**6. Thyroid function and cognitive impairment**

Thyroid hormones are crucial for brain development and function: thyroid failure at any age causes cognition to deteriorate because thyroid hormones are essential for adequately sustaining the energy (glucose)-consuming processes needed for neurotransmission, memory, and other higher brain functions (Herholz, 2010; Patel et al., 2011). Low brain uptake of glucose is commonly associated with deteriorating cognition and Alzheimer's disease and can be present decades before clinical evidence of Alzheimer's disease occurs (Herholz, 2010). Brain hypometabolism therefore appears to be a precursor lesion increasing the risk of at least some forms of cognitive decline. Elevated TSH levels in the range found in patients with overt hypothyroidism have been described to be associated with impaired function in many cognitive domains, but the association between sHT and cognition is less clear (Graham et al., 1997; Gardner, 2004; Chavanne et al., 2011). On the other hand, several cross-sectional studies have observed that high or low TSH levels, still within the normal range (clinically euthyroid), are each related to poor cognitive performance, although some other investigations failed to demonstrate these findings (Prinz et al., 1999; Volpato et al., 2002). It should be underlined, however, that different cognitive deficits possibly related to thyroid failure do not necessarily follow a consistent pattern, and LT4 treatment may not always completely restore normal functioning in patients with hypothyroidism. Giving these premises, we summarize here the growing, conflicting literature on the relationship between cognitive performance and thyroid function from an ageing perspective.

194 Thyroid Hormone

thyroid status and longevity.

**6. Thyroid function and cognitive impairment** 

conducted a randomized, double-blind, crossover study to determine the short-term (12 weeks) effect of LT4 replacement therapy in 100 sHT patients (age range 18-80 yrs, mean 53.8) with serum TSH level>4.0 mIU/L. Primary end points included: serum cholesterol level variations along with improvement in flow-mediated dilation (FMD) as a marker of vascular endothelial function. LT4 treatment significantly reduced either TC or LDLc concentrations, and improved FMD, as compared to placebo group. Moreover, multivariate analysis showed that increased serum FT4 level was the most significant variable predicting reduction in TC or FMD improvement. The Authors hypothesized that if the reduction of LDLc level would be long term sustained, this would result in a relative reduction in 10-yr CV mortality of about 10%, thus supporting the use of LT4 replacement therapy also in patients with slightly elevated TSH value. Long-term studies are nonetheless required to confirm whether these apparent short-term benefits will translate into reduction in CV mortality and morbidity. Moreover, notwithstanding the wide age range of the studied patients, these results

In summary, conflicting results among large prospective cohort studies regarding the relationship between sHT and cardiovascular disease might reflect differences in participants such as age, gender, TSH value, or pre-existing cardiovascular disease. However, as demonstrated by some meta-analyses, the negative effect of sHT on cardiovascular risk is well established in younger people while in moderately old population (>65 and <85 years) it appears no longer evident. Moreover, in the oldest old people (>85 years) one study suggested that high levels of TSH not only do not exert adverse effects but also may favor a prolonged life span (Fig. 1). In this regard, elderly population can be interpreted as a heterogeneous group, nonagenarians representing a genetically selected cluster. Indeed, these subjects may have a genetic background that protects from CVD and/or thyroid hormone deficiency, thus suggesting an intriguing link between gene,

Thyroid hormones are crucial for brain development and function: thyroid failure at any age causes cognition to deteriorate because thyroid hormones are essential for adequately sustaining the energy (glucose)-consuming processes needed for neurotransmission, memory, and other higher brain functions (Herholz, 2010; Patel et al., 2011). Low brain uptake of glucose is commonly associated with deteriorating cognition and Alzheimer's disease and can be present decades before clinical evidence of Alzheimer's disease occurs (Herholz, 2010). Brain hypometabolism therefore appears to be a precursor lesion increasing the risk of at least some forms of cognitive decline. Elevated TSH levels in the range found in patients with overt hypothyroidism have been described to be associated with impaired function in many cognitive domains, but the association between sHT and cognition is less clear (Graham et al., 1997; Gardner, 2004; Chavanne et al., 2011). On the other hand, several cross-sectional studies have observed that high or low TSH levels, still within the normal range (clinically euthyroid), are each related to poor cognitive performance, although some other investigations failed to demonstrate these findings (Prinz et al., 1999; Volpato et al.,

cannot directly transfer to the elderly, especially the oldest old population.

