Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model.

BACKGROUND: Determinations of thyrotropin (TSH) and free thyroxine (FT4) represent the gold standard in evaluation of thyroid function. To screen for novel peripheral biomarkers of thyroid function and to characterize FT4-associated physiological signatures in human plasma we used an untargeted OMICS approach in a thyrotoxicosis model. METHODS: A sample of 16 healthy young men were treated with levothyroxine for 8 weeks and plasma was sampled before the intake was started as well as at two points during treatment and after its completion, respectively. Mass spectrometry-derived metabolite and protein levels were related to FT4 serum concentrations using mixed-effect linear regression models in a robust setting. To compile a molecular signature discriminating between thyrotoxicosis and euthyroidism, a random forest was trained and validated in a two-stage cross-validation procedure. RESULTS: Despite the absence of obvious clinical symptoms, mass spectrometry analyses detected 65 metabolites and 63 proteins exhibiting significant associations with serum FT4. A subset of 15 molecules allowed a robust and good prediction of thyroid hormone function (AUC = 0.86) without prior information on TSH or FT4. Main FT4-associated signatures indicated increased resting energy expenditure, augmented defense against systemic oxidative stress, decreased lipoprotein particle levels, and increased levels of complement system proteins and coagulation factors. Further association findings question the reliability of kidney function assessment under hyperthyroid conditions and suggest a link between hyperthyroidism and cardiovascular diseases via increased dimethylarginine levels. CONCLUSION: Our results emphasize the power of untargeted OMICs approaches to detect novel pathways of thyroid hormone action. Furthermore, beyond TSH and FT4, we demonstrated the potential of such analyses to identify new molecular signatures for diagnosis and treatment of thyroid disorders. This study was registered at the German Clinical Trials Register (DRKS) [DRKS00011275] on the 16th of November 2016.

Effect of Mild Thyrotoxicosis on Performance and Brain Activations in a Working Memory Task.

AIMS: Disturbed levels of thyroid hormones are associated with neuropsychiatric disorders, including memory impairments. The aim of this study was to evaluate effects of mild induced thyrotoxicosis on working memory and its neural correlates. METHODS: Twenty-nine healthy, male subjects with normal thyroid state participated in the study. Functional MRI was acquired during a working memory task (n-back task) before and after ingesting 250 µg L-thyroxin per day for a period of eight weeks. In addition, neuropsychological tests were performed. RESULTS: In the hyperthyroid condition the subjects showed slower reaction times, but a higher accuracy in the 0-back version of the memory tasks. Fewer differences between euthyroid and hyperthyroid state were seen for the more difficult conditions of the n-back task. FMRI revealed effects of difficulty in the parahippocampal gyrus, supplementary motor area, prefrontal cortex, anterior cingulate cortex, posterior cerebellum, rolandic operculum and insula (p<0.05, FWE corrected). When comparing euthyroid and hyperthyroid condition in relation to task-induced activation, differences of activation were found in the right prefrontal cortex as well as in the right parahippocampal area. In the psychological assessment, the alerting effect in the Attention Network Task (ANT) and four out of five parameters of the auditory verbal learning test (AVLT) showed an increase from euthyroid to hyperthyroid state. CONCLUSIONS: It can be concluded that even a short-term intake of thyroid hormones leads to an activation of brain areas associated with working memory and to an improvement of accuracy of working memory tasks.

Effect of Experimental Thyrotoxicosis on Brain Gray Matter: A Voxel-Based Morphometry Study.

BACKGROUND: Hyper-as well hypothyroidism have an effect on behavior and brain function. Moreover, during development thyroid hormones influence brain structure. OBJECTIVES: This study aimed to demonstrate an effect of experimentally induced hyperthyroidism on brain gray matter in healthy adult humans. METHODS: High-resolution 3D T1-weighted images were acquired in 29 healthy young subjects prior to as well as after receiving 250 µg of T4 per day for 8 weeks. Voxel-based morphometry analysis was performed using Statistical Parametric Mapping 8 (SPM8). RESULTS: Laboratory testing confirmed the induction of hyperthyroidism. In the hyperthyroid condition, gray matter volumes were increased in the right posterior cerebellum (lobule VI) and decreased in the bilateral visual cortex and anterior cerebellum (lobules I-IV) compared to the euthyroid condition. CONCLUSIONS: Our study provides evidence that short periods of hyperthyroidism induce distinct alterations in brain structures of cerebellar regions that have been associated with sensorimotor functions as well as working memory in the literature.

Experimentally induced thyrotoxicosis leads to increased connectivity in temporal lobe structures: a resting state fMRI study.

Adult onset hyperthyroidism may impact on different cognitive domains, including attention and concentration, memory, perceptual function, language and executive function. Previous PET studies implicated changed functionality of limbic regions, the temporal and frontal lobes in hyperthyroidism, whereas it is unknown whether cognitive effects of hyperthyroidism may be due to changed brain connectivity. This study aimed to investigate the effect of experimentally induced short-term hyperthyroidism thyrotoxicosis on resting-state functional connectivity using functional magnetic resonance imaging. Twenty-nine healthy male right-handed subjects were examined twice, once prior and once after 8 weeks of oral administration of 250 µg levothyroxine per day. Resting-state fMRI was subjected to graph-theory based analysis methods to investigate whole-brain intrinsic functional connectivity. Despite a lack of subjective changes noticed by the subjects significant thyrotoxicosis was confirmed in all subjects. This induced a significant increase in resting-state functional connectivity specifically in the rostral temporal lobes (0.05 FDR corrected at the cluster level), which is caused by an increased connectivity to the cognitive control network. The increased connectivity between temporal poles and the cognitive control network shown here under experimental conditions supports an important function of thyroid hormones in the regulation of paralimbic structures.