Altered thyroid hormone profile in patients with Alzheimer's disease.

BACKGROUND: Epidemiological studies have linked higher levels of thyroid hormones (THs) to increased risk of Alzheimer's disease (AD), whereas in advanced AD, THs have been unchanged or even decreased. In early AD dementia, little is known whether THs are related to AD neuropathology or brain morphology. METHODS: This was a cross-sectional study of 36 euthyroid AD patients and 34 healthy controls recruited at a single memory clinic. Levels of THs were measured in serum and cerebrospinal fluid (CSF). In addition, we determined AD biomarkers (amyloid-ß1-42, total tau and phosphorylated tau) in CSF and hippocampal and amygdalar volumes using magnetic resonance imaging. RESULTS: Serum free thyroxine (FT4) levels were elevated, whereas serum free triiodothyronine (FT3)/FT4 and total T3 (TT3)/total T4 (TT4) ratios were decreased, in AD patients compared to controls. In addition, serum TT4 was marginally higher in AD (p = 0.05 vs. the controls). Other TH levels in serum as well as CSF concentrations of THs were similar in both groups, and there were no correlations between THs and CSF AD biomarkers. However, serum FT3 correlated positively with left amygdalar volume in AD patients and serum TT3 correlated positively with left and right hippocampal volume in controls. CONCLUSIONS: Thyroid hormones were moderately altered in mild AD dementia with increased serum FT4, and in addition, the reduced T3/T4 ratios may suggest decreased peripheral conversion of T4 to T3. Furthermore, serum T3 levels were related to brain structures involved in AD development.

Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington's disease subjects.

Huntington's disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.

Oxidative modifications of cerebral transthyretin are associated with multiple sclerosis.

Transthyretin (TTR) is a homotetrameric protein of the CNS that plays a role of as the major thyroxine (T4) carrier from blood to cerebrospinal fluid (CSF). T4 physiologically helps oligodendrocyte precursor cells to turn into myelinating oligodendrocytes, enhancing remyelination after myelin sheet damage. We investigated post-translational oxidative modifications of serum and CSF TTR in multiple sclerosis subjects, highlighting high levels of S-sulfhydration and S-sulfonation of cysteine in position ten only in the cerebral TTR, which correlate with an anomalous TTR protein folding as well as with disease duration. Moreover, we found low levels of free T4 in CSF of multiple sclerosis patients, suggestive of a potential role of these modifications in T4 transport into the brain.

Reduced cerebrospinal fluid level of thyroxine in patients with Alzheimer's disease.

BACKGROUND: Little is known of the association between thyroid hormones in the central nervous system and Alzheimer's disease (AD). We determined thyroid hormone levels in serum and cerebrospinal fluid (CSF) in a well-defined homogeneous mono-center population. METHODS: Fifty-nine consecutive patients under primary evaluation for cognitive impairment were recruited. The participants included patients with AD or mild cognitive impairment (MCI) diagnosed with AD upon follow-up (n=31), patients with stable MCI (SMCI, n=13), patients with other dementias (n=15), and healthy controls (n=19). Thyroid hormones in serum and CSF and AD biomarkers in CSF were analyzed using established immunochemical assays. Cognitive impairment was estimated using mini-mental state examination (MMSE). RESULTS: Serum levels of free and total thyroxine (T4) and triiodothyronine (T3) were similar in all groups whereas a marginal increase in serum thyroid-stimulating hormone (TSH) level was observed in the AD patients. The CSF level of total T4 was decreased in patients with AD and other dementias compared to SMCI (both P=0.01) and healthy controls (both P=0.001), whereas CSF levels of TSH and total T3 were unchanged. In the total study population, CSF total T4 level correlated positively with MMSE score (r=0.26, P<0.05) and negatively with CSF total-tau (T-Tau) level (r=-0.23, P<0.05). CONCLUSION: Patients with AD as well as other dementias had signs of mild brain hypothyroidism, which could only to a small extent be detected in serum values.

Independent changes of thyroid hormones in blood plasma and cerebrospinal fluid after melatonin treatment in ewes.