**Figure 1.** Hypothetical relationship between risk of total mortality and age in patients with subclinical hypothyroidism (sHT) (Modified from Mariotti, 2005).

Subclinical hypothyroidism and cognitive function have been investigated in several preclinical experiments and clinical trials. To date, the actual relationship between mild thyroid hormone deficiency and cognitive impairment in the elderly is not well understood. In fact, there are several contrasting data resulting from cross-sectional and clinical experiments (Gussekloo et al., 2004; Roberts et al., 2006; Tan et al., 2008; Ceresini et al., 2009). Moreover, the available published data, in many cases, are not easily comparable considering the differences in inclusion criteria of each clinical study. Several small observational and interventional studies have reported an association, although not homogeneously, between cognitive impairment and sHT and, in some cases, it was described a cognitive performance improvement after LT4 replacement (Etgen et al., 2011; Monzani et al., 1993; Osterweil et al., 1992; St. John et al., 2009; Volpato et al., 2002). Moreover, Hogervost et al. (2008) studied the association between TSH and FT4 levels and cognition at baseline and after 2 years of follow-up in 1047 participants over 64 years of age, without physical frailty or severe cognitive impairment. The study showed that elevated TSH levels were associated with lower MMSE performance at baseline, independently of

FT4 value, age, sex, education and mood. Interestingly, epidemiological surveys using the revised Wechsler Adult Intelligence Scale (WAIS-R) and the Mini-Mental State Examination (MMSE) showed a relationship between plasma thyroid hormone levels and cognitive status in subjects with thyroid function still within the upper limit of the normal range (Prinz et al., 1999; Volpato et al., 2002). Accordingly, altered plasma thyroid hormone concentrations have been recognized as a risk factor for cognitive impairment or dementia (Bulens, 1981; Kalmijn et al., 2000; Tan et al., 2008). More specifically, with the increasing sensitivity of neuropsychological tools, it has become evident that thyroid hormone deficiency might produce measurable deficits in very specific neuropsychological functions (Zoeller & Rovet 2004). In this regard, in a recent prospective, open-labeled interventional study, cognitive impairment associated with (mild) thyroid failure appeared predominantly mnemonic in nature, suggesting that the etiology is not indicative of general cognitive slowing (Correia et al., 2009).

Mild Thyroid Deficiency in the Elderly 197

2011). In a study aimed to examine the feasibility of using thyroid hormone as a therapeutic agent for AD, mice were injected intra-hippocampally with aggregated amyloid betapeptide (Abeta) to produce AD animal model. Intraperitoneal administration of LT4 into Abeta-induced AD model mice prevented their cognitive impairment and improved their memory function. The authors suggested that the mechanisms of LT4 treating AD might be associated with regulating cholinergic function, protecting the brains of AD model mice against damage and rescuing hippocampal neurons from apoptosis. The results of this study seem indicate that the use of thyroid hormone may have some therapeutic potential in AD (Fu et al., 2010). Accordingly, in a post mortem study it was evaluated the brain thyroid hormone levels in AD measured with radioimmunoassay (RIA) samples of prefrontal cortex of patients with pathologically confirmed AD and controls without any primary neurological disease. Thyroxine levels did not differ between groups while T3 levels were significantly lower in Alzheimer's brains respect to controls. These results suggest that the conversion of T4 to T3 may be altered in advanced AD, perhaps due to modifications in deiodinase activity, and the reduced hormone conversion might be associated with both AD pathology and the clinical presentation of dementia (Davis et al., 2008). Moreover, Tan et al. (2008) related serum TSH concentrations to the risk of Alzheimer disease in 1864 cognitively intact, euthyroid participants of the Framingham original cohort (mean age 71 years). During a mean follow-up of 12.7 years, 209 participants (142 women) developed AD. Women in the lowest (<1.0 mIU/L) and highest (>2.1 mIU/L) tertiles of serum TSH concentration were at increased risk for AD compared with those in the middle tertile while, TSH levels were not related to AD risk in men. On the other hand, at odds with these findings, the InChianti study showed an association between subclinical hyperthyroidism and cognitive impairment without any correlation with mild thyroid failure in a large cohort

In conclusion, a certain degree of cognitive (mnemonic) impairment is generally recognized in case of overt hypothyroidism while, the relationship between cognition and sHT is still a disputed field, and it remains unclear whether to treat or not this kind of patients. In particular, there is little or no consensus in the literature whether thyroid failure is associated with impaired cognitive performance in the elderly, especially in the oldest old population. While interpreting the above reported conflicting results it should be outlined, however, that thyroid hormone concentrations change with age and cognitive decline is often concomitant with ageing; therefore, a reciprocal relationship could exist between

