The Role of Transthyretin in Oligodendrocyte Development.

Transthyretin (TTR) is a protein that binds and distributes thyroid hormones (THs) in blood and cerebrospinal fluid. Previously, two reports identified TTR null mice as hypothyroid in the central nervous system (CNS). This prompted our investigations into developmentally regulated TH-dependent processes in brains of wildtype and TTR null mice. Despite logical expectations of a hypomyelinating phenotype in the CNS of TTR null mice, we observed a hypermyelination phenotype, synchronous with an increase in the density of oligodendrocytes in the corpus callosum and anterior commissure of TTR null mice during postnatal development. Furthermore, absence of TTR enhanced proliferation and migration of OPCs with decreased apoptosis. Neural stem cells (NSCs) isolated from the subventricular zone of TTR null mice at P21 revealed that the absence of TTR promoted NSC differentiation toward a glial lineage. Importantly, we identified TTR synthesis in OPCs, suggestive of an alternate biological function in these cells that may extend beyond an extracellular TH-distributor protein. The hypermyelination mechanism may involve increased pAKT (involved in oligodendrocyte maturation) in TTR null mice. Elucidating the regulatory role of TTR in NSC and OPC biology could lead to potential therapeutic strategies for the treatment of acquired demyelinating diseases.

The Thyroid Hormone Inactivating Type 3 Deiodinase Is Essential for Optimal Neutrophil Function: Observations From Three Species.

Neutrophils are essential effector cells of the innate immune system that have recently been recognized as thyroid hormone (TH) target cells. Cellular TH bioavailability is regulated by the deiodinase enzymes, which can activate or inactivate TH. We have previously shown that the TH inactivating enzyme type 3 deiodinase (D3) is present in neutrophils. Furthermore, D3 knockout (D3KO) mice show impaired bacterial killing upon infection. We hypothesized that D3 plays a role in neutrophil function during infection by actively regulating local TH availability. We measured TH concentrations in cerebrospinal fluid (CSF) from patients with bacterial meningitis and controls. Bacterial meningitis resulted in marked changes in CSF TH levels, characterized by a strong increase of thyroxine and reverse-triiodothyronine concentrations. This altered TH profile was consistent with elevated D3 activity in infiltrating neutrophils at the site of infection. D3 knockdown in zebrafish embryos with pneumococcal meningitis resulted in increased mortality and reduced neutrophil infiltration during infection. Finally, stimulated neutrophils from female D3KO mice exhibited impaired NADPH-oxidase activity, an important component of the neutrophil bacterial killing machinery. These consistent findings across experimental models strongly support a critical role for reduced intracellular TH concentrations in neutrophil function during infection, for which the TH inactivating enzyme D3 appears essential.

Intrathecal Thyroid Autoantibody Synthesis in a Subgroup of Patients With Schizophreniform Syndromes.

Schizophreniform syndromes in combination with autoimmune thyroiditis and increased serum thyroid antibodies lead healthcare practitioners to consider a diagnosis of Hashimoto's encephalopathy. To detect specific biomarkers, the authors analyzed whether intrathecal antithyroid antibody synthesis occurred in a subgroup of schizophreniform patients. In doing so, the authors analyzed thyroid antibodies in paired cerebrospinal fluid and serum samples from 100 schizophreniform patients. Increased antibody indices (AIs) for antithyroid peroxidase or antithyroglobulin autoantibodies in 13 schizophreniform patients were found. AIs were increased in 68% of the seropositive patients. These findings support the hypothesis that autoimmune processes may contribute to the pathophysiology in these patients.

Traversing barriers - How thyroid hormones pass placental, blood-brain and blood-cerebrospinal fluid barriers.

Thyroid hormone is essential for normal human fetal growth and brain development. As the fetal thyroid does not secrete thyroid hormones until about 18 weeks gestation, early fetal brain development depends on passage of maternal hormone across the placenta into the fetal circulation. To reach the fetal brain, maternally derived and endogenously produced thyroid hormone has to cross the blood-brain and blood-cerebrospinal fluid barriers. In this review we will discuss the complex biological barriers (involving membrane transporters, enzymes and distributor proteins) that must be overcome to ensure that the developing human brain has adequate exposure to thyroid hormone.

