Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2015 Feb 1.
Published in final edited form as: JAMA Neurol. 2014 Feb;71(2):201–207. doi: 10.1001/jamaneurol.2013.5402

Hypothyroidism and Risk of Mild Cognitive Impairment in Elderly Persons - A Population Based Study

Ajay K Parsaik 1,2,3, Balwinder Singh 2,3,4, Rosebud O Roberts 3,5, Shane Pankratz 6, Kelly K Edwards 6, Yonas E Geda 7, H Gharib 8, Bradley F Boeve 2,3, David S Knopman 2,3, Ronald C Petersen 2,3
PMCID: PMC4136444  NIHMSID: NIHMS612082  PMID: 24378475

Abstract

IMPORTANCE

Association of clinical and subclinical hypothyroidism with mild cognitive impairment (MCI) is not established.

OBJECTIVE

To evaluate the association of clinical and subclinical hypothyroidism with MCI in a large population based cohort.

DESIGN

A cross-sectional, population-based study.

SETTING

Olmsted County, Minnesota.

PARTICIPANTS

Randomly selected participants were aged 70 to 89 years on October 1, 2004, and were without documented prevalent dementia. A total of 2,050 participants were evaluated and underwent in-person interview, neurological evaluation and neuropsychological testing to assess performance in memory, attention/executive function, visuospatial, and language domains. Subjects were diagnosed by consensus as cognitively normal, MCI or dementia according to published criteria. Clinical and subclinical hypothyroidism was ascertained from a medical records-linkage system.

MAIN OUTCOME MEASURES

Association of clinical and subclinical hypothyroidism with MCI.

Results

Among 1904 eligible participants, the frequency of MCI was 16% in 1450 subjects with normal thyroid function, 17% in 313 subjects with clinical hypothyroidism, and 18% in 141 subjects with subclinical hypothyroidism. After adjusting for covariates (age, gender, education, education years, sex, ApoE ε 4, depression, diabetes, hypertension, stroke, BMI and coronary artery disease) we found no significant association between clinical or subclinial hypothyroidism and MCI [OR 0.99 (95% CI 0.66–1.48) and OR 0.88 (95% CI 0.38–2.03) respectively]. No effect of gender interaction was seen on these effects. In stratified analysis, the odds of MCI with clinical and subclinical hypothyroidisn among males was 1.02 (95%CI, 0.57–1.82) and 1.29 (95%CI 0.68–2.44), among females was 1.04 (95% 0.66–1.66) and 0.86 (95% CI 0.37–2.02) respectively.

Conclusion

In this population based cohort of eldery, neither clinical nor subclinical hypothyrpodism was associated with MCI. Our findings need to be validated in a separate settings using the published criteria for MCI and also confirmed in a longitudinal study.

Introduction

Growing evidence has linked the alternation in endocrine system, in particular the thyroid dysfunction to the pathogenesis of Alzheimer’s disease (AD) and other dementias1. Therefore, measurement of serum thyroid stimulating hormone (TSH) has become the standard screening test during the evaluation of patients presenting with cognitive decline2. Subclinical hypothyroidism, which is defined biochemically as a normal serum free thyroxin (T4) concentration in the presence of an elevated TSH concentration, has a controversial association with cognitive impairment. While many investigators have reported positive associations between memory impairment and subclinical hypothyroidism3–7, others have reported better performance in some areas of cognitive functions among patients with decreased thyroid function8, or no association9–15.

Similarly, the association of clinical hypothyroidism with cognitive impairment is controversial, and has been an issue for debate. Some studies have reported a positive association16–19, while others found no relationship between cognitive impairment and hypothyroidism20–24. This inconsistency in the association across studies could be due to various reasons, including differing diagnostic criteria for cognitive impairment or hypothyroidism, measurement instruments and small sample sizes. Moreover, none of the studies have specifically looked for an association between hypothyroidism and mild cognitive impairment (MCI).

The MCI phase of the cognitive trajectory from normal aging to dementia has minimal clinical features with none or minimal functional impairment, and can be identified by the recently published National Institute on Aging (NIA) and Alzheimer’s Association criteria25–29. Currently approved treatments for AD (e.g. cholinesterase inhibitors, memantine) do not provide a “cure” in the fully symptomatic patients, partly because the treatments are administered too late in the disease process. Therefore, recognition of individuals at the earliest stage of the pathophysiological process of cognitive impairment, and understanding the etiological association with thyroid dysfunction is very important. Early interventions focused on treating the underlying etiologies of cognitive decline, may improve cognition or at least prevent further progression27.