The authors measured the effects of exogenous melatonin treatment on the concentrations of total (T) and free (f) fractions of thyroxine (T4) and triiodothyronine (T3) in cerebrospinal fluid (CSF) and blood plasma as well as the expression of their binding/transporter protein, transthyretin (TTR), in the choroid plexus of ewes from May to August. Melatonin implantation in May and July mainly prevented the decrease in plasma for fT3 and TT3 exhibited in untreated group, and induced a limited decrease in TT4 in June. By contrast, melatonin implantation prevented the decrease in CSF fT3 observed in the untreated group. No effect of melatonin was found on the expression of TTR mRNA in the choroid plexus There were a correlations between blood fT4 and CSF TT4 concentrations in both control and melatonin treated group (r(2)-0.4; P < 0.01 vs. r(2)-0.14; P < 0.05), as well as between blood fT3 and CSF TT3 concentrations but only in the melatonin-treated group (r(2)-0.26; P < 0.02). We conclude that T3, the active form of the hormone within the brain, is regulated by melatonin independently of the peripheral changes within the blood. The lack of correlation between plasma fT3 and CSF TT3 in the control group suggests that an increase in local T3 conversion could contribute as an additional source of T3 in the CSF during the period of increasing day length. These data seem to confirm a local nature for recently discovered connections between the pineal melatonin signal and thyroid-dependent seasonal biology in mammals.

Thyroid hormones in the cerebrospinal fluid of the third ventricle of adult female sheep during different periods of reproductive activity.

Thyroid hormones (THs) are obligatory for transition from breeding season to anestrus in sheep. In this process, THs act during a very limited time of the year and primarily within the brain. In ewes chronically equipped for sampling cerebrospinal fluid (CSF) from the third ventricle, we have characterized the concentrations of total and free thyroxine (T4), triiodothyronine (T3), and total reverse T3 (rT3) in the CSF during breeding season, anestrus and during a critical period required for transition to anestrus (December-March). The total T4, T3, rT3 and free T3 average concentrations (+/- SEM) in CSF were 1.5 +/- 0.07 ng/ml, 14.5 +/- 1.2 pg/ml, 43 +/- 7.4 pg/ml, and 0.6 +/- 0.05 pg/ml, respectively, and all were significantly lower (p < 0.001) than in blood plasma except free T4 (12.6 +/- 1.1 pg/ml), which was similar to that in plasma. There was a seasonal trend (p < 0.05) in the concentration of total T3 (highest in December) and free T4 (highest in November) in the CSF that does not follow that in blood plasma. During the period of transition to anestrus the CSF total T3/TT4 molar ratio and free T3/T4 ratio were significantly lower (p < 0.05 and p < 0.01, respectively) than in blood plasma, while the total rT3/T4 ratio was significantly higher (p < 0.01) at the end of this period (March). Additionally, the CSF total rT3 concentrations were also significantly correlated with the CSF total T4 levels (r = 0.57; p < 0.05). In conclusion, the CSF in sheep may serve as a considerable source of thyroid hormones for neuroendocrine events. The lack of significant changes in THs concentrations in the CSF during the period of transition to anestrus indicate that neither seasonal changes of THs circulating in the blood plasma nor THs circulating in the CSF actively drive the transition to anestrus.

Thyroxine (T4) transfer from CSF to choroid plexus and ventricular brain regions in rabbit: contributory role of P-glycoprotein and organic anion transporting polypeptides.

