Disturbance of glucose metabolism may be implicated in cognitive deficits of schizophrenia in its early phases. Many studies have reported the important role of widespread disruption of white matter (WM) connectivity in pathogenesis, cognitive deficit and psychopathology of schizophrenia. However, no study has investigated their inter-relationships in drug-naive first episode (DNFE) patients with schizophrenia. Glucose metabolism parameters including fasting glucose, insulin and homeostasis model of assessment-insulin resistance (HOMA-IR) index, cognitive performance on the MATRICS Consensus Cognitive Battery (MCCB) and the voxel-wised WM fractional anisotropy (FA) values were examined using DTI in 39 DNFE schizophrenia and 31 control subjects. The Positive and Negative Syndrome Scale was utilized for clinical symptoms. The patients showed significantly greater fasting plasma levels of glucose and insulin and HOMA-IR, and poorer cognitive scores, together with widespread reduced FA values in five brain areas, including left and right corpus callosum, superior longitudinal fasciculus, posterior thalamic radiation, and corona radiata (all p < 0.05). Association analysis showed that glucose level was positively associated with Digital Sequence Test and Continuous Performance Test, but negatively with FA values in posterior thalamic radiation and left corpus callosum in patients (all p < 0.05). Furthermore, multiple regression analysis revealed that the interactions of glucose × FA in left corpus callosum, longitudinal fasciculus and corona radiata were independent contributors to the Brief Visuospatial Memory Test (BVMT) of MCCB, while the interaction of glucose × FA in left corpus callosum, or in longitudinal fasciculus was associated with MCCB mazes and Trail Making A Test, respectively. Therefore, abnormal glucose metabolism, cognitive impairment and widespread disruption of WM structure occur in an early course of schizophrenia onset. An interaction between glucose metabolism abnormality and the WM dysconnectivity may lead to cognitive impairment.
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Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, de Hert M. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders—a systematic review and meta-analysis. Schizophr Bull. 2013;39:306–18.
Vancampfort D, Wampers M, Mitchell AJ, Correll CU, De Herdt A, Probst M, et al. A meta-analysis of cardio-metabolic abnormalities in drug naive, first-episode and multi-episode patients with schizophrenia versus general population controls. World Psychiatry. 2013;12:240–50.
Stubbs B, Vancampfort D, De Hert M, Mitchell AJ. The prevalence and predictors of type two diabetes mellitus in people with schizophrenia: a systematic review and comparative meta-analysis. Acta Psychiatr Scand. 2015;132:144–57.
Smith M, Hopkins D, Peveler RC, Holt RI, Woodward M, Ismail K. First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2008;192:406–11.
Holt RI. The prevention of diabetes and cardiovascular disease in people with schizophrenia. Acta Psychiatr Scand. 2015;132:86–96.
Bou Khalil R. Atypical antipsychotic drugs, schizophrenia, and metabolic syndrome in non-Euro-American societies. Clin Neuropharmacol. 2012;35:141–7.
Yogaratnam J, Biswas N, Vadivel R, Jacob R. Metabolic complications of schizophrenia and antipsychotic medications-an updated review. East Asian Arch Psychiatry. 2013;23:21–8.
Ryan MC, Collins P, Thakore JH. Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia. Am J Psychiatry. 2003;160:284–9.
Spelman LM, Walsh PI, Sharifi N, Collins P, Thakore JH. Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia. Diabet Med. 2007;24:481–5.
Fernandez-Egea E, Bernardo M, Donner T, Conget I, Parellada E, Justicia A, et al. Metabolic profile of antipsychotic-naive individuals with non-affective psychosis. Br J Psychiatry. 2009;194:434–8.
Guest PC, Schwarz E, Krishnamurthy D, Harris LW, Leweke FM, Rothermundt M, et al. Altered levels of circulating insulin and other neuroendocrine hormones associated with the onset of schizophrenia. Psychoneuroendocrinology. 2011;36:1092–6.
Wu X, Huang Z, Wu R, Zhong Z, Wei Q, Wang H, et al. The comparison of glycometabolism parameters and lipid profiles between drug-naïve, first-episode schizophrenia patients and healthy controls. Schizophr Res. 2013;150:157–62.
Zhang XY, Chen DC, Tan YL, An HM, Zunta-Soares GB, Huang XF, et al. Glucose disturbances in first-episode drug-naïve schizophrenia: Relationship to psychopathology. Psychoneuroendocrinology. 2015;62:376–80.
