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The Thyroid in Mind: Cognitive Function and Low Thyrotropin in Older People Earn 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 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. (J Clin Endocrinol Metab 97: 3438 –3449, 2012)

ith 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 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 be-

tween 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.

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2012 by The Endocrine Society doi: 10.1210/jc.2012-2284 Received May 22, 2012. Accepted July 13, 2012. First Published Online August 3, 2012

Abbreviations: AD, Alzheimer’s disease; CI, confidence interval; CNS, central nervous system; FT3, free T3; FT4, free T4; HR, hazard ratio; MRI, magnetic resonance imaging; OR, odds ratio; RR, relative risk; SH, subclinical hyperthyroidism; TT3, total T3; TT4, total T4.

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Background to SH and the Aging Thyroid Axis SH is defined as a serum TSH concentration below the reference range, with normal free T4 (FT4) and free T3 (FT3) levels. It can be divided into two groups; patients with a mildly reduced TSH (0.1– 0.4 mU/liter) can be clas-

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


sified 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 rT3 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 agerelated reduction in the secretion of pituitary TSH and/or hypothalamic TRH, due to an increased pituitary thyrotrope sensitivity to peripheral T3/T4 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 back-


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ward 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 T4 levels despite reduced tropic drive from lower pituitary TSH secretion. Therefore, reduced T4 and T3 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 “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, T4 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 ␤ amyloid plaque is the pathological hallmark of AD, and the potential pathways of ␤ 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 di-

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Cognitive Function and Low TSH in Older People

Titles and abstracts identified and screened for retrieval, n=362 Excluded based on headings and abstracts for being irrelevant to the topic, n=278 Full texts retrieved for detailed evaluation, n= 84

Published articles included in the systematic review, n=23

Excluded due to: Studies on overt thyroid dysfunction or subclinical hypothyroidism only Non-English language n=61

FIG. 1. Literature triage for systematic review.

minishing antioxidative enzymes (34, 35). Furthermore, T3 has been shown to affect splicing of certain ␤-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 ␤-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 en-


tities 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 crosssectional 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 MiniMental 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


TABLE 1.


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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)

Categorical analysis of subclinical thyroid disease vs. euthyroidism; or quantiles of serum T4 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)

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)

Van Osch, 2004 (40)

469

⬎52

Euthyroid only

TSH (0.5– 6 mU/liter)

Dobert, 2003 (41)

119

69.8 ⫾ 14

SH and euthyroid

Roberts, 2006 (42)

5868

(65–98)

SH and euthyroid

TSH, FT4, FT3 TSH (0.5– 4.0 mU/liter) FT4 (11–24 pmol/liter) TSH (0.4 –5.5 mU/liter), FT4 (9 –20 pmol/liter) FT3 (3.5– 6.5 pmol/liter)

829

78.2

200

(75–96)

227

De Jongh, 2011 (46)

1219 (34-SH)

Patterson, 2010 (47)

409

van Boxtel, 2004 (48)

120 (healthy volunteers)

Van der Cammen, 2003 (43) Multivariate analysis with thyroid function markers or cognitive performance as continuous variables Wahlin, 1998 (44)

Stuerenburg, 2006 (45)

Thyroid status

Thyroid function indicators (normal range)

All thyroid status (TSH)

TSH (no normal range provided)

Euthyroid only

TSH, FT4 TSH (0.4 –5 mU/liter) FT4 (12–25 pmol/liter)

71.6

All thyroid status (mean TSH 17.3 ⫾ 3.2)

75.5 (68.9 – 82.1)

Euthyroid, SH and subclinical hypothyroidism

FT4, TSH, FT3, TT4, TT3 Lowest FT4 quartile ⬍15.1 Highest FT4 quartile ⬎19.0 TSH, FT4, FT3 TSH (0.3– 4.5 mU/liter)

76.9 (52–94)

Euthyroid only

TSH, FT4 No normal range provided

⬎45

All thyroid status

TSH No normal range provided

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)

Prinz, 1999 (50)

44

72

All thyroid status

TT3, TT4, TSH; no normal range provided

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; APOE␧4, apolipoprotein E␧4; BP, blood pressure; PD, Parkinson’s disease; MI, myocardial infarction.

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, sug-

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TABLE 1.



