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.

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.

Genomics and CSF analyses implicate thyroid hormone in hippocampal sclerosis of aging.

We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer's neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer's Coordinating Center/Alzheimer's Disease Genetic Consortium data; n = 2113, including 241 autopsy-confirmed HS cases). Furthermore, both rs704180 and rs73069071 risk genotypes were associated with widespread brain atrophy visualized by MRI (Alzheimer's Disease Neuroimaging Initiative data; n = 1239). In human brain samples from the Braineac database, both rs704180 and rs73069071 risk genotypes were associated with variation in expression of ABCC9, a gene which encodes a metabolic sensor protein in astrocytes. The rs73069071 risk genotype was also associated with altered expression of a nearby astrocyte-expressed gene, SLCO1C1. Analyses of human brain gene expression databases indicated that the chromosome 12p12 locus may regulate particular astrocyte-expressed genes induced by the active form of thyroid hormone, triiodothyronine (T3). This is informative biologically, because the SLCO1C1 protein transports thyroid hormone into astrocytes from blood. Guided by the genomic data, we tested the hypothesis that altered thyroid hormone levels could be detected in cerebrospinal fluid (CSF) obtained from persons with HS pathology. Total T3 levels in CSF were elevated in HS cases (p < 0.04 in two separately analyzed groups), but not in Alzheimer's disease cases, relative to controls. No change was detected in the serum levels of thyroid hormone (T3 or T4) in a subsample of HS cases prior to death. We conclude that brain thyroid hormone perturbation is a potential pathogenetic factor in HS that may also provide the basis for a novel CSF-based clinical biomarker.

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.

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.

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.

Increased cerebrospinal fluid levels of 3,3',5'-triiodothyronine in patients with Alzheimer's disease.

Cerebrospinal fluid (CSF) levels of rT(3) were evaluated in 21 euthyroid patients with overt Alzheimer's disease (AD) and 18 matched healthy controls. The assessment also included transthyretin and total T(3) and T(4) CSF concentrations. Despite normal circulating thyroid hormone levels, AD subjects showed significantly increased rT(3) levels and an increased rT(3) to T(4) ratio in the face of unchanged CSF total T(4) and transthyretin levels. These results suggest an abnormal intracerebral thyroid hormone metabolism and possibly the occurrence of brain hypothyroidism, either as a secondary consequence of the ongoing process or as a cofactor in the progression of the disease.

[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.

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.

Saturable uptake of [125I]L-triiodothyronine at the basolateral (blood) and apical (cerebrospinal fluid) sides of the isolated perfused sheep choroid plexus.

The uptake of 125I-labelled L-triiodothyronine (T3) was measured on the blood side of the isolated perfused choroid plexus of the sheep using steady-state and single-circulation paired tracer techniques. The steady-state uptake of T3 was 33.5% (perfusion fluid protein content was 0.05 g.dl-1) which could be reduced to 9.4% in the presence of 500 microM unlabelled T3 showing partial saturation. The CSF to blood steady-state [125I]T3 measurements gave plasma/CSF ratio, R%, of 24.6 +/- 4.8% which was reduced to 9.8 +/- 2.1% in the presence of 500 microM unlabelled T3 in the mock CSF. The transport of T3 across the blood face of the choroid plexus and the CSF to blood transport, failed to show sodium dependence. Using the single circulation paired tracer technique, the initial uptake in less than 60 s, Umax of [125I]T3 was 50.4 +/- 3.9% relative to the extracellular marker [3H]D-mannitol. However, when 250 microM unlabelled T3 was present, Umax was reduced by 66%, although further significant inhibition at higher concentrations was not observed. Uptake of T3 at the blood side of the choroid plexus was partially saturated in the presence of unlabelled reverse T3 and DT3, suggesting little uptake stereospecificity. Unlabelled thyroxine (T4) and the amino acid analogues cycloleucine (aminocyclopentane-1-carboxylic acid) and BCH (beta-2-aminobicyclo-[2,2.1]-heptane-2-carboxylic acid) each reduced [125I]T3 uptake significantly, but not to the same degree as T3 stereoisomers. The neutral amino acids alanine and phenylalanine, had no effect on uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral expression of transthyretin: evolution, ontogeny and function.

This paper reviews studies on the synthesis and secretion of the thyroid hormone-binding protein, transthyretin by the choroid plexus. The secretion of transthyretin by the choroid plexus into the cerebrospinal fluid may have an important function in the transport of thyroxine from the blood to the brain. The transthyretin gene is expressed in the choroid plexus of most vertebrates and synthesis of this protein may have evolved in the brain before the liver.

Transport of iodothyronines from bloodstream to brain: contributions by blood:brain and choroid plexus:cerebrospinal fluid barriers.

