Association between Cognitive Impairment and Olfactory Deficits in Systemic Lupus Erythematosus Without Major Neuropsychiatric Syndromes

doi:10.21203/rs.3.rs-1039182/v1

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Research article

Association between Cognitive Impairment and Olfactory Deficits in Systemic Lupus Erythematosus Without Major Neuropsychiatric Syndromes

https://doi.org/10.21203/rs.3.rs-1039182/v1

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posted 08 Nov, 2021

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Objective Cognitive impairment is a common neuropsychiatric manifestation of systemic lupus erythematosus (SLE). However, it is not routinely assessed despite its high morbidity and mortality. The aim of the study was to investigate the utility of a brief neuropsychological battery, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), to evaluate cognitive deficits in patients with SLE and to examine the relationship between cognitive and olfactory function.

Methods Fifty-five SLE patients and 50 age- and sex-matched healthy control subjects were administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), a cognitive screening battery that evaluated five index of cognition including immediate memory (IMME), visuospatial/constructional (Vis/Con), language (LANG), attention (ATT), delayed memory (DEME). Olfactory functions were evaluated using olfactory function assessment by computerized testing including the three stages of smell: threshold (THR), identification (ID) and memory (ME) of the different odors. The disease activity and cumulative damage were assessed by the SLE Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology(ACR) Damage Index (SDI).

Results Patients with SLE exhibited significant lower total RBANS score, IMME, Vis/Con, ATT and DEME index scores than normal controls (P < 0.01 for all and P = 0.027 for attention). Performances on RBANS immediate memory, language, attention and total scores were correlated with education level of SLE patients. Reduced RBANS index and total scores were associated with several organ involvement and autoantibodies. SLE patients with higher SLEDAI-2K scores or with accumulated damage (SDI≥1) showed decreased RBANS scores than patients with lower SLEDAI-2K scores or without accumulated damage. All the olfactory scores (THR, ID and ME) in patients with SLE were significantly decreased than the control group (all P = 0.001). Patients had higher proportion of anosmia (8.57% vs 0%) and hyposmia (28.58% vs 5.72%) than controls (χ² = 10.533, P = 0.015). Multivariable regression analysis revealed that olfactory threshold, identification and memory had a positive effect on RBANS index score. Olfactory memory and total score were significantly correlated with the RBANS delayed memory (r = 0.393, P = 0.021) and total scores (r = 0.429, P = 0.011).

Conclusion The results of this study indicate that significantly correlated cognitive and olfactory functions are impaired in SLE patients. The RBANS is a potentially useful instrument for evaluating neuropsychological status in SLE. Physicians are encouraged to perform routine screening in patients with SLE to detect subtle cognitive dysfunction and strategize early treatment options.

Immunology

General Microbiology

Rheumatology

Systemic lupus erythematosus

Cognition

Olfaction

RBANS

Memory

Impairment

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by multisystem involvement and various manifestations. Cognitive impairment (CI) is one of the most common neuropsychiatric manifestations in SLE (NPSLE) with the prevalence of 15%~90% [1]. The broad range of reported prevalence rates of CI in SLE patients is due to differences in the disease spectrum of patients under study, the selection of neurocognitive tests, and the standardized definition for CI [2]. Cognitive dysfunction in SLE is not always overtly expressed and the signs and symptoms of CI can be easily missed as they can be heterogeneous and mild in the beginning. Thus, there is growing recognition that CI in lupus patients remains underdiagnosed and under-addressed in the clinical setting [3]. However, the impact of CI in SLE extends beyond the psychological impairment and can have cruel socio-economic consequences by negatively impacting patient’s quality of life and employment potential [4]. Given the importance and high prevalence of cognitive dysfunction, early detection of CI is essential for early treatment of SLE patients.

