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9/6/13 11:46 AMClinical Review: The Thyroid in Mind: Cognitive Function and Low Thyrotropin in Older People

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J Clin Endocrinol Metab. 2012 October; 97(10): 3438–3449.

Published online 2012 August 3. doi: 10.1210/jc.2012-2284

PMCID: PMC3496329

Clinical Review

The Thyroid in Mind: Cognitive Function and Low Thyrotropin in Older PeopleEarn H. Gan and Simon H. S. Pearce

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom; and Endocrine Unit, Royal Victoria Infirmary,

Newcastle upon Tyne NE1 4LP, United Kingdom

Corresponding author.

Address all correspondence and requests for reprints to: Dr. Earn Gan, Institute of Genetic Medicine, Newcastle University, International Centre for Life,

Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom. E-mail. [email protected].

Received May 22, 2012; Accepted July 13, 2012.

Copyright © 2012 by The Endocrine Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License

(http://creativecommons.org/licenses/by-nc/3.0/us/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided

the original work is properly cited.

Abstract

Context:

Several studies have reported an association between low serum TSH, or subclinical hyperthyroidism (SH), and

dementia, but little emphasis has been placed on this field because not all studies have demonstrated the same

association. We performed a detailed systematic review to assess the evidence available to support the association

between these two conditions.

Methods:

We performed a systematic search through the PubMed, Embase (1996 to 2012 wk 4), Cochrane Library, and Medline

(1996 to January wk 4, 2012) electronic databases using key search terms encompassing subclinical hyperthyroidism,

TSH, dementia, and cognitive impairment.

Results:

This review examines the 23 studies that provide information about the association between SH or lower serum TSH

within the reference range and cognition. Fourteen of these studies, including several well-designed and well-powered

cross-sectional and longitudinal analyses, have shown a consistent finding of an association between SH with cognitive

impairment or dementia.

Conclusion:

There is a substantial body of evidence to support the association between SH and cognitive impairment, but there is no

clear mechanistic explanation for these associations. Nor is there an indication that antithyroid treatment might

ameliorate dementia. Larger and more detailed prospective longitudinal or randomized controlled trials are required to

inform these important questions.

With ready access to sensitive hormone assays, the last few decades have witnessed a dramatic increase in serum thyroid

function testing. This has raised many issues about the interpretation of minor deviations in thyroid function test results,

particularly in individuals with little or no conventional clinical evidence of thyroid disease. The elderly are

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overrepresented among individuals with minor abnormalities in serum TSH and thyroid hormone concentration, and the

clinical significance of these biochemical abnormalities in older people is the least clear. Overt hypothyroidism is well-

established as a reversible cause of cognitive impairment, which may sometimes be profound. However, overt

hyperthyroidism is also well known to be associated with impairment of concentration, mood changes, and alterations in

perception. A more difficult, but nonetheless important question is whether there is evidence to support a relationship

between more subtle alterations in thyroid function, in particular subclinical hyperthyroidism (SH) or low serum TSH

concentration and cognitive impairment. However, the literature on this subject is heterogeneous with regard to study

design and conclusions. In this review article, we aim to address the question of whether there is an association between

low serum TSH and cognitive impairment and to explore possible underlying mechanisms.

Background to SH and the Aging Thyroid Axis

SH is defined as a serum TSH concentration below the reference range, with normal free T (FT4) and free T (FT3)

levels. It can be divided into two groups; patients with a mildly reduced TSH (0.1–0.4 mU/liter) can be classified as

having grade I SH, whereas those with a serum TSH of less than 0.1 mU/liter, including a completely suppressed TSH

level (<0.01 mU/liter) are classified as having grade II SH (1). The prevalence of SH has been reported to range from

0.63 to 2.1% in epidemiological studies (2–4).

Most people with SH have no symptoms of hyperthyroidism, and relatively few develop specific complications

attributable to SH: atrial fibrillation or osteoporosis (5). Prognostically, many people with SH have only a transient

abnormality of thyroid function, with resolution of biochemical abnormalities found in 25–75% of those with grade I SH

on repeat testing (6, 7). Thus, the majority of individuals with grade I SH do not have intrinsic thyroid disease, and the

low TSH reflects nonthyroidal illness or drug effects. Nevertheless, approximately 1–2% of patients over the age of 60

with SH progress to overt hyperthyroidism, with progression most likely in those with grade II SH. This reflects the

indolent nature of multinodular goiter as the dominant cause in this age group, with mild thyroid autonomy developing

slowly. A small number of individuals with SH have early Graves' disease, and progression to overt hyperthyroidism is

more probable in these cases (7). Conversely, 1–2% of elderly individuals have a persistent and stably low serum TSH

that remains unexplained by any primary thyroid pathology. Thus, these alterations in thyroid function may reflect either

altered physiology or pathology associated with advanced age.

The study of the physiological changes in the thyroid axis during aging is complicated by the presence of confounders

such as medication, chronic illness, and increased risk of thyroid disease with age. Nevertheless, many observational

studies in healthy older individuals, which took into account common confounders, have revealed an age-dependent

decline in serum TSH and FT3 and an age-dependent increase in rT with maintenance of stable serum FT4 levels (8, 9).

A further study demonstrated that thyroid function was well preserved until the eighth decade of life, with a decreased

level of serum FT3 only observed in centenarians (10). However, the upper limit of serum TSH has also been shown to

increase with age (11), leading to a wider spread of the TSH distribution with age, expanding both above and below the

reference intervals for younger individuals. The mechanisms responsible for this age-related decline in serum TSH have

not been fully examined. One hypothesis suggests an age-related reduction in the secretion of pituitary TSH and/or

hypothalamic TRH, due to an increased pituitary thyrotrope sensitivity to peripheral T /T negative feedback (12).