Continued

Objective cognitive measures

Study outcomes

Covariates

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) MMSE was significantly lower in SH group compared to euthyroid group (22.61 ⫾ 6.88 vs. 24.72 ⫾ 4.52; P ⬍ 0.03) HR, 2.26 (95% CI, 1.32–3.91); P ⫽ 0.003 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) Patients with dementia showed 3-fold increased probability of having decreased or borderline TSH values (29%) vs. control (10%) No association between subclinical thyroid dysfunction and cognition or mood

Age, gender, BMI, education, smoking, history of alcohol abuse, hypertension

Overt thyroid dysfunction Patients on thyroid medications

Age, sex, smoking, chronic heart failure, DM, hypertension, Parkinson’s disease, BMI, physical activity

Participants on thyroid medications, amiodarone, lithium; dementia

Smoking, hypertension, stroke, DM, CVD, alcohol. APOE⑀4 genotype, total homocysteine level,

TSH outside normal range; patients on thyroid medications

MMSE

CAMCOG (Cambridge Examinations for Mental Disorders of the Elderly), MMSE MMSE, CERAD, Short Cognitive Performance test, MRI, PDG-PET MMSE, MEAMS (Middlesex Elderly Assessment of Mental State)

depression Age, sex

Dementia, CVD. RA, PVD, psychiatry diseases, osteoporosis, nonspecific thyroid diseases, DM, pulmonary or gastrointestinal diseases, medications (amiodarone, lithium, ␤-blocker, antiepileptics, antidepressants, kelp, tranquilizers, steroid, morphine) No information available

Diagnostic and Statistical Manual of Mental Disorders to diagnose AD

No differences in TSH level between AD patients and those without dementia

Two-letter fluency tasks; Block design test with WAIS-R; Trail Making Test; Episodic memory tests MMSE

Positive association between low normal TSH and worse episodic memory (P ⬍ 0.01)

Age, education, mood symptoms

Significant inverse correlation between plasma FT4 and MMSE score (Spearman rank correlation ⫽ ⫺0.14; P ⫽ 0.04) Subclinical hyper- or hypothyroidism was not associated with impaired global cognitive function

Smoking, hypertension, LDL, HDL, APOE⑀4 allele,

MMSE, the Raven’S colored progressive matrices (RCPM), the coding task and the audiotry verbal learning test NART (National Adult Reading Test); MMSE; HVLT (Hopkins Verbal Learning test) MAAS test battery (memory, sensorimotor speed, information processing, cognitive flexibility Trail Making Test; RAVLT delayed recall; Block design; Token test; Boston Naming test, Stroop test etc

No relationship between cognitive function and thyroid hormones. Higher FT4 was associated with worse functional independence (P ⬍ 0.001) Higher TSH was associated with poorer memory (P ⬍ 0.05), but this association disappeared after correction for depression score 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)

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)

Exclusion criteria

History of overt thyroid disease; patients on thyroid medications or contrast medium 4 wk before the laboratory testing Overt thyroid diseases or taking thyroid medications

No exclusion criteria (patients with overt thyroid disease were included)

Overt thyroid dysfunction, patients on neuroleptic or antithyroid medications, TFT outside the normal range, psychiatric illness No exclusion criteria

depression Age, sex, alcohol use, smoking, educational level, mean arterial pressure, BMI, heart rate, total cholesterol, and physical activity

Antithyroid or T4 medications

Age, sex, mood

No exclusion criteria

Depression, education, overt thyroid diseases

Dementia, PD, CVD, epilepsy, chronic psychotropic drug usage, CNS tumor

Age, sex, BMI, total cholesterol, HDL, LDL, BP, use of T4, ␤-blocker and estrogen

Psychiatric disorders, depression, systemic illness, diabetes, cerebral tumor, CNS infection, chronic alcoholism, patients on steroid treatments, patients with dementia Overt thyroid diseases, DM, dementia (MMSE score ⬍27) depression, MI, BMI ⬎18 or ⬍33 kg/m2, hypertension, CNS

Age, education

medication used (including 2 wk prior to testing), head/trauma or infection, other systemic illness, neurological, alcohol, sleep disorder

gesting 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


TABLE 2.


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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

68.8 (54 –94)

2– 4

SH and euthyroid

TSH, FT4, TT4 TSH (0.4 – 4.0 mU/liter) FT4 (11–25 pmol/liter)

12.7

SH and euthyroid

TSH (0.5–5.0 mU/liter)

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)

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)

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)

77.5

3

Euthyroid only

TSH, FT4. TSH (0.3–5.0 mU/liter); FT4 (4.5–12.5 ng/dl)

(64 –94)

2

Euthyroid only

TSH, FT4. TSH (0.3– 4.8 mU/liter); FT4 (13–23 pmol/ liter)

3.7

All thyroid status

TSH, FT4, FT3. TSH (0.3– 4.8 mU/liter); FT4 (13–23 pmol/liter)