Levothyroxine replacement therapy for reducing sHT associated CV risk factors is still controversial, especially in the elderly. The lack of specific randomized trials, enrolling either old or very old subjects, aimed to evaluate the efficacy of hormonal replacement on overall survival and cardiovascular risk reduction as well as the possible negative effects of LT4 supplementation, makes the decision to treat elderly people very difficult. Generally,

changes of thyroid function and cognitive decline during normal ageing.

of older people (Ceresini et al., 2009).

**7. Conclusions** 

Conflicting data were obtained by large, population-based studies, leading to uncertain conclusions regarding the association between (mild) thyroid failure and cognition (Gussekloo et al., 2004; Roberts et al., 2006; Tan et al., 2008; Ceresini et al., 2009). In this setting, one critical point that could affect the results of these studies is the diverse age groups of the enrolled patients (moderate or very old) as well as the presence of comorbidity. Cognitive impairment observed in older sHT individuals might be also an epiphenomenon of the increased risk for atherosclerosis or the effect of thyroid hormone on vasculature. Indeed, arterial stiffness is a potential mechanism of advancing cognitive decline in sHT (Yamamoto et al., 2012) and elevated TSH values might negatively affect vascular function through systemic low-grade inflammation (Taddei et al., 2006). Moreover, whereas in moderate older people sHT might produce a detrimental effect on cognitive performance, in very old individuals (mild) thyroid failure might be not associated to a negative outcome (Gussekloo et al., 2004; Tan et al., 2008). To determine whether subclinical thyroid dysfunction should be treated in old age and the long-term impact of thyroid dysfunction on performance and survival in the elderly, a prospective, observational, population-based survey was carried out within the Leiden 85-Plus Study. A total of 599 participants were followed up from age 85 years through age 89 years. Plasma levels of TSH and FT4 were not associated with disability in daily life, depressive symptoms, and cognitive impairment at baseline or during follow-up. Conversely, increasing levels of TSH were associated with a lower mortality rate that remained after adjustments were made for baseline disability and health status (Gussekloo et al., 2004). It is noteworthy, however, that similarly to CHD risk, these results should be confirmed by stratified analyses in future prospective large cohort studies with a wide age range.

Another important aspect is the possible relationship between sHT and the risk to develop Alzheimer disease (AD). On this basis, many studies investigated a possible association between AD and thyroid dysfunction. Increasing evidence supports an extensive interrelationship between thyroid hormones and the cholinergic system, which is selectively and early affected in AD. Thyroid hormones negatively regulate expression of the amyloidbeta protein precursor, which plays a key role in the development of AD (Belakavadi et al., 2011). In a study aimed to examine the feasibility of using thyroid hormone as a therapeutic agent for AD, mice were injected intra-hippocampally with aggregated amyloid betapeptide (Abeta) to produce AD animal model. Intraperitoneal administration of LT4 into Abeta-induced AD model mice prevented their cognitive impairment and improved their memory function. The authors suggested that the mechanisms of LT4 treating AD might be associated with regulating cholinergic function, protecting the brains of AD model mice against damage and rescuing hippocampal neurons from apoptosis. The results of this study seem indicate that the use of thyroid hormone may have some therapeutic potential in AD (Fu et al., 2010). Accordingly, in a post mortem study it was evaluated the brain thyroid hormone levels in AD measured with radioimmunoassay (RIA) samples of prefrontal cortex of patients with pathologically confirmed AD and controls without any primary neurological disease. Thyroxine levels did not differ between groups while T3 levels were significantly lower in Alzheimer's brains respect to controls. These results suggest that the conversion of T4 to T3 may be altered in advanced AD, perhaps due to modifications in deiodinase activity, and the reduced hormone conversion might be associated with both AD pathology and the clinical presentation of dementia (Davis et al., 2008). Moreover, Tan et al. (2008) related serum TSH concentrations to the risk of Alzheimer disease in 1864 cognitively intact, euthyroid participants of the Framingham original cohort (mean age 71 years). During a mean follow-up of 12.7 years, 209 participants (142 women) developed AD. Women in the lowest (<1.0 mIU/L) and highest (>2.1 mIU/L) tertiles of serum TSH concentration were at increased risk for AD compared with those in the middle tertile while, TSH levels were not related to AD risk in men. On the other hand, at odds with these findings, the InChianti study showed an association between subclinical hyperthyroidism and cognitive impairment without any correlation with mild thyroid failure in a large cohort of older people (Ceresini et al., 2009).