Interestingly, the pattern of TSH pulsatility is also changed in the healthy elderly, with a blunted nocturnal TSH peak

being observed, followed by a 1- to 1.5-h backward shift in the circadian rhythm of TSH secretion, leading to an earlier

peak (13, 14). Equally compelling, a primary defect in thyroid hormone inactivation and disposal might explain the

observation of unchanged serum T levels despite reduced tropic drive from lower pituitary TSH secretion. Therefore,

reduced T and T degradation and clearance may lead to reduced throughput of hormone and a lower tone for the axis

(15).

Brain and Thyroid Function

The population prevalence of dementia is about 7%, and this rises to more than 30% in those aged 85 yr and above (16,

17). Dementia can be classified as primary or secondary depending on its etiology. Alzheimer's disease (AD), frontal

temporal lobe dementia, and Lewy body dementia are caused by primary degeneration of the brain, comprising about

70% of cases of primary dementia (18). Vascular dementia accounts for a further 15% of primary cases (19). The

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“cholinergic hypothesis” of AD pathogenesis is well accepted, with characteristic depletion of acetylcholine and

presynaptic cholinergic markers in AD cortex and hippocampus (20, 21). Studies using single photon emission computed

tomography or magnetic resonance spectroscopy have found similar characteristics in AD and in cognitively impaired

patients with hyperthyroidism (22–24). Correspondingly, reduced levels of choline-related compounds in the brain have

been demonstrated in hyperthyroidism, with a gradual normalization after antithyroid medication (22). Paradoxically, T

administration led to an enhancement of rats' learning ability, along with increased cholinergic activity in the frontal

cortex and hippocampus (25). Interestingly, TRH has also been shown to exert strong stimulant action on the cholinergic

pathways of the cortex and hippocampus (26). Intraseptal injection and intracerebroventricular administration of TRH

increased the turnover of acetylcholine in rat hippocampus and parietal cortex, respectively (27, 28). Hence, reduced

TRH secretion could contribute to acetylcholine depletion, which is associated with the cognitive changes in AD.

The β amyloid plaque is the pathological hallmark of AD, and the potential pathways of β amyloid-mediated neurotoxicity

include inhibition of acetylcholine activity in the cortex and hippocampus, oxidative stress from free radical damage,

mitochondrial dysfunction, and ultimately apoptotic cell death (29–33). At the same time, thyroid function has been

shown to influence systemic oxidative stress. Experimental and clinical studies have demonstrated increased reactive

oxygen species and lipid peroxidases in the hyperthyroid state, resulting in diminishing antioxidative enzymes (34, 35).

Furthermore, T has been shown to affect splicing of certain β-amyloid precursor protein isoforms, which are

preferentially expressed in the AD brain (36). Therefore, thyroid hormones could also have a role in modulating the

intracellular and extracellular contents of β-amyloid precursor protein isoforms and directly influence the pathogenesis

of AD (36, 37).

Methods

Search strategy and analysis (Fig. 1)

We performed a systematic search through the PubMed, Embase (1996 to 2012 wk 4), Cochrane Library, and Medline

(1996 to January wk 4, 2012) electronic databases. The key search terms were “subclinical hyperthyroidism,” “subclinical

thyroid disorders or dysfunction,” “cognitive decline or *impairment,” “dementia,” and “Alzheimer's disease.” The fields

evaluated were “treatment, epidemiology, complication and mortality.” We included all cross-sectional or longitudinal

studies published or translated into the English language. Meta-analysis has not been performed in light of the

heterogeneity in study design, statistical analysis methods, and outcome measures among the studies.

Results

Systematic review of the relationship between SH and cognitive function

Eighty-four studies were identified that investigated the relationship between thyroid dysfunction or serum thyroid

parameters and cognitive impairment. We excluded investigations that involved participants with overt thyroid disorders

and only included published papers that examined the relationship between SH, or variations of thyroid function within

reference intervals, with cognitive function. Twenty-three studies published from 1996 to January 2012, evaluating a total

of 31,482 patients, fulfilled the inclusion criteria. Fifteen studies indicated the correlation between thyroid function and

dementia as the primary study objective. Eight studies included other entities such as cardiovascular or osteoporosis risk

or imaging changes as the primary outcome, with the correlation of thyroid function and cognition as a secondary

objective.

Of the 23 studies, 13 were case-control or cross-sectional single-phase trials, and the remaining 10 studies had a

prospective longitudinal population-based design. To date, there have been no randomized interventional studies

examining the effects of antithyroid treatment on cognition in SH.

Cross-sectional/case-control studies (38–50)

Categorical analysis of subclinical thyroid disease vs. euthyroidism; or quantiles of serum TSH concentration (38–43)

Six studies made a categorical analysis, either of SH vs. euthyroidism or of quantiles of serum TSH and thyroid hormone

concentration in relation to cognitive function (Table 1). The Sao Paulo Ageing and Health Study, a large cross-sectional

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study comprising 1119 community-dwelling participants aged 65 yr and over, found an association between SH and

dementia after multivariate adjustment (38). The effect was strongest for vascular dementia [odds ratio (OR) for all types

of dementia, 4.9; 95% confidence interval (CI), 1.5–15.7; vascular dementia OR, 5.8; 95% CI, 1.4–33.1]. This was

confirmed using an analysis of quintiles of TSH; those with the lowest serum TSH quintile showed more than a 3-fold

increase in risk for all types of dementia [age-adjusted OR for dementia, 3.6 (95% CI, 1.4–8.9); vascular dementia, 9.3

