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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 7 2569-2573
Copyright © 2006 by The Endocrine Society

Thyroid Hormones, Dementia, and Atrophy of the Medial Temporal Lobe

Frank Jan de Jong, Tom den Heijer, Theo J. Visser, Yolanda B. de Rijke, Hemmo A. Drexhage, Albert Hofman and Monique M. B. Breteler

Departments of Epidemiology and Biostatistics (F.J.d.J., T.d.H., A.H., M.M.B.B.), Neurology (F.J.d.J., T.d.H.), Internal Medicine (T.J.V., Y.B.d.R.), and Immunology (H.A.D.), Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. Monique M. B. Breteler, Department of Epidemiology and Biostatistics, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands. E-mail: m.breteler{at}erasmusmc.nl.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Thyroid function has been related to Alzheimer disease (AD), but it remains unclear whether thyroid dysfunction results from or contributes to developing AD.

Objective: The objective of the study was to determine the association between thyroid function and both medial temporal lobe atrophy on brain magnetic resonance imaging (MRI) as putative early sign of AD and risk of dementia.

Design and Participants: This was a population-based cohort study among 1077 elderly subjects aged 60–90 yr and dementia free at baseline (1995–1996).

Main Outcome Measures: Nonfasting serum levels of TSH, free T4 (fT4), T3, and rT3 were available in 1025 subjects followed up for incident dementia until 2005. In a subset of 489 nondemented elderly, we assessed volumes of the hippocampus and amygdala on brain MRI. Subjects using thyroid medication were excluded.

Results: During 5657 person-years of follow-up (mean 5.5 yr), 63 subjects were diagnosed with dementia (46 with AD). TSH and thyroid hormones were not associated with risk of dementia or AD. TSH and T3 were also not related to brain atrophy, whereas nondemented subjects with higher fT4 levels had more hippocampal and amygdalar atrophy on MRI. Similar associations were found for rT3. Excluding subjects with thyroid disorders or incipient AD did not change the results.

Conclusion: In our study, TSH was related neither to risk of AD nor with early MRI markers thereof, arguing against an important role of thyroid function in the development of AD. Whether the association of higher fT4 and rT3 levels with brain atrophy on MRI has functional significance remains to be elucidated.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CLINICAL THYROID DISORDERS may negatively influence cognitive performance (1), which is the reason that thyroid function is evaluated when a diagnosis of dementia is considered (2). It is, however, uncertain whether thyroid function also influences the risk of developing the most frequent subtype of dementia, Alzheimer disease (AD). Studies showed inconsistent results, reporting either no significant association (3, 4) or an association between hypothyroidism and AD (5, 6). Yet these studies had several methodological shortcomings, including selection bias due to the case-control design, retrospectively obtained information on thyroid function, and small numbers of subjects. An earlier study from our group suggested subclinical hyperthyroidism to be associated with a higher risk of AD, especially in the presence of serum antibodies to thyroid peroxidase (TPO-Ab) (7). Conversely, others have shown low T4 to increase risk of cognitive impairment among physically impaired elderly women (8).

Although thyroid dysfunction could be related to clinical symptoms of AD, the underlying mechanism is unclear. In particular it is unclear whether thyroid dysfunction results from or contributes to AD pathology. The hippocampus and amygdala are structures in the medial temporal lobe that can be easily visualized on magnetic resonance imaging (MRI) of the brain and are reduced in volume early in the process of AD (9, 10). Both structures also have a high density of thyroid hormone receptors and are an important target of thyroid hormones entering the brain (11, 12). In addition, mild Alzheimer patients have more hippocampal and amygdalar atrophy on MRI, compared with healthy elderly (13).

The aim of this study was to assess whether thyroid function is associated with risk of dementia, including AD, and hippocampal or amygdalar atrophy on MRI of nondemented elderly.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study sample

The study was based on subjects in the Rotterdam Scan Study. This study was designed to investigate determinants and consequences of brain abnormalities on MRI in the elderly (14). Between 1995 and 1996, we randomly selected subjects aged 60–90 yr in strata of age (5 yr) and sex from the ongoing population-based Zoetermeer and Rotterdam studies (15, 16). As part of the eligibility criteria, we excluded persons who were demented or blind or had MRI contraindications at time of selection (17). Complete information, including a cerebral MRI scan, was obtained in 1077 persons who gave written informed consent (participation rate 63%). The study was conducted in accordance with the tenets of the Declaration of Helsinki. The Medical Ethics Committee of Erasmus Medical Center, Rotterdam, The Netherlands, approved the study.