This study investigated the transfer of T4 from cerebrospinal fluid (CSF) into the choroid plexuses (CP) and ventricular brain regions, and the role of P-glycoprotein (P-gp), multidrug resistance protein 1 (mrp1) and organic anion transporting polypeptides (oatps). During in vivo ventriculo-cisternal (V-C) perfusion in the anesthetized rabbit (meditomidine hydrochloride 0.5 mg kg(-1), pentobarbitone 10 mg kg(-1) i.v.), 125I-T4 was perfused continuously into ventricular CSF with reference molecules 14C-mannitol and blue dextran. Over 2 h, 36.9+/-4.6% 125I-T4 was recovered in cisternal CSF. Addition of P-gp substrate verapamil increased CSF 125I-T4 recovery to 51.4+/-2.8%, although mrp1 and oatp substrates had no significant effect. In brain, 125I-T4 showed greatest accumulation in the CP (1.52+/-0.31 ml g(-1)), followed by ventricular regions (caudate putamen, ependyma, hippocampus, 0.05-0.14 ml g(-1)). At the CP, verapamil and probenecid (but not indomethacin) significantly increased 125I-T4 accumulation, implicating a role for P-gp and oatps. Of other brain regions, all three drugs increased accumulation in caudate putamen 3-5 times, and indomethacin and probenecid increased accumulation in ependyma 4-5 times. The role of P-gp was investigated further in isolated incubated CPs using 5 microg/ml C219 anti-P-gp antibody. Both 125I-T4 and 3H-cyclosporin accumulation increased by 80%, suggesting that P-gp is functional in the CP and has a role in removal of T4. Combined with the in vivo results, these studies suggest that P-gp provides a local homeostatic mechanism, maintaining CSF T4 levels. We conclude that P-gp and oatps contribute to the transfer of 125I-T4 between the CSF, CP and brain, hence regulating 125I-T4 availability in CSF.

Role of transthyretin in thyroxine transfer from cerebrospinal fluid to brain and choroid plexus.

The transport of 125I-labeled thyroxine (T4) from the cerebrospinal fluid (CSF) into brain and choroid plexus (CP) was measured in anesthetized rabbit [0.5 mg/kg medetomidine (Domitor) and 10 mg/kg pentobarbitonal sodium (Sagatal) iv] using the ventriculocisternal (V-C) perfusion technique. 125I-labeled T4 contained in artificial CSF was continually perfused into the lateral ventricles for up to 4 h and recovered from the cisterna magna. The %recovery of 125I-labeled T4 from the aCSF was 47.2+/-5.6% (n=10), indicating removal of 125I-labeled T4 from the CSF. The recovery increased to 53.2+/-6.3% (n=4) and 57.8+/-14.8% (n=3), in the presence of 100 and 200 microM unlabeled-T4, respectively (P<0.05), indicating a saturable component to T4 removal from CSF. There was a large accumulation of 125I-labeled T4 in the CP, and this was reduced by 80% in the presence of 200 microM unlabeled T4, showing saturation. In the presence of the thyroid-binding protein transthyretin (TTR), more 125I-labeled T4 was recovered from CSF, indicating that the binding protein acted to retain T4 in CSF. However, 125I-labeled T4 uptake into the ependymal region (ER) of the frontal cortex also increased by 13 times compared with control conditions. Elevation was also seen in the hippocampus (HC) and brain stem. Uptake was significantly inhibited by the presence of endocytosis inhibitors nocodazole and monensin by >50%. These data suggest that the distribution of T4 from CSF into brain and CP is carrier mediated, TTR dependent, and via RME. These results support a role for TTR in the distribution of T4 from CSF into brain sites around the ventricular system, indicating those areas involved in neurogenesis (ER and HC).

Dose-dependent transthyretin inhibition of T4 uptake from cerebrospinal fluid in sheep.

Transthyretin (TTR), synthesized by the choroid plexuses (CP) has an important role in transporting thyroxine from blood to cerebrospinal fluid (CSF). However, the role of TTR on thyroxine transport from CSF to either blood or brain is not clear. By using the incubated isolated ovine brain tissues technique, we found the CP accumulated most 125I-T4 compared to ventricular ependymal, frontal cortex or cerebellum. The accumulation was higher in the young CP than the old. There was dose-dependent inhibition by TTR on 125I-T4 accumulation in the brain tissues, and kinetics of T4 accumulation in presence of TTR was obtained by plotting a double reciprocal of B (bound) versus TTR concentration curve. The KD of 125I-T4 binding to TTR was higher in the CP compared to other tissues, suggesting that CP competes with TTR for T4 binding to a greater extent than the other tissues. Using the isolated perfused CP preparation, TTR significantly inhibited 125I-T4 efflux across CP from the CSF to blood side. Bovine serum albumin (BSA) was also able to inhibit 125I-T4 accumulation in the incubated tissues, but required higher concentrations to reach the level of inhibition seen with TTR. In conclusion, this study found a significant role for CSF TTR in preventing T4 loss to blood across the CP, and TTR inhibited both CP and selected brain tissue uptake in a dose-dependent manner. The physiological relevance of TTR may relate to preventing T4 loss from CSF and encouraging redistribution of hormone around the brain in CSF.