(95% CI, 1.1–75.5)]. Similarly, the InCHIANTI Study, a population-based study of 916 Italians aged 65 yr and older,

demonstrated a significantly lower Mini-Mental State Examination (MMSE) score among those with SH compared with

the euthyroid group (22.61 ± 6.88 vs. 24.72 ± 4.52; P < 0.03) (39). Furthermore, SH was associated with more than a 2-

fold risk of scoring less than 24 out of 30 on the MMSE; a standard threshold for significant dementia [hazard ratio (HR)

= 2.26 (95% CI, 1.32–3.91); P = 0.003]. These two large studies were well designed with more than a 90% participant

response rate, and both carefully excluded patients with overt thyroid dysfunction as well as those taking thyroid

medication. Two smaller studies [van Osch et al. (40) and Dobert et al. (41)], involving 469 and 119 participants,

respectively, supported these findings. van Osch et al. (40) investigated a cognitively intact group and an AD cohort aged

greater than 52 yr. Interestingly, the euthyroid participants with a TSH level in the lowest tertile (TSH, 0.5–1.3 mU/liter)

had more than a 2-fold increase in AD prevalence compared with those with serum TSH in the highest tertile (2.1–6.0

mU/liter) [OR, 2.04 (95% CI, 1.18–3.53); P = 0.01]. Similarly, Dobert et al. (41) demonstrated a significantly lower TSH

level in participants with both AD and vascular dementia (P < 0.01) compared with controls without cognitive

impairment.

In contrast, the largest cross-sectional population-based study, involving 5868 participants, showed no association

between SH and cognition (42). However, this study invited participants by mail, and the response rate was poor at 38%.

Although the responders were representative of the regional population with respect to demographic characteristics, the

average MMSE score was above 27 in all subgroups, suggesting that the responder population was skewed toward a

cognitively intact group. Another cross-sectional observational study, involving 829 consecutive unselected referrals to a

hospital geriatric clinic, did not demonstrate any difference in TSH level between the group with AD and the cohort

without dementia (43). However, comorbidities and medication use were not described, so the results may be

confounded by nonthyroidal illness, thyroid medication, or overt thyroid dysfunction.

Serum thyroid function markers (TSH/FT4/TT3) or cognitive performance as continuous variables (44–50)

An additional seven studies performed multivariate analyses to explore the relationship between cognition and thyroid

function. Wahlin et al. (44) were the first to suggest an association between poorer cognitive performance and lower

serum TSH concentrations within the reference range. A significant positive correlation was found between a lower

episodic memory score and serum TSH concentration (P < 0.01) in 200 healthy, euthyroid, community-dwelling

participants aged over 75 yr. In keeping with these findings, Stuerenburg et al. (45) demonstrated an inverse correlation

(P = 0.04) between serum FT4 level and MMSE score in 227 patients aged 49–91 yr with mild to moderate AD.

In contrast, the remaining five studies of this design failed to demonstrate any association between cognition and low

serum TSH or high serum FT4 level (46–50). In a cross-sectional study involving 1219 community-dwelling participants,

global cognitive impairment was not increased in those with SH (n = 34) (46). In a hospital-based study involving 409

euthyroid patients aged 52–94 yr diagnosed with probable AD, no association was found between serum TSH or FT4 and

dementia (47). Two smaller studies involving 120 healthy volunteers and 69 hospital-based participants, respectively,

showed similar findings (48, 49). Paradoxically, a study of 44 healthy, community-dwelling male volunteers with a mean

age of 72 yr observed a significant association between higher total T (TT4) levels and better cognition [Verbal

performance in Wechsler Adult Intelligence Scale (P < 0.05) and global cognitive performance (P < 0.01)] but failed to

reproduce this trend with TT3 and FT4 (50). It is worth noting that almost all of these studies have relatively small

sample sizes, that each made a single measurement of thyroid function, and they used different cognitive performance

tests, which limits the generalizability of these results.

Prospective longitudinal studies (51–60)

Categorical analysis of subclinical thyroid disease vs. euthyroidism; or quantiles of serum TSH concentration (51–56)

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Six studies performed categorical analyses, either of SH vs. euthyroidism or quantiles of serum thyroid hormone

concentration in relation to cognitive function (Table 2). The Rotterdam study was the first longitudinal study to examine

the relationship between SH and dementia in 1893 population-based subjects (mean age, 69 yr) (51). Over a 2-yr follow-

up, a 3-fold increased risk of dementia from all causes [relative risk (RR), 3.5; 95% CI, 1.2–10] and AD (RR, 3.5; 95% CI,

1.1–11) was found among those with a low baseline TSH level (<0.4 mU/liter). This study was limited by the small

number of the SH group with dementia (n = 25) and a short follow-up period. Nevertheless, the positive findings in this

study are supported by two well-conducted, large population-based studies with a longer follow-up period. The first

study, a community-based observational study, was carried out over a period of 12 yr by Tan et al. (52) in 1864 patients

who were free of dementia for 3 yr at recruitment. The patients were then divided into three tertiles according to baseline

TSH: T1, less than 1.0 mU/liter; T2, 1.0–2.1 mU/liter; and T3, more than 2.1 mU/liter. A positive correlation in women

with a serum TSH level in the lowest (T1) tertile (HR, 2.26; 95% CI, 1.36–3.77; P = 0.002) and the highest (T3) tertile

(HR, 1.84; 95% CI, 1.10–3.08; P = 0.003) with AD risk was found. This relationship was not found in men, but other

indices of thyroid function were not studied. However, the two aforementioned large prospective studies involved only a

single measurement of thyroid function. This limitation has recently been addressed by the largest observational study

involving 12,115 participants (2,004 with SH; 10,111 euthyroid individuals) with a mean age of 66.5 yr and a median

follow-up period of 5.6 yr (53). This well-designed, population-based study had a carefully selected SH cohort, including

only individuals with two confirmatory measurements of serum TSH at least 4 months apart. Patients whose TSH

normalized or who developed overt thyroid disease during the course of follow- up were excluded. A positive association

between SH and dementia was observed (adjusted HR, 1.64; 95% CI, 1.20–2.25). Interestingly, when patients were

divided into two groups according to the TSH level (0.1–0.4 vs. <0.1 mU/liter), no relationship could be established

between suppressed TSH (<0.1 mU/liter) and dementia, but a significant association remained for the group with TSH at

0.1–0.4 mU/liter.