Formal neurocognitive testing is considered the current gold standard for assessing cognitive functioning. The most frequently used battery of tests to assess cognition in SLE, are comprehensive traditional assessments that are often administered by a psychologist [5]. However, such batteries require specialized training to administer, are time consuming (4 hours), and often are cost prohibitive, which prevent widespread use of conventional neuropsychological testing in the medical setting. Recently, the ACR-SLE battery has been shown to be a relatively good CI evaluating tool in SLE patients [6], its main barrier is the significant time (1 hours) and resources it requires for administration, making it challenging for routine use. Some computer-based tools for detecting cognition include Automated Neuropsychological Assessment Metric (ANAM), permits efficient assessment by nonexperts, but they may fail to identify higher-level cognitive impairment [7]. Other approach involves the use of very concise screening instruments such as the Mini-Mental State Exam (MMSE) and the Montreal Cognitive Assessment (MoCA) [8]. While this strategy remedies the problem of lengthy administration and interpretation times, extremely brief tests may be less effective in identifying mild cognitive impairment and insensitive to the type and magnitude of the impairments typically observed in SLE. Hence, identifying and validating a reliable screening and monitoring tool for CI that is both sensitive and specific, as well as technically feasible in the clinical setting, are of the utmost importance.

The Repeatable Battery for Assessment of Neuropsychological Status (RBANS) was originally developed for cognitive screening of dementia in the aged [9]. Recently, it has been used to detect CI in patient populations such as multiple sclerosis, Parkinson’s disease, cerebrovascular disease, stroke and so on [10]. The RBANS’ major strengths include brevity (30 min), sensitivity to mild cognitive impairment, demographic age corrections, and strong correlation with more extensive neuropsychological batteries [11]. Unlike screening assessments such as MMSE or MoCA that provide a single summary score, the RBANS yields separate scores for several cognitive domains, including attention, memory, language, and visuospatial processing, which provides a guarantee for research on the pathological mechanism of functional decline in different cognitive domains. There are excellent norms for the RBANS and a growing literature that supports its good validity and utility for inpatient evaluations. Until now, there is no study on the use of RBANS for the evaluation of cognitive function in SLE patients.

Olfactory dysfunction has been confirmed in various neurologic, neurodegenerative and autoimmune diseases. Dementia is well known to be associated with olfactory impairment, which has been highlighted as a potential early biomarker in Alzheimer’s disease [12]. In SLE patients, impaired smell function was associated with disease activity and neuropsychiatric manifestations [13, 14]. In previous study, olfactory assessment in SLE patients was performed using the Sniffin' Sticks kit (SST), which consists of three stages of smell as threshold, discrimination, and identification of odors [15]. Right now, there is no study to conduct a complete examination of olfactory threshold, identification and memory, nor to investigate the relationship between olfactory dysfunction and different impaired cognitive domains in SLE patients.

The purpose of this study was to determine the RBANS characterizes cognitive dysfunction in patients with SLE and to elucidate which clinical and laboratory variables were associated with poorer performances on the RBANS index and total scores. A secondary goal of this study was to investigate the relationship between impaired cognition and olfactory disturbance in SLE patients.

Patients

Total 55 SLE patients (50 women and 5 men) and 50 healthy individuals were included. All patients fulfilled the 1997 American College of Rheumatology (ACR) classification criteria for SLE [16]. To assure the sociodemographic similarities of the SLE and control groups, the healthy controls were selected from the community based on sex, age, education and demographic background. This study was approved by the Ethics Committee of the Nanjing Drum Tower Hospital and was carried out in compliance with the Helsinki Declaration. All participants were informed about the nature of the study and gave voluntary consent before enrollment. Subjects were excluded if they: (1) had history of neurologic disease other than NPSLE (e.g., stroke, traumatic head injury); (2) had other diagnosed psychiatric disorder, including schizophrenia or bipolar disease; (3) history of alcoholism, drug abuse, or mental retardation; (4) had current serious medical conditions (e.g., recent heart attack, poorly controlled diabetes); (5) could not read or write; (6) were pregnant or breastfeeding; (7) a history of posttraumatic or upper respiratory infection-induced olfactory loss, or other medical condition that could alter their olfactory function.

Clinical assessment

Complete medical histories including demographics, disease manifestations, physical examination, laboratory evaluation and current therapies were obtained from medical records and case managers. Organ involvement was defined according to the criteria described previously: nephritis = urinary casts (heme-granular or red blood cell casts), or hematuria ( > 5 red blood cell/high power field), or proteinuria ( > 0.5g/24hours), or pyuria ( > 5 white blood cell/high power field), mucosal ulcers = oral or nasal ulcerations, rash = inflammatory type rash, serositis = pleurisy or pericarditis, pulmonary fibrosis = bibasilar fibrosis on chest radiography and high-resolution CT, pulmonary arterial hypertension (PAH) = pulmonary arterial pressure (PAP)≥35 mmHg (transthoracic echocardiography), hyperglobulinemia = the levels of serum globulin IgG or IgM above the upper limit of normal for testing laboratory, hypocomplementemia = the levels of serum complement C3 or C4 below the lower limit of normal for testing laboratory. Global SLE disease activity was measured by the SLE Disease Activity Index 2000 (SLEDAI-2K). Scores > 3 were considered active disease [17]. Cumulative SLE related damage was determined in all patients using the Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index (SDI). Damage was considered if scores≥1 [18].

