Systemic Lupus Erythematosus : A Blood-oxygen-level Dependent Functional Spatial Working Memory Impairment in Patients with Non-neuropsychiatric

Objective. Using ethology and functional magnetic resonance imaging (fMRI) to explore mild cognitive dysfunction and spatial working memory (WM) impairment in patients with systemic lupus erythematosus (SLE) without overt neuropsychiatric symptoms (non-NPSLE) and to study whether any clinical biomarkers could serve as predictors of brain dysfunction in this disease. Methods. Eighteen non-NPSLE patients and 18 matched subjects were all tested using the Montreal cognitive assessment scale test and scanned using blood-oxygen-level dependent fMRI while performing the n-back task to investigate the activation intensity of some cognition-related areas. Results. Ethology results showed that non-NPSLE patients had mild cognitive dysfunction and memory dysfunction (p < 0.05). The fMRI scan confirmed a neural network consisting of bilateral dorsolateral prefrontal cortex (DLPFC), premotor area, parietal lobe, and supplementary motor area (SMA)/anterior cingulate cortex (ACC) that was activated during the n-back task, with right hemisphere dominance. However, only the right SMA/ACC showed a load effect in the non-NPSLE group; the activation intensity of most WM-related brain areas for the non-NPSLE group was lower than for the control group under 3 memory loads. Further, we found that the activation intensity of some cognition-related areas, including the bilateral caudate nucleus/insula and hippocampus/parahippocampal gyrus were lower than the control group under the memory loads. An inverse correlation existed between individual activation intensity and disease duration. Conclusion.Non-NPSLE–related brain damage with right DLPFC-posterior parietal lobe and parahippocampal gyrus default network causes impairment of spatial WM and mild cognitive dysfunction. Patients with longer disease duration would be expected to exhibit increased central nervous system damage. (J Rheumatol First Release January 15 2017; doi:10.3899/jrheum.160290) Key Indexing Terms: SYSTEMIC LUPUS ERYTHEMATOSUS SPATIAL WORKING MEMORY FUNCTIONAL MAGNETIC RESONANCE IMAGING From the Department of Radiology, First Affiliated Hospital, Medical College of Shantou University; Guangdong Key Laboratory of Medical Molecular Imaging, Shantou, Guangdong; Graduate School of Beijing Normal University, Zhuhai, China. Contract grant sponsors and contract grant numbers: National Natural Science Foundation of China, 81373745, 81072905, 81370925; Natural Science Foundation of Guangdong Province of China, S2011010005019, 10151503102000015; Science and Technology Planning Project of Guangdong Province of China, 2009B030801323, 2010B031600023; Shantou Technology Bureau Science Foundation of China; Shantou Government Technology, [2006] 85, [2011] 46. C.M. Zhu, MD, Department of Radiology, First Affiliated Hospital, Medical College of Shantou University, and Guangdong Key Laboratory of Medical Molecular Imaging; L. Xie, MD, Department of Radiology, First Affiliated Hospital, Medical College of Shantou University, and Guangdong Key Laboratory of Medical Molecular Imaging; J.Z. Huang, MD, Department of Radiology, First Affiliated Hospital, Medical College of Shantou University, and Guangdong Key Laboratory of Medical Molecular Imaging, and Department of Radiology, Chaonan Minsheng Hospital of Shantou; Z.B. Sun, MD, Department of Radiology, First Affiliated Hospital, Medical College of Shantou University, and Guangdong Key Laboratory of Medical Molecular Imaging, and Department of Radiology, Chaonan Minsheng Hospital of Shantou; S.X. Duan, MD, Department of Radiology, First Affiliated Hospital, Medical College of Shantou University, and Guangdong Key Laboratory of Medical Molecular Imaging; Z.R. Lin, MD, Department of Radiology, First Affiliated Hospital, Medical College of Shantou University, and Guangdong Key Laboratory of Medical Molecular Imaging; J.J. Yin, MD, Department of Radiology, First Affiliated Hospital, Medical College of Shantou University, and Guangdong Key Laboratory of Medical Molecular Imaging; H.B. Le, MD, Department of Radiology, First Affiliated Hospital, Medical College of Shantou University, and Guangdong Key Laboratory of Medical Molecular Imaging; D.M. Sun, MD, Department of Radiology, First Affiliated Hospital, Medical College of Shantou University, and Guangdong Key Laboratory of Medical Molecular Imaging; S.H. Ma, PhD, Professor, Department of Radiology, First Affiliated Hospital, Medical College of Shantou University, and Guangdong Key Laboratory of Medical Molecular Imaging, and Chaonan Minsheng Hospital of Shantou; Y. Ma, MD, Graduate School of Beijing Normal University; W.C. Xu, PhD, Department of Radiology, First Affiliated Hospital, Medical College of Shantou University. Chun-Min Zhu and Ye Ma contributed equally to this work. Address correspondence to S.H. Ma, Professor, Department of Radiology, First Affiliated Hospital, Medical College of Shantou