In addition to these three large population-based studies, de Jong et al. (54) carried out a smaller prospective study

among 615 Japanese-American men in the Honolulu Heart Program. The cohort had a mean age of 77.5 yr, and the mean

duration of follow-up was 5 yr. This study observed a 20 and 30% increased risk for dementia and AD, respectively, for

each SD increase in serum FT4 (HR for dementia, 1.21; 95% CI, 1.04–1.40; and HR for AD, 1.31; 95% CI, 1.14–1.51). In

addition, neuropathological examinations from the autopsy program instituted as part of this study demonstrated a

higher neocortical neurofibrillary tangle count per SD increase in TT4 (0.25; 95% CI, 0.05–0.46).

In contrast with the studies discussed so far, the Rotterdam Scan study, another prospective community-based study

involving 1025 subjects aged 60–90 yr with a mean follow-up interval of 5.5 yr, showed no association between dementia

and serum TSH or thyroid hormone levels (55). Nevertheless, they found a positive association between a higher FT4 and

rT and greater atrophy at the hippocampus and amygdala on magnetic resonance imaging (MRI), in keeping with the

finding in the Honolulu aging study. Although the Rotterdam Scan study had greater power than the original Rotterdam

study, due to a larger-sized dementia cohort (n = 60 vs. 25) and a longer follow-up period, it is limited by single

measurements of thyroid function and a small number of dementia cases with low TSH (n = 7).

Finally, a community-based study involving 464 euthyroid women aged 65 yr or older found an association between

lower FT4 concentrations within the reference range and cognitive impairment over a 3-yr period (RR, 1.97; 95% CI,

1.10–3.5) (56). However, the same pattern was not exhibited in those with a frankly low TSH or an elevated FT4 level.

There was a 14% dropout rate during follow-up, largely due to missing MMSE scores, which might have introduced a

significant bias.

Serum thyroid function markers (TSH/FT4/TT3) or cognitive performance as continuous variables (57–60)

Four studies made multivariate analyses using thyroid function parameters or cognitive function (MMSE) as continuous

variables. Hogervorst et al. (57) conducted a large prospective study involving 1047 community-dwelling patients aged

64–94 yr with MMSE scores of at least 25 in the United Kingdom and Wales. Higher serum FT4 concentrations within

the reference range were associated with lower baseline MMSE scores and accelerated cognitive decline after 2 yr [OR,

1.13 (95% CI, 1.03–1.23); P = 0.006]. This study was limited by a single measurement of thyroid function. Prospective

follow-up of 558 individuals aged 85 living in Leiden, The Netherlands, demonstrated an association between higher

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serum TSH and better memory function (β, 0.13; P = 0.03) (58). Nevertheless, this study had a small sample size and a

41.5% loss of follow-up due to death or refusal to continue participation.

After the cross-sectional study in 1998 (44), Wahlin et al. (59) conducted a follow-up survey on the same cohort and

found an association between low serum TSH levels within the reference range and decreased verbal memory or episodic

recall deficits at the 6-yr follow-up (β, 0.290; P < 0.05). Similarly, in a small hospital-based study, Annerbo et al. (60)

demonstrated that for each unit decrease in serum TSH, the OR of developing dementia increased by 3.5.

Summary of observational studies

Twenty-three studies that met our criteria have examined the association between SH and cognition. Fourteen of these

studies, including several well-designed and well-powered cross-sectional and longitudinal analyses, have shown a

consistent finding of an association of SH, or low serum TSH within the reference interval, with cognitive impairment or

dementia. In particular, this association was seen in more than three fourths of the prospective longitudinal studies,

providing reliable evidence from robust studies. Several of the studies that did not confirm this result are potentially

compromised by small samples sizes, recruitment from hospital environments, or the challenging nature of working with

participants with cognitive problems (e.g. failure to return questionnaires).

Discussion

Given the weight of information suggesting an association of SH and lower serum TSH concentrations with cognitive

impairment summarized above, we need to consider several explanations that could explain these findings (Table 3). A

conventional explanation (explanation A) might be that mild endogenous SH reflects true thyroid overactivity causing

excessive thyroid hormone action on the central nervous system. “Toxic” effects of thyroid hormones on the brain could

be mediated by increased brain oxidative stress caused by the mild hyperthyroidism, which promotes reactive oxygen

species production (35). Alternatively, thyroid hormone effects on the heart could mediate vascular dementia via

thromboembolism from a combination of atrial fibrillation, myocardial and endothelial dysfunction, and

hypercoagulability (5). However, we believe this explanation to be unlikely for several reasons. First, only about 20% of

individuals with SH have a suppressed TSH (grade II SH), and so most don't have true endogenous hyperthyroidism.

Clearly, neither do those people with serum TSH concentrations in the lower centiles of the healthy reference range.