Euthyroid only

TSH, FT4. TSH (0.4 –5 mU/liter); FT4 (12–25 pmol/ liter)

All thyroid status

TSH (no normal range provided)

Thyroid function indicators (normal range)

Categorical analysis of subclinical thyroid disease vs. euthyroidism; or quantiles of serum T4 concentration Kalmijn, 2000 (51)

1893 community

Tan, 2008 (52)

1864 community

Vadiveloo, 2011 (53)

12,115 community; SH- 2004; euthyroid, 10,111

de Jong, 2009 (54)

615 community

de Jong, 2006 (55)

1,025 community

Volpato, 2002 (56)

464 community

Multivariate analysis with thyroid function markers or cognitive performance as continuous variables Hogervorst, 2008 (57)

1,047 community

Gussekloo, 2004 (58)

558 community

Wahlin, 2005 (59)

200 community

Annerbo, 2006 (60)

93 hospital-based

71

85

75–96

3, then 6 yr

Men, 64.7; women, 65.4

5

GMS-A, Geriatric Mental State schedule; CAMDEX, Cambridge examination for disorders of the elderly; BMI, body mass index; APOE␧4, apolipoprotein E␧4; DM, diabetes mellitus; PVD, peripheral vascular disease; RAI, radioiodine therapy; TFT, thyroid function test.

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 hospitalbased participants, respectively, showed similar findings (48, 49). Paradoxically, a study of 44 healthy, communitydwelling male volunteers with a mean age of 72 yr observed a significant association between higher total T4 (TT4) levels and better cognition [Verbal performance in

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TABLE 2.


Continued

Objective cognitive measures

MMSE GMS-A CAMDEX MMSE

Diagnosis of dementia, ICD9 and 10

CASI (100 point Cognitive Ability Screening Instruments)

MMSE, GMS-A, CAMDEX

MMSE

MMSE; AGECAT (Automated Geriatric Examination and Computer Assisted Taxonomy) MMSE; Stroop test; Letter Digit Coding test; Word Learning test Two-letter fluency tasks; Block design test with WAIS-R; Trail Making Test; Episodic memory tests MMSE


Study outcomes

Covariates

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

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 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) 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 (limited by small number of patients with TSH ⬍0.1)

Age, plasma homocysteine levels, BMI, education, APOE⑀4 allele, stroke, atrial fibrillation

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 No association between increased risk of dementia or AD with TSH or thyroid hormone Higher FT4 associated with greater atrophy at

Age, education level, depression, albumin level, BMI, cholesterol , DM, hypertension, smoking, patients on T4, ␤-blocker or other cardiac

hippocampus and amygdala on MRI Low T4 within the normal range was associated with cognitive impairment over a 3-yr period (RR, 1.97; 95% CI, 1.10 –3.5)

High normal FT4 had a negative association with baseline MMSE and accelerated cognitive decline after 2 yr (P ⫽ 0.03) Increased level of TSH was associated with better memory on follow-up (P ⫽ 0.03), when participants on T4 were excluded Positive association between decreased level of TSH with increased episodic recall deficits at 6-yr follow-up (␤ 0.290; P ⬍ 0.05) No association found in 3-yr follow-up 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)

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) 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

Age, gender, history of dementia and psychiatry disease

antiarrhythmic drugs Sex, educational level, smoking, depression, medication use (amiodarone, ␤-blocker, steroids), BMI, cholesterol, homocysteine, smoking, creatinine APOE⑀4 genotype, diabetes, atrial fibrillation Age, race, educational level, coronary heart disease, hypertension, stroke, diabetes, PVD, depression, cancer

Exclusion criteria

Dementia at baseline, patients on amiodarone, ␤-blocker or thyroid medications Dementia at baseline

Age ⬍18 yr, patients treated with antithyroid medications/RAI/ thyroidectomy before and during the first year after the first abnormal TFT, patient on amiodarone, T4 replacement during the study period, pregnancy. Patient on long-term steroid replacement/ pituitary disease T4 level out of normal range

Blindness, dementia, contraindication to MRI, patients on thyroid medications

Nil

Age, sex, education, MMSE at baseline, mood, vascular risk factor (smoking, hypertension, heart disease, DM, stroke) Age, education

MMSE ⬍18

Age, education, mood symptoms

Over thyroid diseases, thyroid medications, psychiatric illness (but dementia is not excluded due to small sample size)

Stroke, cardiovascular disease, T4 treatment



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 rT3 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


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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 serum TSH and better memory function (␤, 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 (␤, 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 wellpowered 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

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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.

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 TRHsecreting 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 gluco-


corticoids, 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.

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. 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].


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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.

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