MRI procedures

In 1995–1996 standard T1, T2, and proton-density weighted MR sequences of the brain in a 1.5-Tesla MR unit were made in all study subjects (VISION MR; Siemens, Erlangen, Germany; and Gyroscan; Philips, Best, The Netherlands) (17). For the 563 subjects of the Rotterdam Study, a custom-made, double-contrast, three-dimensional (3D), half-Fourier acquisition single-shot turbo spin echo (HASTE) sequence was added for volumetric assessments of the hippocampus and amygdala. MRI acquisition parameters have been described (18). Fifty-two persons developed claustrophobia during the scanning period, leaving 511 subjects with a 3D HASTE sequence for volumetric assessments.

Ascertainment of incident dementia

All subjects were free of dementia at baseline, and the cohort was followed up for incident dementia. The diagnosis of dementia was made following a three-step protocol (19, 20). Briefly, all subjects were screened at follow-up visits (1997–1999, 1999–2000, and 2000–2003) with two brief tests of cognition [Minimental State Examination (21) and Geriatric Mental State Schedule (22)]. Screen-positives (Minimental State Examination score < 26 or Geriatric Mental State Schedule organic level > 0) underwent the Cambridge examination for mental disorders of the elderly (Camdex). Subjects who were suspected of having dementia were examined by a neuropsychologist if additional neuropsychological testing was required for diagnosis. In addition, the total cohort was continuously monitored for incident dementia through computerized linkage between the study database and digitalized medical records from general practitioners and the Regional Institute for Outpatient Mental Health Care until January 1, 2005. The diagnosis of dementia and subtype of dementia was made in accordance with internationally accepted criteria for dementia (Diagnostic and statistical manual of mental disorders, 3rd edition revised) (23) and Alzheimer disease (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association) (24) by a panel consisting of a neurologist, neuropsychologist, and research physician.

Hippocampal and amygdalar volumes

For the 511 subjects with a 3D HASTE sequence, we reconstructed a series of coronal brain slices (contiguous 1.5-mm slices) aligned to be perpendicular to the long axis of the hippocampus. The procedure of segmenting the hippocampus and amygdala has been described and was performed by two raters without knowledge of clinical information (18). Briefly, we manually traced the boundaries of the hippocampi and amygdalae on each slice by means of a mouse-driven pointer. We proceeded from posterior to anterior, starting on the slice at which the crux of the fornices was in full profile. Entering the outlined areas (square millimeters) into a spreadsheet program, we multiplied the summed areas on each side with slice thickness to yield estimates of the left and right hippocampal and amygdalar volume (milliliters). Total hippocampal or amygdalar volume was calculated by summing the left and right hippocampal or amygdalar volume. Fourteen randomly selected scans were used to evaluate intra- and interrater agreement, which showed good overall agreement (all intra- and interclass correlation coefficients exceeded r = 0.77).

We measured midsagittal area (square centimeters) by tracing the inner skull to obtain a proxy for intracranial volume. Head size differences across individuals were corrected for by dividing the uncorrected volumes by the participant’s calculated head size area and subsequently multiplying this ratio by the average head size area (men and women separately) (13).

Assessment of thyroid function

At the time of the MRI, nonfasting blood samples were collected and put on ice immediately. Within 30 min serum was separated by centrifugation and stored at –80 C. Multiple biochemical markers were used to investigate thyroid function. TSH, free T4 (fT4), and T3 were all measured by chemoluminescence assays (Vitros ECI immunodiagnostic system; Ortho-Clinical Diagnostics, Rochester, NY). rT3 was measured with an in-house RIA (25). Serum TPO-Abs were assessed with an immunometric assay (Diagnostic Products Corp., Los Angeles, CA).