A novel mutation in the monocarboxylate transporter 8 gene in a boy with putamen lesions and low free T4 levels in cerebrospinal fluid.

We describe brain lesions in a patient with a monocarboxylate transporter 8 mutation. Imaging showed a high T2 lesion in the left putamen at age 3 and a right putamen lesion at age 6. Cerebrospinal fluid free thyroxine concentrations were low, with normal 3,3',5-triiodothyronine concentrations.

Evidence that thyroid hormones act in the ventromedial preoptic area and the premammillary region of the brain to allow the termination of the breeding season in the ewe.

Thyroid hormones are permissive for various species to enter seasonal anestrus. In the ewe they act centrally to permit the onset of potent estradiol-negative feedback responsible for anestrus, but the specific sites of action are unknown. Therefore, we tested whether T(4) replacement via chronic microimplants in any of five brain areas could reverse the reproductive effects of thyroidectomy. Diffusion of (125)I-T(4) from the microimplant was largely (>98%) limited to a 1.2-mm radius. A marked decline in LH concentration in ovariectomized, estradiol-treated ewes was used as an index for anestrus. In experiment 1, all thyroidectomized (THX) ewes with microimplants in the medial preoptic area, A15 area, and medial basal hypothalamus failed to enter anestrus; instead, LH levels remained elevated, similar to those in untreated THX controls. In ventromedial preoptic area (vmPOA)-microimplanted ewes, only the two animals with the most caudal microimplants entered anestrus, as did thyroid-intact controls and THX ewes receiving icv or sc T(4) replacement. In experiment 2, all vmPOA-treated ewes with similar placements to those effective in experiment 1 along with all ewes microimplanted in the premammillary region entered neuroendocrine anestrus. Thus, the premammillary region and vmPOA are brain sites in which thyroid hormones act to permit the onset of seasonal anestrus.

[Cerebral low T3 syndrome]. / Mozgovoi sindrom nizkogo T3.

The authors studied the time course of changes in the parameters of the cerebral thyronergic system (total and free triiodthyronine (T3) and thyroxin (T4), thyroxine-binding globulin (TBG), thyroid-stimulating hormone (TSH) by radioimmunoassay (Immunotech, Czechia; CIS, France), proinflammatory cytokine of TNF-alpha by enzyme immunoassay (Innogenetic, Belgium) in the blood and cerebrospinal fluid (CSF) in 59 patients (37 males and 22 females whose age ranged from 21 to 64 years) in acute subarachnoidal hemorrhage due to arterial aneurysmal rupture. On admission, the condition of 47 (79.7%) was rated as grades III-VI according to the Hunt-Hess scale, which was responsible for high mortality rates (33.89% in the assessment of outcomes according to the Glasgow outcome scale). The causes of death were ischemic and hemorrhagic insults, edema of the brain, cerebral stem wedging. Laboratory findings were analyzed in relation to the clinical condition of patients, outcomes, and the degree of secondary vasospasm assessed by Doppler transcranial study by the average blood flow velocity in the middle cerebral artery. They revealed a significant depression of thyroidal metabolism with developed the total low T3 syndrome just before surgical treatment in patients with deterioration in the early postoperative period. The significant correlations found by the authors between the decreased blood T3 and TSH levels and 1) the severity of neurological disorders; 2) the degree of vasospasm, and 3) the outcome of disease, as well as negative correlations of elevated TNF-alpha levels not only in the blood, but also in CSF with the content of CT3, CT4 and with the severity of neurological symptomatology are indicative of the development of isolated syndrome in the brain, which is characterized by specific thyroidal metabolic disorders, which the author propose to call the cerebral low T3 syndrome (by taking into account the presence of the autonomic systems of thyroidal homeostatic provision).

