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1 A pilot study of the relationship between thyroid status and neuropsychiatric symptoms in patients with Alzheimer disease ZHANG Nan,1,2 DU Hong-jian,1,2 WANG Jing-hua,2 and CHENG Yan,1,2 1 Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China 2 Tianjin Neurological Institute; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, China Address for correspondence: CHENG Yan Department of Neurology, Tianjin Medical University General Hospital, 154, Anshan Road, Heping District, Tianjin, China Tel: 8622-60814504; Fax: 8622-27837604; email: [email protected] This work was funded by the Tianjin Science and Technology Development Project of Colleges and Universities (grant no. 20110116). 2 Background Growing evidence links alternation of the thyroid function to the pathogenesis and progression of Alzheimer disease (AD). However, only a few studies evaluate the association between thyroid hormone levels and neuropsychiatric manifestations in patients with AD. This study was designed to investigate the relationship of thyroid hormone levels and neuropsychiatric symptoms in euthyroid patients with AD. Method Forty patients with AD (26 women and 14 men), with no prior AD treatment within 4 weeks before study entry, were evaluated on their thyroid status (total triiodothyronine [TT3], total thyroxine [TT4] and thyroid-stimulating hormone [TSH]), cognition (Mini-Mental State Examination [MMSE] and Alzheimer’s disease Assessment Scale–Cognitive Subscale [ADAS-cog]), neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI]) and depression (Hamilton Rating Scale for Depression [HAMD17]). The unique relationship between thyroid hormones and cognitive function and mood was examined with multivariate linear regression analyses. The thyroid status between the neuropsychiatric symptoms group and the non-neuropsychiatric symptoms group was examined with independent-samples t-test. Results In euthyroid AD patients with agitation and irritability has lower TSH serum level than those without these symptoms. (t=-2.130, P<0.05; t=-2.657, P<0.05), and core score of HAMD is significant associated with the serum level of TSH (β=0.395, P<0.01). There is no significant association between thyroid hormone levels and cognition (MMSE, ADAS-cog and its subscale score). 3 Conclusions There might be a relationship between thyroid hormone levels and the neuropsychiatric symptoms in euthyroid patients with AD. Key words: Alzheimer disease; cognition; depression; neuropsychiatric symptom; thyroid 4 Introduction ALZHEIMER’S DISEASE (AD) is a degenerative disorder of the central nervous system (CNS) characterized by loss of neurons in the limbic system, association neocortex, and basal forebrain accompanied by neuritic plaques, neurofibrillary tangles, and neuropil thread formation. The relationship between the thyroid status and the risk of dementias in particular Alzheimer disease (AD), as well as cognition decline, has been extensively investigated over the last two decades. Van Osch et. [1] found lower thyroid-stimulating hormone (TSH), as an independent risk factor, was associated with the increased risk of AD for more than twofold. The Framingham study [2] found low and high TSH levels were associated with an increased risk of incident AD in women. Kalmijn et. and Thomas et. [3, 4] demonstrated that the deviation of thyroid hormone levels could be a risk for AD. Volpato et. [5] found the low thyroxine (T4) levels, within the normal range, were associated with a greater risk of cognitive decline over a 3-year period in older women. However, a prospective, observational, population-based follow-up study found thyrotropin (TSH) and free thyroxine (FT4) levels were not associated with cognitive impairment and depressive symptoms [6]. Moreover, the subclinical thyroid disease and the variations in thyroid function within the normal range had been demonstrated to be related to cognitive impairment in the healthy elderly, as well as in the patients with dementias. Several studies [7-10] have reported that subclinical hypothyroidism (normal T4 with elevated TSH), even 5 the alteration of TSH levels were within the normal range, are associated with cognitive impairment in older individuals. Prinz et