Indeed, the low but not suppressed TSH in the 0.1–0.4 mU/liter range is most commonly seen as a manifestation of

nonthyroidal illness and is associated with a lowering of circulating FT3, rather than thyroid hormone excess. Second, for

this explanation to be true, we would expect to see a biological gradient with cognitive defects being worse in individuals

with the lowest TSH. In fact, this was not observed in the study of Vadiveloo et al. (53) where, if anything, the cognitive

effects were most marked in the grade I SH group.

An alternative explanation (explanation B) is that the organic brain diseases causing cognitive impairment also reduce

TRH secretion from the hypothalamus and other brain areas. This would have a “knock-on” effect leading to lower TSH

secretion and hence reduced thyroid hormone turnover (production and excretion)—in effect, a state of mild central

hypothyroidism. There is little evidence to either support or refute this contention. It is known that there are projections

from many areas of the brain to the paraventricular nucleus containing the TRH-secreting neurons, such as the C1–3

adrenergic neurons of the brainstem, the hypothalamic arcuate nucleus, and the neurons of the hypothalamic

dorsomedial nucleus, which exert different effects on the hypophysiotropic TRH neurons (61–66). Furthermore, TRH is

not only released from the paraventricular nucleus of hypothalamus but is also localized in neurons of the septal nuclei,

preoptic area, raphe nuclei of the medulla oblongata, and spinal cord (67–69). Thus, TRH has a more generalized role as

a central nervous system (CNS) neurotransmitter, and the brain involution of the dementia process may lead to a

widespread perturbation of neurotransmitters, including TRH. If we accept this explanation as being plausible, then

paradoxically, a study of thyroid hormone supplementation in dementia might be warranted.

A third explanation refers back to our understanding of thyroid hormone metabolism in older age. With this mechanism,

one has to consider that low serum TSH (and indeed higher FT4) may be a marker of biological age, reflecting reduced

hepatic clearance of thyroid hormones (including reduced type 1 deiodinase activity) and a consequent reduction in

thyroid axis turnover. The well-established observation that older people with hypothyroidism require less levothyroxine















replacement is the clinical correlate of this phenomenon (15, 70). In effect, the epidemiological studies reviewed above

identify a group of individuals within a cohort who have more advanced biological age, using TSH as the biomarker (1).

These individuals therefore have an excess of the degenerative disorders of advanced age, which includes cognitive

impairment and dementia. Compellingly, SH is also associated with excess rates of atrial fibrillation, vascular events, low

bone mineral density, fracture, and reduced muscle strength (71–74). Thus, dementia can be viewed as another

noncausal association of low TSH/SH (1).

Individuals with cognitive impairment and dementias have a high burden of comorbidity and associated medication use.

This may include many episodic intercurrent illnesses, such as transient infection, as well as more chronic degenerative

conditions. All of these comorbidities can lead to reduced serum TSH, consequent to the well-described changes in

serum thyroid hormones associated with nonthyroidal illness, known as “euthyroid sick syndrome.” Similarly, a wide

variety of medications for conditions other than thyroid diseases including glucocorticoids, opiates, L-DOPA,

amiodarone, and metformin are known to reduce serum TSH concentrations (1, 75). Thus, the combination of excess

comorbidity and the consequent additional medications that may be prescribed for this may also explain a noncausal

association of SH/low TSH with cognitive impairment. The fact that most of the studies performed in this field have

relied upon a single TSH measurement makes these data particularly vulnerable to this interpretation. Nevertheless,

although it is possible that this explanation contributes to some of the association between SH and dementia, it is

unlikely to be the dominant factor. The large study of Vadiveloo et al. (53) involving 12,115 patients showed that this

association persists after stringent ascertainment of a cohort categorized as having SH after repeated serum TSH

measurement.

At the current time, we believe that there are insufficient data to allow discrimination between the various mechanistic

possibilities outlined above (Table 3). Indeed, it is likely that there may be contributions from several of the above factors

to the observed association between SH or low serum TSH and cognitive impairment. Until such time as more

information becomes available, this remains an open question.

Conclusion

We have performed the first detailed review of a large and heterogeneous literature relating to the association between

low serum TSH and cognitive impairment in older people. Overall, taking into account the largest and most robustly

designed studies, there is a strong body of evidence to support the association between SH and cognitive impairment.

However, there is no clear mechanistic explanation for these associations, nor is there any evidence to support the use of

antithyroid measures to prevent or improve cognitive decline in this patient group. Larger and more detailed prospective

longitudinal or randomized controlled trials are required to inform these important questions.

Supplementary MaterialLicense:

Acknowledgments

We thank Professor John O'Brien, Professor of Old Age Psychiatry in the Institute for Aging and Health (Newcastle

University), for his kindness in providing helpful comments about this manuscript.

The preparation of this manuscript was supported by the Medical Research Council (Grant G0500783).

Disclosure Summary: S.H.S.P. has accepted speaker fees from Merck Serono. E.H.G. has nothing to declare.

FootnotesAbbreviations:

AD Alzheimer's diseaseCI confidence intervalCNS central nervous system

FT3 free T

FT4 free T

HR hazard ratio

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MRI magnetic resonance imagingOR odds ratioRR relative riskSH subclinical hyperthyroidism

TT3 total T

TT4 total T .

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Figures and Tables



Fig. 1.

Literature triage for systematic review.



Table 1.

Cross-sectional and case control studies on the relationship between SH and cognitive decline (1996–2011)

First

author,

year (Ref.)

