In this community-based sample of 489 volunteers 40–88 years old, there was no association between TSH levels (0.3–10.0
mIU/L) and any cognitive factor when evaluated in the total sample, or when evaluated in younger (age
60) or older (age
60) groups. Gender-stratified analyses showed that females with higher levels of TSH recalled significantly more words on a verbal learning test than females with lower levels of TSH.
Because of equivocal findings among studies, possibly due to differences in sample populations, cognitive domains studied, and tests utilized, it has been suggested that tests specifically assessing processing speed, sustained attention, and working memory, using populations of older men and women, might better capture deficits that may occur with subclinical hypothyroidism (2
). Although we did use tests measuring these subdomains (e.g., Symbol Digit and Letter–Number Sequencing), in a middle-aged and older population of men and women, we did not detect any association between mildly elevated TSH levels and these cognitive domains. Our null finding for the association between TSH and processing speed and sustained attention (Symbol Digit Modalities Test [SDMT]) is in agreement with others who have examined these domains using the SDMT (or Digit Symbol Modalities Test) in mildly elevated TSH populations (20
). Our null finding for the association between TSH and working memory, using Letter–Number Sequencing, is in agreement with some studies (20
), but not others (23
). It is not in agreement with two recent studies that both used an N-back task as a measure for working memory. Zhu et al.
) found that newly identified, untreated, subclinical hypothyroid clinic patients (n
11, 10 female, age 17–47 years old [mean
mIU/L) scored significantly lower on a two-back task compared to euthyroid subjects (p
0.012). This finding was supported by functional MRI results showing reduced activity in the frontal cortex of these patients. Samuels et al.
, using a randomized, double-blind, cross-over trial of usual dose versus lower dose of L-T4 on hypothyroid patients (n
19 females, 20–75 years old), found that patients had significantly lower scores on a three-back task on the lower dose (TSH
3.04), compared to their scores on the usual dose (TSH
). The major difference between our study and these two studies is population: both used younger, predominantly female, subclinical, or hypothyroid patients, with markedly higher TSH levels. In our older population of subjects with mildly elevated TSH, we used Letter–Number Sequencing to assess working memory because it is viewed as sensitive to working memory deficits, better standardized, and more widely used than N-back tasks.
The significant positive association we found for women between increasing levels of TSH and immediate recall of word list learning is novel and in the opposite direction commonly hypothesized, but has been previously reported (26
). The significant negative association between TSH and performance on the immediate recall of a paragraph among older individuals is in agreement with two other studies conducted among young to middle-aged women, with higher levels of TSH [5.6–28.6
)]. However, it was not reported if this deficit was in both the immediate and delayed recall of the paragraph. Our significant findings could be due to a chance association given the number of analyses that were performed. Even if replicated, the clinical significance of these two findings may be questioned, because there was no significant association between levels of TSH and either the delayed recall of the paragraph or the delayed recall of the word list.
Our generally null findings are in overall agreement with the recent large community- or population-based studies (n
281–5865) of older individuals (mean age
60, approximately equal numbers of males and females) examining the effects of mildly elevated TSH and/or subclinical hypothyroidism on cognition (20
). Two of these studies used a test battery similar to our own, measuring several cognitive domains [attention, psychomotor speed, cognitive flexibility, fluency, and immediate and delayed memory (20
)]. In contrast, a small study of community-dwelling elderly (mean age
97) found that individuals with mildly elevated TSH levels (4.0–8.78
mIU/L) performed significantly worse on the immediate and delayed recall of a word list and the Mini-Mental State Exam, but not differently on tests measuring working memory or processing speed, compared to individuals with normal TSH levels (0.4–4.0
mIU/L), after controlling for depression (21
We found no association between log TSH levels and depression, as assessed by the CES-D (β [SE]
0.68 [0.54], p
0.21). Other studies examining the relationship between subclinical hypothyroidism and depression or depressive symptoms have been equivocal. However, our null finding between TSH levels and depressive symptoms is in agreement with two recent randomized placebo-controlled, double-blind studies examining the effect of thyroxine replacement in subclinical hypothyroidism, using a similar TSH range (≤10.0
mIU/L). Both studies found no differences between thyroxine-treated and placebo groups on depressive symptoms (20
). Two recent studies that have reported levels of well-being to be significantly lower in hypothyroid patients versus the general population, or for depression to occur significantly more often in subclinical hypothyroid patients than in individuals with overt hypothyroidism, did not find significant associations between levels of well-being or depression and TSH levels (31
Our overall null findings are at variance with research on mechanisms by which TH affects cognition and mood (33
). However, such studies have included young to middle-aged animal or human subjects with much higher TSH levels (>10.0
mIU/L) indicative of marked hypothyroidism. Extrapolating these results to populations with lower TSH levels, other age groups, and equally to men and women may not be appropriate, as suggested by our results and others noted above.
Our study has several limitations. Participants were chosen based on their fasting homocysteine level (≥8.5
μmol/L). Although they were in otherwise good health and although we adjusted for homocysteine levels in our analysis, homocysteine is also associated with cognition (34
), and our results may not generalize to individuals with lower homocysteine levels. Additionally, hyperhomocysteinemia may be associated with hypothyroidism (35
), although in our study homocysteine and TSH levels were not correlated (r
Secondly, although we did measure TPOAb status, the prevalence of which is comparable to (although slightly lower than) a large population-based study (36
), we did not measure thyroxine and triiodothyronine and thus were not able to accurately determine whether subjects with mildly elevated TSH had subclinical hypothyroidism and/or mild thyroid failure. Additionally, TSH values were drawn only once; laboratory protocol specifies multiple testing to accurately measure thyroid status. Thus, the poor association we found between TSH levels and the cognitive data could be due to reduced TSH reliability. However, our results are in agreement with other studies that were able to classify thyroid status, suggesting that our population was no different. Further, although we were interested in mildly elevated TSH levels, restricting the range of TSH values may have lead to a loss of power in identifying TSH-cognitive associations. Finally, because this was a cross-sectional study, we were not able to ascertain the associations of cognition with chronically elevated TSH levels. Our ability to detect associations between cognition and mild TSH elevation is reduced if cognitive outcomes depend on the chronicity of TSH elevations.
The strengths of our study include the relatively large sample size of both middle-aged and older adults and a diverse racial-ethnic population. This large sample size enabled us to detect correlations as small as r
0.13, with 80% power for n
0.17 for n
0.19 for n
222). Additionally, we used a comprehensive neuropsychological battery that assessed multiple cognitive domains. Finally, we were able to measure and control for several important confounders.
In sum, we found that elevated TSH levels within the range of 0.3–10.0
mIU/L were not associated with notably reduced cognitive performance in middle-aged and older individuals. These results challenge the notion that the elderly may be more cognitively vulnerable to higher TSH levels. Our exploratory analyses raise the possibility of a gender effect that may be of interest for future studies.