Table 2.

Summary of the 14 articles which evaluated cognitive dysfunction in patients with neuropsychiatric systemic lupus erythematosus using brain functional MRI and/or SPECT

First author (reference number), country/year	Sample size	Intervention	Main findings in patients with cognitive dysfunction	Examined paradigms	Imaging findings
Driver et al. (22), USA/2008	37 NP-SLE1 patients, 19 normal controls (mean age: 42 years)	99mTc-ECD2 brain SPECT3	30 (81.1%) cases out of 37 NP-SLE patients had abnormal scans	Cognitive dysfunction	The scans revealed markedly decreased perfusion in the watershed areas of the frontal lobes bilaterally. Severe cognitive dysfunction was associated with severe perfusion deficits, compared to mild cognitive dysfunction.
Zhang et al. (24), China/2005	43 patients with SLE (22 cases with NP-SLE and 21 cases with non-NP-SLE)	99mTc-ECD brain SPECT, MRI4	6 cases out 7NP-SLE patients with cognitive dysfunction had abnormal SPECT	Cognitive dysfunction	19 (95.0%) out of 20 abnormal SPECT scans showed moderate to severe perfusion defect, mostly affecting multiple regions (17/20), especially in the frontal and parietal lobes and the basal ganglia (15, 11, 11, and 3 cases in the frontal, parietal, basal ganglia, and temporal lobes, respectively). In the NP-SLE patients with diffuse presentations, SPECT revealed 16/18 versus 6/18 abnormalities in MRI.
DiFrancesco et al. (12), USA/2007	10 childhood-onset SLE patients (7 cases with cognitive dysfunction)	Brain fMRI5	Six out of 10 childhood-onset SLE patients showed a statistically significant increased activation of brain in special areas involved in the CPT6, n-back, and verb generation tasks	Attention, working memory, and language processing	Language: childhood-onset lupus patientsshowed greater activation in the Broca’s area and non-activation of the Wernicke’s area. Attention: SLE patients exhibited more extensive activation than control subjects in the large tracts of the fusiform gyrus and visual associative cortex with abnormal attention Memory: the patient group had greater activation in the hippocampus and prefrontal regions.
Oh et al. (23), Korea/ 2011	19 SLE patients (6 cases with memory impairment)	Brain SPECT	In NP-SLE patients, 6 out of 9 regions of interest had a greater activation during working memory activity	Cognitive function and memory function	Significant hypoperfusion was observed in the right precuneus in the patients with memory impairment, which was possibly due to the association between impaired intrinsic functional connectivity in the default network and memory impairments in SLE
Shapira-Lichter et al. (14), England/2013	23 SLE patients (12 cases without clinically overt neuropsychiatric manifestations and 11 matched healthy controls)	fMRI	3cases out of 12 SLE patients without overt NP symptoms complained of cognitive dysfunction manifested as a difficulty in remembering names and words	Learning and recall function	The anterior medial prefrontal cortex of the DMN7 appeared to be the only region where brain activity dynamics were altered during the learning process and within free-recall period attempts. A significantly different brain activation dynamics was demonstrated in the patients with SLE as compared to that in the healthy controls.
Waterloo et al. (25), Norway/2001	57 SLE patients	Brain SPECT and MRI	No association was detected between cognitive dysfunction and rCBF8 in NP-SLE patients	Different areas of cognition, such as memory, attention, language, visuospatial processing, psychomotor speed, and executive function	Abnormal global CBF was observed in 31 patients. 17 patients had focal lesions of reduced blood flow. 50% of the patients had generalized bilateral CBF reduction, mostly in the temporal or frontal lobes. The areas of hypoperfusion were most frequently in the frontal, temporal, and parietal regions. 31/56 patients (55 %) showed CBF global reduction of> 15%. Significantly reduced rCBF was seen in the superior part of the frontal,frontal inferior, parietal superior, parietal inferior,and temporal lobes of 32, 17, 13, 26, and 43 patients, respectively.
Fitzgibbon et al. (13), New Zealand/2008	27 female patients (9 SLE patients, 9 healthy controls. and 9 rheumatic arthritis controls)	Brain BOLD-fMRI9	Greater frontoparietal activation in NP-SLE patients during the memory task	Working memory	The NP-SLE patients had greater degrees of cortical activation (i.e., increased cortical blood flow to activated areas) at six of the nine studied ROIs10 during performing the memory tasking, which was significant in three regions, namely the posterior inferior parietal lobules of both hemispheres separately and combined and supplementary motor area (mid-line frontal lobe).
Nishimura et al. (21) , Japan/2016	43 corticosteroid-naive patients with SLE	MRI and EEG	16.7% and 41.7% of the patients with NIC hadabnormal brain MRI and EEG, respectively	NCI	Patients with SLE had lower scores than the control subjects for RAVLT trials, reflecting immediate recall and psychomotor speed. Lower psychomotor speed was concluded to result from reduction in corpus callosum volume or other white matter abnormalities.
Ichinose et al. (20), Japan/2015	32 NP-SLE patients	MRI	17 (53.1%) cases out of 32 patients had abnormal MRI findings	NCI	Cytokines/chemokines were significantly higher in the NPSLE patients, compared to the MS/NMO patients.
Sarbu et al. (19), UK/2015	108 patients with neuropsychiatric lupus	MRI	Brain abnormalities were detectedin 59.3% of the patients	Cognitive dysfunction	Approximately, WMH, especially in frontal and parieto-occipital regions, was observed in half of the patients; however, only focal WMH with low lesion burden was observed in patients with normal MRI.
Zimmermann et al. (18), Brazil/2017	40 patients with SLE	MRI and fMRI	47% of the patients had abnormal MRI findings	Cognitive dysfunction	A decreased volume was reported in the left hippocampus, amygdala, and the right hippocampus in the SLE patients with cognitive dysfunction.
Cesar et al. (17), USA/2015	23 patients with neuropsychiatric systemic lupus	MRI	---	Cognitive dysfunction	Increased T2 lesion number and volume as well as greater lesion attenuation in the left superior and a small portion of the right posterior corona radiata were observed in the patients with NPSLE.
Piga et al. (16),Italy/2015	30 patients with longstanding SLE	MRI and fMRI	53.3% of the patients had MRI abnormalities, and 80% of them showed abnormalities in the follow-up MRI	Cognitive dysfunction	mMSS, cerebral volume loss, and new ischemic parenchymal lesions were observed in some cases.
Al-Obaidi et al. (15), UK/2016	27 Childrenwith NP-SLE	MRI	Cognitive dysfunction was observed in 14.8% of the patients	Cognitive dysfunction and anxiety disorder	The majority of the patients had no MRI abnormalities despite the signs and symptoms of active NPSLE. T2-weighted imaging showed cortical grey matter lesions, brain atrophy, basilar artery territory infarction, and focal white matter hyperintensities in some cases.

NP-SLE= Neuropsychiatric systematic lupus erythematous; ECD= ethyl cysteinate dimer; CPT= Continuous performance task; NMO= Neuromyelitis optica; DMN= Default mode network; rCBF= Regional cerebral blood flow; BOLD-fMRI= blood-oxygen-level-dependent functional MRI; ROIs= Regions of interest; NIC= Neurocognitive impairment; mMSS= Modified MRI scoring system; NCI= Neurocognitive impairment; RAVLT= Rey Auditory Verbal Learning Test