The TRH stimulation test in Alzheimer's disease and major depression: Relationship to clinical and CSF measures

doi:10.1016/0006-3223(91)90026-I

Biological Psychiatry

Volume 30, Issue 6, 15 September 1991, Pages 567-576

https://doi.org/10.1016/0006-3223(91)90026-I Get rights and content

Abstract

A blunted thyroid-stimulating hormone (TSH) response to exogenous thyrotropin-releasing hormone (TRH) has been reported to occur consistently in patients with major depression and less consistently in patients with Alzheimer's disease (AD). In this study we compared the TSH response to TRH in a large group (n = 40) of AD patients, elderly patients with major depression (n = 17), and age-matched controls (n = 14) to further characterize how it may relate to clinical variables, baseline thyroid function tests, and cerebrospinal fluid measures. Comparisons of TRH stimulation test response across all three groups revealed that patients with major depression had lower stimulated TSH levels (ΔmaxTSH) (p < 0.02) and higher (though still within normal limits) mean thyroxine (T₄) levels (p < 0.05) than the AD patients or controls. AD patients with a blunted TSH response had a significantly higher mean free T₄ (FT₄) level (p < 0.03) and tended to be more severely demented (p < 0.01) than those with a nonblunted response.

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Thyroid stimulating hormone and prospective memory functioning in old age
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Citation Excerpt :
For the analyses of T4, the radioimmunoassay method was used (Giles, 1982). Thyroid functioning has been linked to mood alterations (Denicoff et al., 1990; Molchan et al., 1991; Biondi and Cooper, 2008). Also, previous research on thyroid function and cognition has identified mood status as a potential mediator (van Boxtel et al., 2004).
Alterations of thyroid functioning are common in old age. Even among persons free from thyroid disorders, subclinical variations in thyroid functioning may affect cognitive performance. However, it is unknown whether prospective memory (ProM) is related to thyroid stimulating hormone (TSH) variations. An association could be expected, as changes in the thyroid gland have been linked to alterations in frontal brain regions that play a key role in prospective remembering. Thus, the aim of this study was to examine whether subclinical variations in thyroid functioning affect ProM performance. We studied 103 participants, 75 years and older, who were free from thyroid disorders and had serum levels of TSH and thyroxine (T4) within normal ranges. Interestingly, we found a non-linear association between TSH and ProM performance, where persons with TSH levels above the fourth quartile performed substantially better than persons in the other quartiles. T4 levels were unrelated to ProM performance. This pattern suggests that the previously identified “normal-range” interval for TSH should be moved further up in old age, at least when cognitive functioning is considered.
Thyroid function, the risk of dementia and neuropathologic changes: The Honolulu-Asia Aging Study
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The absence of an effect of thyrotropin in our study could thus in part be due to differences in time of blood collection or in certain characteristics of the population studied. Moreover, a blunted response of thyrotropin to thyrotropin-releasing hormone has been reported in elderly with major depression or AD (Molchan et al., 1991), indicating that in these conditions thyrotropin does not always adequately reflect thyroid function (Mariotti et al., 1995). Whereas, thyrotropin was not associated with AD in our study, both T4 and fT4 were associated with an increased risk.
Thyroid dysfunction is associated with cognitive impairment and dementia, including Alzheimer's disease (AD). It remains unclear whether thyroid dysfunction results from, or contributes to, Alzheimer pathology. We determined whether thyroid function is associated with dementia, specifically AD, and Alzheimer-type neuropathology in a prospective population-based cohort of Japanese-American men. Thyrotropin, total and free thyroxine were available in 665 men aged 71–93 years and dementia-free at baseline (1991), including 143 men who participated in an autopsy sub-study. During a mean follow-up of 4.7 (S.D.: 1.8) years, 106 men developed dementia of whom 74 had AD. Higher total and free thyroxine levels were associated with an increased risk of dementia and AD (age and sex adjusted hazard ratio (95% confidence interval) per S.D. increase in free thyroxine: 1.21 (1.04; 1.40) and 1.31 (1.14; 1.51), respectively). In the autopsied sub-sample, higher total thyroxine was associated with higher number of neocortical neuritic plaques and neurofibrillary tangles. No associations were found for thyrotropin. Our findings suggest that higher thyroxine levels are present with Alzheimer clinical disease and neuropathology.
Exploratory neuropharmacological evaluation of a conformationally constrained thyrotropin-releasing hormone analogue
2007, Brain Research Bulletin
A conformationally constrained peptidomimetic derived from the endocrine and neuroactive tripeptide thyrotropin-releasing hormone (pGlu-His-Pro-NH₂) was synthesized by convenient solid-phase organic chemistry and evaluated as a potential central nervous system agent. While this ethylene-bridged peptide analogue has been reported to lack the hormonal effect of the native peptide, we have shown in animal models that it possesses central nervous system activity characteristic of thyrotropin-releasing hormone. Compared to control, the peptidomimetic showed significant analeptic and antidepressant-like potencies. Moreover, an enhanced selectivity in antidepressant-like effect was measured when compared to that of the native peptide. Immobilized artificial membrane chromatography and in vitro metabolic stability studies also revealed that this constrained peptidomimetic has higher affinity to the blood–brain barrier than the native peptide and is metabolically stable. Consequently, this structure may be used as a template to design centrally selective and metabolically stable thyrotropin-releasing hormone analogues as potential neuropharmaceutical agents.
