Zusammenfassung. Schilddrüsenhormone interagieren mit mannigfaltigen physiologischen und psychologischen Funktionen des Körpers. In dieser Übersichtsarbeit werden Effekte durch Variationen von Schilddrüsenhormonen, der Schilddrüsenhormonrezeptoren und der Schilddrüsenhormontransporter auf psychoneuroendokrinologische Mechanismen beschrieben. Erhöhte oder erniedrigte Serum-Konzentration der Schilddrüsenhormone beeinflussen u.a. die kognitive Entwicklung in der Kindheit, Arbeitsgedächtnis, Aufmerksamkeit, Konzentration und exekutive Funktionen. Schilddrüsenhormone interagieren zudem mit der Psychomotorik, der Sprachentwicklung, der Kognition und den intellektuellen Fähigkeiten. Veränderungen in Schilddrüsenhormon-Transportern können die Ängstlichkeit, die Risikobereitschaft und andere Emotionen modulieren. Die wissenschaftliche Analyse und das Verständnis dieser komplexen Interaktionen ist für die gezielte Prävention und die Behandlung zahlreicher schwerwiegender und lebenslanger Erkrankungen von zentraler Bedeutung.

The pleiotropic function of thyroid hormones (TH) is mediated by an organ specific expression of thyroid hormone transporters, deiodinases and TH receptors. In a series of studies we used the model of an experimentally induced hyper- or hypothyroidism in human volunteers to delineate TH action on the brain. A battery of neuropsychological testing paradigms was employed and complemented by structural and functional multimodal neuroimaging. Experimentally induced mild thyrotoxicosis for 6 weeks was associated with changes in brain structure (determined with voxel-based morphometry), resting state functional connectivity, and task-related functional activation in a working memory paradigm. Partial withdrawal of TH replacement in patients without thyroid (subclinical hypothyroidism) likewise lead to changes on multiple functional and structural brain measures. Importantly, the series of studies reviewed here identified the cerebellum as one crucial site of action.

Thyroid hormones are modulators of cognitive functions, and changes in hormone levels affect intelligence, memory, attention and executive function. Single nucleotide polymorphisms (SNPs) of transporter proteins MCT8, MCT10 and deiodinase 2 (DIO2) influence thyroid metabolism and could therefore contribute to inter-individual variance of cognitive functions. This study investigates the influence of these SNPs using an extensive neuropsychological test battery. 656 healthy participants aged 18–39 years were genotyped for four SNPs: MCT8 (rs5937843 and rs6647476), MCT10 (rs14399) and DIO2 (rs225014) and underwent eleven different neuropsychological tests as well as four personality questionnaires. Test results were compared between homo- and heterozygous carriers and for the X-linked MCT8 additionally between men and women. Personality questionnaires revealed that Risk Seeking was reduced in homozygous T carriers and highest in homozygous C carriers of the DIO2 SNP and that both polymorphisms of MCT8 had an additive effect on Physical Aggression in men. Neuropsychological testing indicated that MCT10 affects nonverbal reasoning abilities, DIO2 influences working memory and verbal fluency and MCT8 influences attention, alertness and planning. This pilot study suggests an influence of polymorphisms in thyroid hormone transporter genes and deiodinase on cognitive domains and personality traits.

Hypothyroidism is associated with memory impairments. The present study aimed to evaluate the effects of partial withdrawal of levothyroxine on working memory tasks and brain function. Fifteen subjects under long‐term levothyroxine substitution as a result of complete hypothyroidism participated in the present study. Functional magnetic resonance imaging (MRI) was performed using a working memory task (n‐back task) and neuropsychological tests were performed before and 52‐54 days after the induction of subclinical hypothyroidism by reducing the pretest levothyroxine dosage by 30%. Reaction time of subjects under partial levothyroxine withdrawal was significantly longer and less accurate with respect to solving the working memory tasks. Functional MRI revealed significant activation changes after medication withdrawal in the cerebellum, insula, parietal, frontal, temporal and occipital lobes, lingual gyrus, and the cuneus. Partial withdrawal of levothyroxine may lead to deficits in a working memory task and to an activation of brain areas associated with working memory ability.

Objective: The aim of this study was to experimentally evaluate the effects of subclinical mild hypothyroidism on brain network connectivity as determined by resting state fMRI (rsfMRI) which serves as a proxy for global changes in brain function. Methods: Fifteen otherwise healthy patients with complete hypothyroidism under stable, long term levothyroxine substitution volunteered for the study. They reduced their pretest levothyroxine dosage by 30% for 52-56 days. Basally and after partial levothyroxine withdrawal, rsfMRl along with a neuropsychological analysis was performed. RsfMRI was subjected to graph-theory-based analysis to investigate whole-brain intrinsic functional connectivity. Results: The desired subclinical hypothyroidism was achieved in all subjects. This was associated with a significant decrease in resting-state functional connectivity specifically in the cuneus (0.05 FWE corrected at cluster level) which was mainly caused by a weaker functional connectivity to the cerebellum and regions of the default mode network, i.e. the medial prefrontal cortex, the precuneus and the bilateral angular gyri. The decrease in cuneus connectivity was correlated to the increase in TSH serum levels. A working memory task showed a slightly longer reaction time and less accuracy after partial levothyroxine withdrawal. Conclusion: Even short-term partial levothyroxine partial withdrawal leads to deficits in working memory tasks and to a weaker integration of the cuneus within the default mode network.