Hypothyroidism was defined as a concentration of serum TSH above the upper limit of the reference range (0.4–4.3 µU/dl) and fT4 or T3 concentrations below the reference range (0.85–1.94 and 92.8–162.9 ng/dl, respectively). Hyperthyroidism was defined as a concentration of serum TSH below the reference range and fT4 or T3 concentrations above the reference range. Serum TSH levels were high in 20 and low in 87 subjects (10 and 44 in the subset with hippocampal and amygdalar atrophy). However, in the majority of those with high or low TSH levels, fT4 and T3 concentrations were within the reference range. Of the 20 subjects with high TSH levels, three subjects had hypothyroidism, whereas 17 subjects had an isolated high TSH, indicating subclinical hypothyroidism. Of the 87 subjects with low TSH levels, 18 subjects had hyperthyroidism, whereas 69 had isolated low TSH levels, which may be consistent with subclinical hyperthyroidism or may be due to nonthyroidal illness or drug effects. Although useful to indicate thyroid status, reference values might be less appropriate in an elderly population because thyroid hormone concentrations change with aging (26). Therefore, we also assessed thyroid function according to the continuous distribution of the thyroid hormones in our population.

Evaluation of thyroid function in the elderly is complicated by an increased prevalence of nonthyroidal illness (27). Several conditions including malnutrition, starvation, and inflammatory processes accompanying disease are known to alter thyroid hormone and TSH concentrations, without overt thyroid dysfunction being present. In these situations, T4 is converted preferentially to rT3 instead of T3 (28). We assessed rT3 (reference range 9.1–22.1 ng/dl), an inactive metabolite of T4, to obtain an indicator of peripheral thyroid hormone metabolism. The ratio of T3 over rT3 (T3/rT3) was considered to be a marker of nonthyroidal illness (29). Serum TPO-Abs, which may be the cause of either hypo- or hyperthyroidism, were determined to indicate autoimmune activity against the thyroid gland. We considered subjects TPO-Ab positive if serum levels exceeded 35 IU/ml.

Complete thyroid hormone assessments were available in 1047 subjects. Those using thyromimetic or thyrostatic medications (n = 22) were excluded from the analyses, leaving 1025 subjects for the analyses on dementia and 489 subjects for the analyses on hippocampal and amygdalar atrophy on MRI.

Covariates

Several variables may confound an association between thyroid hormones and measures of brain atrophy, such as age at time of thyroid assessment, sex, educational level, depressive symptoms, smoking habits, medication use, atrial fibrillation, diabetes mellitus, body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared), cholesterol, creatinine, homocysteine levels, and apolipoprotein E (APOE) genotype. Educational status was defined as the highest education according to United Nations Educational, Scientific and Cultural Organization and dichotomized into primary education only and more than primary education (30). Depressive symptoms were assessed with a validated Dutch version of the Center for Epidemiologic Studies Depression scale (31). Smoking status was categorized into current, former, and never smoking. We included reported use of cardiac medication (including amiodarone), ß-blocking agents, and systemic use of corticosteroids (Anatomical Therapeutical Chemical codes c01, c07, and h02). Presence of atrial fibrillation was based on analysis of digitally stored standard 12-lead electrocardiograms using the modular electrocardiogram analysis system (32). Diabetes mellitus was defined as reported use of oral antidiabetic treatment or insulin or a random serum glucose concentration 202 ng/dl or greater. Serum total and high-density lipoprotein (HDL) cholesterol and creatinine levels were determined using an automated enzymatic procedure. Homocysteine levels were determined by a fluorescence polarization immunoassay (33). APOE genotype testing was performed on coded DNA samples (34).

Statistical analyses

Cox proportional hazards models were used to estimate the association between thyroid function and dementia. Duration of follow-up for each participant was calculated from baseline examination until death, diagnosis of dementia, or the end of follow-up, whichever came first. Multivariate linear regression models were used to quantify the relation between thyroid function and measures of brain atrophy.

The association between thyroid function and the outcome measures was analyzed in two ways. First, thyroid status was analyzed in categories based on the cut-off values of TSH [>4.3 mU/liter (high), 0.4–4.3 mU/liter (normal), and < 0.4 mU/liter (low)]. In these analyses, the reference group consisted of subjects with TSH levels within the reference range. Second, thyroid hormone levels were analyzed according to their distribution, in quintiles as well as continuously (per SD increase) if the observed association was not obviously nonlinear.