al. [11] suggested that the variate of total thyroxine (TT4) within the normal range is positively associated with general cognition in the healthy elderly men. Stuerenburg [12] suggested that elevated FT4 would aggravate the cognition impairment and associate with depression in AD patients. Thyroid is closely associated with the cognition in the persons with dementia and the healthy elderly, as well as the mood and the other psychiatric symptoms in the former. It has been observed that hypothyroidism and hyperthyroidism have significant neuropsychiatric implications [13, 14]. For example, the central nervous system activity in patients with hypothyroidism will slow down with the clinical symptoms of depressed mood, emotional liability, and apathy. Patients with hyperthyroidism frequently present with impaired concentration, anxiety, and irritability. Although it has been demonstrated that the thyroid function plays a role in the cognition of the patients with AD, the relationship is unclear between thyroid status and the neuropsychiatric symptoms in euthyroid patients with AD. In a previous study, Stern [15] found FT4 concentrations were negatively correlated with self-reported feelings of fear and fatigue in euthyroid patients with Alzheimer disease, but no significant relationships between thyroid hormones and cognition and other depressive and anxiety symptoms were found. Thus we assume that the lower thyroid level may associate with the earlier cognition decline as well as apathy and depression, while high thyroid level may relate to agitation and irritability. In this study, we try to 6 explore the association between the normal ranged thyroid function and the neuropsychiatric symptoms in the patients with AD by evaluating the thyroid status and the neuropsychiatric symptoms. METHODS Ethics An informant was required to participate in the interviews. Written informed consent approved by the Ethics Committee of Tianjin Medical University General Hospital was obtained from all participants and caregivers. The study procedure had been fully explained as well as the potential risks and benefits. Participants Diagnosis of probable AD was made according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-Ⅳ) [16] and of the National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) [17]. Consecutive subjects were from the memory clinic of General Hospital of Tianjin Medical University, age ranged from 50-90, Mini-Mental State Examination (MMSE) score of 3 to 24, with reliable caregivers. All patients enrolled in this study had brain imaging evaluation (computed tomography or magnetic resonance imaging, performed within past 12 months. All patients had no prior AD treatment, including but not limited to acetyl-cholinesterase inhibitors (AchEIs) and memantine, within 4 7 weeks before the study entry. Exclusion criteria included a history of thyroid disease, cerebral vascular disorders, head injury, dementia or clinically significant neurologic disease due to conditions other than Alzheimer disease, serious and unstable medical conditions, concomitant anti-depressants and other psychotropic medications, concomitant amiodarone and other medications may alter thyroid hormone levels, or delirium at the time of assessment. Procedures Clinical assessment of cognition and neuropsychiatric symptoms, and blood concentration of thyroid hormones (TT3, TT4, and TSH), were conducted within two days of recruitment of each subject. Thyroid Hormone Measurement Fasting serum samples were obtained between 8:00 to 9:00 hours AM and immediately sent to the laboratory. Ultrasensitive measurement of TSH, TT3 and TT4 were performed for all subjects. The measurement was conducted in accordance with the standardized laboratory procedures of the Bayer ADVIA Centaur_ immunoassay system. Instruments Cognition The (MMSE) [18] was applied as a brief indicator of cognitive impairment. 