Comparison of Serum Triiodothyronine with Biomarkers for Alzheimer's Disease Continuum in Euthyroid Subjects.

BACKGROUND: Accumulating studies have implicated thyroid dysfunction in the pathogenesis of Alzheimer's disease (AD). OBJECTIVE: This study aimed to explore the association between thyroid hormone (TH) levels and cerebrospinal fluid (CSF) biomarkers for AD continuum among euthyroid subjects. METHODS: In all, 93 clinically euthyroid subjects with a cognitive decline were included in this prospective cross-sectional study and were divided into groups with abnormal AD biomarkers (belonging to the "Alzheimer's continuum"; A+ patients) and those with "normal AD biomarkers" or "non-AD pathological changes" (A-patients), according to the ATN research framework classification for AD. A partial correlation analysis of serum thyroid-stimulating hormone (TSH) or TH levels with CSF biomarkers was conducted. The predictor for A+ patients was analyzed via binary logistic regressions. Finally, the diagnostic significance of individual biochemical predictors for A+ patients was estimated via receiver operating characteristic curve analysis. RESULTS: Serum total triiodothyronine (TT3) and free triiodothyronine (FT3) levels were found to affect the levels of CSF amyloid-ß (Aß)42 and the ratios of Aß42/40. Further, FT3 was found to be a significant predictor for A+ via binary logistic regression modeling. Moreover, FT3 showed a high diagnostic value for A+ in euthyroid subjects. CONCLUSION: Even in a clinical euthyroid state, low serum FT3 and TT3 levels appear to be differentially associated with AD-specific CSF changes. These data indicate that serum FT3 is a strong candidate for differential diagnosis between AD continuum and non-AD dementia, which benefits the early diagnosis and effective management of preclinical and clinical AD patients.

L-thyroxine treatment in primary hypothyroidism does not increase the content of free triiodothyronine in cerebrospinal fluid: a pilot study.

The association between cerebrospinal fluid (CSF) and serum concentration of thyroid hormones and pituitary thyrotropin stimulating hormone (TSH) was studied in nine hypothyroid patients (HT) before and in seven after L-thyroxine treatment. With L-thyroxine, median free T4 increased 4-fold in serum (3.5 pmol/L vs 17.5 pmol/L) and 3-fold in CSF, (3.9 pmol/L vs 11.5 pmol/L). Correspondingly, total T3 in serum increased two-fold (0.9 nmol/L vs 2.2 nmol/L). Unexpectedly, free T3 concentration in CSF was similar (1.5 pmol/L vs.1.5 pmol/L) before and during treatment. In HT, TSH in serum correlated with TSH in CSF as did free T4 in serum and in CSF. During L-thyroxine, the correlation with TSH in serum and CSF remained. Likewise, the free T4 concentration in serum correlated with that in CSF. However, no correlation was found between T3 in serum and free T3 in CSF. It seems evident that free T4 in serum equilibrates with that in the CSF both in the HT and during L-thyroxine. Despite a two-fold increase in total serum T3, free T3 in CSF remained unchanged, which agrees with previous results in rats showing that T3 is less exchangeable between serum and CSF. Alternatively, an accelerated conversion of T4 to T3 might have maintained the concentration of T3, due to strongly increased levels of TSH found in the hypothyroid state. The notion that free T4 in serum reflects the CSF concentration of free T4 is consistent with previous reports from studies in animals.

Morphological and functional alterations in the adenohypophysis in cases of brain death.

In order to examine the function of the adenohypophysis during brain death, levels of adrenocorticotropic hormone (ACTH), growth hormone (GH), and thyroid stimulating hormone (TSH) were investigated during forensic autopsy. Cases examined were those of brain death (n=12; within 24h postmortem; time to cardiac death after cerebral death was diagnosed, approximately 4-25 days), including those in which the cause of death was head injury (subdural hematoma or brain contusion, n=10) and asphyxia (strangulation, n=2). The concentrations of ACTH and TSH were measured by enzyme chemiluminescent immunoassay (ECLIA), and that of GH by radioimmunoassay (RIA). The immunoreactivities of ACTH, GH, and TSH in the adenohypophysis were observed and analyzed with electron microscopy. Morphological studies revealed partial necrosis of the central anterior lobe, but preservation of its periphery. Immunohistochemical staining revealed the appearance of peripheral adenohypophysis with each hormone. Ultrastructural findings for the pituitary and hypothalamus indicated swelling of the mitochondria and dilation of both the smooth endoplasmic reticulum and Golgi apparatus. Furthermore, in most cases, concentrations of the anterior pituitary hormones in the serum and cerebrospinal fluid (CSF) were generally within the clinical reference range. These results indicate that the pituitary is partially preserved after brain death.