Thyroid hormone entering the brain from the cerebral circulation must first cross barriers at the the blood:brain and choroid plexus:cerebrospinal fluid interfaces. The route taken after entry through those barriers might bring about selective delivery of hormone to different regions of the brain and those differences might be crucial for the ultimate functional effects of the hormone. To determine whether and how distribution of hormone in the brain might vary according to the route of entry, film autoradiograms of serially sectioned brains were prepared after delivery of a pulse of 125I-labeled thyroid hormone into either the right lateral cerebral ventricle or the femoral vein. The results after intrathecal injection, reflecting the penetration of hormone into brain after crossing the choroid plexus:cerebrospinal fluid barrier, revealed a markedly limited, essentially periventricular distribution of radioactivity at both 3 and 48 h after hormone administration. Results after i.v. administration, which allows hormone access across both barriers, revealed an initial distribution pattern (at 3 h) generally similar to that seen after administration of markers of cerebral blood flow; at 48 h there was strong resolution in selected brain regions never noted to be labeled after intrathecal hormone injection. The functional implications of the differences in results produced by the two different routes of hormone entry are not known. However, ready access to circumventricular organs would appear to be favored by hormone crossing the choroid plexus:cerebrospinal fluid barrier whereas access to the panoply of nuclear triiodothyronine receptors would be favored by hormone crossing the blood:brain barrier. Therefore both routes of barrier transport should be taken into account in assessing the kinetics and actions of thyroid hormones in the central nervous system.

T4, T3 and rT3 levels in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

Thyronine (T4), triiodothyronine (T3), and reverse-triiodothyronine (rT3) levels were evaluated in cerebrospinal fluid (CSF) and in serum of 12 patients with definite amyotrophic lateral sclerosis (ALS) by specific radioimmunoassays. Circulating microsomal and thyroglobulin antibodies were also evaluated. In all patients serum levels of T4, T3 and rT3 were within normal limits. In CSF, the rT3 levels were significantly elevated to 0.118 micrograms/l (mean), the T4 levels were not significantly elevated, and the T3 levels were below the detection limit of 0.03 micrograms/l. A correlation between the elevated rT3 levels in CSF and the severity or type of ALS could not be demonstrated by this study. The antithyroid antibodies (thyroglobulin antibodies, microsomal antibodies) showed normal titres and did not suggest disturbances of thyroid autoimmunity in the patients with ALS.

[L-thyroxine and triiodo-L-thyronine in the cerebrospinal fluid and hypothalamo-hypophyseal axis of hyper- or hypothyroid rats]. / L-tiroxina y triiodo-L-tironina en líquido cefalorraquídeo y eje hipotálamo hipofisario de ratas, hiper- e hipotiroideas.

L-thyroxine and triiodo-L-thyronine concentrations in cerebrospinal fluid (CSF), hypothalamus and pituitary gland are measured in male albino-Wistar rats under several experimental thyroid disfunction : including hyperthyroidism induced by L-T3 and L-T4 treatments and surgical hypothyroidism. Radioimmunoassay is carried out by Nejad's method modified in this work. The pattern of thyroid hormone concentrations in CSF is similar to that in serum, but the values obtained are lower. Thyroid hormone concentrations in adenohypophysis as opposed to hypothalamus or cerebral cortex, show an inverse change to functional thyroid status.

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.

Iodothyronine levels in human cerebrospinal fluid.

Iodothyronines were measured by RIA in concentrated human cerebrospinal fluid (CSF). In measurements performed in one laboratory at a 4-fold concentration of CSF, rT3 was detected in all 30 patients in whom the measurement was attempted and averaged 15.1 +/- 2.8 ng/dl (mean +/- SE). IN an independent laboratory, rT3 measurements at this 4-fold concentration were performed on 11 different samples and averaged 9.3 +/- 0.9 ng/dl, while at a 40-fold CSF concentration, rT3 averaged 13.1 +/- 0.72 ng/dl. CSF T3 values were detected in only 4 of 30 patients as a 4-fold concentration and averaged 8.2 +/- 3.1 ng/dl, while in pooled CSF at a 40-fold concentration, 4 of 4 samples were detectable and averaged 2.6 +/- 0.4 ng/dl. Levels of T4 could only be detected in CSF concentrated 40-fold and averaged 0.22 +/- 0.04 microgram/dl. Values for the percent dialyzable thyronines were 0.44 +/- 0.03% for T4, 4.39 +/- 0.29% for T3, and 0.91 +/- 0.04% for rT3. TSH was detected in CSF concentrated 4-fold, averaging 0.43 +/- 0.05 microunits/ml; in an independent assay with CSF concentrated 40-fold, TSH averaged 0.06 +/- 0.02 microunits/ml. Thyroid binding globulin was undetectable (less than 0.1 mg/dl). We have confirmed the presence of thyroid hormones (T4 and T3) in human CSF and have shown that rT3 is present as well. The role these hormones play in the development, function, and nourishment of the central nervous system and the role the CSF plays in the transport of these hormones into the central nervous system remains to be determined.