素10的關系. 實用放射學雜志, 2019, 35(7): 1029-1033, 1041.
34.	陶敏, 張文靜, 楊培鋒, 等. 精神分裂癥合并代謝綜合征患者認知功能與Hcy及糖脂代謝的關系. 國際精神病學雜志, 2025, 52(6): 1725-1729.
35.	Al-Juboori A A, Badran S A, Sulaiman I I, et al. Clinical implications of sagittal stratum damage: laterality, neuroanatomical developmental considerations, and functional outcomes. Surg Neurol Int, 2025, 16: 4.
36.	Clark K, Narr K L, O'Neill J, et al. White matter integrity, language, and childhood onset schizophrenia. Schizophr Res, 2012, 138(2-3): 150-156.
37.	Stranahan A M, Arumugam T V, Cutler R G, et al. Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci, 2008, 11(3): 309-317.
38.	Chen H F, Huang L L, Li H Y, et al. Microstructural disruption of the right inferior fronto-occipital and inferior longitudinal fasciculus contributes to WMH-related cognitive impairment. CNS Neurosci Ther, 2020, 26(5): 576-588.
39.	Santiago C, Herrmann N, Swardfager W, et al. White matter microstructural integrity is associated with executive function and processing speed in older adults with coronary artery disease. Am J Geriatr Psychiatry, 2015, 23(7): 754-763.
40.	Pasternak O, Westin C F, Bouix S, et al. Excessive extracellular volume reveals a neurodegenerative pattern in schizophrenia onset. J Neurosci, 2012, 32(48): 17365-17372.
41.	Lesh T A, Maddock R J, Howell A, et al. Extracellular free water and glutathione in first-episode psychosis-a multimodal investigation of an inflammatory model for psychosis. Mol Psychiatry, 2021, 26(3): 761-771.

1. Keefe R S E, Fox K H, Harvey P D, et al. Characteristics of the MATRICS consensus cognitive battery in a 29-site antipsychotic schizophrenia clinical trial. Schizophr Res, 2011, 125(2-3): 161-168.
2. McCutcheon R A, Keefe R S E, Mcguire P K. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Mol Psychiatry, 2023, 28(5): 1902-1918.
3. Hagi K, Nosaka T, Dickinson D, et al. Association between cardiovascular risk factors and cognitive impairment in people with schizophrenia: a systematic review and meta-analysis. JAMA Psychiatry, 2021, 78(5): 510-518.
4. Arango C, Dragioti E, Solmi M, et al. Risk and protective factors for mental disorders beyond genetics: an evidence-based atlas. World Psychiatry, 2021, 20(3): 417-436.
5. Mitchell A J, Vancampfort D, Sweers K, et al. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders--a systematic review and meta-analysis. Schizophr Bull, 2013, 39(2): 306-318.
6. De Nijs J, Schnack H G, Koevoets M G J C, et al. Reward-related brain structures are smaller in patients with schizophrenia and comorbid metabolic syndrome. Acta Psychiatr Scand, 2018, 138(6): 581-590.
7. Boyer L, Testart J, Michel P, et al. Neurophysiological correlates of metabolic syndrome and cognitive impairment in schizophrenia: a structural equation modeling approach. Psychoneuroendocrinology, 2014, 50: 95-105.
8. Kelly S, Jahanshad N, Zalesky A, et al. Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group. Mol Psychiatry, 2017, 23(5): 1261-1269.
9. Spangaro M, Mazza E, Poletti S, et al. Obesity influences white matter integrity in schizophrenia. Psychoneuroendocrinology, 2018, 97: 135-142.
10. Hidese S, Ota M, Matsuo J, et al. Association of obesity with cognitive function and brain structure in patients with major depressive disorder. J Affect Disord, 2018, 225: 188-194.
11. 田慧, 楊明慧, 李亮, 等. 磁共振擴散張量成像對青少年單純性肥胖胼胝體微結構的研究初探. 新疆醫科大學學報, 2017, 40(11): 1410-1412.
12. Zhang X, Yang M, Du X, et al. Glucose disturbances, cognitive deficits and white matter abnormalities in first-episode drug-naive schizophrenia. Mol Psychiatry, 2020, 25(12): 3220-3230.
13. 翁深宏, 王高華, 徐順生, 等. 首發精神分裂癥腦白質微結構異常與臨床癥狀、認知損害及早期轉歸的關系. 中華行為醫學與腦科學雜志, 2021, 30(11): 997-1004.
14. Wu X, Chen X, Liao K, et al. Characterization of the white matter networks in schizophrenia patients with metabolic syndrome undergoing risperidone or clozapine treatment. Front Neurosci, 2025, 19: 1579810.
15. Alberti K G Z P, Shaw J. Metabolic syndrome--a new world-wide definition: a consensus statement from the International Diabetes Federation. Diabet Med, 2006, 23(5): 469-480.
16. Bastiani M, Cottaar M, Fitzgibbon S P, et al. Automated quality control for within and between studies diffusion MRI data using a non-parametric framework for movement and distortion correction. Neuroimage, 2019, 184: 801-812.