Chen DC, Du XD, Yin GZ, Yang KB, Nie Y, Wang N, et al. Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia: relationships with clinical phenotypes and cognitive deficits. Psychol Med. 2016;46:3219–30.
Paquin K, Wilson AL, Cellard C, Lecomte T, Potvin S. A systematic review on improving cognition in schizophrenia: which is the more commonly used type of training, practice or strategy learning? BMC Psychiatry. 2014;14:139.
Schaefer J, Giangrande E, Weinberger DR, Dickinson D. The global cognitive impairment in schizophrenia: consistent over decades and around the world. Schizophr Res. 2013;150:42–50.
Harvey PD. When does cognitive decline occur in the period prior to the first episode of schizophrenia? Psychiatry. 2009;6:12–4.
Irani F, Kalkstein S, Moberg EA, Moberg PJ. Neuropsychological performance in older patients with schizophrenia: a meta-analysis of cross-sectional and longitudinal studies. Schizophr Bull. 2011;37:1318–26.
Rajji TK, Mulsant BH. Nature and course of cognitive function in late-life schizophrenia: a systematic review. Schizophr Res. 2008;102:122–40.
Manschot SM, Biessels GJ, de Valk H, Algra A, Rutten GE, van der Grond J, et al. Metabolic and vascular determinants of impaired cognitive performance and abnormalities on brain magnetic resonance imaging in patients with type 2 diabetes. Diabetologia. 2007;50:2388–97.
Kumar R, Looi JC, Raphael B. Type 2 diabetes mellitus, cognition and brain in aging: a brief review. Indian J Psychiatry. 2009;51(Suppl 1):S35–8.
Gold SM, Dziobek I, Sweat V, Tirsi A, Rogers K, Bruehl H, et al. Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia. 2007;50:711–9.
Bruehl H, Wolf OT, Sweat V, Tirsi A, Richardson S, Convit A. Modifiers of cognitive function and brain structure in middle-aged and elderly individuals with type 2 diabetes mellitus. Brain Res. 2009;1280:186–94.
Nooyens AC, Baan CA, Spijkerman AM, Verschuren WM. Type 2 diabetes and cognitive decline in middle-aged men and women: the Doetinchem Cohort Study. Diabetes Care. 2010;33:1964–9.
Zhen YF, Zhang J, Liu XY, Fang H, Tian LB, Zhou DH, et al. Low BDNF is associated with cognitive deficits in patients with type 2 diabetes. Psychopharmacology. 2013;227:93–100.
Dickinson D, Gold JM, Dickerson FB, Medoff D, Dixon LB. Evidence of exacerbated cognitive deficits in schizophrenia patients with comorbid diabetes. Psychosomatics. 2008;49:123–31.
Han M, Huang XF, Chen DC, Xiu M, Kosten TR, Zhang XY. Diabetes and cognitive deficits in chronic schizophrenia: a case-control study. PLoS ONE. 2013;8:e66299.
Epstein KA, Cullen KR, Mueller BA, Robinson P, Lee S, Kumra S. White matter abnormalities and cognitive impairment in early-onset schizophrenia-spectrum disorders. J Am Acad Child Adolesc Psychiatry. 2014;53:362–72.
Scholz J, Klein MC, Behrens TE, Johansen-Berg H. Training induces changes in white-matter architecture. Nat Neurosci. 2009;12:1370–1.
Bennett IJ, Madden DJ, Vaidya CJ, Howard DV, Howard JJ. Age-related differences in multiple measures of white matter integrity: a diffusion tensor imaging study of healthy aging. Hum Brain Mapp. 2010;31:378–90.
Ellison-Wright I, Bullmore E. Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res. 2009;108:3–10.
Liu X, Lai Y, Wang X, Hao C, Chen L, Zhou Z, et al. Reduced white matter integrity and cognitive deficit in never-medicated chronic schizophrenia: a diffusion tensor study using TBSS. Behav Brain Res. 2013;252:157–63.
Perez-Iglesias R, Tordesillas-Gutierrez D, McGuire PK, Barker GJ, Roiz-SantianezR, Mata I, et al. White matter integrity and cognitive impairment in first-episode psychosis. Am J Psychiatry. 2010;167:451–8.
Sugranyes G, Kyriakopoulos M, Dima D, O'Muircheartaigh J, Corrigall R, Pendelbury G, et al. Multimodal analyses identify linked functional and white matter abnormalities within the working memory network in schizophrenia. Schizophr Res. 2012;138:136–42.