Anti-thyroid antibodies and cerebrospinal fluid findings in neuromyelitis optica spectrum disorders.

OBJECTIVE: To determine the differences of thyroid diseases and ATAbs in multiple sclerosis (MS) and NMOSDs, and to assess the independent impact factors of longitudinally extensive transverse myelitis (LETM) in NMOSDs. RESULTS: Anti-thyroid peroxidase antibodies-positive (TPOAb(+)) and anti-thyroglobulin antibodies-positive (TGAb(+)) were most frequent in NMOSDs. LETM and lesions ≥6 vertebral segments were more frequent in TPOAb(+) NMOSDs than in TPOAb-negative (TPOAb(-)) NMOSDs. TGAb(+) NMOSDs with LETM were significantly more frequent than TGAb-negative (TGAb(-)) NMOSDs. TPOAb(+) and cerebrospinal fluid (CSF) abnormalities were independently associated with LETM. CONCLUSIONS: Our findings demonstrate that ATAbs and thyroid diseases are significantly different in MS and NMOSD patients and CSs. TPOAb(+) and CSF abnormalities may be possible predictors of the severity of spinal cord lesions.

Brain tumor as a prototype of severe brain lesion in patients with "low T3 syndrome".

The purpose of our study was to contribute to better understanding of cerebrospinal fluid (CSF) as a valuable biological material in the research of brain tumors within the "low T3 syndrome", and to discuss the role of thyroid hormones in the central nervous system in subjects with severe cerebral lesions. We studied the levels of total triiodothyronine (tT3), total thyroxine (tT4), free triiodothyronine (fT3), free thyroxine (fT4), reverse triiodothyronine (rT3) and thyrotropin (TSH) in serum, and fT3, fT4, rT3 and TSH levels in CSF of patients with brain tumor, and compared the results with control group. Study results indicated a statistically significantly higher level of rT3 in serum and CSF of brain tumor patients vs. control group (p < 0.05). The rT3/fT3 ratio was highest in CSF and serum of brain tumor patients, yielding a statistically significant difference (p < 0.05). These results could suggest higher permeability of the blood-brain barrier in brain tumor patients. We also assume that rT3, in the framework of"cerebral low T3 syndrome", is also generated through local intracerebral conversion. Disruption of this process in severe cerebral lesion can lead to increased rT3 concentrations, i.e. development of the "low T3 syndrome".

Photoperiod modulates access of 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) to the brain and its effect on gonadotropin and thyroid hormones in adult ewes.

The effects of photoperiod on the cerebrospinal fluid (CSF) concentration of six ortho-substituted polychlorinated biphenyls (PCBs: PCB28, PCB52, PCB101, PCB138, PCB153, and PCB180), the effects of an orally administered low dose of PCB153 (0.3mg/kg, three times a week for three weeks) on PCBs and thyroid hormones (THs) concentrations in the CSF and plasma, and the release of luteinizing hormone (LH) were determined in ovariectomized, estradiol-implanted ewes (2.5 years old) maintained indoors under artificial long day (LD, 16L: 8D) and short day (SD, 8L: 16D) conditions. Concentrations of two PCBs (PCB28 and PCB153) in the plasma and four PCBs in the CSF (PCB101, PCB138, PCB153, and PCB180) were significantly higher during LD than SD. Following PCB153 treatment, its concentration in the plasma was higher in SD (1.2 ± 0.3 ng/ml) than LD (0.2 ± 0.05 ng/ml), but similar in the CSF (10.2 ± 3.7 pg/ml vs. 13 ± 0.7 pg/ml) under both photoperiods. During SD, the concentration of PCB153 in the CSF was higher in treated animals than controls, while no differences were noted under LD. These findings indicate that in ewes, exposure of the brain to more highly chlorinated, ortho-substituted PCBs may be modulated by photoperiod. PCB153 treatment had no effect on plasma THs, but reduced total triiodothyronine concentration during LD and free thyroxine during SD in the CSF. Under both photoperiods, PCB153 reduced basal plasma LH and reinforced the inhibition of pulsatile LH release during LD. As PCB153 reduced LH and THs (which are involved in the seasonal control of reproduction in ewes), it may have a braking effect on seasonal transitions between active and inactive phases of reproduction.

Impaired hepatic function and central dopaminergic denervation in a rodent model of Parkinson's disease: a self-perpetuating crosstalk?