17. Hayes A F. Introduction to mediation, moderation, and conditional process analysis: a regression-based approach. New York: Guilford Press, 2013.
18. Di Carlo D T, Benedetto N, Duffau H, et al. Microsurgical anatomy of the sagittal stratum. Acta Neurochir (Wien), 2019, 161(11): 2319-2327.
19. Catani M, Jones D K, Donato R, et al. Occipito-temporal connections in the human brain. Brain, 2003, 126(9): 2093-2107.
20. Spieker E A, Kochunov P, Rowland L M, et al. Shared genetic variance between obesity and white matter integrity in Mexican Americans. Front Genet, 2015, 6: 26.
21. Shimoji K, Abe O, Uka T, et al. White matter alteration in metabolic syndrome: diffusion tensor analysis. Diabetes Care, 2013, 36(6): 696-700.
22. Papageorgiou I, Astrakas L G, Xydis V, et al. Abnormalities of brain neural circuits related to obesity: a diffusion tensor imaging study. Magn Reson Imaging, 2017, 37: 116-121.
23. Repple J, Opel N, Meinert S, et al. Elevated body-mass index is associated with reduced white matter integrity in two large independent cohorts. Psychoneuroendocrinology, 2018, 91: 179-185.
24. Jensen D E A, Ebmeier K P, Akbaraly T, et al. Association of diet and waist-to-hip ratio with brain connectivity and memory in aging. JAMA Netw Open, 2025, 8(3): e250171.
25. Andica C, Kamagata K, Uchida W, et al. White matter fiber-specific degeneration in older adults with metabolic syndrome. Mol Metab, 2022, 62: 101527.
26. Asmal L, Kilian S, Du Plessis S, et al. Childhood trauma associated white matter abnormalities in first-episode schizophrenia. Schizophr Bull, 2019, 45(2): 369-376.
27. O’Hanlon E, Leemans A, Kelleher I, et al. White matter differences among adolescents reporting psychotic experiences: a population-based diffusion magnetic resonance imaging study. JAMA Psychiatry, 2015, 72(7): 668-677.
28. Barth C, Kelly S, Nerland S, et al. In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis. Mol Psychiatry, 2023, 28(3): 1159-1169.
29. Surbeck W, Hanggi J, Scholtes F, et al. Anatomical integrity within the inferior fronto-occipital fasciculus and semantic processing deficits in schizophrenia spectrum disorders. Schizophr Res, 2020, 218: 267-275.
30. Matrone M, Kotzalidis G D, Romano A, et al. Treatment-resistant schizophrenia: addressing white matter integrity, intracortical glutamate levels, clinical and cognitive profiles between early- and adult-onset patients. Prog Neuropsychopharmacol Biol Psychiatry, 2022, 114: 110493.
31. Luckhoff H K, Du Plessis S, Scheffler F, et al. Fronto-limbic white matter fractional anisotropy and body mass index in first-episode schizophrenia spectrum disorder patients compared to healthy controls. Psychiatry Res Neuroimaging, 2020, 305: 111173.
32. Minichino A, Ando A, Francesconi M, et al. Investigating the link between drug-naive first episode psychoses (FEPs), weight gain abnormalities and brain structural damages: relevance and implications for therapy. Prog Neuropsychopharmacol Biol Psychiatry, 2017, 77: 9-22.
33. 付桂, 張文靜, 劉杰克, 等. 精神分裂癥患者腦白質微結構改變與外周血白細胞介素10的關系. 實用放射學雜志, 2019, 35(7): 1029-1033, 1041.
34. 陶敏, 張文靜, 楊培鋒, 等. 精神分裂癥合并代謝綜合征患者認知功能與Hcy及糖脂代謝的關系. 國際精神病學雜志, 2025, 52(6): 1725-1729.
35. Al-Juboori A A, Badran S A, Sulaiman I I, et al. Clinical implications of sagittal stratum damage: laterality, neuroanatomical developmental considerations, and functional outcomes. Surg Neurol Int, 2025, 16: 4.
36. Clark K, Narr K L, O'Neill J, et al. White matter integrity, language, and childhood onset schizophrenia. Schizophr Res, 2012, 138(2-3): 150-156.
37. Stranahan A M, Arumugam T V, Cutler R G, et al. Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci, 2008, 11(3): 309-317.
38. Chen H F, Huang L L, Li H Y, et al. Microstructural disruption of the right inferior fronto-occipital and inferior longitudinal fasciculus contributes to WMH-related cognitive impairment. CNS Neurosci Ther, 2020, 26(5): 576-588.
39. Santiago C, Herrmann N, Swardfager W, et al. White matter microstructural integrity is associated with executive function and processing speed in older adults with coronary artery disease. Am J Geriatr Psychiatry, 2015, 23(7): 754-763.
40. Pasternak O, Westin C F, Bouix S, et al. Excessive extracellular volume reveals a neurodegenerative pattern in schizophrenia onset. J Neurosci, 2012, 32(48): 17365-17372.
41. Lesh T A, Maddock R J, Howell A, et al. Extracellular free water and glutathione in first-episode psychosis-a multimodal investigation of an inflammatory model for psychosis. Mol Psychiatry, 2021, 26(3): 761-771.

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