Cognition, depression, fatigue, and quality of life in primary Sjögren's syndrome: correlations

Abstract Objective The aim of the present study was to investigate the prevalence and pattern of cognitive dysfunction observed in primary Sjögren's syndrome (PSS) and to examine the relationships between cognitive abilities, depression, fatigue, and quality of life. Materials and Methods Thirty‐two subjects with PSS were compared with 19 healthy controls on comprehensive neuropsychological, depression, fatigue, health state, and daily‐life activities tests. Results There was low performance in Clock Drawing, COWAT, Paced Auditory Serial Addition Test (PASAT), Colorless Word Reading (Stroop1) and Recognizing Colors (Stroop2) Patterns of STROOP test, SDLT, Auditory–Verbal Learning Test (AVLT), immediate and long‐term verbal memory, Benton Judgment of Line Orientation Test (BJLOT), and in all the patterns of RCFT in PSS patients compared to the healthy control group (p < .05). It was observed an increased depression frequency and fatigue severity, impairment in health condition, and a decreased quality of life in PSS cases compared to the healthy controls (p < .05). All the depression, fatigue severity, and quality of life tests showed a significant positive correlation with each other (p < .05). A significant negative correlation between Clock Drawing and SF‐36‐BP (p = .031, r = −.382) and SF‐36‐GH (p = .027, r = −.392) was observed. Conclusions Clock Drawing, PASAT, and AVLT are very useful tests to determine the subclinical and clinical cognitive dysfunction to evaluate attention, information processing speed, executive functions, and short‐term and long‐term verbal memory in PSS patients. Depression and fatigue may not affect the neuropsychological tests performance.

. It is seen nine times more in women in the age group of 40-50 years compared to men (Morreale et al., 2014). Incidence of neurological involvement in SS is 25-30%. Involvement of the central nervous system can be seen in optic neuropathy, multiple cranial neuropathy, transverse myelitis, aseptic meningitis, encephalomyelitis, epilepsy or ischemic stroke clinic (Delalande et al., 2004;Mellgren et al., 2007). In case of xerostomia and xerophthalmia, fatigue, cognitive symptoms, and pain are frequently present (Lafitte et al., 2001).
The purpose of this study is to determine the presence, frequency, and type of cognitive dysfunction in the patients who had no symptoms and findings of other central nervous system but were diagnosed with PSS along with and without cognitive symptoms and findings.
Depression, fatigue severity, health state, and daily living activities are measured in the patients by using objective tests. The correlation between presence of cognitive dysfunction and depression, fatigue, health state, and daily living activities was examined in the patients.

| Patients
Thirty-two patients with PSS, who were admitted to Gazi University Medical Faculty outpatient clinic of Neurology Department between July 2011 and August 2013, were included in the study. All patients met the criteria of European-American Consensus Group for classification as PSS (Vitali et al., 2002). Twenty normal subjects were included as controls. The patients and healthy controls were matched in terms of age, sex, and education level, and there was no significant difference between the two groups. No patients or controls were taking benzodiazepines, neuroleptics, antidepressants, or alcohol, and none had a history of head injury or other central nervous system, any other connective tissue disease, and psychiatric, metabolic, or endocrinological disease (Lafitte et al., 2001;Segal et al., 2012). No history of neurological involvement of PSS was investigated. The PSS patients underwent complete physical and neurological examinations, hemogram, total biochemical and urine analyses, and complete immunological investigations, including erythrocyte sedimentation rate, antinuclear antibodies, antibodies to Ro/SSA, La/SSB, rheumatoid factor (RF), C-reactive protein, serum IgG, IgA, and IgM, complement C3 and C4 fractions, cryoglobulinemia. Specimens of minor salivary gland biopsy were obtained from all patients according to standard procedures.
Candidates with severe motor or visual impairments that might interfere with cognitive testing were excluded from the study. All the patients had normal hearing thresholds. All the participants gave the informed consent before they were included in the study. Table 1 shows the demographic characteristics of PSS and control groups.

| Neuropsychological assessment
Before the psychometric test battery, language function was assessed and no participant showed abnormalities in either oral or written comprehension. A comprehensive neuropsychological battery of tests was used to assess the cognitive performance of PSS patients and healthy subjects. All the tests used are standard normalized tests for which normal subject performances are known. Individual test performance was considered as abnormal when it was below the normal control mean. A defect in one of the tests was interpreted as a loss of function in that area. It was considered that neuropsychological assessment revealed CNS pathological involvement when at least two test results were abnormal.
In these cases attention, information processing speed, short-and  were administered. Attention and executive functions using Stroop test, verbal fluency using COWAT, naming confrontation using BNT, verbal learning using SDLT, and immediate, short-and long-term verbal memory using RCFT were investigated and measured (Lafitte et al., 2001;Martinez et al., 2010;Segal et al., 2012;Tombaugh, Kozak, & Rees, 1999