Transthyretin, thyroxine, and retinol-binding protein in human cerebrospinal fluid: effect of lead exposure.

Transthyretin (TTR), synthesized by the choroid plexus, is proposed to have a role in transport of thyroid hormones in the brain. Our previous studies in animals suggest that sequestration of lead (Pb) in the choroid plexus may lead to a marked decrease in TTR levels in the cerebrospinal fluid (CSF). The objectives of this study were to establish in humans whether TTR and thyroxine (T(4)) are correlated in the CSF, and whether CSF levels of Pb are associated with those of TTR, T(4), and/or retinol-binding protein (RBP). Eighty-two paired CSF and blood/serum samples were collected from patients undergoing clinical diagnosis of CSF chemistry. Results showed that the mean value of CSF concentrations for TTR was 3.33 +/- 1.60 microg/mg of CSF proteins (mean +/- SD, n = 82), for total T(4) (TT(4)) was 1.56 +/- 1.68 ng/mg (n = 82), for RBP was 0.34 +/- 0.19 microg/mg (n = 82), and for Pb was 0.53 +/- 0.69 microg/dl (n = 61 for those above the detection limit). Linear regression analyses revealed that CSF TTR levels were positively associated with those of CSF TT(4) (r = 0.33, p < 0.005). CSF TTR concentrations, however, were inversely associated with CSF Pb concentrations (r = -0.29, p < 0.05). There was an inverse, albeit weak, correlation between CSF TT(4) and CSF Pb concentrations (r = -0.22, p = 0.09). The concentrations of TTR, TT(4), and Pb in the CSF did not vary as the function of their levels in blood or serum, but RBP concentrations in the CSF did correlate to those of serum (r = 0.39, p < 0.0005). Unlike TTR, CSF RBP concentrations were not influenced by PB: These human data are consistent with our earlier observations in animals, which suggest that TTR is required for thyroxine transport in the CSF and that Pb exposure is likely associated with diminished TTR levels in the CSF.

Transthyretin regulates thyroid hormone levels in the choroid plexus, but not in the brain parenchyma: study in a transthyretin-null mouse model.

Transthyretin (TTR) is the major T4-binding protein in rodents. Using a TTR-null mouse model we asked the following questions. 1) Do other T4 binding moieties replace TTR in the cerebrospinal fluid (CSF)? 2) Are the low whole brain total T4 levels found in this mouse model associated with hypothyroidism, e.g. increased 5'-deiodinase type 2 (D2) activity and RC3-neurogranin messenger RNA levels? 3) Which brain regions account for the decreased total whole brain T4 levels? 4) Are there changes in T3 levels in the brain? Our results show the following. 1) No other T4-binding protein replaces TTR in the CSF of the TTR-null mice. 2) D2 activity is normal in the cortex, cerebellum, and hippocampus, and total brain RC3-neurogranin messenger RNA levels are not altered. 3) T4 levels measured in the cortex, cerebellum, and hippocampus are normal. However T4 and T3 levels in the choroid plexus are only 14% and 48% of the normal values, respectively. 4) T3 levels are normal in the brain parenchyma. The data presented here suggest that TTR influences thyroid hormone levels in the choroid plexus, but not in the brain. Interference with the blood-choroid-plexus-CSF-TTR-mediated route of T4 entry into the brain caused by the absence of TTR does not produce measurable features of hypothyroidism. It thus appears that TTR is not required for T4 entry or for maintenance of the euthyroid state in the mouse brain.

Lack of correlation between cerebrospinal fluid thyrotropin-releasing hormone (TRH) and TRH-stimulated thyroid-stimulating hormone in patients with depression.