All analyses were adjusted for age and sex. To account for changes in thyroid hormone levels due to concomitant disease, the models were additionally adjusted for T3/rT3. To investigate whether associations were modified by autoimmune thyroid disease, analyses were repeated according to presence or absence of TPO-Abs (in the analysis on abnormal serum TSH levels in combination with positive TPO-Abs, subjects without raised TPO-Abs who were euthyroid were reference). Further adjustments included educational level and depressive symptoms, cigarette smoking, cardiac medication, ß-blocking agents, systemic corticosteroid use, atrial fibrillation, diabetes mellitus, BMI, total and HDL cholesterol, and creatinine and homocysteine levels. In addition, all analyses were repeated after exclusion of subjects with hypo- (n = 3) or hyperthyroidism (n = 18). Finally, we repeated the analyses in strata of APOE genotype. We classified subjects into those with and without an {epsilon}4 allele. Those with APOE genotype {epsilon}2/{epsilon}4 were excluded. All statistical analyses were performed using SPSS statistical software (version 11; SPSS Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline characteristics are shown in Table 1Go. During a total of 5657 person-years of follow-up (mean per person 5.5 yr), 63 subjects developed dementia, of whom 46 were diagnosed with AD. When we made cut-offs in serum TSH values, the risk of dementia did not differ significantly between subjects with TSH concentrations within the reference range and those with a high or low TSH concentration (Table 2Go). Subjects with low TSH in the presence of TPO-Abs had a nearly 4-fold increased risk of dementia, although this was not significant (Table 2Go). Serum levels of TSH were not associated with the risk of dementia, nor were serum levels of the thyroid hormones (Table 3Go).


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  		TABLE 1. Baseline characteristics of the total study sample and the subset with data on hippocampal and amygdalar volume

 

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  		TABLE 2. Thyroid status and risk of dementia in the total sample (n = 1025)

 

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  		TABLE 3. Thyroid hormone levels and risk of dementia and AD in the total sample (n = 1025)

 
TSH was not associated with the extent of atrophy, either when analyzed according to cut-offs in serum TSH values or when analyzed according to quintiles of the distribution of TSH serum levels in our population (Tables 4Go and 5Go). Figure 1Go shows the association between serum levels of fT4 and hippocampal atrophy on MRI. Subjects with higher levels of fT4 had on average more hippocampal atrophy. Likewise, higher rT3 levels were also associated with more hippocampal atrophy on MRI (Fig. 1Go). Similar associations were found for amygdalar atrophy. fT4, rT3, and T3/rT3 were linearly related to both measures of brain atrophy, yet no such associations were found for both TSH and T3 levels (Table 5Go). TPO-Abs did not modify the results between either TSH in categories (Table 4Go) or thyroid hormone levels and measures of brain atrophy (data not shown).


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  		TABLE 4. Thyroid status and atrophy of the medial temporal lobe on MRI (n = 489)

 

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  		TABLE 5. Thyroid hormone levels and atrophy of the medial temporal lobe on MRI (n = 489)

 

Figure 1
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  		FIG. 1. Hippocampal volume according to quintiles of serum fT4 and rT3. The mean hippocampal volume (SE) is plotted at the median of each quintile and is adjusted for age and sex.

 
Additional adjustment for T3/rT3 slightly attenuated the associations between fT4 and brain atrophy [difference in hippocampal volume per SD increase in fT4 levels, –0.07 ml [95% confidence interval (CI) –0.15; 0.01] and amygdalar volume –0.09 ml (95% CI –0.16; –0.02)]. Adjustment for all other confounders, exclusion of subjects with a low or high TSH concentration, or stratification for APOE {epsilon}4 did not change any of the above-mentioned associations.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this community sample, there was no relation between thyroid function and the risk of dementia or AD. In contrast, we found that persons with higher serum levels of fT4 and rT3 had more hippocampal and amygdalar atrophy on MRI. The major strengths of this study were the population-based design, long follow-up for incident dementia, large number of volumetric MRI assessments of the hippocampus and amygdala, and extensive assessment of different indicators of thyroid function. A limitation is the lack of follow-up on the thyroid status of the study participants.