| Mini-Mental State Score
The "mini-mental state" (MMS) is scored form of the cognitive mental status examination (Folstein, Folstein, & McHugh, 1975), which includes 11 questions, requires only 5-10 min to administer, and is therefore practical to use serially and routinely. It concentrates only on the cognitive aspects of mental functions, and excludes questions concerning mood, abnormal mental experiences, and the form of thinking. The MMSE is a paper-based test with a maximum score of 30, with lower scores indicating more severe cognitive problems.
The cut point established for the MMSE defines "normal" cognitive function and is usually set at 24, although theoretically it could fall anywhere from 1 to 30.  (Bush, Frazier, Haggerty, & Kubu, 2005).

Auditory-Verbal Learning Test: This test measures verbal learning
and memory (Hohol et al., 1997), including functions of the left temporal zone such as immediate recall and learning of verbal information, keeping the information in memory, and storing it in long-term memory. The test is sensitive to damage in the hippocampus and temporal lobe, particularly lesions of the left hemisphere (Grammaldo et al., 2006). The total number of words recalled during five consecutive presentations of a list of 15 words, and the number of words recalled after a 20-min delay were recorded (Mataro et al., 2003).

| Tests for evaluating visual memory and visual-spatial perception
1. Benton Judgment of Line Orientation Test: This test measures visuospatial perception and orientation. It is particularly sensitive to damage in the right cerebral hemisphere and right parietal lobe (Karakaş et al., 2004). Figure Test: This is a test of visuospatial learning and delayed recall (Hohol et al., 1997). It evaluates visual perception, perceptional organization, visual learning, and storing of visual information in short-and long-term memory. The test measures right hemisphere function (Karakaş et al., 2004).

3.
Writing test: This test measures motor skills and writing speed (Karakaş et al., 2004).  (Lafitte et al., 2001;Vitali et al., 2002). The subject is requested to find words and animal names beginning with the letters K, F, A, and S, excluding proper nouns, numbers, and plurals, within 1 min (Karakaş et al., 2004).

Stroop Interference Test (SIT):
This test measures resistance to interference, ability to perform an unusual behavior, and focused attention. It is particularly sensitive to damage in the left frontal lobe and orbitofrontal cortex (Karakaş et al., 2004).

| Assessment of depression, fatigue, health state, and daily living activities
The presence of depression was examined by using Hamilton Depression Scale and Beck Depression Inventory (BDI).

| Hamilton Depression Scale
This is a 17-item questionnaire that measures mood. A score of ≥8 indicates clinical depression. Scores in the range of 0-7 reflect no depression and scores between 8 and 15 reflect mild depression, whereas score ≥16 is suggestive of moderate to severe depression (Hamilton, 1967).

| Beck Depression Inventory
The BDI is the most used self-rating scales for measuring depression.
BDI-II is a 21-item self-report depression screening measure (Shulman, 2000). Each item is rated on a 4-point Likert-type scale ranging from 0 to 3, with higher scores indicating higher levels of depression. The measures ask respondents to endorse statements characterizing how they have been feeling throughout the past 2 weeks. The maximum total score for all 21 items is 63 (Segal, Coolidge, Cahill, & O'Riley, 2008). The cut-off score of ≥13 is commonly used to identify current clinical depression (Beck, Steer, & Brown, 1996). According to the BDI-II manual, scores of 0-13 denote minimal depression, scores of 14-19 denote mild depression, scores of 20-28 denote moderate depression, and scores of 29-63 denote severe depression .
The Short-Form 36 (SF-36) evaluating the daily living activities, EQ-5D questionnaire evaluating the health state, and fatigue severity scale (FSS) measuring the severity of fatigue were administered.

| The medical outcomes study, 36-item short-form health survey (SF-36)
The SF-36 questionnaire is designed to evaluate health-related quality of life within the previous 4 weeks. It involves 36 questions, with eight scales assessing two dimensions. The first dimension is physical health function and includes the following four specific scores: physical functioning (the extent to which health interferes with various activities), physical role functioning (the extent to which health interferes with usual daily activities such as work, housework, and school), bodily pain, and general health. These physical scores are summarized by the physical composite score (PCS). The second dimension is mental health function, which includes the following four specific scores: vitality, social functioning, emotional role functioning (limitations due to emotional problems), and mental health. These four mental scores are summarized by the mental composite score (MCS). Each scale gives a standardized raw score that ranges from 0 to 100, with 0 implying the worst possible health state and 100 implying the best possible health state (Ware & Gandek, 1998;Ware & Sherbourne, 1992).
An individual's perception of his or her health is recorded on a 0-100 visual analog scale (VAS) with 0 being "worst imaginable health state" and 100 being "best imaginable health state" with EQ-5D1. The EQ-5D2 assesses five different dimensions of health (mobility, self-care, ability to usual activities, pain/discomfort, and anxiety/depression).
Each dimension can be scored by three possible responses: no problem, some/moderate problems, or severe problems, corresponding to a score of 0-2 (Segal et al., 2009). The best state was evaluated as three points and the worst state was evaluated as 15 points (The EuroQol Group, 1990).