Laboratory tests

Routine haematological and biochemical tests were analyzed in the hospital laboratory. Plasma was tested for antinuclear antibodies (ANA) using indirect immunofluorescence with HEp-2 cells as the antigen substrate (Immuno Concepts, Sacramento, USA). The antibodies to double-stranded DNA (dsDNA) were verified by a Nova Lite dsDNA Crithidia luciliae 708200 indirect immunofluorescence assay (Nova Diagnostics, San Diego, California, USA). The presence of anti-Smith, anti-histone, anti-ribomsomal P and anti-nucleosome antibodies were confirmed by indirect immunofluorescence assay (Oumeng Medical Laboratory Diagnosis Co., Hangzhou, China).

Cognitive tests

The RBANS (Form A) [9] which was translated for local application, was applied to evaluate cognitive functioning in SLE patients. The examiners of the patients were nurses who had substantial training in neuropsychological assessment and in the administration and scoring of the RBANS. RBANS assessed cognitive function in 12 subtests (composed of list learning, story memory, figure copy, line orientation, picture naming, semantic fluency, digit span, coding, list recall, list recognition, story recall and figure recall). Five domains of cognition were derived from these 12 subtests: immediate memory (IMME), visuospatial/constructional (Vis/Con), language (LANG), attention (ATT), delayed memory (DMME). The total scale score was calculated by summarizing these 5 index scores according to the guidelines published in the administration manual. The index scores and total scale score were demographically adjusted for age with an average of approximately 100 and a standard deviation (SD) of approximately 15 reported in the RBANS manual. The total scale of scores range from 40 to 160, and the lower the total RBANS score, the poorer the cognitive function. The RBANS has been confirmed to have good validity and reliability in Chinese people [19].

Olfactory assessment

All the participants were blind to the examiner using Olfactory Function Assessment by Computerized Testing (OLFACT-CTM, Osmic Enterprises, Inc.). It comprises tests for odour threshold (THR), odour identification (ID) and odour memory (ME). The olfactory threshold test (score range, 1~13.5) was determined based on a series of binary dilutions of the n-butanol solution. Scores of 8~10 were considered normosmia, and scores of 4~7 were identified as hyposmia, while scores of 1~3 signified anosmia, scores above 10 suggested sensitive olfaction. The olfactory identification and memory tests consisted two tasks, and assessed subject’s ability to identify and remember odors. The test beginning with the presentation of 10 odors (task A, score range, 0~10), the participant was asked to identify each one from 4 choices. Followed by a 10 minutes break, 20 odors containing the 10 old odors from task A and 10 new odors were presented (task B, score range, 0~20), and the participant was asked to identify the odor and also determine if the odor was one of the old odors or a new odor (old odors and new odors score range, 0~10, respectively). This provided measures of both semantic and episodic odor memory. The three tests took approximately 45 min. At the end of the testing procedure, the sum of the THR, ID and ME scores was referred to as the TIM (Threshold + Identification + Memory).

Statistical analysis

The statistical analysis was performed using SPSS software (version 20.0, SPSS Inc., Chicago, IL, USA). Data were presented as mean ± SD. An independent samples t-test was used for comparing normally distributed continuous variables in the patient and control groups. In the case of multiple comparisons, one-way analysis of variance with Bonferroni’s multiple comparisons test was used. A chi-square test was used to compare dichotomous variables, and Pearson’s correlations were used to measure the strength and direction of linear relationships between pairs of continuous variables. A multivariate linear regression analysis was applied to adjust for characteristics such as age and education and evaluate relations between different measurements. All differences were considered significant at P < 0.05.