In conclusion, a certain degree of cognitive (mnemonic) impairment is generally recognized in case of overt hypothyroidism while, the relationship between cognition and sHT is still a disputed field, and it remains unclear whether to treat or not this kind of patients. In particular, there is little or no consensus in the literature whether thyroid failure is associated with impaired cognitive performance in the elderly, especially in the oldest old population. While interpreting the above reported conflicting results it should be outlined, however, that thyroid hormone concentrations change with age and cognitive decline is often concomitant with ageing; therefore, a reciprocal relationship could exist between changes of thyroid function and cognitive decline during normal ageing.

#### **7. Conclusions**

196 Thyroid Hormone

al., 2009).

FT4 value, age, sex, education and mood. Interestingly, epidemiological surveys using the revised Wechsler Adult Intelligence Scale (WAIS-R) and the Mini-Mental State Examination (MMSE) showed a relationship between plasma thyroid hormone levels and cognitive status in subjects with thyroid function still within the upper limit of the normal range (Prinz et al., 1999; Volpato et al., 2002). Accordingly, altered plasma thyroid hormone concentrations have been recognized as a risk factor for cognitive impairment or dementia (Bulens, 1981; Kalmijn et al., 2000; Tan et al., 2008). More specifically, with the increasing sensitivity of neuropsychological tools, it has become evident that thyroid hormone deficiency might produce measurable deficits in very specific neuropsychological functions (Zoeller & Rovet 2004). In this regard, in a recent prospective, open-labeled interventional study, cognitive impairment associated with (mild) thyroid failure appeared predominantly mnemonic in nature, suggesting that the etiology is not indicative of general cognitive slowing (Correia et

Conflicting data were obtained by large, population-based studies, leading to uncertain conclusions regarding the association between (mild) thyroid failure and cognition (Gussekloo et al., 2004; Roberts et al., 2006; Tan et al., 2008; Ceresini et al., 2009). In this setting, one critical point that could affect the results of these studies is the diverse age groups of the enrolled patients (moderate or very old) as well as the presence of comorbidity. Cognitive impairment observed in older sHT individuals might be also an epiphenomenon of the increased risk for atherosclerosis or the effect of thyroid hormone on vasculature. Indeed, arterial stiffness is a potential mechanism of advancing cognitive decline in sHT (Yamamoto et al., 2012) and elevated TSH values might negatively affect vascular function through systemic low-grade inflammation (Taddei et al., 2006). Moreover, whereas in moderate older people sHT might produce a detrimental effect on cognitive performance, in very old individuals (mild) thyroid failure might be not associated to a negative outcome (Gussekloo et al., 2004; Tan et al., 2008). To determine whether subclinical thyroid dysfunction should be treated in old age and the long-term impact of thyroid dysfunction on performance and survival in the elderly, a prospective, observational, population-based survey was carried out within the Leiden 85-Plus Study. A total of 599 participants were followed up from age 85 years through age 89 years. Plasma levels of TSH and FT4 were not associated with disability in daily life, depressive symptoms, and cognitive impairment at baseline or during follow-up. Conversely, increasing levels of TSH were associated with a lower mortality rate that remained after adjustments were made for baseline disability and health status (Gussekloo et al., 2004). It is noteworthy, however, that similarly to CHD risk, these results should be confirmed by stratified analyses in future

Another important aspect is the possible relationship between sHT and the risk to develop Alzheimer disease (AD). On this basis, many studies investigated a possible association between AD and thyroid dysfunction. Increasing evidence supports an extensive interrelationship between thyroid hormones and the cholinergic system, which is selectively and early affected in AD. Thyroid hormones negatively regulate expression of the amyloidbeta protein precursor, which plays a key role in the development of AD (Belakavadi et al.,

prospective large cohort studies with a wide age range.

Levothyroxine replacement therapy for reducing sHT associated CV risk factors is still controversial, especially in the elderly. The lack of specific randomized trials, enrolling either old or very old subjects, aimed to evaluate the efficacy of hormonal replacement on overall survival and cardiovascular risk reduction as well as the possible negative effects of LT4 supplementation, makes the decision to treat elderly people very difficult. Generally, LT4 replacement therapy should be considered for three main reasons: i) to prevent progression of sHT to overt hypothyroidism which, however, is much more important in young patients; ii) to reduce the symptoms associated with mild thyroid failure, which are especially scarce in the elderly; iii) to improve the lipid profile and other risk factors that may contribute to atherosclerosis progression and CV events.

