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Relation of serum uric acid level with cognitive functions and number of plaques in patients with relapsing-remitting multiple sclerosis/Relapsing-remitting multipl skleroz hastalarinda serum urik asit duzeyinin kognitif fonksiyonlar ve plak sayisi ile iliskisi.

Introduction

Cognitive disorder is an important condition that can appear in any phase of multiple sclerosis (MS) and can impair quality of life by affecting the social and professional activities of patients (1). The relation between cognitive disorders and brain tissue damage in MS patients has not been fully clarified yet, although it seems to be influenced by many factors (2).

Investigators studying the effects of uric acid (UA), a natural antioxidant, on cognitive functions have reported that UA has positive effects on these functions. Euser et al. noted that the risk of dementia is reduced and cognitive functions are better preserved in subsequent periods in patients with high serum UA levels (3). Irizzary et al. found slower deterioration in patients with high UA levels in a study performed on patients with mild cognitive disorders (4). Some authors investigating the serum UA level in MS patients have detected a remarkable correlation between serum UA level and disease activity, while others have not found any relation (5). Drulovic et al. reported a close relation between UA level and clinical and cranial magnetic resonance imaging (MRI) activity in MS (6). Our objective in this study was to investigate the relation of UA level to cognitive functions and lesions detected on cranial MRI in patients with relapsing-remitting multiple sclerosis (RRMS). We could not find any previous publication exploring the association between serum UA level and cognitive functions in RRMS patients in the English or Turkish literature. This study, which investigated patients with RRMS in the silent period between MS attacks, is beneficial in demonstrating the serum UA level in this period and the relation between UA levels and cognitive functions in RRMS patients.

Methods

Fifty patients with diagnosis of RRMS, who were randomly selected from the out-patient register of our center, were included in the study. All patients signed an informed consent. Patients suffering from depression or another central nervous system disease coexisting with MS, and patients using drugs affecting the serum UA level (such as acetylsalicylic acid, thiazide diuretics, or steroids), were excluded from the study.

The MS diagnosis was made according to the Poser criteria and, the patients were evaluated in the silent period between attacks (7). All patients were evaluated and scored using the Expanded Disability Status Scale (EDSS) (8).

Samples were collected from the patients in the fasting state in the morning and the serum UA levels were measured in our hospital laboratories using an enzymatic evaluation method on the same day. The levels considered normal for serum UA levels in our center are 2.4-5.7 mg/dl in females and 3.5-7.2 mg/dl in males.

The cranial MRI examinations of the patients were performed using a 1.5-Tesla device (Siemens Magnetom, Germany). Sequence parameters were TR/TE 7000/60 msec, inversion time 150 msec, NEX 1, slice thickness 5 mm, and slice count 20 with an FOV value of 200x175. Scanning time for each region was 3 minutes. The cranial MRI investigation took 25-30 minutes for each patient. A gadolinium injection was performed at a dose of 0.ss mmol/kg in patients displaying one or more plaques on the MRI examination. T1-weighted sequences were repeated 15 minutes after the contrast agent injection. Patients with active (contrast-enhancing) plaques were excluded from the study. The plaque numbers detected on cranial MRI were recorded.

The Hamilton Depression Rating Scale (HDRS) (9,10) together with Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) (11,12), applied for detailed assessment of cognitive functions, were administered to each patient by a psychologist trained in neuropsychological tests. These two tests were completed on the same day by each patient. HDRS was performed first and, patients with depression were excluded from the study; thus, the cognitive tests were administered to the remaining (non-depressed) 50 patients. The ADAS-cog test consists of 12 subtests using a 5-point scoring system. The best score that can be achieved by each patient is "0", while the worst one is "5". The total ADAs-cog score was calculated as the sum of scores obtained from all subtests.

Statistical evaluation was performed using the Statistical Package for the Social Sciences (SPSS) 15.0 for Windows. The frequency of descriptive characteristics, mean numerical values, and standard deviations were determined. Serum UA levels, cognitive scores obtained on the tests, EDSS scores, and the number of lesions detected on cranial MRI were evaluated using the regression analysis and Mann-Whitney U tests. A p-value lower than 0.05 was considered statistically significant.

Results

A total of 50 patients (30 females and 20 males) were included in the study. The patients' ages ranged from 19 to 57 with a mean age of 33.6[+ or -]8.65 years. The mean disease duration was 2.4[+ or -]1.76 years. The EDSS scores varied between 0 and 7 and the mean EDSS score was 2.09[+ or -]2.01. The age and disease information of each patient by gender are presented in Table 1.

Eighteen patients were using interferon 1b, 12-interferon 1a, 3-glatiramer acetate and 4-azothioprine, while 13 had received pulse steroid treatment only during the attacks. Since the numbers of patients allocated to each treatment subgroup were insufficient for statistical evaluation, the tests performed according to these treatment groups were not taken into account in the statistical evaluation.

