Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism

Department of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
European Journal of Endocrinology (Impact Factor: 4.07). 01/2006; 153(6):747-53. DOI: 10.1530/eje.1.02025
Source: PubMed


Hypothyroidism is associated with neurocognitive impairment. Sparse data suggest that treatment of hypothyroidism, resulting in a return to euthyroidism, may be associated with only partial recovery of overall neurocognitive functioning. The aim of this study was to assess neurocognitive functioning and well-being in euthyroid patients with primary hypothyroidism on adequate thyroxine (T4) treatment. We also investigated whether serum TSH and thyroid antibodies are determinants of neurocognitive functioning and well-being.
We assessed neurocognitive functioning and well-being in 141 patients with primary hypothyroidism.
Neurocognitive test results and scores on questionnaires measuring well-being of 141 patients were compared with the reference values for these tests as published and used in Dutch clinical neuropsychological practice. Assessment of neurocognitive functioning included tests for cognitive or psychomotor speed, attention, working memory as well as learning and memory. Well-being was measured with the Symptom Check List-90 total score and the Rand 36-item Health Survey subscales for 'mental health' and 'vitality'.
Patients showed poor performance on various domains of neurocognitive functioning compared with mean standard reference values, especially on a complex attention task and on verbal memory tests. Levels of well-being were significantly lower for patients compared with those of the general population. Neither serum TSH nor thyroid antibodies were determinants of neurocognitive functioning and well-being.
The results of this study suggest that neurocognitive functioning as well as psychological well-being may not be completely restored in patients with hypothyroidism, despite T4 treatment.