In Parkinson's disease (PD), aside from the central lesion, involvement of visceral organs has been proposed as part of the complex clinical picture of the disease. The issue is still poorly understood and relatively unexplored. In this study we used a classic rodent model of nigrostriatal degeneration, induced by the intrastriatal injection of 6-hydroxydopamine (6-OHDA), to investigate whether and how a PD-like central dopaminergic denervation may influence hepatic functions. Rats received an intrastriatal injection of 6-OHDA or saline (sham), and blood, cerebrospinal fluid, liver and brain samples were obtained for up to 8 weeks after surgery. Specimens were analyzed for changes in cytokine and thyroid hormone levels, as well as liver mitochondrial alterations. Hepatic mitochondria isolated from animals bearing extended nigrostriatal lesion displayed increased ROS production, while membrane potential (ΔΨ) and ATP production were significantly decreased. Reduced ATP production correlated with nigral neuronal loss. Thyroid hormone levels were significantly increased in serum of PD rats compared to sham animals while steady expression of selected cytokines was detected in all groups. Hepatic enzyme functions were comparable in all animals. Our study indicates for the first time that in a rodent model of PD, hepatic mitochondria dysfunctions arise as a consequence of nigrostriatal degeneration, and that thyroid hormone represents a key interface in this CNS-liver interaction. Liver plays a fundamental detoxifying function and a better understanding of PD-related hepatic mitochondrial alterations, which might further promote neurodegeneration, may represent an important step for the development of novel therapeutic strategies.

Clinical evaluation of the function of hypothalamo-pituitary-thyroid axis in children with central nervous system infections.

BACKGROUND: It is well known that certain non-thyroidal critical illness may lead to euthyroid sick syndrome(ESS). There are little reports about the change of thyroid hormone in the children's central nervous system (CNS) infections. RESULTS: The results of serum TT3, TT4 and TSH in these children were compared with those in 20 cases of healthy adults and 20 cases of adults with primary hypothyroidism. Serum T3 and T4 were decreased in 34/78 children with CNS infections, T3 and T4 were much lower than those of healthy adult (p < 0.05), but still higher than that of the primary hypothyroidism (p < 0.05), and TSH levels were not significant differences among children with CNS infections and children with non-CNS infections (p > 0.05). Low T3 and T4 levels in serum and cerebrospinal fluid(CSF)were predominant in children with serious infections of CNS, 31/34 (percent 91.17) cases of serious CNS infection had low serum TT3 and/or TT4. The low T3 with low T4 was seen in 14/34 children of severe CNS infections, 3 of them died. The levels of CSF T3 (X ± SD = 0.39 ± 0.47 ng/ml) and T4 (x ± SD = 1.02 ± 1.27 ug/dl) in the serious CNS infections were lower than that of non-CNS infections T3 (x ± SD = 0.93 ± 1.23 ng/ml), and T4 (x ± SD = 2.42 ± 1.70 ug/dl), 7 died children were all in the subjects of low T3 and/or low T4. In 22 children with non-CNS infections, serum T3 and T4 levels were lower than that of healthy adult, but have not significant difference(p > 0.05). CONCLUSIONS: These results suggest that detection of TT3, TT4 and TSH in serum and/or CSF simultaneous or alone in analyses would be valuable in correctly judging thyroid function and evaluating the prognosis of the children with infections of CNS. Measuring a little amount of blood (1 ml)or CSF required for this method is a simple, convenient and accurate method.

Neurochemical measures co-vary with personality traits: forensic psychiatric findings replicated in a general population sample.

Neurobiological markers in cerebrospinal fluid (CSF) and in serum, previously found to co-vary with destructive personality traits in violent offenders, were explored in a general population sample of 21 patients undergoing knee surgery. Results on the Karolinska Scales of Personality (KSP) and the Temperament and Character Inventory (TCI) were compared with CSF/serum albumin ratios and serum concentrations of beta-trace protein (betaTP) (as markers for blood-brain barrier (BBB) permeability), to CSF/serum albumin ratios between the dopamine and serotonin metabolites homovanillic acid (HVA)/5-hydroxyindoleacetic acid (HIAA) and to CSF and serum ratios between activated thyroid hormone (T3) and its precursor T4. Serum betaTP concentrations correlated with CSF/serum albumin ratios (P=0.018), but not with preoperative serum creatinine concentrations. Serum betaTP correlated significantly with Monotony Avoidance and Impulsiveness; CSF HVA/5-HIAA ratios with Irritability and low Cooperativeness. The betaTP is a potential serum marker for the integrity of the BBB that does not necessitate lumbar puncture. Thyroid hormones did not correlate with personality traits. As reported in forensic psychiatric patients, aggressive, unempathic personality traits were thus associated with increased dopaminergic activity in relation to the serotonergic activity and impulsivity to increased BBB permeability also in a general population group.