BACKGROUND: It has been proposed that elevated central thyrotropin-releasing hormone (TRH) is associated with the blunted thyroid-stimulating hormone (TSH) response to TRH in patients with depression. Few studies have directly evaluated this relationship between central nervous system and peripheral endocrine systems in the same patient population. METHODS: 15 depressed patients (4 male, 11 female, 12 bipolar, and 3 unipolar) during a double-blind, medication-free period of at least 2 weeks duration, underwent a baseline lumbar puncture followed by a TRH stimulation test. Cerebrospinal fluid (CSF) TRH and serial serum TSH, free thyroxine, triiodothyronine, prolactin, and cortisol were measured. A blunted response to TRH was defined as a delta TSH less than 7 microU/mL. RESULTS: There was no significant difference in mean CSF TRH between "blunters" (2.82 +/- 1.36 pg/mL) and "non-blunters" (3.97 +/- 0.62 pg/mL, p = .40). There was no evidence of an inverse relationship between CSF TRH and baseline or delta TSH. There was no correlation between CSF TRH and the severity of depression or any other endocrine measure. CONCLUSIONS: These data are not consistent with the prediction of hypothalamic TRH hypersecretion and subsequent pituitary down-regulation in depression; however, CSF TRH may be from a nonparaventricular nucleus-hypothalamic source (i.e., limbic area, suprachiasmatic nucleus, brain stem-dorsal raphe) and thus, not necessarily related to peripheral neuroendocrine indices.

Inhibition by lead of production and secretion of transthyretin in the choroid plexus: its relation to thyroxine transport at blood-CSF barrier.

Long-term, low-dose Pb exposure in rats is associated with a significant decrease in transthyretin (TTR) concentrations in the CSF. Since CSF TTR, a primary carrier of thyroxine in brain, is produced and secreted by the choroid plexus, in vitro studies were conducted to test whether Pb exposure interferes with TTR production and/or secretion by the choroid plexus, leading to an impaired thyroxine transport at the blood-CSF barrier. Newly synthesized TTR molecules in the cultured choroidal epithelial cells were pulse-labeled with [35S]methionine. [35S]TTR in the cell lysates and culture media was immunoprecipitated and separated by SDS-PAGE, and quantitated by autoradiography and liquid scintillation counting. Pb treatment did not significantly alter the protein concentrations in the culture, but inhibited the synthesis of total [35S]TTR (cells + media), particularly during the later chase phase. Two-way ANOVA of the chase phase revealed that Pb exposure (30 microM) significantly suppressed the rate of secretion of [35S]TTR compared to the controls (p < 0.05). Accordingly, Pb treatment caused a retention of [35S]TTR by the cells. In a two-chamber transport system with a monolayer of epithelial barrier, Pb exposure (30 microM) reduced the initial release rate constant (kr) of [125I]T4 from the cell monolayer to the culture media and impeded the transepithelial transport of [125I]T4 from the basal to apical side of epithelial cells by 27%. Taken together, these in vitro data suggest that sequestration of Pb in the choroid plexus hinders the production and secretion of TTR by this tissue. Consequently, this may alter the transport of thyroxine across this blood-CSF barrier.

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.

Reduction of thyroxine uptake into cerebrospinal fluid and rat brain by hexachlorobenzene and pentachlorophenol.

In the present study the effects of hexachlorobenzene (HCB) and the metabolite pentachlorophenol (PCP) were investigated with respect to uptake of thyroxine (T4) into cerebrospinal fluid (CSF) and brain structures of rats. [125I]T4 was taken up into CSF of control rats by a relatively slow process, reaching a steady state after about 3 h. Both repeated dosing of HCB and single doses of PCP caused decreased uptake of [125I]T4 into CSF, total brain tissue as well as specific brain structures, such as occipital cortex, thalamus, and hippocampus. Although HCB-treatment caused a build-up of HCB and PCP levels in serum in brain only HCB was present in significant amounts (16% of the serum level). In CSF, both HCB and PCP concentrations were below detection levels. Separate experiments with PCP showed, however, a dose- and time-dependent uptake of PCP into CSF. The present results indicate that PCP and the parent compound HCB are able to affect brain supply of T4. This may have consequences for an adequate development of the brain or proper brain function in adults. The exact mechanisms of interference of PCP and/or HCB in brain uptake of T4 remain to be established.