Roalf DR, Gur RE, Verma R, Parker WA, Quarmley M, Ruparel K, et al. White matter microstructure in schizophrenia: associations to neurocognition and clinical symptomatology. Schizophr Res. 2015;161:42–9.
Ciarmiello A, Cannella M, Lastoria S, Simonelli M, Frati L, Rubinsztein DC, et al. Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington's disease. J Nucl Med. 2006;47:215–22.
Tamura Y, Kimbara Y, Yamaoka T, Sato K, Tsuboi Y, Kodera R, et al. White matter hyperintensity in elderly patients with diabetes mellitus is associated with cognitive impairment, functional disability, and a high glycoalbumin/glycohemoglobin ratio. Front Aging Neurosci. 2017;9:220.
Green MF, Nuechterlein KH, Gold JM, Barch DM, Cohen J, Essock S, et al. Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biol Psychiatry. 2004;56:301–7.
Zou YZ, Cui JF, Wang J, Chen N, Tan SP, Zhou DF, et al. Clinical reliability and validity of the Chinese version of measurement and treatment research to improve cognition in schizophrenia consensus cognitive battery. Chin J Psychiatry. 2009;42:29–33.
Zhang XY, Fan FM, Chen DC, Tan YL, Tan SP, Hu K, et al. Extensive white matter abnormalities and clinical symptoms in drug-naive patients with first-episode schizophrenia: a voxel-based diffusion tensor imaging study. J Clin Psychiatry. 2016;77:205–11.
Jenkinson M, Bannister P, Brady M, Smith S. Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage. 2002;17:825–41.
Ikuta T, Shafritz KM, Bregman J, Peters BD, Gruner P, Malhotra AK, et al. Abnormal cingulum bundle development in autism: a probabilistic tractography study. Psychiatry Res. 2014;221:63–8.
Kochunov P, Du X, Moran LV, Sampath H, Wijtenburg SA, Yang Y, et al. Acute nicotine administration effects on fractional anisotropy of cerebral white matter and associated attention performance. Front Pharm. 2013;4:117.
Smith SM. Fast robust automated brain extraction. Hum Brain Mapp. 2002;17:143–55.
Long Z, Xu Q, Miao HH, Yu Y, Ding MP, Chen H, et al. Thalamocortical dysconnectivity in paroxysmal kinesigenic dyskinesia: combining functional magnetic resonance imaging and diffusion tensor imaging. Mov Disord. 2017;32:592–600.
Andersson JL. Maximum a posteriori estimation of diffusion tensor parameters using a Rician noise model: why, how and but. Neuroimage. 2008;42:1340–56.
Winkler AM, Ridgway GR, Douaud G, Nichols TE, Smith SM. Faster permutation inference in brain imaging. Neuroimage. 2016;141:502–16.
McCleery A, Ventura J, Kern RS, Subotnik KL, Gretchen-Doorly D, Green MF, et al. Cognitive functioning in first-episode schizophrenia: MATRICS consensus cognitive battery (MCCB) profile of impairment. Schizophr Res. 2014;157:33–9.
Petrikis P, Tigas S, Tzallas AT, Papadopoulos I, Skapinakis P, Mavreas V. Parameters of glucose and lipid metabolism at the fasted state in drug-naïve first-episode patients with psychosis: Evidence for insulin resistance. Psychiatry Res. 2015;229:901–4.
Stranahan AM. Models and mechanisms for hippocampal dysfunction in obesity and diabetes. Neuroscience. 2015;309:125–39.
McNay EC, Fries TM, Gold PE. Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task. Proc Natl Acad Sci USA. 2000;97:2881–5.
Baskin DG, Figlewicz DP, Woods SC, Porte D Jr, Dorsa DM. Insulin in the brain. Annu Rev Physiol. 1987;49:335–47.
Kamal A, Biessels GJ, Urban IJ, Gispen WH. Hippocampal synaptic plasticity in streptozotocin–diabetic rats: impairment of long–term potentiation and facilitation of long–term depression. Neuroscience. 1999;90:737–45.
Zhang WJ, Tan YF, Yue JT, Vranic M, Wojtowicz JM. Impairment of hippocampal neurogenesis in streptozotocin-treated diabetic rats. Acta Neurol Scand. 2008;117:205–10.