8 Global cognition was measured with the Alzheimer’s disease Assessment Scale–Cognitive Subscale (ADAS-cog) [19], a 12 item scale of memory, language, orientation, and praxis functions. For further analyses, 11 items (except attention) of the ADAS-cog were aggregated into 3 clusters referred to the previous publication of ADAS-Cog factor analysis: language (commands, language, comprehension of spoken language, word finding), memory (word recall, naming objects and fingers, orientation, word recognition, remembering test instructions), and praxis (constructional praxis, ideational praxis) [20]. Neuropsychiatric symptoms Neuropsychiatric symptoms were evaluated by the Neuropsychiatric Inventory (NPI) [21]. Total frequency and severity scores for all 12 items served as the primary outcome variables in data analyses. Item score >1 was regarded as the existence of this particular symptom. Depression Depression was evaluated by the 17-item Hamilton Rating Scale for Depression (HAMD17) [22]. Assessments included the HAMD17 total score and score of the factor so called depression/retardation (sum of Items 1, 2, 3, 7 and 8), which reflects the core symptoms of depression [23]. A trained investigator who was blind to the subjects’ thyroid status administered the MMSE, ADAS-Cog, NPI and HAMD. 9 Statistical Analysis Data analyses were conducted with the Statistical Package for the Social Sciences (SPSS V13.0). The unique relationship between thyroid hormones and cognitive function and mood was examined with multivariate linear regression analyses, because thyroid hormones may also be related to age and education. We also performed independent-samples t-test (two-tailed) to examine the thyroid status between the neuropsychiatric symptoms group and the non-neuropsychiatric symptoms group. And results were considered significant at the level of P<0.05. RESULTS Forty patients with AD (26 women and 14 men) aged from 54 to 80 years were enrolled in this study from Oct 19, 2006 to Jul 2, 2007. Participants’ average age was 67.08 years (SD = 6.9), with an average schooling of 9.25 years (SD = 5.0). Demographic and clinical characteristics of the subjects are presented in Table 1. A paired-sample test showed no significant differences in the serum level of TT3, TT4, and TSH between men and women. Multivariate linear regression analyses were then conducted to examine the relationship between thyroid hormone concentrations, demographics and cognitive and mood measurements (Table 2, Table 3). Age, education, illness duration and scores of scales were independent variable, and the thyroid hormone levels were dependent variable. There were no significant correlation between age, education, 10 illness duration and thyroid hormone levels. Core score of HAMD is significant associated with the serum level of TSH (β=0.395, P<0.01). There was no significant association between thyroid hormone levels and cognition (MMSE and ADAS-cog total score, and three clusters of ADAS-cog). The neuropsychiatric symptoms results indicated that AD patients with agitation and irritability had lower TSH serum level than those without these symptoms. (t=-2.130, P<0.05; t=-2.657, P<0.05) (Table 4). DISCUSSION It had been recognized that there are three stages of thyroid hormone (TH) dependent neurological development in humans, which include 16-20 weeks post-conception, the remainder of pregnancy after the onset of foetal thyroid function, and the neonatal and post-natal period. During these stages, thyroid hormone exposure influences neuronal proliferation and migration of neurons in the cerebral cortex, hippocampus and medial ganglionic eminence. During the second stage, thyroid hormone dependent processes include neurogenesis, neurone migration, axonal outgrowth, dendritic branching and synaptogenesis, together with the initiation of glial cell differentiation and migration and the onset of myelination. During the third stage, migration of granule cells in the hippocampal dentate gyrus and cerebellum, pyramidal cells in the cortex and Purkinje cells in the cerebellum are sensitive to thyroid hormones and thyroid hormone-dependent gliogenesis and myelination continues [24]. The thyroid function plays important role in both 11 neurodevelopment process and neurodegenerative process [25]. It is possible that the thyroid function is related to the Alzheimer’s disease. Although the neuropathologic mechanism of altered thyrotropin levels occur before or after the onset of AD is unclear, it is generally assumed that the thyroid dysfunction increases AD risk by a direct adverse effect of thyroxine depletion on cholinergic neurons, adverse