COGNITIVE DECLINE IN RELATION TO THYROID DYSFUNCTION IS STILL A QUESTION?

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1 Acta Medica Mediterranea, 2014, 30: 703 COGNITIVE DECLINE IN RELATION TO THYROID DYSFUNCTION IS STILL A QUESTION? ANA CAPISIZU 1, 3, SORINA MARIA AURELIAN ², 3 1 Geriatric Department, University of Medicine and Pharmacy Carol Davila, Bucharest - 2 Titu Maiorescu University, Bucharest - 3 Hospital for Chronic Diseases Sf Luca, Bucharest, Romania ABSTRACT Background: Numerous studies have analysed the relationship between the thyroid function and cognitive decline, but they gave contradictory results. About Romanian population, to our knowledge, there haven t been any published data from clinical studies investigating the connection between thyroid status and cognitive decline in elderly. Methods: Observational cross-sectional one year study ( ), on 93 geriatric inpatients (69 females, 24 males, mean age 79.95±6.60 years) with cognitive decline. We assessed the cognitive deficit by psychological tests: Mini Mental State Examination (MMSE), Clock test, Reisberg scale and the thyroid function by determining thyroid-stimulating hormone/tsh, total triiodothyronine/tt3, and free thyroxine/ft4 plasma levels. Statistical analysis included linear correlations, general linear models and data comparison, using t test or Mann-Whitney test. Results: We found no significant linear correlations between cognitive scores and thyrotropin/thyroid hormones (R 0.090, p 0.050, for all bivariate correlations investigated). To further investigate we stratified the patients by TSH tertiles. The analysis showed that patients in the low TSH tertile had significantly better MMSE scores than those in the middle (p=0.045) and high tertile (0.039); we found no significant differences between MMSE scores for patients in the middle TSH tertile versus the third one (p>0.050). The Clock test and Reisberg Scale scores were similar in the 3 groups (p>0.050). Conclusions: No linear relationship between cognitive scores and thyroid function were found. After stratification, MMSE scores were significantly higher for patients with lower TSH (which means hyperthyroid). There were no significant differences between the Clock test s and Reisberg scale s scores about thyroid function. Key words: Elderly, cognitive decline, thyroid function. Received February 18, 2014; Accepted March 24, 2014 Introduction The normal thyroid functioning is essential in the cognitive function development throughout the life. The two hormones secreted: triiodotyron (T3) and thyroxin (T4) by the hypothalamo-hypofise regulation (through TSH) dominate the whole body functioning. A lot of recent studies have investigated the thyroid function role in the ageing process (1). Recently, it has been demonstrated the fact that the TSH level increases with the age, suggesting in this way the decrease of the thyroid function (2). In what concerns other tests of the thyroid function - the serum concentration of free T3 and T4 are closely related to the age decline (3). But there are also studies in which the thyroidal activity tests (TSH) are decreasing. The results of these tests are hardly interpretable due to the high prevalence of the chronic affections and the use of diverse treatments. There are proofs that the low activity level of the thyroidal hormones can be beneficial to the old patients (4) since the sub-clinic hyperthyroidism is a mortality predictor (5) this being demonstrated on the long life subjects having high TSH (6) levels. The iodine default (very necessary in the hormones production process) can produce important hormonal

2 704 Ana Capisizu, Sorina Maria Aurelian et Al disorders, to the endemic goitre. Statistics show that, in Romania, 5% of the population suffers of endemic goitre, with differences in point of incidence from a geographic region to another (7, 8). To our knowledge, there haven t been any published data from Romanian clinical studies investigating the connection between thyroid status and cognitive decline in elderly. moderate and severe deficits are found mainly in men over years (Fig. 1). The values for all studied parameters are shown in (Table 2). We found no significant linear correlations between cognitive scores and thyrotropin/thyroid hormones (R 0.090, p 0.050, for all bivariate correlations investigated). Methods It is an observational cross-sectional one year study ( ), on 93 geriatric inpatients (69 females, 24 males, mean age 79.95±6.60 years) from St Luke Hospital, Bucharest, Romania, with cognitive decline. The participants gave their written informed consent after receiving detailed information about the aims and study procedures. The study was approved by The Ethics Committee of The University of Medicine and Pharmacy Carol Davila (Bucharest, Romania) and was conducted following the ethical guidelines. Since we sought to analyze the relationship (if existent) between thyroid status and cognitive decline in elderly, regardless of the degenerative cerebral disorders, we recruited patients with vascular dementia, Alzheimer s disease, as well as no demented patients. The study included euthyroid, as well as hypoand hyperthyroid patients. TSH varied between μiu/ml (normal range: μiu/ml), mean 2.06±2.3. We assessed the cognitive deficit by psychological tests: MMSE, Clock test, Reisberg scale (9, 10, 11) and the thyroid function by determining thyrotropin/tsh, total triiodothyronine/tt3, and free thyroxine/ft4 plasma levels. Statistical analysis included linear correlations, general linear models and data comparison, using t test or Mann- Whitney test. Results Women are more numerous, representing 70.83% of the study group as compared to men. The largest number of patients (42) have an average degree of severity of cognitive impairment (MMSE = 10-19) (Table 1). Women age groups are in the greatest proportion (10%) with mild cognitive deficits. Severity score (MMSE <9) is obtained with the highest proportion (3%) of women <75 years. The proportion of men with mild cognitive deficits is greatest (4%) in the age group 75-79, and To further investigation, we stratified the patients by TSH tertiles (lower tertile: , N=31; middle tertile , N=31; higher tertile: μiu/ml, N=31). The chi square test found significant differences in MMSE scores when group by TSH tertiles (p=0.042); analysis showed that patients in the low TSH tertile had significantly better MMSE scores than those in the middle (t student two-tailed: p=0.045) and high tertile (t student: p=0.039). We found no significant