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    • "The study design included laboratory assessment of TSH, TPO-ab, free triiodothyronine (fT3) and free thyroxine (fT4). Moreover, we used mood parameters from Quinque et al. (2013) for correlation analyses and performed a highload cognitive test battery to detect subtle deficits in functions discussed in hypothyroidism: memory, working memory, psychomotor speed and attention (Wekking et al., 2005). In order to reduce noise within neuropsychological, laboratory and MRI data, we performed all measurements twice and averaged the data (Van Dijk et al., 2010). "
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    ABSTRACT: The current study investigated neuropsychological and underlying structural and functional brain alterations in long-term adequately treated patients with Hashimoto's thyroiditis in order to examine much discussed residual complaints in patients in relation to possible long-term neural alterations with a specific interest in the underlying autoimmune process. Eighteen patients with treated hypothyroidism due to Hashimoto's thyroiditis (mean age 32, range 18–54 years; two males; mean treatment duration 4.4 years) and 18 healthy matched control subjects underwent 3-Tesla magnetic resonance imaging (MRI). Voxel-based morphometry was used to investigate grey matter density, resting-state functional MRI to analyse the brain connectivity of areas known to be altered in hypothyroidism and event-related functional MRI to examine brain activity during associative memory encoding. Neuropsychological assessment included memory, working memory, psychomotor speed and attention. We previously reported subclinically reduced mood in this study population and investigated its neural correlates here. Thyroid stimulating hormone, free triiodthyronine, free thyroxine and thyroid peroxidase antibodies were measured in serum. We did not find cognitive deficits or alterations in grey matter density, functional connectivity or associative memory-related brain activity in comparison to the control group and cognition was unrelated to thyroid serum measures in the patient group. Thyroid peroxidase antibodies in the patient group correlated with increased grey matter density in right amygdala and enhanced connectivity between subcallosal and parahippocampal areas. Treatment duration was associated with brain structure in frontal and occipital cortex and connectivity between left amygdala and frontal cortex. Mood correlated with brain areas associated with distinct functional networks, but not with those most prominently affected in depression. In conclusion, no cognitive or neural alterations were detected in this young and otherwise healthy cohort of patients in comparison to a healthy control group and current mood status could not be related to depression-related networks. However, autoimmune activity and treatment duration showed a relationship with depression and hypothyroidism-related brain structure and function. They are thus promising factors to further investigate residual complaints despite biochemically adequate treatment in patients with Hashimoto's thyroiditis. Given the small sample size, all findings require replication.
    Full-text · Article · Apr 2014 · Psychoneuroendocrinology
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    • "Levothyroxin (thyroxin) replacement therapy improves memory in subclinical hypothyroid subjects (Osterweil et al., 1992; Monzani et al., 1993; Baldini et al., 1997; Jensovsky et al., 2002). However, clinical reports show variable results as to whether the thyroid hormone replacement therapy fully restores the hypothyroidism-induced impaired learning and memory (Treadway et al., 1967; Jaeschke et al., 1996; Capet et al., 2000; Miller et al., 2006; but see Mennemeier et al., 1993; Leentjens and Kappers, 1995; Wekking et al., 2005; Samuels et al., 2007b). While a large body of literature is available on the effect of thyroid hormone deficiency during the developmental stage (e.g. "
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    ABSTRACT: Cyclic-AMP response element binding protein (CREB) is a transcription factor crucial for late phase long-term potentiation (L-LTP) induction and maintenance. Upon Multiple high frequency stimulation (MHFS), large Ca(2+) influx activates adenylyl cyclase. This, in turn, activates PKA, which by itself or through MAPK p42/p44 can activate (phosphorylate) CREB. Upon phosphorylation, P-CREB activates multiple genes essential for L-LTP generation. Calcium calmodulin kinase IV (CaMKIV) is also activated by calcium and can directly activate CREB. We have shown previously that hypothyroidism impairs L-LTP and reduces the basal protein levels of CREB, MAPK p42/p44, and CaMKIV in area CA1 of the hippocampus. In the present study, levels of these signaling molecules were determined in area CA1 during the induction and maintenance phases of L-LTP. Standard MHFS was used to evoke L-LTP in the CA1 area of hypothyroid, levothyroxin treated hypothyroid and sham control anaesthetized adult rats. Chronic levothyroxin treatment reversed hypothyroidism-induced L-LTP impairment. Five minutes after MHFS, western blotting showed an increase in the levels of P-CREB, and P-MAPK p42/p44 in sham-operated control, and levothyroxin treated hypothyroid animals, but not in hypothyroid animals. The protein levels of total CREB, total MAPK p42/p44, BDNF and CaMKIV were not altered in all groups five minutes after MHFS. Four hours after MHFS, the levels of P-CREB, and P-MAPK p42/p44 remained unchanged in hypothyroid animals, while they were elevated in sham-operated control, and levothyroxin treated hypothyroid animals. We conclude that normalized phosphorylation of essential kinases such as P-CREB and P-MAPK p42/p44 may account for restoration of normal L-LTP induction and maintenance in the CA1 area of levothyroxin-treated hypothyroid animals.
    Full-text · Article · Nov 2013 · Brain research bulletin
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    • "In a community-based survey, patients on levothyroxine, despite having normal TSH, were found to have significantly reduced psychological wellbeing as compared with age-matched and gender-matched controls.11 Likewise, a cohort study showed poorer quality of life and decreased neurocognitive functioning in 141 hypothyroid patients on adequate doses of levothyroxine as compared with the general population.46 Indeed, many patients on levothyroxine do not achieve a physiological Free T3/Free T4 (FT3/FT4) ratio despite serum TSH being within the reference range,47,48 suggesting that hepatic and renal conversion of thyroxine to triiodothyronine may be impaired in these patients and this may account for the persistence of their symptoms. "
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    ABSTRACT: Primary hypothyroidism is the most common endocrine disease. Although the diagnosis and treatment of hypothyroidism is often considered simple, there are large numbers of people with this condition who are suboptimally treated. Even in those people with hypothyroidism who are biochemically euthyroid on levothyroxine replacement there is a significant proportion who report poorer quality of life. This review explores the historical and current treatment options for hypothyroidism, reasons for and potential solutions to suboptimal treatment, and future possibilities in the treatment of hypothyroidism.
    Full-text · Article · Jan 2012 · Drug Design, Development and Therapy
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