The serum UA levels of the patients varied between 2 and 9 mg/dl, and the mean serum UA level was 4.38[+ or -]1.59 mg/dl. The serum UA levels were grouped according to the normal laboratory values and it was found that they were low in 4 (8%) patients, normal in 40 (80%) patients, and high in 6 (12%) patients. No statistically significant difference was detected between the serum UA levels of male and female patients (mean values: 4.04[+ or -]1.51 mg/dl in females and 4.89[+ or -]1.62 mg/dl in males).

Total ADAS-cog scores varied between 0 and 13. Cognitive disturbance was detected on the ADAS-cog in 22 (44%) patients, while the results were completely normal in 28 (56%) patients. The mean ADAS-cog score was 2.30[+ or -]3.28. The worst subtest scores were on the word recognition subtest (1.28[+ or -]1.73), while the best scores were on the orientation and comprehension subtests. Values obtained with the ADAS-cog subtests are presented in Table 2. The mean total ADAS-cog scores were 2.43[+ or -]2.96 in females and 2.10[+ or -]3.76 in males. There was no statistically significant difference between the total ADAS-cog scores for male and female patients. When the male and female patient groups were compared according to the ADAS-cog subtests, it was observed that females showed greater disturbance in the "configuration", "design skills", and "test directions" subtests, while the males were similarly affected only in the "spontaneous speech" subtest. This difference between the two groups was statistically significant (p<0.05). No statistically significant relation was detected between the total ADAS-cog score and serum UA level. A statistically significant correlation was observed between the scores of the concentration and distractibility subtests of the ADAS-cog test and serum UA levels (p=0.01). However, the effects of exhaustion and emotional disorders on this relation can not be excluded.

A minimum of 1 and maximum of 20 plaques with a mean cranial plaque number of 8.52[+ or -]4.31 were detected on the cranial MRI examinations. The mean plaque count was 8.46[+ or -]4.65 in females and 8.60[+ or -]3.84 in males. There was no statistically significant difference between the plaque numbers of the two groups. No statistically significant association was found between the plaque numbers on cranial MRI and serum UA levels; however, p value was close to the statistically significant level.

The p values obtained from the statistical evaluation performed between the cognitive test results and the disease durations, number of lesions, EDSS scores, and serum UA levels are presented in Table 3.

Discussion

UA is a powerful antioxidant occurring as a natural product of purine metabolism. The relationship between UA and neurological diseases has especially become a focus of interest for investigators after the publication of studies reporting that UA had prevented the production of free radicals and suppressed the development of experimental autoimmune encephalomyelitis (1,14). In addition to studies investigating the effects of serum UA level on occurrence and prognosis of MS, the effects of serum UA level on cognitive functions is currently a focus of attention (3). Authors exploring the relation between UA and dementia have reported that elevated UA levels reduce the risk of dementia (15). In this study, we investigated the association between serum UA level and cognitive disorders or number of cranial plaques in early-stage RRMS patients.

The prevalence rates of cognitive disorders in MS patients varied from 20% to 70% (1,16). This wide range of results may be explained by some factors such as investigation of different patient groups and use of different tests to measure cognitive functions (17-21).

The results of the ADAS-cog test, which is a more detailed test, indicated that 22 patients (44%) had been affected. A statistically significant correlation was observed between the scores of the concentration and distractibility subtests of the ADAS-cog test and serum UA levels (p=0.01). Fatigue and emotional disturbance are factors increasing the rates of cognitive disorders in MS patients (24,25). In this study, the HDRS was applied to evaluate the depression status before administering the cognitive tests and the patients with depression were excluded from the study. However, a complaint of fatigue was not among the exclusion criteria and this might have increased the influence rates of cognitive decline detected in our patients. Although the findings and severity of cognitive dysfunction vary widely from patient to patient in MS, the most commonly affected components are learning, memory, attention, information processing speed, visual spatial abilities, and executive functions; dementia and language disorders are rarely encountered (26,27). In this study, we investigated 12 cognitive components and the most affected of them according to our results are related to memory and attention. Our interpretations regarding the correlation detected between attention disorder and serum UA level are limited since it is well known that fatigue affects attention and it was not among the exclusion criteria of our study. Some of the previous studies have found that serum UA level is lower in MS sufferers compared to patients with other diseases or healthy individuals (28,29).

Sotgiu and et al. conducted a hospital-based study aimed at determining possible differences in serum UA levels in relation to MS clinical status. According to their results, MS patients had significantly lower serum UA levels than controls, however, UA levels did not significantly correlate with disease activity, duration, disability or course (30).

Serum UA level has been found to be especially low in the early phase of the disease (31). A critical appraisal of one studies favors the view that reduced UA in MS is secondary to its peroxynitrite scavenging activity during inflammatory disease activity, rather than a primary deficiency (32). We found serum UA levels to be within normal limits in the majority of patients (80%). Patients diagnosed with clinically isolated syndrome were not included in our study and we may have found normal serum UA levels due to the inclusion of patients who were in a more advanced phase.