Cerebrospinal fluid levels of iodothyronines and nerve growth factor in patients with multiple sclerosis and neuromyelitis optica.

OBJECTIVE: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system (CNS) and a major cause of neurological disability among adults in North America and Europe. Neuromyelitis optica (NMO) is a very severe disease of inflammatory demyelination located in the optic chiasm, nerves and the spinal cord. The aim of this study is to assess thyroid hormone (TH) and nerve growth factor (NGF) levels in cerebrospinal fluid (CSF) of MS, NMO patients and controls, and investigate whether there is any correlation between TH and NGF levels in the CSF. PATIENTS AND METHODS: 38 relapsing-remitting multiple sclerosis (RRMS), 10 NMO and 19 controls were investigated whether there was any correlation between TH and NGF levels in the CSF. RESULTS: MS and NMO patients exhibited significantly higher CSF NGF (respectively P<0.05, P<0.05), TT4 levels (P<0.001) and higher TT4/ rT3 ratio (respectively P<0.01, P<0.01) compared with the controls. Significant correlation was found between CSF NGF levels and CSF rT3 levels or TT4/ rT3 ratio in controls (respectively P<0.01, P<0.05). EDSS was significantly correlated with CSF rT3 levels and TT4/ rT3 ratio in MS patients (respectively P<0.05, P<0.001). CONCLUSIONS: These results indicate that an abnormal thyroid hormone may exist within the brain in the patients with MS. CSF rT3 levels and TT4/ rT3 ratio could be regarded as useful markers of underlying disease activity.

Association between thyroid hormone levels and monoaminergic neurotransmission during surgery.

BACKGROUND: Human studies assessing thyroid hormone metabolism in relation to brain monoaminergic activity in vivo are scarce. The few studies that do exist suggest significant associations between thyroid function and monoaminergic activity, but the cause-and-effect relationships are far from elucidated. METHODS: We simultaneously collected cerebrospinal fluid (CSF) and serum samples from 35 patients undergoing orthopaedic surgery before, 3h after and the morning after interventions and performed analyses for thyroid hormones and monoamine metabolites. RESULTS: At baseline, the CSF 3-methoxy-4-hydroxyphenylglycol concentrations were significantly correlated to the serum T(3)/T(4) ratio (rho=0.41, p=0.017). During surgery, serum thyroid hormones and the T(3)/T(4) ratio decreased (p<0.0001), while the CSF T(3)/T(4) ratio increased (p=0.0009). There were no correlations between serum and CSF levels of T(3) and T(4) at any of the samplings. Strong correlations were noted between baseline CSF thyroid hormone concentrations and subsequent increases in CSF 5-hydroxyindoleacetic acid (5-HIAA), and homovanillinic acid (HVA), but not vice versa. CONCLUSIONS: Thyroid hormone levels in serum and CSF during stress seem to be distinctly regulated. Baseline thyroid hormone activity may facilitate changes in brain monoaminergic neurotransmission in response to stress.

Central metabolic messengers and the effects of nutrition on gonadotrophin secretion in sheep.