effects of excessive levels of thyroid hormone, and vascular-mediated mechanisms. According to several in vitro and in vivo studies [26-28], TH might play a role in the development of AD by regulate the amyloid precursor protein (APP) gene expression and the accumulation of β-amyloid peptide. The presence of oxidative stress and the decrease of anti-oxidant metabolites have been confirmed in hyperthyroid patients [29]. Exposure to TH has been shown to augment necrotic neuron death [25]. The cognitive impairment is believed to be associated with the cholinergic cell death and the result of acetylcholine deficit in AD. A small case-control study showed increased reverse triiodothyronine (rT3) levels and an increased rT3 to T4 ratio in the cerebrospinal fluid (CSF) of patients with AD, suggesting the presence of abnormal intracerebral TH metabolism and brain hypothyroidism [30]. Circulating TH enter the CSF via the choroid plexus. Although in vivo studies illustrated that the circulating TH levels do not properly reflect TH metabolism in the CNS [31-34], evidence existed in the clinical studies showed that the thyroid function plays an important role in the cognition in euthyroid elderly [5, 11] or subclinical 12 hypothyroidism adults without dementia [35]. In this preliminary cross-sectional study in euthyroid patients with AD, significant positive associations had been found between TH concentrations and aspects of behavior and mood, i.e., lower serum level of TSH with higher levels of agitation and irritability from NPI, and higher TSH with depression from core subscale of HAMD17. Similarly, Wahlin et al. [36] demonstrated a positive relationship between TSH and depressive mood symptoms (Comprehensive Psychopathological Rating Scale, CPRS) in nondemented adults between the ages of 75 to 96 years. These results were also consistent with the previously reported finding that high TSH levels are associated with depression [37, 38]. The mechanisms of the association between TH and neuropsychiatric symptoms in AD patients were unclear. As our knowledge, a prospective population-based cohort study [39] about the relationship between thyroid function and AD and its neuropathology confirmed that higher total thyroxine was associated with higher number of neocortical neuritic plaques and neurofibrillary tangles. And neurofibrillary tangles, especially in the frontal cortex, were associated with psychosis and behavioral symptoms in AD patients [40, 41]. Furthermore a recent study demonstrated that TSH level was significantly inversely correlated with regional cerebral blood flow (rCBF) in the middle and inferior temporal regions of right cerebral hemisphere in patients with AD [42]. The major functions of TSH are to maintain the biosynthesis and secretion of the T4 and T3. These results suggest that TSH may be more sensitive to neuropsychiatric symptoms in AD patients than T3 and T4, that reflect the fact that TSH is the major modulator of thyroid functioning. 13 No significant relationships have been detected between TH and cognitive functioning, as measured by the MMSE, ADAS-Cog and its subscales. This is consistent with the result of previous research [15] that has also failed to identify a significant relationship between global cognition (MMSE and ADAS-cog) and current TH concentrations in euthyroid patients with AD. However, more comprehensive, sensitive and specific cognition assessment instruments should be implemented in the further study. It is also possible that free T3 and free T4 may be associated with cognitive function impairment in AD patients. We should measure more thyroid hormones in further study. Although these associations between thyroid status and neuropsychiatric symptoms were identified, the cross-sectional design and small sample size limit the interpretation of these findings. No gender difference was found in this pilot study in terms of the correlation of thyroid function and neuropsychiatric symptoms in patients with AD, however in the Framingham study low and high thyrotropin levels were both associated with an increased risk of incident AD in women but not in men [2]. The findings of this study should be tested in larger sample and gender issue should be carefully considered. Moreover, it is worthwhile to explore the possibility of regulation of thyroid function in the treatment of neuropsychiatric disorder in AD In conclusion, this preliminary study indicates a possible relationship between thyroid state and neuropsychiatric symptoms in euthyroid patients with AD. This may be helpful in understanding the mechanism of neuropsychiatric disorder in patients 14 with AD and exploring new therapeutic strategy. 