Hypo‐ and hyperthyroidism have effects on brain structure and function, as well as cognitive processes, including memory. However, little is known about the influence of thyroid hormones on brain perfusion and the relationship of such perfusion changes with cognition. The present study aimed to demonstrate the effect of short‐term experimental hyperthyroidism on brain perfusion in healthy volunteers and to assess whether perfusion changes, if present, are related to cognitive performance. It is known that an interaction exists between brain perfusion and cerebral oxygen consumption rate and it is considered that neural activation increases cerebral regional perfusion rate in brain areas associated with memory. Measuring cerebral blood flow may therefore represent a proxy for neural activity. Therefore, arterial spin labelling (ASL) measurements were conducted and later analysed to evaluate brain perfusion in 29 healthy men before and after ingesting thyroid hormones for 8 weeks. Psychological tests concerning memory were performed at the same time‐points and the results were correlated with the imaging results. In the hyperthyroid condition, perfusion was increased in the posterior cerebellum in regions connected with cerebral networks associated with cognitive control and the visual cortex compared to the euthyroid condition. In addition, these perfusion changes were positively correlated with changes of performance in the German version of the Auditory Verbal Learning Task [AVLT, Verbaler Lern‐und‐Merkfähigkeits‐Test (VLMT)]. Cerebellar perfusion and function therefore appears to be modulated by thyroid hormones, likely because the cerebellum hosts a high number of thyroid hormone receptors.

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.

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.

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.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Parkinson’s disease (PD) is a common neurodegenerative disorder for which genetic causes and susceptibility factors have been identified using linkage and association studies [1]. Many candidate genes have been investigated as risk factors for PD (www.pdgene.org) and several genome-wide association studies (GWAS) as well as three meta-analyses have been reported [5, 9, 10]. All GWAS indicate a strong association to several polymorphisms within the alpha-Synuclein (SNCA) gene, encoding a protein highly concentrated at presynaptic nerve terminals [13]. Most studies also confirm an association with the H1/H2 haplotype of the microtubule-associated protein tau (MAPT) gene that is enriched in axons [6]. In addition, the S18Y (rs5030732) polymorphism in the ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), a neuron-specific enzyme that is involved in protein degradation, has been shown to modify enzymatic activity and to protect against PD [7]. N-acetyl transferase 2 (NAT2) is an enzyme responsible for the biotransformation of neurotoxins. An inherited defect, which results in a slower rate of metabolism can lead to greater vulnerability to neurotoxins and to a higher susceptibility of PD.[3] However, to date, all known risk factors explain only part of the heritability of PD and thus suggest additional genetic contributions. This might include interactions of genetic risk factors. After obtaining informed consent, we included 400 Caucasian PD patients enrolled in a clinical study in the US [12] and 353 controls from the US from the NINDS Human Genetics DNA Repository at the Coriell Institute for Medical Research. For diagnosis, the presence of bradykinesia was required in combination with at least one other cardinal symptom, i. e. rigidity, resting tremor or postural instability [2]. All patients were diagnosed within five years of enrollment. The study was approved by the local ethics committees and performed in accordance with the Declaration of Helsinki. We genotyped seven polymorphisms in six genes (Table 1A) previously reported as common genetic risk factors for PD.2 Genotyping methods included polyacrylamide gel electrophoresis, melting curve analysis, PCR fragment length determination and direct sequencing. NAT2 metabolizer phenotype was inferred using a validated discriminator [4]. PD risk attributable to each gene and their two-way interactions were estimated by logistic regression controlling for age and gender. Two-tailed p-values for the seven single-gene effects and for the 21 possible two-gene interactions were adjusted for multiple comparisons using a step-down Bonferroni correction. Table 1 Influence of genetic risk factors and the interaction of NAT2 and UCHL1 on PD risk, adjusted for age and gender. Consistent with the current literature [9], a significant association of PD risk was detected for both SNCA polymorphisms (Table 1A). No single gene association was found for any of the other genes including MAPT. Of note, the association of MAPT and PD depends on ethnicity [14]. Interestingly, we observed a significant interaction between NAT2 and UCHL1 genotypes (p = 0.013; Table 1B). The combination of either a slow NAT2 metabolizer genotype plus a UCHL1 A/A or A/C genotype, or an intermediate or rapid NAT2 metabolizer gentoype plus a UCHL1 C/C genotype, was significantly associated with an increased risk of PD but the alternative combinations were not associated with increased risk (Table 1B). There is increasing evidence that PD is not caused by a single factor, but rather by a complex interaction of genetic and environmental factors [11]. Single association studies in UCHL1 or NAT2 in Caucasians have resulted in contradictory results, i. e. demonstrating an association in only a third of the studies [8]. These inconsistencies may be explained, at least partly, by the interaction of the genotypes of these two genes as shown in the present study thus providing one more piece of the puzzle in the etiology of PD. Our results warranting further research to confirm this and elucidate other relevant interactions of genetic risk factors.