Nutrition influences the reproductive axis via alteration of gonadotrophin secretion. However, a link between nutrition and the secretion of GnRH, which drives the axis, has yet to be established. The aim of the present study was to measure the change in the concentrations of metabolic substances in the cerebrospinal fluid of adult male sheep offered a diet designed to maintain constant gonadotrophin secretion (Group M; n = 6), or a diet known to increase gonadotrophin secretion (Group M + L; n = 6). On days 1, 3 and 10 of the dietary treatments, cerebrospinal fluid and jugular blood were sampled and analysed for metabolic fuels (glucose, amino acids and free fatty acids) and metabolic hormones (insulin, insulin-like growth factor I, GH, prolactin, cortisol and the thyroid hormones). On day 11 of the dietary treatment, LH pulse frequency and mean FSH concentrations in Group M + L had increased relative to Group M and to day 0. Plasma concentrations of prolactin and insulin on days 3 and 10, and glucose and insulin-like growth factor I on day 10, were higher in Group M + L than in Group M, but only cerebrospinal fluid concentrations of insulin, glucose and certain amino acids were affected by the dietary treatments on days 3 and 10. Cerebrospinal fluid, but not plasma, concentrations of aspartate, tyrosine, cystine, phenylalanine and arginine on day 3, and glutamine, gamma-aminobutyric acid, threonine, alanine on days 3 and 10, were higher in Group M + L relative to Group M. On day 10, plasma and cerebrospinal fluid concentrations of arginine, phenylalaine, proline, tyrosine, methionine and phosphoserine, but only the plasma concentrations of linoleic acid, aspartate and serine, were higher in Group M + L than in Group M. Concentrations of triiodothyronine, thyroxine, and cortisol in plasma and cerebrospinal fluid were not affected. These results show that the nutritional stimulation of gonadotrophin secretion is accompanied primarily by fluctuations in plasma and cerebrospinal fluid concentrations of insulin and certain amino acids, which suggests that, when nutritional status is improved, insulin, amino acids and possibly glucose interact to modulate GnRH secretion.

Growth hormone treatment affects brain neurotransmitters and thyroxine [see comment].

OBJECTIVE: Binding sites specific for growth hormone have been identified in the brain, but the action of GH on the central nervous system is still poorly understood. DESIGN: In a double-blind, placebo-controlled 21-month trial with a cross-over design, with each treatment period lasting for 9 months, we investigated the long-term effect of GH on the cerebrospinal fluid (CSF) concentrations of some brain neurotransmitters and thyroid hormones of importance for mood and cognition. PATIENTS: Twenty-four patients with documented GH deficiency acquired in adult life took part. RESULTS: Analysis of CSF collected at the end of the two treatment periods showed that the GH concentration was related to the administered dose of rhGH (r = 0.56, P = 0.0044). After rhGH treatment the concentration of the dopamine metabolite homovanillic acid (HVA) had decreased from 218 +/- 80 to 193 +/- 82 nmol/l (P = 0.002) and that of the excitatory acid aspartate had increased from 233 +/- 81 to 313 +/- 116 nmol/l (P = 0.032). No effects were observed on the concentrations of 5-hydroxyindoleacetic acid (the serotonin metabolite) and of 3-methoxy-4-hydroxyphenyl glycol (the noradrenaline metabolite), or on those of glutamate, glycine and beta-endorphin. However, both CSF and serum levels of free T4 decreased, from 19.8 +/- 6.1 to 16.6 +/- 5.7 nmol/l (P = 0.0002) and 17.0 +/- 5.0 to 13.7 +/- 4.3 nmol/l (P = 0.0001), respectively. The concentration of total T3 was not measurable in CSF but increased in serum from 1.41 to 1.53 nmol/l (P = 0.01). CONCLUSION: The study demonstrates a passage of GH from the circulation into the CSF. The observed changes in homovanillic acid and free T4 are similar to those reported after successful treatment of depressive disorders with antidepressant drugs, and may reflect a beneficial effect of GH on mood and behaviour.

Neuroendocrinology of cerebrospinal fluid: peptides, steroids, and other hormones.

Cerebrospinal fluid (CSF) has been implicated as a conduit in neuroendocrine integration. Evidence suggests that the ventricular CSF may promote the central distribution, enable the dilutional inactivation (sink effect), and facilitate the peripheral delivery of neurally secreted hormones. This discussion of the sites of origin and concentration gradients of CSF hormones and of both physiological and pharmacological variations in the hormonal content of the CSF provides insight into the putative role of CSF in neuroendocrine regulation. Normal or control concentrations of peptides, steroids, and other hormones present in human lumbar CSF are listed to provide a physiological base line to which the CSF hormonal profile of patients may be compared. The individual, somatotopic, chronological, endocrinological, pharmacological, and possible artifactual variations in CSF hormonal composition are presented to facilitate the formulation of clinical protocols and to eliminate possible sources of error.