Study

size (n)

Mean

age

(range)

Thyroid

status

Thyroid

function

indicators

(normal

range)

Objective

cognitive

measures

Study

outcomes Covariates Exclusion criteria

Categorical

analysis of

subclinical

thyroid

disease vs.

euthyroidism;

or quantiles

of serum T

concentration

Benseñor,

2010 (38)

(Sao Paulo

study)

1119 Patients

with

dementia:

78.5 (8)

Non-

dementia,

71.9 (6.1)

SH and

euthyroid

TSH, FT4;

TSH (0.4–

4.0

mIU/liter)

FT4 (0.8–

1.9

mg/liter)

CSI-D

(Community

Screening

Instrument

for

Dementia),

Geriatric

Mental State

(GMS), HAS-

DDS (History

and Aetiology

Schedule

Dementia

Diagnosis and

Subtype)

SH increased

the risk of

developing

dementia,

especially

vascular

dementia

All type of

dementia (OR,

4.9; 95% CI,

1.5–15.7)

Vascular

dementia (OR,

5.8; 95% CI,

1.4–33.1)

AD (OR, 2.5;

95% CI, 0.3–

20.8; P, NS)

Age-adjusted

OR for

dementia, 3.6

(95% CI, 1.4–

8.9); vascular

dementia OR,

9.3 (95% CI,

1.1–75.5)

Age, gender, BMI,

education, smoking,

history of alcohol

abuse, hypertension

Overt thyroid

dysfunction

Patients on thyroid

medications

Ceresini,

2009 (39)

(InCHIANTI

study)

916 >65 SH and

euthyroid

TSH, FT3,

FT4

TSH

(0.46–4.68

mU/liter)

FT4 (0.77–

2.19 ng/dl)

MMSE MMSE was

significantly

lower in SH

group

compared to

euthyroid

group (22.61 ±

6.88 vs. 24.72

Age, sex, smoking,

chronic heart

failure, DM,

hypertension,

Parkinson's disease,

BMI, physical

activity

Participants on

thyroid medications,

amiodarone, lithium;

dementia

4





± 4.52; P <

0.03)

HR, 2.26 (95%

CI, 1.32–3.91);

P = 0.003

Van

Osch, 2004

(40)

469 >52 Euthyroid only TSH (0.5–

6 mU/liter)

CAMCOG

(Cambridge

Examinations

for Mental

Disorders of

the Elderly),

MMSE

Lowest tertile

of TSH was

associated with

a more than 2-

fold increased

risk of AD,

compared to

the highest

tertile (OR,

2.04; 95% CI,

1.18–3.53; P =

0.01)

Smoking,

hypertension,

stroke, DM, CVD,

alcohol. APOEϵ4

genotype, total

homocysteine level,

depression

TSH outside normal

range; patients on

thyroid medications

Dobert, 2003

(41)

119 69.8 ± 14 SH and

euthyroid

TSH, FT4,

FT3

TSH (0.5–

4.0

mU/liter)

FT4 (11–24

pmol/liter)

MMSE,

CERAD,

Short

Cognitive

Performance

test, MRI,

PDG-PET

Patients with

dementia

showed 3-fold

increased

probability of

having

decreased or

borderline TSH

values (29%)

vs. control

(10%)

Age, sex History of overt

thyroid disease;

patients on thyroid

medications or

contrast medium 4

wk before the

laboratory testing

Roberts,

2006 (42)

5868 (65–98) SH and

euthyroid

TSH (0.4–

5.5

mU/liter),

FT4 (9–20

pmol/liter)

FT3 (3.5–

6.5

pmol/liter)

MMSE,

MEAMS

(Middlesex

Elderly

Assessment

of Mental

State)

No association

between

subclinical

thyroid

dysfunction

and cognition

or mood

Dementia, CVD. RA,

PVD, psychiatry

diseases,

osteoporosis,

nonspecific thyroid

diseases, DM,

pulmonary or

gastrointestinal

diseases,

medications

(amiodarone,

lithium, β-blocker,

antiepileptics,

antidepressants,

kelp, tranquilizers,

steroid, morphine)

Overt thyroid

diseases or taking

thyroid medications

Van

der Cammen,

2003 (43)

829 78.2 All thyroid

status (TSH)

TSH (no

normal

range

provided)

Diagnostic

and Statistical

Manual of

Mental

Disorders to

diagnose AD

No differences

in TSH level

between AD

patients and

those without

dementia

No information

available

No exclusion criteria

(patients with overt

thyroid disease were

included)

Multivariate

analysis with







thyroid

function

markers or

cognitive

performance

as continuous

variables

Wahlin, 1998

(44)

200 (75–96) Euthyroid only TSH, FT4

TSH (0.4–

5 mU/liter)

FT4 (12–25

pmol/liter)

Two-letter

fluency tasks;

Block design

test with

WAIS-R;

Trail Making

Test; Episodic

memory tests

Positive

association

between low

normal TSH

and worse

episodic

memory (P <

0.01)

Age, education,

mood symptoms

Overt thyroid

dysfunction, patients

on neuroleptic or

antithyroid

medications, TFT

outside the normal

range, psychiatric

illness

Stuerenburg,

2006 (45)

227 71.6 All thyroid

status (mean

TSH 17.3 ±

3.2)

FT4, TSH,

FT3, TT4,

TT3

Lowest FT4

quartile

<15.1

Highest

FT4

quartile

>19.0

MMSE Significant

inverse

correlation

between

plasma FT4

and MMSE

score

(Spearman

rank

correlation =

−0.14; P =

0.04)

Smoking,

hypertension, LDL,

HDL, APOEϵ4

allele, depression

No exclusion criteria

De

Jongh, 2011

(46)

1219 (34-

SH)

75.5

(68.9–

82.1)

Euthyroid, SH

and subclinical

hypothyroidism

TSH, FT4,

FT3

TSH (0.3–

4.5

mU/liter)

MMSE, the

Raven'S

colored

progressive

matrices

(RCPM), the

coding task

and the

audiotry

verbal

learning test

Subclinical

hyper- or

hypothyroidism

was not

associated with

impaired global

cognitive

function

Age, sex, alcohol

use, smoking,

educational level,

mean arterial

pressure, BMI, heart

rate, total

cholesterol, and

physical activity

Antithyroid or T

medications

Patterson,

2010 (47)

409 76.9 (52–

94)

Euthyroid only TSH, FT4

No normal

range

provided

NART

(National

Adult

Reading

Test); MMSE;

HVLT

(Hopkins

Verbal

Learning test)

No relationship

between

cognitive

function and

thyroid

hormones.