Disorders of eating behavior: Correlation between hypothalamo-pituitary- thyroid function and psychopathological aspects
2006, Psychoneuroendocrinology
Altered pituitary–thyroid (PT) function (TSH, FT4, FT3 plasma levels) was correlated with symptoms of Eating Disorders (ED) in 137 patients (65 ANR, 12 ANP, 19 ANBP, 26 BN, 8 EDNOS-AN, 7 EDNOS-BN) and 30 controls. PT hormone concentrations were assessed by immunofluorimetry and psychopathology by EDI-2 and HSCL-90. Values of TSH were decreased in ANP, BN, EDNOS-AN, of T4 in ANR, ANP, AN-BP, of T3 in ANR, ANP, ANBP, BN, EDNOS-AN, EDNOS-BN. TSH values correlated negatively with ineffectiveness in BN and EDNOS-AN, and with depression in EDNOS-AN. FT4 values correlated positively with perfectionism in ANR, ANP and ANBP, with interoceptive awareness in EDNOS-AN, and negatively with depression in EDNOS-AN and with body dissatisfaction in EDNOS-BN. FT3 values correlated positively with perfectionism in ANBP and BN, with ineffectiveness in ANR and ANP, with depression in EDNOS-AN, with hostility in ANR and EDNOS-BN, with interpersonal sensibility in ANP, with somatization in EDNOS-BN, and negatively with interpersonal distrust in EDNOS-AN. Prospective studies are needed to confirm whether or not altered PT parameters correlate with ED symptoms during the course of the diseases.
The combined T3/TRH test in depressed patients and healthy controls
2005, Psychoneuroendocrinology
It is well established that depressed patients show a blunted TSH response in the TRH-stimulation test. However, it has not been investigated so far whether pre-treatment with 3,5,3′-triiodothyronine (T3) is able to further suppress the TRH-induced TSH response in depressed patients or whether it may cause an escape-phenomenon with paradoxically enhanced TSH stimulation in a subsequent TRH test. In 20 drug-free depressed patients (eight men, 12 women) suffering from a major depressive episode according to DSM-IV criteria and in 20 age- and sex-matched healthy controls, the single TRH-stimulation test (administration of 200 μg TRH at 09:00 h) was carried out followed by a combined T3/TRH test (pre-treatment with 40 μg T3 at 23:00 h the night before; administration of 200 μg TRH at 09:00 h the next day). Compared to the controls, the depressed patients showed a significantly blunted TSH response in the single TRH test. However, the percentage suppression of TRH-induced TSH stimulation after pre-treatment with 40 μg T3 was comparable in the depressive patients (61.07%) and the healthy volunteers (64.20%). Prolactin secretion did not differ between patients and controls either in the single TRH test or in the combined T3/TRH test. Apparently, in contrast to the hypothalamo-pituitary–adrenocortical (HPA) system, no disturbance of feedback control in regulation of the hypothalamo-pituitary–thyroid (HPT) axis secretion can be demonstrated in depressed patients when using the combined T3/TRH test.
Thyroid function, depressed mood, and cognitive performance in older individuals: The Maastricht Aging Study
2004, Psychoneuroendocrinology
The hypothesis was tested that thyroid function, as indicated by serum thyroid-stimulating hormone (TSH) level, is associated with cognitive performance in a healthy aging population. In a random sample of 120 participants recruited from the Maastricht Aging Study (MAAS), aged between 49 and 71 years, we assessed TSH level, mood state (Symptom Check List, subscale depression), and three domains of cognitive function: verbal memory, general sensorimotor speed, and complex flexibility. After correction for age, sex, and educational level, a negative association between TSH and memory function was apparent: higher levels of TSH predicted lower levels of memory performance. Exclusion of individuals with TSH levels suspect for thyroid disorder (n=2) or who were on thyroid relpacement (n=3) attenuated this association. Furthermore, additional control for mood status reduced the association below the significance level. No interaction between age and TSH on cognition was found, which indicated that the TSH-memory association was independent of age group level. We conclude that the association between TSH level and memory performance was small and dependent on mood status and the presence of (possible) thyroid disease in this relatively healthy population based sample. Prospective studies are needed to address the role of thyroid function in age-related cognitive decline.

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The TRH stimulation test in Alzheimer's disease and major depression: Relationship to clinical and CSF measures

Abstract

J Neurol Sci

Biol Psychiatry

Psychoneuroendocrinology

Psychoneuroendocrinology

Psychoneuroendocrinology

Psychoneuroendocrinology

Regul Pept

Biol Psychiatry

Biol Psychiatry

Anal Biochem

Psychiatry Res

Biol Psychiatry

Brain Res

Elevation of immunoreactive CSF TRH in depressed patients

Am J Psychiatry

The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects

Br J Psychiatry

Methods for reliable longitudinal observation of behavior

Arch Gen Psychiatry

Anterior pituitary response to thyrotropin releasing hormone in senile dementia (Alzheimer type) and elderly normals

Acta Psychiatr Scand

Neuroendocrinological function in Alzhiemer's disease

Neuroendocrinology