| Fatigue severity scale
Fatigue was evaluated by using the FSS. Fatigue severity scale is a selfadministered instrument developed to assess the impact and severity of fatigue. The questionnaire includes nine statements to explore a person's severity fatigue symptoms as it relates to daily activities such as physical functioning, exercise, work, and family and social life. The scores for each item range from 1 to 7, with the lower score indicating less fatigue. In FSS, behavioral result of fatigue is evaluated by a 9-point question. In every question, the score range is between 1 and 7 (best condition is 9 points; worst condition is 63 points). We used a cut-off score ≥4 to define fatigue. A FSS score ≥4 reliably differentiates subjects with fatigue from control subjects (Epstein et al., 2014;Krupp, LaRocca, Muir-Nash, & Steinberg, 1989;. All subjects gave their informed consent prior to sample acquisition. The study was approved by the local Ethics Committee of Gazi University School of Medicine.  cases for 9-11 years, and 10 cases for 12-15 years; and in the healthy control group, 5 cases had an education for 5-8 years, 4 cases for 9-11 years, and 10 cases for 12-15 years. Table 1 shows the demographic characteristics of PSS and healthy control groups (Table 1).  (Figure 1). Thus, it was observed that there was a dysfunction in the tests evaluating attention, information processing pace, verbal learning and immediate short-term and long-term verbal memory, and visual-spatial perception.

| The findings of neuropsychological cognitive tests
It was observed that as the educational level increased, performance increase was found in all tests (p < .05). When the educational level was classified as 5-8 years, 9-11 years, and 12 years and above in both groups, it was found that the educational level of 5-8 years had

| The findings of depression, fatigue, health state, and daily living activity following
It was observed that there were an increase in depression frequency and fatigue severity, impairment in health condition, and a decrease in daily living activities in PSS cases compared to the healthy controls (p < .05). It was observed that while in PSS group there was a significant impairment in role functioning physical, bodily pain, general health, vitality, and role functioning emotional patterns of daily living activities; physical function, social functioning, and mental health did not impair (p > .05) ( Table 3).
While depression was regarded as available in cases obtaining eight scores and above from Hamilton Depression Scale (HDS), it was regarded as unavailable in cases with 0-7 scores. In this case, the presence of depression was determined in 40.6% (n = 13) frequency in PSS patients group. On the other hand, the presence of depression was determined only as 5.3% (n = 1) in the healthy control group.

| Correlation between neuropsychological cognitive tests and depression, fatigue, health state, and daily-life activities
When it was evaluated whether or not there was a correlation between the neuropsychological tests and depression, fatigue severity, health state, and daily-life activities in PSS cases, it was observed that there was a significant negative correlation between Clock Drawing and SF-36-BP (p = .031, r = −.382) and SF-36-GH (p = .027, r = −.392).
All the depression, fatigue severity, health state, and quality of life tests showed a significant positive correlation with each other (p < .05) ( Table 4).  (Coates et al., 1999;Mataro et al., 2003). The examination of Tc-ECD brain SPECT is sensitive to displaying subcortical cognitive dysfunction in PSS (Gerraty, McKelvie, & Byrne, 1993;Le Guern et al., 2010). In PSS cases without neurological involvement, it was found that there was a significant hypoperfusion at left frontal, left parietal, left temporal, right frontal, and right hippocampal cortex, and also it was shown that there was a strong correlation between the hypoperfusion specified at frontal, parietal, temporal, cingulate, and hippocampal areas, and the dysfunction of the executive functions (Le Guern et al., 2010).