Evaluation of postmortem serum and cerebrospinal fluid levels of thyroid-stimulating hormone with special regard to fatal hypothermia.

The aim of the present study was to undertake, during routine forensic work, a comprehensive analysis of the serum and cerebrospinal fluid (CSF) levels of thyroid-stimulating hormone (TSH) and to examine hypophyseal TSH immunopositivity in relation to the cause of death, with particular regard to fatal hypothermia. Medicolegal autopsy cases (n=120; within 48 h postmortem; survival time, <24 h), including cases of blunt injury (n=9), sharp instrument injury (n=8), fire fatality (n=18), mechanical asphyxiation (n=10), drowning (n=21), poisoning (n=6), hypothermia (n=10), and acute ischemic heart disease (n=38), were examined. Serum and CSF TSH concentrations were measured using an electrochemiluminescence immunoassay. TSH immunoreactivity in adenohypophysis was quantitatively analyzed. Serum and CSF TSH levels were significantly lower in cases of hypothermia than in the other groups (p<0.05 and p<0.001, respectively). TSH immunopositivity in adenohypophysis was significantly lower in cases of hypothermia, but exhibited a large case-to-case variation for poisoning. These observations suggest that a decrease in serum and CSF TSH levels in hypothermia is related to hypothalamic adenohypophyseal dysfunction.

The efficacy of intratechal administration of a very low dose potirelin after acute spinal cord injury.

BACKGROUND AND OBJECT: The objective of this study was to determine the effect of a very low dose protirelin in cerebrospinal fluid (CSF) glucose, magnesium and lactate levels after spinal cord trauma (SCT) in rabbits. We also aimed to evaluate whether this very low dose might induce analeptic effect. MATERIAL AND METHODS: Twenty rabbits were divided equally into two groups: group I (n=10) was the control group, suffered from SCT but received only saline after SCT. Group II (n=10) (treatment group), received a very low dose of 0.05 mg/kg thyrotropin releasing hormone (TRH), analogue protirelin intratechally after SCT. The basal CSF glucose, magnesium and lactate levels were recorded in both groups. CSF lactate, glucose and magnesium contents were recorded at the same time (an hour before and after) SCT. Serum thyroid stimulating hormone (TSH), freetriiodothyronine (FT3) and freethyroxine (FT4) were measured in all rabbits before and after SCT. RESULTS: Before spinal cord trauma, there were not any significant differences in glucose, lactate and magnesium levels between group I and II whereas, after spinal cord trauma in group II, the significant suppression in elevation of lactate and glucose depletion (p<0.05) were observed while no significant suppression was observed in magnesium level (p>0.05) as compared with group I (Table 3). In respect of serum TSH levels, there were not any significant differences between two groups before and after SCT. CONCLUSIONS: This study showed that intratechal TRH has no analeptic effect on serum TSH, FT3 and FT4 levels but can attenuate the increase of lactate levels following spinal cord trauma. No significant decrease in magnesium level and also suppression of glucose decline in group II, may be related to the neuroprotective effects of TRH.

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.

[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).

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.

RIA examinations of CSF hormones as a method of demonstrating leakage through the blood-brain and brain-CSF barriers.

Radioimmunoassay determinations of the levels of total T3, total T4, TSH, and prolactin in the CSF were performed on samples taken from 36 healthy individuals. The obtained reference values are the first of their kind. It is considered that RIA determinations of CSF hormone levels may provide a sensitive method for demonstrating pathological leakage through the blood-brain and brain-CSF barriers.

Adenohypophyseal hormone levels in the cerebrospinal fluid of patients with pituitary disease.

Measurement of adenohypophyseal hormones in the cerebrospinal fluid (CSF) was recently proposed as an useful procedure to differentiate pituitary intra and extrasellar tumors. So far, data reported are conflicting. We measured the concentrations of GH, TSH, LH and PRL in CSF and plasma in 30 controls and in 37 patients with various pituitary diseases (18 intrasellar adenomas, 14 extrasellar adenomas and 5 empty sella syndromes). The concentrations of examined hormones in CSF were very low or undetectable in all control subjects. In most patients with pituitary tumors, adenohypophyseal hormones were found to be present in CSF, in great amounts. No significant differences were found between intra and extrasellar tumors. In agreement with recently reported data, no significant correlation was found between GH, TSH, FSH and LH levels in CSF and plasma, while a significant correlation (p less than 0.01) was obtained between CSF and plasma levels of PRL, either in all patients or in those with extrasellar tumors only. All patients bearing an empty sella had PRL detectable in CSF: in 2 cases PRL levels were very high. In conclusion our data do not confirm that measurement of adenohypophyseal hormones in CSF represents an useful screening to differentiate tumors with extrasellar extension. PRL data deserve interest in order to gain understanding of the hormone dynamics between CSF and vascular compartments.