Wright RL, Lightner EN, Harman JS, Meijer OC, Conrad CD. Attenuating corticosterone levels on the day of memory assessment prevents chronic stress–induced impairments in spatial memory. Eur J Neurosci. 2006;24:595–605.
Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP. Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci 2008;11:309–17.
MacLullich AM, Deary IJ, Starr JM, Ferguson KJ, Wardlaw JM, Seckl JR. Plasma cortisol levels, brain volumes and cognition in healthy elderly men. Psychoneuroendocrinology. 2005;30:505–15.
Łopuszańska UJ, Skorzyńska-Dziduszko K, Lupa-Zatwarnicka K, Makara-Studzińska M. Mental illness and metabolic syndrome-a literature review. Ann Agric Environ Med. 2014;21:815–21.
Zhang XY, Zhou DF, Cao LY, Wu GY, Shen YC. Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia: association with psychopathology and response to antipsychotics. Neuropsychopharmacology. 2005;30:1532–8.
Yao L, Lui S, Liao Y, Du MY, Hu N, Thomas JA, et al. White matter deficits in first episode schizophrenia: an activation likelihood estimation meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2013;45:100–6.
Jakobsen J, Sidenius P, Gundersen HJ, Osterby R. Quantitative changes of cerebral neocortical structure in insulin-treated long-term streptozocin-induced diabetes in rats. Diabetes. 1987;36:597–601.
De Silva PN. Does the association with diabetes say more about schizophrenia and its treatment?–the GLUT hypothesis. Med Hypotheses. 2011;77:529–31.
Fontán-Lozano A, Sáez-Cassanelli JL, Inda MC, de los Santos-Arteaga M, Sierra-Domínguez SA, López-Lluch G. et al. Caloric restriction increases learning consolidation and facilitates synaptic plasticity through mechanisms dependent on NR2B subunits of the NMDA receptor. J Neurosci. 2007;27:10185–95.
Chan O, Inouye K, Akirav EM, Park E, Riddell MC, Matthews SG, et al. Hyperglycemia does not increase basal hypothalamo–pituitary–adrenal activity in diabetes but it does impair the HPA response to insulin–induced hypoglycemia. Am J Physiol Regul Integr Comp Physiol. 2005;289:R235–46.
Montaron MF, Drapeau E, Dupret D, Kitchener P, Aurousseau C, Le Moal M, et al. Lifelong corticosterone level determines age–related decline in neurogenesis and memory. Neurobiol Aging. 2006;27:645–54.
Messier C. Impact of impaired glucose tolerance and type 2 diabetes on cognitive aging. Neurobol Aging. 2005;26(Suppl 1):S26–30.
Tan X, Fang P, An J, Lin H, Liang Y, Shen W, et al. Micro-structural white matter abnormalities in type 2 diabetic patients: a DTI study using TBSS analysis. Neuroradiology. 2016;58:1209–16.
Hsu JL, Chen YL, Leu JG, Jaw FS, Lee CH, Tsai YF, et al. Microstructural white matter abnormalities in type 2 diabetes mellitus: a diffusion tensor imaging study. NeuroImage. 2012;59:1098–105.
Falvey CM, Rosano C, Simonsick EM, Harris T, Strotmeyer ES, Satterfield S, et al. Macro- and microstructural magnetic resonance imaging indices associated with diabetes among community-dwelling older adults. Diabetes Care. 2013;36:677–82.
Xie Y, Zhang Y, Qin W, Lu S, Ni C, Zhang Q. White Matter Microstructural Abnormalities in Type 2 Diabetes Mellitus: A Diffusional Kurtosis Imaging Analysis. Am J Neuroradiol. 2017;38:617–25.
Wykes TL, Lee AA, McKibbin CL, Laurent SM. Self-efficacy and hemoglobin A1C among adults with serious mental illness and type 2 diabetes: the roles of cognitive functioning and psychiatric symptom severity. Psychosom Med. 2016;78:263–70.
Funding for this study was provided by the CAS Pioneer Hundred Talents Program, the National Natural Science Foundation of China (81371477, 61533006, U1808204, 61806042), the project of the Science and Technology Department in Sichuan province (2017JY0094).
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Zhang, X., Yang, M., Du, X. et al. Glucose disturbances, cognitive deficits and white matter abnormalities in first-episode drug-naive schizophrenia. Mol Psychiatry 25, 3220–3230 (2020). https://doi.org/10.1038/s41380-019-0478-1
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