University, Shantou, Guangdong, China. E-mail: mshmshu@163.com Accepted for publication November 25, 2016. Journal of Rheumatology The on January 19, 2017 Published by www.jrheum.org Downloaded from Systemic lupus erythematosus (SLE) is a chronic auto immune disease characterized by multisystem involvement and diverse clinical manifestations. According to the American College of Rheumatology (ACR), a neuropsychiatric SLE (NPSLE) diagnosis is defined by clinical, multimodal neurological examinations and a neuropsychological assessment. Cognitive impairment is identified as one of the 19 NPSLE manifestations and defined as significant deficits in any or all of the following cognitive functions: complex attention, executive skills, memory, visual–spatial processing, language, and psychomotor speed1. Cognitive functioning of patients with NPSLE is inferior to those without overt neuropsychiatric symptoms (non-NPSLE), and over 25% of non-NPSLE patients are cognitively impaired when compared with controls in areas such as learning, memory, attention, reasoning, and fluency2,3. Functional magnetic resonance imaging (fMRI) of the brain while subjects were performing cognitive function tasks including working memory, attention, and language proces sing, was significantly altered in patients with NPSLE compared with healthy subjects4,5. However, because these fMRI studies involved patients with NPSLE, the findings failed to explore whether the brain activities in non-NPSLE subjects were altered. Such knowledge is meaningful because it is currently believed that non-NPSLE patients perform worse on neuropsychiatric tests than healthy subjects6. This would lead to a better understanding of the pathogenesis of NPSLE, and provide potential direction for the development of early interventions. A study using the Rey Auditory Verbal Learning Test to assess working memory (WM) in non-NPSLE patients demonstrated significantly increased brain activities in the anterior medial prefrontal cortex during the learning process. Patients also showed significant positive correlations between learning efficiency and hippocampal activity7. Another group of investigators using the Paced Visual Serial Addition Test to test non-NPSLE8 patients for sustained attention, WM, and speed of information processing demonstrated attenuated brain activities in the cerebellum, posterior cingulate, and the adjacent precuneus in the default mode network. WM is defined as a component of short-term memory and has been widely considered an important cognitive function, consisting of verbal, object, and spatial WM that handle different types of information9. It has been closely linked with other cognitive behaviors10. In addition, WM is a limited capacity system that temporarily stores and processes information for use in guiding behavior11. The WM capacity refers to the number of items of information that can be maintained over a short interval and contributes to performance in a wide variety of cognitive tasks12. Because both of the previous studies focused on the verbal WM, which is different from spatial WM in neural pathway processing13,14, it is necessary to study whether spatial WM is impaired in non-NPSLE patients. Therefore, the goal of our study was to map the potential functional abnormalities of spatial WM-related brain areas of non-NPSLE patients under a block-designed n-back task and to study whether any clinical biomarkers could serve as a predictor of brain dysfunction in this disease. We hypothesized that patients have poorer behavior and activation intensity during the WM task. MATERIALS AND METHODS Study participants. Eighteen right-handed patients with SLE were recruited from the Department of Rheumatology, the First Affiliated Hospital of Shantou University. All patients satisfied the ACR classification criteria for SLE15 and had no overt neuropsychiatric syndromes in ACR case definition of NPSLE1 (e.g., cerebrovascular disease, psychosis, seizures, dysauto nomia, neuropathies, or myasthenia gravis). The Systemic Lupus Erythe matosus Disease Activity Index (SLEDAI)16 and the Systemic Lupus International Collaborating Clinics/ACR Damage Index (SLICC/DI)17 were used to evaluate disease activity of SLE. Four patients had high levels of disease activity, as indicated by SLEDAI scores > 4, while the other 14 patients had SLEDAI scores ≤ 4. Serum levels of complement components (C3, C4) and anti-dsDNA antibodies were measured in the hospital clinical laboratory. At the time of study enrollment, all patients were taking prednisone; 6 were also prescribed immunosuppressants and 4 nonsteroidal antiinflammatory drugs. Eighteen healthy volunteers were matched with the patient group according to sex, age, handedness, and duration of education. Sociodemographic and clinical characteristics of all the subjects are shown in Table 1. Participants were ineligible for our study if they had organic brain disorders; alcohol or drug abuse; pregnancy; any physical illness such as hepatitis, brain tumors, or epilepsy; a history of a psychiatric diso