Pituitary hormone concentrations in cerebrospinal fluid in patients with prolactin and growth hormone-secreting tumors.

GH, PRL, LH, FSH and TSH were measured in serum and in cerebrospinal fluid (CSF) in 16 patients with chromophobe adenomas, in 8 with acromegaly and in 18 subjects with neurological diseases without endocrine troubles. Elevated mean GH and PRL levels in serum and in CSF were found in patients with chromophobe adenomas and with acromegaly. No constant correlation was observed between serum and CSF values. The highest hormonal levels in CSF were usually observed in adenomas with suprasellar extension, but this finding was inconstant. The determination of hormonal levels in CSF does not seem to supply any reliable information about the characteristics of pituitary tumors.

Adenohypophyseal hormones in the CSF.

The presence of adenohypophyseal hormones in human cerebrospinal fluid (CSF) had been firmly established by radioimmunoassay procedures. The hormones can originate from the adenohypophysis itself and from brain, as well as from peripheral sites of production. These peptide hormones enter the CSF through the choroid plexus or by direct secretion. The hormones entering by direct secretion into the CSF have a higher CSF-blood ratio than the hormones entering through the choroid plexus. Elevated CSF levels of adenohypophyseal hormones are most likely to occur in the presence of hormone-producing pituitary tumors with suprasellar extension. Although the CSF concentrations of adenohypophyseal hormones may merely reflect their blood concentrations, it is more likely that these hormones also have paracrine as well as endocrine effects.

Anterior pituitary hormone levels in the cerebrospinal fluid of patients with pituitary and parasellar tumors.

Cerebrospinal fluid (CSF) concentrations of growth hormone, prolactin (PRL), adrenocorticotropin, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and the glycoprotein hormone alpha subunit were determined in 30 patients with pituitary and parasellar tumors. Although many of the patients had elevated hormone levels, no differentiation between patients with intrasellar tumors and those with pituitary tumors with suprasellar extension or primary suprasellar tumors could be made based upon the absolute CSF hormone concentration. A highly significant correlation between serum and CSF PRL concentrations was found (r = 0.87; P less than 0.001), suggesting that CSF PRL is derived from the serum. No correlation was found between the serum and CSF concentrations of the other anterior pituitary hormones.

Blood-C.S.F. barriers dysfunction in the chronic organic brain syndrome; a R.I.A. study.

C.S.F. samples of 35 patients, who suffered from verified chronic, non-tumorous organic brain syndrome, were radioimmunoassayed for T4 and T.S.H., and were compared to C.S.F.-R.I.A. samples from a control group of patients who underwent myelography because of lumbar disc. In addition T4 and T.S.H. plasma levels were evaluated in the O.B.S. patients. C.S.F. T4 and T.S.H. levels were significantly higher in 65% of the O.B.S. group of patients than those of the control group. The average determinations for T4 were: 0.77 muh/100 ml in O.B.S. group as against 0--0.4 micrograms/100 ml in the C.S.F.'s of the control group. P greater than 0,001 T.S.H. C.S.F. levels were 1.33 microU/ml in the O.B.S. group, and 0--0.6 microU/ml in the control group (P greater than 0.005). It is suggested that the elevated R.I.A. values of these hormones in the C.S.F. of the O.B.S. patients reflect a disruption of blood-C.S.F. barriers. Therefore in the organic brain syndrome there seems to exist a pathophysiological dysfunction of brain barriers in addition of the neural damage.

Effect of chlorpromazine treatment on prolactin levels in cerebrospinal fluid and plasma of psychotic patients.

In psychotic patients, levels of prolactin in cerebrospinal fluid (CSF) and plasma were determined by radioimmunoassay before and after 2 and 4 weeks of treatment with chlorpromazine (CPZ). CPZ was given in one of three randomly selected fixed doses: 200, 400 or 600 mg per day. Before treatment, low levels of immunoreactive prolactin-like material (PRL) were found in the CSF of most patients. The concentration in CSF was about 20% of the plasma level. In CSF but not in plasma, the pre-treatment level of PRL was significantly higher in women than in men. During CPZ treatment, the PRL levels in CSF as well as in plasma were significantly elevated in both sexes after 2 as well as 4 weeks. The elevation was significantly greater in women, and was similar at the two time intervals studied. There was a significantly positive relationship between the dose of CPZ and the PRL elevation in both body fluids in both men and women. Before treatment no significant correlation between the PRL levels in CSF and plasma in either sex could be observed. During treatment, there was a significant correlation between the change in PRL levels in CSF and plasma in both men and women. CPZ treatment did not increase the levels of total protein, follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH) or oestradiol-(17-beta) in either the CSF or the plasma.