Patient cohort

The demographic characteristics for SLE patients were summarized in supplementary Table 1, 55 patients with SLE were investigated. There were 5 (9.09%) males (ages ranged from 22 to 46 years, mean age of 31.61 ± 9.34 years) and 50 (90.91%) females (ages ranged from 20 to 53 years, mean age of 32.74± 11.01 years). The duration of the disease ranged from 0.1 to 22 years, with mean duration of 6.42 ± 4.85 years. For the control group, there were 5 males (ages ranged from 22 to 48 years, mean age of 32.25 ± 8.18 years) and 45 females (ages ranged from 21 to 55 years, mean age of 33.17 ± 10.76 years). No participants were taking medication known to interfere with cognition or smell.

Cognitive test performance

The RBANS total and index scores of SLE patients and control individuals were depicted in Table 1, patients with SLE exhibited statistically significant lower RBANS total scale score, immediate memory, visuospatial/constructional, attention and delayed memory index scores than normal controls (P < 0.01 for all and P = 0.027 for attention). There was no significant difference between SLE patients and controls in language index scores (P = 0.325), and both of picture naming and semantic fluency subtests which composed of language index scores were not impaired.

The total scale scores in SLE patients were approximately one standard deviations below the normative data reported in the RBANS manual (normal mean = 100, SD = 15), with only 16.36% (9/55) of cases scoring at or above the normal mean and only 43.64% (24/55) scoring 85 or above (i.e., within 1 SD of the normal mean), compared with that of healthy controls (48% (24/50) and 78% of (39/50) cases, respectively). Moreover, when the cutoff value was set as 2 SD below the normal mean, 12 patients (21.82%) and none of healthy subjects were impaired on RBANS, respectively.

RBANS and disease activity

As Table 2 indicated, level of education was highly correlated with RBANS total scale score (P = 0.004) in SLE patients. Age did not demonstrate a relationship with RBANS total scale score, which was expected because the RBANS uses age-adjusted standard score. No correlation was demonstrated between all of the index scores and duration of disease or sex.

Consequently, the correlation between RBANS scores and clinical and laboratory parameter were assessed in SLE patients. Patients with involvement of the kidney showed significantly diminished scores for IMME and total scale scores (P = 0.04, and P = 0.022) (Fig. 1a). Patients with serositis had significantly lower scores for IMME, LANG, ATT, DEME and total scale scores (P =0.007, P = 0.003, P = 0.009, P = 0.048 and P =0.002, respectively) (Fig. 1b). In addition, patients with rash had significantly decreased scores for IMME, Vis/Con, LANG, DEME and total scale scores (P = 0.03, P = 0.016, P = 0.007, P = 0.035 and P = 0.004, respectively) and patients with mucosal ulcers had significantly lower scores for IMME, Vis/Con, LANG, ATT, DEME and total scale scores (P = 0.022, P = 0.034, P = 0.003, P = 0.032, P = 0.047 and P = 0.003, respectively) (Fig. 1c, d). No correlation was observed between RBANS scores and other organ involvement, including pulmonary fibrosis, pulmonary hypertension, arthritis, myositis and thrombocytopenia (data not shown). ANOVA indicated that there were no significant differences between patients with proteinuria and patients without proteinuria in total scale scores (Fig. 1e), although patients with large amounts of proteinuria (>3.5g/24h) seemed to have a downward trend in total score (F = 2.117, P = 0.152).

SLE patients were divided into four groups according to SLEDAI-2K, and difference in RBANS total score among the four groups was significant (F = 14.876, P < 0.001) (Fig. 1f). Furthermore, multivariable regression analyse revealed that SLEDAI had a strong negative influence on five index scores and total scale score (b = -1.294, P = 0.003; b = -1.579, P = 0.001; b = -1.312, P = 0.001; b = -1.071, P = 0.001; b = -2.097, P = 0.001; b = 1.74, P = 0.001; respectively) (Table 2). Moreover, SLE patients with accumulated damage (SDI≥1) showed decreased RBANS scores than patients without accumulated damage (Fig. 1g). Therefore, SLE disease activity and accumulated damage have a strong negative effect on the cognitive function.