Previously we showed that subclinical hyperthyroidism increases the risk of dementia and AD over a 2-yr follow-up, especially in the presence of TPO-Abs (7). In the present study, using data from a study sample that was independent of, yet very similar to, the population studied in the previous report, low TSH was not related to risk of dementia over a nearly 6-yr follow-up. The observation that low TSH in the presence of TPO-Abs was associated with a nearly 4-fold increased risk of dementia is consistent with our previous findings, although this did not reach statistical significance. However, in both studies the number of dementia cases with high or low TSH was relatively small. Moreover, in the previous study, thyroid status was assessed only in a subgroup of the cohort. In addition, due to the small overall number of dementia cases in this subgroup (n = 25), thyroid function was not studied within the normal range. The relatively small sample size restricted the power, and together with the short follow-up, this may have minimized precision. In the current report, follow-up for dementia was longer and the number of dementia cases larger (n = 63), which enabled us to study thyroid function also within the normal range. TSH was not related to dementia when analyzed continuously according to the distribution in our population. Neither did we find an association between TSH and hippocampal or amygdalar atrophy, which may be indicative of early AD (10). To our knowledge, low TSH levels have thus far been related to AD in only one other study (35), which used a case-control design. Together with our findings, this suggests that variation in TSH levels within the normal range is not likely to affect the development of dementia and that the reported associations between low TSH and AD are more likely to result from imminent AD rather than developing Alzheimer pathology.

Interestingly, both higher fT4 and rT3 levels were associated with brain atrophy. Because concomitant diseases and associated comorbid conditions are known to change both fT4 and rT3 levels (36), we considered that comorbidity or frailty might explain the associations we found with both fT4 and rT3 in this elderly population. Although adjustment for T3/rT3 as a measure of nonthyroidal illness and other confounders potentially reflecting comorbidity only slightly attenuated the association between fT4 and brain atrophy, we cannot exclude residual confounding. Because both hippocampal and amygdalar atrophy on MRI in nondemented elderly have been reported to predict risk of AD during a 6-yr follow-up period (9), it could also be argued that the association of fT4 and rT3 with brain atrophy reflects incipient AD. However, exclusion of all subjects who developed AD during nearly 6 yr of follow-up did not change the results. In combination with the absence of a relation between fT4 or rT3 levels and risk of AD, this limits the possibility that early AD accounts for the association between thyroid hormone levels and brain atrophy on MRI. We must also keep in mind that not all persons with atrophy develop dementia.

Taken together, these findings argue against an important role of thyroid function in the development of AD. Future studies are needed to elucidate whether the association of higher fT4 and rT3 levels with brain atrophy on MRI has functional significance.


   Acknowledgments
 
We thank Hans van Toor and Harm de Wit for carrying out the thyroid hormone and thyroid peroxidase antibody measurements. We also gratefully acknowledge the staff of the Rotterdam Study center and the cooperating general practitioners in Ommoord and Zoetermeer for their assistance in the data collection.


   Footnotes
 
This work was supported by the International Foundation of Alzheimer Research (Internationale Stichting Alzheimer Onderzoek Grant 01500), The Netherlands Organisation for Scientific Research, and the Health Research and Development Council (Zorg Onderzoek Nederland-Medische Wetenschappen).

Disclosure summary: F.J.d.J., T.d.H., T.J.V., Y.B.d.R., H.A.D., A.H., and M.M.B.B. have nothing to declare.

First Published Online April 24, 2006

Abbreviations: AD, Alzheimer disease; APOE, apolipoprotein E; BMI, body mass index; CI, confidence interval; 3D, three-dimensional; fT4, free T4; HASTE, half-Fourier acquisition single-shot turbo spin echo; HDL, high-density lipoprotein; MRI, magnetic resonance imaging; TPO-Ab, antibodies to thyroid peroxidase.

Received March 2, 2006.

Accepted April 17, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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The Association of Polymorphisms in the Type 1 and 2 Deiodinase Genes with Circulating Thyroid Hormone Parameters and Atrophy of the Medial Temporal Lobe
J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 636 - 640.
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