| DISCUSSION
When the brain MRI was normal, it was found that the presence of hypoperfusion in parietal, temporal, and frontal lobes was 56.3% in PSS cases with neuropsychiatric symptoms and findings and 17.6% in PSS cases with no neuropsychiatric symptoms and findings at the brain Tc-ECD SPECT and this result increased the sensitivity of the  the vasculopathy based on small vein vasculitides in pathogenesis of the SS (Gerraty et al., 1993;Le Guern et al., 2010;Mataro et al., 2003).
It was revealed that there was an increase in the presence of subjective cognitive symptoms, frequency of depression, and fatigue severity in PSS compared to healthy control (Martinez et al., 2010;Mataro et al., 2003;Morreale et al., 2014;Segal et al., 2012). A strong correlation was observed between the presence of subjective cognitive symptoms and depression, fatigue severity and pain severity, quality of life, and dysfunction in attention, executive functions, working memory, and verbal memory among objective cognition tests (Coates et al., 1999). In the series of Segal et al. (2012), the subjective cognitive symptoms, depression, fatigue severity, and pain scores were found to be higher compared to the healthy control group. In the PSS patient group, prevalence of depression was 47% and the presence of subjective symptoms was more in the depressed cases. PSS cases with depression had a low performance only in Wisconsin Card Sorting Test (WCST) measuring the executive functions in a statistically significant way compared to cases without depression and also had a low performance in Trails Making Test B evaluating attention, working memory, and executive functions and in HVLT test evaluating verbal memory compared to cases without depression even though it did not show a statistically difference. In PSS group, there was a positive correlation between the subjective symptoms, depression score, and fatigue severity, and also a positive correlation was found between the severity of the subjective cognitive symptom and low verbal memory (p = .048). The objective determination of depression and pain existence affected negatively attention and working memory in the cognitive tests . It is known that depression and pain decrease working memory and executive function's performance; however, verbal memory is not affected by pain and depression (Lafitte et al., 2001), therefore patients with depression were excluded from the study. In this study no statistically significant difference was  (Martinez et al., 2010;Yoshikawa et al., 2012). In the depression and fatigue scores, there was no change at the end of 8 years follow-up (Martinez et al., 2010). Therefore, administration of detailed neuropsychological tests is useful in the diagnosis of subclinical cognitive disorder and for directing the treatment.
In recent years, there is a limited number of studies that examine the effect of the disease on quality of life in PSS. Decreased quality of life has already been revealed in patients with PSS by using the Short-Form 36. It were showed that all eight scales of the SF-36 significantly decreased in patients with PSS (Baturone et al., 2009;Champey et al., 2006;Ibn Yacoub et al., 2012;Inal, Kitapcioglu, Karabulut, Keser, & Kabasakal, 2010;Lendrem et al., 2014;Meijer et al., 2009;Segal et al., 2009;Strömbeck et al., 2003). In 57 case series of Ibn Yacoub et al. Group, 1990). Lendrem et al. (2014) showed that the patients with PSS reporting any problem in mobility, self-care, usual activities, pain/discomfort, and anxiety/depression were 42.2%, 16.7%, 56.6%, 80.6%, and 49.4%, respectively, compared to 5.4%, 1.6%, 7.9%, 30.2%, and 15.7%, respectively, in general population. They mentioned depression and pain as the most important predictors of EQ-5D utility values, and fatigue, anxiety, and body mass index were other statistically significant predictors of utility values in lesser variability in PSS. The weak effect of somatic fatigue on EQ-5D is explained by the combination of physical and psychological component of EQ-5D.
Fatigue is the most common symptom in patients with PSS.
Abnormal fatigue is defined as enduring and generalized tiredness and can be characterized in terms of intensity, duration, and effects on daily activities . A number of studies revealed that there is a high prevalence of fatigue in PSS patients between 67% and more severe symptoms of fatigue than controls on all subscales of fatigue such as degree of fatigue, reduced activity, and its effect on daily living Hartkamp et al., 2004;Ibn Yacoub et al., 2012). In the focusing on correlation between VAS scores for fatigue and both PCS of quality of life and psychological distress in PSS patients, PCS of quality of life and psychological distress are closely affected from fatigue (Champey et al., 2006). In addition, Ibn Yacoub et al. (2012) showed that there was a high negative correlation between VAS fatigue scores, fatigue severity, and physical and psychological components of SF-36. Depression was reported more frequently in patients with PSS than controls, and the prevalence of depression was reported to be 32-45.8% (Bowman, 2008;Lafitte et al., 2001;Morreale et al., 2014;. Recent studies have showed a significant correlation between the severity of fatigue and the level of depression, and depression has been considered as a strongest predictor of fatigue (Barendregt et al., 1998;Bax et al., 2002;. Segal et al. determined significantly higher mean FSS scores in the group of subjects with depression (mean FSS score 5.5 ± 1.3 in depressed patients and 4.2 ± 1.5 in nondepressed patients, p .001), but 59% fatigued patients were not depressed and they reported that depression is not the primary cause of fatigue in PSS (The EuroQol Group, 1990). We found that all the depression, fatigue severity, health state, and quality of life tests showed a significant positive correlation with each other.
In conclusion, using the comprehensive neuropsychological tests

CONFLICTS OF INTEREST
None declared.