According to the levels of ANA titer, the patients were divided into three groups, and IMME, LANG, DEME and total scale scores were lower in SLE patients with high titer (ANA≥1:1000) than those with low titer (ANA≤1:320) (F =5.599, P =0.022; F =4.633, P =0.036; F =5.031, P =0.029; F =6.94, P =0.011; respectively)(Fig. 2a). Vis/Con, ATT and total scale scores were decreased in patients with anti-dsDNA antibody compared to those without (P =0.002, P = 0.026, and P =0.011, respectively) (Fig. 2b). Besides, patients with anti-ribosomal P antibody had significantly diminished scores for LANG, DEME and total scale scores (P = 0.019, P = 0.041, and P = 0.012, respectively)(Fig. 3c). However, no significant differences were observed in cognitive assessment between patients with anti-Smith antibody, anti-nucleosome antibody or anti-histone antibody and those without (Fig. 2d-f). There was no correlation of RBANS scores with antiphospholipid (aPL) antibodies, serum IgG, complement C3, C4, CRP or ESR in SLE patients (data not shown). No significant association was observed between SLE subjects’ RBANS scores and current prednisone dose or use of immunosuppressant medication (data not shown).

Smell test performance

A significant decrease in olfactory function was observed in patients with SLE compared to healthy controls, as illustrated in Table 3. In fact, patients had significantly lower smell threshold, smell identification and smell memory scores compared with controls (all P <0.01). Meanwhile, overall olfactory sum (TIM scores) were significantly reduced in SLE cohort compared to the control group.

Furthermore, anosmia was present exclusively in the SLE group (8.57% of patients vs 0% of controls), and hyposmia was more prevalent in patients with SLE than in controls (28.58% of patients vs 5.72% of controls). Normal sense of smell seemed to be decreased in SLE patients than controls (17.14% of patients vs 25.71% of controls), however, sensitive olfaction was more prevalent in controls than in patients (68.57% of controls vs 45.71% of patients) (χ² =10.533, P =0.015) (Supplementary Fig. 1). Our results suggest that SLE patients had increased rates of anosmia and hyposmia.

Correlation of the smell test results of SLE patients with disease activity

Patients with PAH or rash showed significantly diminished scores for olfactory THR than those without PAH or rash (P =0.033, and P =0.005) (Supplementary Fig. 2a and b). While, no significant difference in olfactory function scores were found between SLE patients with nephritis or mucosal ulcers and those without (Supplementary Fig. 2c and d). No correlation was observed between olfactory function scores and other organ involvement, including pulmonary fibrosis, serositis, arthritis, myositis and thrombocytopenia (data not shown).

There was no correlation of smell test scores with duration of disease, SLEDAI-2K, accumulated damage, autoantibodies, aPL antibodies, proteinuria, hypocomplementemia or hyperglobulinemia in SLE patients (data not shown).

Correlation of cognition impairment with olfactory deficit

In multivariable regression models, olfactory threshold and memory had a positive influence on RBANS total score (b =2.088, P =0.013; b =3.217, P =0.012, respectively)(Table 4). Significant associations of olfactory threshold with cognitive domain performances were observed for immediate memory (b =3.087, P =0.004) and for delayed memory (b =2.986, P =0.002). Olfactory identification also showed a positive effect on visuospatial/construction and language (b =2.608, P =0.022; b =1.97, P =0.035, respectively). Olfactory memory was associated with better performance in visuospatial/construction, language, attention and delayed memory (b =3.502, P =0.012; b =4.667, P =0.001; b =2.676, P =0.011; b =3.098, P =0.032; respectively).

In addition, olfactory TIM score was significantly correlated with the RBANS total score (r = 0.429, P = 0.011) and there was also an positive relation between olfactory memory score and RBANS delayed memory scores (r = 0.393, P = 0.021) (Fig. 3a and b). Lower smell scores may be a useful marker of possible co-occuring cognitive dysfunction.

To the best of our knowledge, RBANS has not been utilized in evaluating neuropsychological status in SLE. In this study, RBANS was used to assess cognitive function for the first time, and the close relationship between cognitive dysfunction and olfactory deficits was reported. Our results revealed that SLE patients exhibit significantly deteriorated cognitive and olfactory function. SLE disease activity and cumulative damage had negative impact on cognitive function. Decreased RBANS index and total scores were associated with several organ involvement and autoantibodies. In addition, olfactory threshold, olfactory identification, olfactory memory and olfactory total score were associated with better performance in RBANS index scores and total score respectively. Collectively, these data highlight the close relationship between cognitive dysfunction and olfactory deficits. RBANS may be used as a useful and simple screening tool to help physicians detect subtle cognitive dysfunction and monitor cognitive change in patients with SLE.