Distribution of growth hormone and thyroid-stimulating hormone in cerebrospinal fluid and pathological compartments of the central nervous system.

Human growth hormone (HGH) radio-immunoassay (RIA) was adapted for an accurate measurement of immunoreactive HGH concentrations in the CSF in different cases of hypothalamic-somatotropin dysfunctions. In control subjects (n = 43) mean HGH levels were 0.35 +/- 0.03 ng/ml in CSF and 1.95 +/- 0.2 ng/ml in plasma with a CSF/plasma ratio of 17%. The thyroid-stimulating hormone (TSH) RIA gave in controls mean basal levels of 2.65 +/- 0.2 muU/ml in CSF and 5.95 +/- 0.3 muU/ml in plasma with a CSF/plasma ratio of 44%. HGH and TSH concentrations in CSF and plasma show a very good correlation; but the regression curves for both hormones are distinctly different and appear specific for each polypeptide hormone. Hypothalamic-somatotropin hyperreactivity was reported in diabetic retinopathy (DR). CSF and plasma HGH concentrations in a group of diabetic patients with progressing retinopathy (n = 27) were not different from those in normal subjects (respectively 0.35 +/- 0.05 in CSF and 2.10 +/- 0.25 ng/ml in plasma with a CSF/plasma ratio of 16%). The HGH regression curve obtained in diabetics is similar to that of controls. These data do not substantiate the hypothesis of an HGH hyperreactivity in diabetic retinopathy. In somatotropin hypersecretion (acromegaly) without adenoma suprasellar extension, higher HGH concentrations recorded in CSF than in plasma cannot be attributed to an anatomical break-down of the CSF blood-brain barrier and suggest an active transport process of pituitary hormones to the CNS. HGH and TSH concentrations were measured in the cystic fluid of CNS tumors. In 1 case of a cystic dysembryoma, the HGH and TSH of CF were considerably increased. In gliomas (n = 8) the HGH and TSH cystic fluid concentrations were more elevated (respectively 0.72 +/- 0.2 ng/ml and 3.6 +/- 0.7 muU/ml) than in the CSF of controls.

Cerebrospinal fluid hormone concentration in the evaluation of pituitary tumors.

Cerebrospinal fluid (CSF) concentrations of corticotropin, growth hormone, thyrotropin, prolactin, luteinizing hormone, and follicle stimulating hormone were measured in 28 patients with various neurologic disorders, in 49 patients with pituitary tumors of whom 22 had suprasellar extension, and in 6 patients with craniopharyngiomas. With the exception of 1 patient with pseudotumor cerebri, CSF adenohypophyseal hormone concentrations were low in patients with neurologic disease and in patients with pituitary tumor without suprasellar extension. In marked contrast, 21 to 22 patients with suprasellar extension of a pituitary tumor and 2 of 6 patients with a craniopharyngioma had elevations of one or more CSF adenohypophyseal hormones. Posttreatment CSF adenohypophyseal hormone levels fell from previously elevated levels in 4 of 5 patients. These data suggest that an elevated CSF adenohypophyseal hormone concentration is a sensitive indicator of suprasellar extension of a pituitary tumor, and posttreatment measurements are useful in determining efficacy of therapy.

[Development of hypothalamic control over thyrotropin secretion during human prenatal life]. / Razvitie gipotalamicheskogo kontrolia nad sekretsiei tireotropina v prenatal'noi zhizni cheloveka

It was shown in the tissue culture experiments that the human hypophysis secreted autonomously the thyrotrophin during the last three fourths of the prenatal life. The intensity of secretion is the highest in the end of the first third of this period, then it decreases, but during the last third it increases reliably again. During the second half of development the level of thyrotrophin in female foetuses in reliably higher than in the male ones. In the beginning of the second third of prenatal life, the hypothalamic factors decrease the autonomous thyrotrophin secretion twice in foetuses of both the sexes. In the end of the second third, sexual differences appear in their effect; they decrease reliably the autonomous thyrotrophin secretion in the male foetuses, whereas no such effect is observed in the female ones. The stimulating effect of the hypothalamic thyrotrophin releasing hormone manifests itself during the last third of prenatal life in foetuses of both the sexes. During the second half of prenatal life, the thyrotrophin concentration in blood of female foetuses is also reliably higher than in male foetuses. There is a positive correlation in female foetuses between the thyrotrophin concentration in blood and the level of hypophysial secretion under the effect of hypothalamic factors. Thyrotrophin is found in the cranial fluid of foetuses. In some cases its concentration in the cranial fluid is higher than in the blood. No correlation was found between the levels of the hormone in fluid and blood in female foetuses; a positive correlation was found in male foteuses.