Previous studies have demonstrated no relation between serum UA level and MRI activity, disease time, and disability (29,30). Our results seem to be in accordance with those of previous studies investigating the relation between MS and serum UA level.

It is thought that the factors affecting cognitive functions in MS patients are pathological lesions, MS type and duration, affective disorders such as depression, and drugs affecting the central nervous system (33). Although homogeneous in terms of type of MS, our study group was heterogeneous in terms of treatment, which is a limitation of our study. Some studies reported that the drugs being used in the treatment of MS affect cognitive functions, while some drugs slow down the cognitive collapse (1). No statistical results could be obtained regarding serum UA levels, which are lower and higher than normal since the majority of our patients had normal serum UA levels and the number of patients with abnormal serum UA levels was inadequate for statistical evaluation. These characteristics limit our study and our interpretations.

Conclusion

We found normal serum UA levels in 80% of early-stage RRMS patients, who were in the silent period between attacks. Although not statistically significant, association was found between serum UA levels and cognitive disturbance or cranial plaque numbers. However, more comprehensive clinical and experimental studies are required to clarify the relation between cognitive functions and serum UA level.

DOI: 10.4274/npa.y5720

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Tahir Kurtulus YOLDAs, Hava DONMEZ KEKLIKOGLU, Ozkan ZENGIN *, Elif Banu SOLAK, Selda KESKIN

Diskapi Yildirim Beyazit Egitim ve Arastirma Hastanesi, 3. Noroloji Bolumu, Ankara, Turkiye

* Diskapi Yildirim Beyazit Egitim ve Arastirma Hastanesi, Noroloji Bolumu, Ankara, Turkiye

Address for Correspondence/Yazisma Adresi: Dr. Tahir Kurtulus Yoldas, Diskapi Yildirim Beyazit Egitim ve Arastirma Hastanesi, 3. Noroloji Bolumu, Ankara, Turkiye

Gsm: +90 506 598 20 98 E-posta: yoldas@gmail.com Received/Gelis tarihi: 14.07.2010 Accepted/Kabul tarihi: 31.08.2010
Table 1. Age, disease duration, and the plaque counts detected
in EDSS and cranial MRl of the patients included in the study
by gender

                          Gender     Mean      Std. Deviation

Patient's age (years)     female     31.53          7.87
                           male      36.80          9.00

RRMS duration (years)     female      2.16          1.57
                           male       2.75          1.99

EDSS                      female      1.93          1.92
                           male       2.32          2.18

Plaque count detected     female      8.46          4.65
in the cranial MRl         male       8.60          3.84

Table 2. ADAS-cog total and subtest scores

                                                   Maximum
                                       Minimum    Score/Test
Name of the test or subtest             Score      maximum     Mean

Total ADAS-cog                            0         13/60      2.30
Language ability                          0          1/5       0.04
Comprehension                             0          0/5        0
Praxis commands to asses ability to       0          2/5       0.24
  follow direction
World-finding difficulty                  0          2/5       0.06
World recognition                         0          1/5       0.02
Naming of objects                         0          1/5       0.02
Constructional praxis                     0          3/5       0.16
Ideational praxis                         0          3/5       0.56
Orientation in time or place              0          0/5        0
Word recall                               0          5/5       1.28
Receptive speech                          0          5/5       0.86
Attention and concentration               0          2/5       0.38
  scatteredness

                                                   Effected
                                        Std.      patient's
Name of the test or subtest           Deviation     number

Total ADAS-cog                          3.28       22 (44%)
Language ability                        0.19        2 (4%)
Comprehension                             0           0
Praxis commands to asses ability to     0.52       10 (20%)
  follow direction
World-finding difficulty                0.31        2 (4%)
World recognition                       0.14        1 (2%)
Naming of objects                       0.14        1 (2%)
Constructional praxis                   0.51        5 (10%)
Ideational praxis                       0.76       14 (28%)
Orientation in time or place              0           0
Word recall                             1.73       20 (40%)
Receptive speech                        1.24       19 (38%)
Attention and concentration             0.60       13 (26%)
  scatteredness

Table 3. p values belonging to the linear regression analysis
between the cognitive functions, uric acid, and lesion counts

Assessed parameters                            p value

ADAS-cog total score-Serum uric acid level       0.99
ADAS-cog total score-EDSS                        0.98
ADAS-cog total score-Cranial plaque count        0.27
Serum uric acid level-Cranial plaque count       0.09
ADAS-cog subtests-Serum uric acid level        p > 0.05
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Title Annotation:Research Article/Arastirma Makalesi
Author:Yoldas, Tahir Kurtulus; Keklikoglu, Hava Donmez; Zengin, Ozkan; Solak, Elif Banu; Keskin, Selda
Publication:Archives of Neuropsychiatry
Article Type:Report
Geographic Code:7TURK
Date:Dec 1, 2010
Words:3404
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