Currently, the screening and diagnosis of CI in SLE is delayed and its monitoring is not well developed. This situation is likely due to the lack of appropriate cognitive screening assessment tools for this population. The RBANS has been widely used in many settings as a screening tool for cognitive impairment and to track changes in cognition related to disease progression or treatment [20, 21]. In our cohort, SLE patients had a significantly higher frequency of impairment in the area of attention, visuospatial/construction, and immediate and delayed memory compared with controls, while performing similar to the normal controls on language index. The Language index consists of the picture naming and semantic fluency subtests. Semantic fluency is the ability to form and express words compatible with required criteria and is a good indicator of frontal lobe dysfunction [22]. Thus, language index score was relatively intact in SLE patients, which reflects preservation of this ability relative to other impaired cognitive domains. Our findings are in keeping with previous studies which found most commonly affected cognitive domains are attention, visuospatial skills, learning, memory, information processing and executive function [23, 24]. Results from our study also confirmed decreased global cognitive functioning among SLE patients as measured by RBANS total score. In our study, the frequency of cognitive impairment was 21.8~56.3% of cases, depending on the stringency of the definition rules (norms-SD or norms-2SD), which consistent with reported prevalence of CI between 14% and 54% in non-NPSLE patients [25].

Performances on RBANS immediate memory, attention, language, and total index scores were correlated with education, suggesting a modest, expectable association between cognitive performance and educational levels. There was no association between performance on any of the RBANS index scores or total scores and patient characteristics including age, sex and disease duration. We found patients with kidney involvement showed significantly diminished RBANS scores compare to those without kidney involvement. This is consistent with prior report of more frequent renal involvement in patients with cognitive dysfunction [26]. Moreover, RBANS scores of lupus patients with serositis or rash or mucosal ulcers were significantly lower than those without serositis, rash or mucosal ulcer. These clinical manifestations are related to disease activity. SLEDAI-2K and accumulated damage had significant negative effects on RBANS index and total score, which indicates that SLE disease activity and disease severity are associated with cognitive performance. The results are in line with the previous studies in which disease activity and chronic damage on cognitive function in SLE patients [27–29].

RBANS index scores and total scale score were found to be correlated with various immunological parameters in lupus patients, including the presence of high titer ANA, anti-dsDNA antibody or anti-ribosomal P antibody. The positive correlation between positive autoantibodies and cognitive dysfunction found in our study is supported by several other cross-sectional studies where autoantibodies have been associated with cognitive decline in patients with SLE [30, 31]. The exact pathological mechanism of cognitive dysfunction in the setting of SLE remains elusive, but are primarily attributed to vascular abnormalities and interaction between autoantibodies and inflammatory mediator. Several autoantibodies have been proved to exert a potential pathogenic role on cognitive decline, among these aPL antibody, anti-ribosomal P proteins, anti N-methyl-D-aspartate receptor (NMDAR) types NR2A or NR2B (anti-NR2) antibodies[32–34]. These neurotoxic antibodies recognize neuronal surface antigens that are distributed in hippocampus and amygdala, which play an important modulatory role in cognitive processing, involving in memory, perception, attention and learning[35, 36]. Anti-NMDAR autoantibodies are a subset of anti-dsDNA autoantibodies that cross-react with the NR2A subunits of NMDA glutamate receptors [37], suggesting that anti-dsDNA antibody can participate in neuronal damage through similar pathways. In our study, there was no correlation of RBANS scores with aPL antibody. This could be attributed to the fact that only 38% of the patients in our cohort were tested for anticardiolipin antibodies due to financial limitations.

Immune-mediated mechanisms for decreased olfaction have been implicated in patients with several central nervous system (CNS) diseases, such as PD, AD, and multiple sclerosis[38]. The results of our study revealed SLE patients had significant olfactory deficits and all three subtest of smell function were impaired when compared to age-matched healthy controls. Moreover, patients had higher proportion of anosmia and hyposmia than controls. Our findings are in line with previous studies in which the impairment of smell function in patients with SLE has been reported [14, 39]. We found patients with PAH or rash showed significantly diminished olfactory threshold scores than those without PAH or rash, suggesting that olfactory impairment may correlate with SLE disease activity. Although no correlation was observed between olfactory function scores and autoantibodies in our cohort, it is reported that some autoantibodies are capable of binding and penetrating neuronal cells of the limbic areas (hippocampus and amygdala) that are associated with olfaction [40]. Reduction of the sense of smell could be induced in mouse by passive infusion of anti-ribomsomal P antibodies or autoantibody-rich cerebrospinal fluid (CSF) from CNS SLE patients into the brains [41–43]. These olfactory deficits are proposed to reflect a consequence of autoimmunity in lupus, however the pathologic mechanisms underlying their origin remain poorly understood.