15 References 1. van OLA, Hogervorst E, Combrinck M, Smith AD. Low thyroid-stimulating hormone as an independent risk factor for Alzheimer disease. Neurology 2004; 62(11): 1967-1971. ( PMID:15184598) 2. Tan ZS, Beiser A, Vasan RS, Au R, Auerbach S, Kiel DP, et al. Thyroid function and the risk of Alzheimer disease: the Framingham Study. Arch Intern Med 2008; 168(14): 1514-1520. (PMID:18663163) 3. Kalmijn S, Mehta KM, Pols HA, Hofman A, Drexhage HA, Breteler MM. Subclinical hyperthyroidism and the risk of dementia. The Rotterdam study. 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J Neuropsychiatry Clin Neurosci 1995; 7(4): 476-484. (PMID:8555751) 42. Kimura N, Kumamoto T, Masuda H, Hanaoka T, Hazama Y, Okazaki T, et al. Relationship between thyroid hormone levels and regional cerebral blood flow in Alzheimer disease. Alzheimer Dis Assoc Disord 2011; 25(2): 138-143. (PMID:20975518) 22 Table 1. Demographic and Clinical Characteristics Demographic and Clinical Characteristics Mean(SD) Age(years) Education(years) Illness Duration (years) Height(cm) Weight(kg) MMSE ADAS-cog NPI HAMD17 TT3(nmol/L) TT4(nmol/L) TSH(uU/ml) 67.08(6.92) 9.25(5.04) 3.58(1.77) 160.55(8.23) 60.90(11.17) 13.80(5.81) 36.18 (14.85) 16.45(16.15) 8.53(3.36) 2.00(0.52) 113.52 (31.01) 1.86 (1.30) Reference range for TT3=0.92-2.79 nmol/L; TT4=58.1-140.6 nmol/L; TSH=0.3-5.0 uU/ml. Table 2. Multivariate regression analysis of Thyroid Hormone Concentrations, Demographics, Cognition and Mood Variables Outcome Measurements Age Education Duration ADAS-cog (total score) MMSE (total score) HAMD17 (total score) TT3 TT4 TSH β P β P β P -0.006 0.024 -0.114 0.002 -0.006 0.053 0.643 0.263 0.092 0.893 0.859 0.117 -0.543 1.286 -2.108 0.363 1.475 1.743 0.496 0.331 0.602 0.680 0.450 0.395 0.019 0.039 0.144 -0.013 0.008 0.022 0.561 0.477 0.392 0.715 0.920 0.796 All statistical tests P>0.05 Table 3. Multivariate regression analysis of Thyroid Hormone Concentrations, Demographics, ADAS-cog and HAMD Factor Scores Outcome Measurements Age Education Duration ADAS-cog (language) ADAS-cog (memory) ADAS-cog (praxis) HAMD17 (core) *P<0.01 TT3 TT4 TSH β P β P β P -0.010 0.005 -0.107 0.003 -0.020 0.085 0.107 0.458 0.818 0.113 0.922 0.284 0.139 0.070 -0.809 0.943 -1.824 -0.734 -0.213 1.145 2.360 0.341 0.517 0.673 0.716 0.862 0.756 0.530 -0.007 -0.010 0.002 -0.044 -0.081 0.118 0.395* 0.806 0.853 0.991 0.537 0.071 0.037 0.005* 23 Table 4. Comparison of Thyroid Hormone Concentrations among Groups with/without Neuropsychiatric Symptoms with NPI Outcome Measurements TT3 A Delusions Hallucinations Agitation Dysphoria Anxiety Apathy Irritability Euphoria§ Disinhibition§ Aberrant motor behavior Nighttime behavior disturbances Appetite and eating abnormalities † B TT4 ‡ 1.95(0.45) 1.89(0.35) 2.03(0.44) 1.92(0.34) 1.96(0.42) 2.05(0.33) 1.96(0.45) 2.01(0.64) 2.39(0.79) 1,95(0.63) 2.13(0.72) 2.18(0.81) 1.99(0.55) 2.06(0.61) 1.97(0.45) 1.93(0.36) 2.00(0.53) 2.08(0.67) 2.10(0.68) 2.02(0.49) † TSH B ‡ t A -0.753 -1.870 0.389 -1.065 -0.750 0.353 -0.591 NA NA -0.489 -0.940 -0.068 112.25(30.82) 110.41(29.11) 114.75(32.06) 114.34(30.56) 114.87(29.57) 104.00(23.10) 114.80(32.03) 116.15(32.51) 124.25(36.64) 111.47(30.16) 112.16(32.79) 108.11(37.99) 115.20(32.19) 111.60(30.34) 113.54(30.40) 109.42(31.89) 112.54(31.65) 113.48(34.10) 119.07(29.81) 122.38(26.46) B‡ t 1.72(1.03) 1.88(1.20) 1.51(1.06) 1.58(1.05) 1.71(1.06) 1.23(0.78) 1.39(0.69) 2.16(1.74) 1.78(1.68) 2.44(1.48) 2.32(1.56) 2.45(1.97) 1.97(1.35) 2.56(1.67) 1.88(1.19) 1.60(1.20) 1.86(1.35) 1.81(1.62) 2.21(1.38) 1.83(0.89) -0.857 0.169 -2.130|| -1.627 -1.026 -1.882 -2.657|| NA NA 0.126 -1.471 0.068 t A -0.362 -1.042 0.325 0.208 0.469 -1.025 0.320 NA NA 0.005 -0.983 -0.691 † † A is non-neuropsychiatric symptoms group. ‡ B is neuropsychiatric symptoms group. § No further statistical analyses due to the sample size. || P<0.05.