Higher FT4

was associated

with worse

functional

independence

(P < 0.001)

Age, sex, mood No exclusion criteria

van 120 >45 All thyroid TSH MAAS test Higher TSH Depression, Dementia, PD, CVD,

4







Boxtel, 2004

(48)

(healthy

volunteers)

status No normal

range

provided

battery

(memory,

sensorimotor

speed,

information

processing,

cognitive

flexibility

was associated

with poorer

memory (P <

0.05), but this

association

disappeared

after correction

for depression

score

education, overt

thyroid diseases

epilepsy, chronic

psychotropic drug

usage, CNS tumor

Quinlan,

2010 (49)

69 60.9–

66.8

All thyroid

status:

TSH, FT4,

TT4, TT3

Only TT3

level given

(1.4–1.6

nmol/liter)

Trail Making

Test; RAVLT

delayed

recall; Block

design; Token

test; Boston

Naming test,

Stroop test

etc

MCI group

with higher

TT3 showed

more cognitive

impairment in

episodic

memory (P =

0.0080),

language (P =

0.001), and

executive

function (P =

0.012)

Age, sex, BMI, total

cholesterol, HDL,

LDL, BP, use of T ,

β-blocker and

estrogen

Psychiatric

disorders,

depression, systemic

illness, diabetes,

cerebral tumor, CNS

infection, chronic

alcoholism, patients

on steroid

treatments, patients

with dementia

Prinz, 1999

(50)

44 72 All thyroid

status

TT3, TT4,

TSH; no

normal

range

provided

MMSE;

CATMEAN

(category

fluency),

FASMEAN

(verbal

fluency) etc

Higher TT4

was

significantly

associated with

better WAIS

score (P <

0.05) and

global cognitive

performance (P

< 0.01)

Age, education Overt thyroid

diseases, DM,

dementia (MMSE

score <27)

depression, MI, BMI

>18 or <33 kg/m ,

hypertension, CNS

medication used

(including 2 wk

prior to testing),

head/trauma or

infection, other

systemic illness,

neurological,

alcohol, sleep

disorder

NS, Nonsignificant; MMSE, Mini-Mental State Examination; CERAD, Consortium to Establish a Registry for Alzheimer's

disease; BMI, body mass index; DM, diabetes mellitus; CVD, cardiovascular disease; RA, rheumatoid arthritis; PVD,

peripheral vascular disease; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TFT, thyroid function test;

APOEε4, apolipoprotein Eε4; BP, blood pressure; PD, Parkinson's disease; MI, myocardial infarction.

4

2






Table 2.

Longitudinal populational-based studies on the relationship between SH and cognitive decline (1996–2011)

Author and

year of

publication

Study size

(n) and

setting

Mean

age

(range)

Follow-

up

interval

(yr)

Participants'

thyroid

status

Thyroid

function

indicators

(normal

range)

Objective

cognitive

measures

Study

outcomes Covariates

Exclusion

criteria

Categorical

analysis of

subclinical

thyroid

disease vs.

euthyroidism;

or quantiles

of serum T

concentration

Kalmijn,

2000 (51)

1893

community

68.8

(54–94)

2–4 SH and

euthyroid

TSH, FT4,

TT4

TSH (0.4–4.0

mU/liter)

FT4 (11–25

pmol/liter)

MMSE

GMS-A

CAMDEX

SH increased

the risk of

dementia and

AD 3-fold after

a 2-yr follow-

up (RR, 3.5;

95% CI, 1.2–

10)

Age, sex,

education,

smoking

status, atrial

fibrillation,

depression

Dementia at

baseline, patients

on amiodarone,

β-blocker or

thyroid

medications

Tan, 2008

(52)

1864

community

71 12.7 SH and

euthyroid

TSH (0.5–5.0

mU/liter)

MMSE Positive

association

between

women with

serum TSH in

the lowest

(<1.0

mIU/liter) and

highest (>2.1

mIU/liter) and

increased risk

of AD

Age, plasma

homocysteine

levels, BMI,

education,

APOEϵ4 allele,

stroke, atrial

fibrillation

Dementia at

baseline

Risk of AD for:

lowest TSH

tertile (HR, 2.26;

95% CI, 1.36–

3.77); highest

TSH tertile (HR,

1.84; 95% CI,

1.10–3.08)

Vadiveloo,

2011 (53)

12,115

community;

SH- 2004;

euthyroid,

10,111

66.5 ±

15.9

Median,

5.6 yr

SH and

euthyroid

TSH (0.4–4.0

mU/liter);

FT4 (10–25

pmol/liter);

FT3 (0.9–2.6

nmol/liter) (at

least 2

measurements

of TSH,

minimally 4

months apart)

Diagnosis of

dementia,

ICD9 and 10

Positive

association

between SH

and dementia.

Adjusted HR

1.64 (95% CI,

1.20–2.25)

No relationship

established

between TSH

concentration

(0.1–0.4) vs.