Multivariable regression analysis revealed that olfactory threshold, identification and memory scores showed significantly negative association with RBANS index and total score respectively. In addition, olfactory memory score was positively correlated with the RBANS delayed memory score. This is the first study using olfactory memory test to evaluate the ability of SLE patients to remember previously presented odors. Our results showed that both semantic memory and episodic memory were impaired and olfactory memory score was associated with most impaired cognitive domains in SLE cohort. Memory is the most common impaired cognitive process in SLE patients, which is consistent with hippocampal changes associated with lupus [44]. Olfactory dysfunction is common in neurodegenerative diseases, such as PD and AD, usually several years earlier than the diagnosis[45]. It has been found that poor olfactory ability is related to the structural brain changes in the hippocampus and entorhinal cortex, two regions affected by cognitive impairment [46]. Thus, the use of smell decrement as an early and predictive marker for neurodegenerative diseases will contribute to the characteristics of precursor stages and early diagnosis strategies of these neurodegenerative diseases. In concordance with previous studies, our current findings suggest that olfactory deficit is a useful predictor of overall neurocognitive impairment and the early diagnosis of CI in SLE.

The current study is convincing for the utility of the RBANS to demonstrate statistically significant impairment in patients with SLE compare with control group. However, there are some limitations of the study. First, due to time and cost constraints, neither traditional neuropsychological assessment such as ACR-SLE neuropsychological battery nor brain imaging screening was used to look for clinical behavioral and neuroanatomical correlates of the abnormalities finding on RBANS testing. Another limitation is the small sample size and only patients with no major cognitive impairment were involved; however, we believe the current study provides preliminary support for designing a larger, more focal effort. Third, we did not account for the presence of mood disturbance in our sample. Indeed, altered mood including depression and anxiety is a common feature of patients with SLE, and given the well-established relationship between mood disturbance and cognitive functioning [13]. Finally, the patients and controls did not undergo repeat testing with RBANS to determine whether the detected differences remained stable over time. Further investigation should perform using larger samples, longitudinal assessment, more comprehensive cognitive evaluations, neuroimaging and a combination of mood disturbance and the RBANS for this population.

In summary, our results demonstrated a significant reduction in the cognitive function and olfactory abilities of SLE patients and revealed a close correlation between CI and olfactory deficits. RBANS is both cost- and time-efficient and requires less training to administer than traditional neuropsychological tests. We believe that RBANS is a useful tool to assess cognition in patients with SLE in a busy clinical practice and olfaction testing may be an excellent indicator of future cognitive decline among lupus patients. Testing panels including RBANS and smell assessment should be optimized and developed as screening evaluation for SLE patients to identify early risk of cognitive decline and to prevent development and progression of CI.

SLE

Systemic lupus erythematosus

Cognitive impairment

RBANS

The Repeatable Battery for the Assessment of Neuropsychological Status

IMME

Immediate memory

Vis/Con

Visuospatial/constructional

LANG

Language

ATT

Attention

DEME

Delayed memory

TIM

Threshold + Identification + Memory

Acknowledgements

Not applicable.

Authors’s contributions

Study design: XX, WK, LYG, JL and LYS. Acquisition of the data: XX, WK, LYG, CC, HLY, WTK, BJW, WJB, SWC, RJX, JL and LYS. Analysis and interpretation of the data: XX, WK, LYG, HLY, JL and LYS. Manuscript preparation: XX, WK, LYG, JL and LYS. All authors read and approved the final manuscript.

Funding

This work was supported by the grants from the National Natural Science Foundation of China [81871283][81801555]; Research Project of Jiangsu Province Health Committee [H2019060]; Key Project supported by Medical Science and technology development Foundation [YKK20072].

Availability of data and materials

The datasets analyzed during the study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The Ethics Committee of the Nanjing Drum Tower Hospital approved the study, and informed consent was obtained from all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Table 2. Associations between raw scores on RBANS scores and selected clinical and laboratory variables in 55 patients with SLE*

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Association between Cognitive Impairment and Olfactory Deficits in Systemic Lupus Erythematosus Without Major Neuropsychiatric Syndromes

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