Mild Thyroid Deficiency in the Elderly 199

**Author details** 

**8. References** 

1050-7256 (Linking).

Giuseppe Pasqualetti, Angela Dardano, Sara Tognini, Antonio Polini and Fabio Monzani

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Arem, R., Rokey, R., Kiefe, C., Escalante, D.A., Rodriguez, A. (1996). Cardiac systolic and diastolic function at rest and exercise in subclinical hypothyroidism: effect of thyroid hormone therapy. Thyroid, Vol. 6, No. 5 (Oct 1996), pp. 397-402, issn 1050-7256 (Print)

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Bakker, S.J., ter Maaten, J.C., Popp-Snijders, C., Slaets, J.P., Heine, R.J., Gans, R.O. (2001). The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. J Clin Endocrinol Metab, Vol. 86, No. 3

Baloch, Z., Carayon, P., Conte-Devolx, B., Demers, L.M., Feldt-Rasmussen, U., Henry, J.F., LiVosli, V.A., Niccoli-Sire, P., John, R., Ruf, J., Smyth, P.P., Spencer, C.A., Stockigt, J.R. (2003). Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid, Vol. 13, No. 1 (Jan 2003), pp. 3-126, issn

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Subclinical thyroid failure causes changes in cardiac function similar to, but less marked than, those occurring in patients with overt hypothyroidism. Diastolic dysfunction both at rest and upon effort is the most consistent cardiac abnormality in patients with sHT, even in those with slightly elevated TSH levels (>6 mIU/L) (Arem et al., 1996; Biondi & Cooper, 2012;). Mild thyroid failure may also increase diastolic blood pressure as a result of increased systemic vascular resistances (Faber et al., 2002; Kahaly, 2000; Luboshitzky et al., 2002). Interestingly, restoration of euthyroidism by LT4 replacement is able to reduce systemic hypertension as well as improve left ventricular myocardial function (Brenta et al., 2003). Moreover, sHT has been claimed to be a risk factor for atherosclerosis and ischemic CVD, therefore, it is appropriate to consider whether treatment confers some protection from such a risk. Although a consensus is still lacking, the strongest evidence for a beneficial effect of levothyroxine replacement therapy is the substantial demonstration that restoration of euthyroidism can lower TC and LDLc levels in most patients with sHT. Besides hypercholesterolemia several emerging risk factors for CHD have been claimed to be associated with sHT. Among them, altered coagulation parameters, endothelial dysfunction, and elevated CRP levels are consistently regarded to combine with the raised LDLc levels of untreated patients with sHT to enhance the cardiovascular risk.

As a whole, these findings suggest that the decision to treat patients with sHT should depend on the presence of risk factors, rather than on a TSH threshold. International organizations and guidelines suggest starting replacement therapy in patients who have TSH concentrations greater than 10 mIU/liter and in those with evidence of autoimmunity, and in symptomatic patients with TSH levels between 4.5 and 10 mIU/L (Gharib et al., 2005a,b; Surks et al., 2004). However, the treatment of sHT patients, especially the elderly, must be individualized once any underlying coexisting morbidity or pharmacologic interference has been excluded. Generally LT4 replacement results effective and safe in young patients, providing that excessive dosing is avoided by monitoring serum TSH level. Indeed, LT4 replacement therapy can always be discontinued if there is no apparent benefit. It is noteworthy that, once a stable, elevated TSH value is detected, the costs of annual follow-up with clinical assessment and laboratory testing are relatively similar whether or not a patient is treated with LT4 (Cooper et al., 2001). On the other hand, the possibility that restoring euthyroidism may be harmful in the older population has been raised, and should be taken into account in making the decision of treating such patients, especially those older than 85 years. In this setting, hormonal replacement might be considered in old patients on the base of a specific evaluation of the possible thyroid dysfunction causes, pre-existent cardiovascular risk including cholesterol level, hearth failure as well as the presence of comorbidities or frailty and the level of TSH. However, until adequate data are accumulated, clinicians should consider each patient a unique situation, and best clinical practice continues to be a combination of clinical judgment and the patient's preference.