<0.1 mU/liter

and dementia

Age, gender,

history of

dementia and

psychiatry

disease

Age <18 yr,

patients treated

with antithyroid

medications/RAI/

thyroidectomy

before and during

the first year after

the first

abnormal TFT,

patient on

amiodarone, T

replacement

during the study

period,

4

4






(limited by

small number

of patients

with TSH <0.1)

pregnancy.

Patient on long-

term steroid

replacement/

pituitary disease

de

Jong, 2009

(54)

615

community

77.3–

78.6

5 SH and

euthyroid

TSH, FT4,

TT4. TSH

(0.4–4.3

mIU/liter);

FT4 (0.85–

1.94 ng/dl)

CASI (100

point

Cognitive

Ability

Screening

Instruments)

Higher TT4

and FT4 were

associated with

dementia (HR

1.21; 95% CI,

1.04–1.40); AD

(HR, 1.31; 95%

CI, 1.14–1.51)

and

neuropathology

Age, education

level,

depression,

albumin level,

BMI,

cholesterol ,

DM,

hypertension,

smoking,

patients on

T , β-blocker

or other

cardiac

antiarrhythmic

drugs

T level out of

normal range

de

Jong, 2006

(55)

1,025

community

72.3

(60–90)

5.5 Euthyroid

only

TSH, FT4,

FT3. TSH

(0.4–4.3

mU/liter);

FT4 (0.85–

1.94 ng/dl)

MMSE,

GMS-A,

CAMDEX

No association

between

increased risk

of dementia or

AD with TSH

or thyroid

hormone

Higher FT4

associated with

greater atrophy

at

hippocampus

and amygdala

on MRI

Sex,

educational

level, smoking,

depression,

medication

use

(amiodarone,

β-blocker,

steroids), BMI,

cholesterol,

homocysteine,

smoking,

creatinine

APOEϵ4

genotype,

diabetes, atrial

fibrillation

Blindness,

dementia,

contraindication

to MRI, patients

on thyroid

medications

Volpato,

2002 (56)

464

community

77.5 3 Euthyroid

only

TSH, FT4.

TSH (0.3–5.0

mU/liter);

FT4 (4.5–12.5

ng/dl)

MMSE Low T within

the normal

range was

associated with

cognitive

impairment

over a 3-yr

period (RR,

1.97; 95% CI,

1.10–3.5)

Age, race,

educational

level, coronary

heart disease,

hypertension,

stroke,

diabetes, PVD,

depression,

cancer

Nil

Multivariate

analysis with

thyroid

function

markers or

4

4

4






cognitive

performance

as continuous

variables

Hogervorst,

2008 (57)

1,047

community

(64–94) 2 Euthyroid

only

TSH, FT4.

TSH (0.3–4.8

mU/liter);

FT4 (13–23

pmol/liter)

MMSE;

AGECAT

(Automated

Geriatric

Examination

and

Computer

Assisted

Taxonomy)

High normal

FT4 had a

negative

association

with baseline

MMSE and

accelerated

cognitive

decline after 2

yr (P = 0.03)

Age, sex,

education,

MMSE at

baseline,

mood,

vascular risk

factor

(smoking,

hypertension,

heart disease,

DM, stroke)

MMSE <18

Gussekloo,

2004 (58)

558

community

85 3.7 All thyroid

status

TSH, FT4,

FT3. TSH

(0.3–4.8

mU/liter);

FT4 (13–23

pmol/liter)

MMSE;

Stroop test;

Letter Digit

Coding test;

Word

Learning test

Increased level

of TSH was

associated with

better memory

on follow-up

(P = 0.03),

when

participants on

T were

excluded

Age, education No exclusion

criteria

Wahlin, 2005

(59)

200

community

75–96 3, then

6 yr

Euthyroid

only

TSH, FT4.

TSH (0.4–5

mU/liter);

FT4 (12–25

pmol/liter)

Two-letter

fluency

tasks; Block

design test

with WAIS-

R; Trail

Making Test;

Episodic

memory

tests

Positive

association

between

decreased level

of TSH with

increased

episodic recall

deficits at 6-yr

follow-up (β0.290; P <

0.05)

No association

found in 3-yr

follow-up

Age,

education,

mood

symptoms

Over thyroid

diseases, thyroid

medications,

psychiatric illness

(but dementia is

not excluded due

to small sample

size)

Annerbo,

2006 (60)

93

hospital-

based

Men,

64.7;

women,

65.4

5 All thyroid

status

TSH (no

normal range

provided)

MMSE Low TSH

predicted risk

of developing

AD after

controlled for

other risk

factors (OR for

square root of

TSH, 0.287;

95% CI,

0.088–0.931)

Stroke,

cardiovascular

disease, T

treatment

No exclusion

criteria

GMS-A, Geriatric Mental State schedule; CAMDEX, Cambridge examination for disorders of the elderly; BMI, body mass

4

4







index; APOEε4, apolipoprotein Eε4; DM, diabetes mellitus; PVD, peripheral vascular disease; RAI, radioiodine therapy;

TFT, thyroid function test.



Table 3.

Possible mechanism for association of cognitive impairment with SH or low serum TSH

A. Excess circulating thyroid hormone resulting in neuronal loss.

B. Primary neurodegeneration causes reduced central nervous system TRH secretion, hence lower TSH.

C. SH and low TSH are biomarkers for age, and so are associated with other diseases of advanced age including dementias.

D. Subjects with cognitive impairment have a high burden of comorbidity, and association is due to nonthyroidal illness and drug effects on

serum TSH.

Articles from The Journal of Clinical Endocrinology and Metabolism are provided here courtesy of The Endocrine Society

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