3 Cognitive decline in relation to thyroid dysfunction is still a question? 705 differences between MMSE scores for patients in the middle TSH tertile versus the third one (p>0.050) (Fig.2). The clock test and Reisberg Scale scores were similar in the 3 groups (chi square test: p=0.903, respectively p=0.779) (Fig. 3). When stratifying the patients by ft4 and T3 tertiles, though the observed tendency was for worse cognitive results in patients with lower ft4 and T3, we found no statistically significant differences in cognitive scores (MMSE, clock test, Reisberg scale) between the obtained groups (chi square test: p>0.050 for all tests). Discussion There is not yet a consensus in the medical literature concerning the thyroidal dysfunction and the cognitive performances to the aged persons. The thyroidal dysfunction is one of the potential reversible causes of dementia, so that the sub-clinic hypothyroidism can play a role in the MCI. The prevalence of the sub-clinic hypothyroidism (increased TSH in the presence of normal T3 and T4) increases by the age (>25% of the persons who are over 60 years old) (12). Also, the prevalence of the sub-clinic hyperthyroids (decreased TSH, normal T3, T4) increases with the age, being more present in the regions showing a high iodine deficit (13). The sub-clinic hypothyroids can be a cognitive troubling factor (14). There are many unsolved questions. Some previous studies found low serum TSH to be associated with cognitive impairment and dementia (15, 16) while others found no such association (17). Interestingly, a recent study (18) found lower levels of thyroid hormones in the cerebrospinal fluid of euthyroid dementia patients; if dementia is, in fact, associated with mild brain hypothyroidism, then it might make sense for lower serum TSH levels and hyperthyroidism to exert some brain-protective effects. Other studies demonstrate that the clinic and sub-clinic hypothyroidism, as well as the hyperthyroids are associated to the cognitive deficit, especially with the memory, spatial orientation, attention and reaction time to events, at any age, including at the old age. Other studies (19) found regional (temporal) cerebral blood flow inversely correlated with serum TSH (but not with ft4 or T3) in Alzheimer s disease, again suggesting a protective impact of low thyrotropin levels on brain. A significant body of research supports a significant association between high serum TSH and cognitive impairment and dementia (20). For example, there is a controversy: which of the hormones T3, T4, or TSH is the best indicator of the thyroidal function and the best predictor of the cognitive decline, especially to the aged persons (21). It is well-known the fact that the circulating TSH cannot be sensible enough to directly measure the thyroidal function in a cognitive dysfunction, due to the fact that it can be influenced by the value of other hormones, as the cortisol, somatostatine or cytokine (22). Two studies show that the risk of cognitive trouble is 2-3 times higher to the persons suffering of sub-clinic hyper-thyroids (23, 24). An important part of clinic and laboratory or epidemiologic studies shows the relationship between the thyroidal hormones and the path physiology of the Alzheimer s disease (25, 26). Different studies showing the relationship between the TSH and the Alzheimer s disease have given inconsistent results. The low TSH, as well as the high values of the T4 has been proposed as risk factors for the Alzheimer s disease in some of the studies (27), but not in some other (28). However, there hasn t been discovered any significant correlation between TSH, the Free T4 level and the global thinking to the patients in state of euthyroidy with the Alzheimer s disease (29). Conclusion: Women are more numerous, representing 70.83%. The largest number of patients have an average degree of severity of cognitive impairment (MMSE = 10-19). The highest percentage of patients is the age group of years with mild cognitive impairment (MMSE =10-19). Severity score of cognitive impairment (MMSE <9) was obtained by women <75 years and men over 85 years in higher proportion. There were no linear relationship between cognitive scores and thyroid function. The patients with lower TSH have high MMSE scores compared to the ones with thy-

4 706 Ana Capisizu, Sorina Maria Aurelian et Al rotropin values situated in the second and third tertile, suggesting a protective effect of thyrotropin against cognitive decline. MMSE scores were lower in subjects with higher TSH levels than in those with middle tertile thyrotropin, this difference was not statistically significant in our study. There were no significant differences between the Clock test's and Reisberg scale's scores, even if stratified by TSH tertiles. Limitations of our analysis, like other previous studies, may have been encumbered by recruitment biases, such as the small sample size, especially the small number of dysthyroid patients and study inclusion of both, dementia patients and no demented elderly. Despite some previous research results, lower serum thyrotropin levels may be associated with better cognitive performance in old age, but this relationship needs to be further investigated, on large cohorts, using more complex cognition assessment tools. 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