The main objective of our study was to investigate the association of subclinical and clinical hypothyroidism (treated and untreated) with MCI, in a population-based cohort of elderly persons from Olmsted County, MN. We hypothesized that clinical and subclinical hypothyroidism are the important risk factors for MCI.

Methods

Study Sample

Our study was approved by the Institutional Review Boards of Mayo Clinic, MN and Olmsted County Medical Center, MN. All subjects signed an informed consent to participate in the study and only those who provided authorization to review their medical records for research purposes were included. In 2004, the Mayo Clinic Olmsted Study of Aging (MCSA; also known as the Alzheimer’s disease Patient Registry) used the resources of Rochester Epidemiology Project (REP), to establish a population-based cohort of subjects aged 70–89 years on October 1, 2004. The detailed study design and participant recruitment has been described in our previous report30. In brief, using REP resources a total of 9,953 persons between the ages of 70–89 years were identified, and a sample of 5,233 was randomly selected for recruitment. Of the 5,233 selected subjects, 402 had dementia at baseline, 263 subjects died before they could be contacted, 56 were in hospice care, and 114 could not be contacted. Of the 4,398 eligible subjects, 2,719 participated in the baseline evaluation. The baseline evaluation was conducted from October 1, 2004 through July 31, 2007, and consisted of a telephone interview only in 669 subjects, and in-person full participation in 2,050 subjects30.

Participant evaluation, measurement of cognition function and diagnostic criteria

Each participant was initially evaluated by a nurse or study coordinator to assess the demographics, medical comorbidities, and included memory questionnaires administered to the participant. The Clinical Dementia Rating Scale (CDR)31 and Functional Activities Questionanaires (FAQ)32 were administered to an informant.

Participants also underwent extensive psychometric testing to assess performance in memory, executive function, language and visuospatial skills domains. Psychometric tests involved 9 cognitive tests: Logical Memory–II [delayed recall] and Visual Reproduction–II [delayed recall] from the Wechsler Memory Scale–Revised and the Auditory Verbal Learning Test for memory domains33, 34 Trail Making Test B and Digit Symbol Substitution from Wechsler Adult Intelligence Scale– Revised [WAIS-R] for executive function35, 36; Boston Naming Test and Category Fluency Test37, 38 for language; Picture Completion and Block Design from the Wechsler Adult Intelligence Scale–Revised for visuospatial skills36. Each of the raw tests scores were transformed to age-adjusted scores using the normative date from the Mayo’s Older American Normative Studies and scaled to a mean of 10 and a standard deviation (SD) of 339. Age-adjusted scaled scores in each domain were summed up to get the domains score, and impairment in a domain was determined by comparing the scores to the mean (SD) of the population norms. Cognitive impairmment was considered possible if the average score was ≥ 1.0 SD below the mean, when compared to normative data derived from Olmsted County39. A neurological evalution of each participant was performed by a physician or neurologist, and involved administration of the Short Test of Mental Status (STMS)40, medical history review, and a detailed neurological examination. The final diagnosis of cognitive impairment in a domain was based on the conseus agreement between evaluating physician, nurse and neuropsychologist after taking into account the other important information like education, occupation, visual impaitment and deafness41.

The following published criteria were used to make the the diagnosis of MCI: memory concern raised by the research participants during the nurse interview, by informants (CDR), coordinators, or examining physicians; impairment in 1 or more of the 4 cognitive domains from cognitive battery; essentially normal functional activities from CDR and FAQ; and absence of dementia42. MCI subjects were further divided into amnestic MCI (a-MCI) if the memory domain was impaired and nonamnestic MCI (na-MCI) if the memory domain was not impaired but at least one memory domain was impaired. Dementia was diagnosed based on the DSM-IV criteria43. Persons who did not meet criteria for MCI or dementia, and performed within the nomal cognitive range of the normative data for this community39, were considered as cognitively normal.

Ascertainment of Thyroid Dysfunction

Diagnosis of hypothyroidism and hyperthyroidism was ascertained from the medical record linkage system44. Subjects were considered to have hypothyroidism if they had International Classification of Disease code for hypothyroidism (using International Classification of Diseases [ICD], Ninth Revision or International Classification of Diseases, Eighth Revision, Adapted Codes for Hospitals [HICDA]45, 46). ICD-9 codes were 244, 244.0, 244.1, 244.2, 244.3, 244.8, 244.9, 243, and HICDA codes were 02430240, 02440110, 02448111, 02449120, 02449130, 02440111, 02442110, 02442111, 02448110, 02449110, 02441120. Clinical hypothyroidism was diagnosed as a medical record documention of clinical hypothyroidism by treating physicians along with the confirmation of thyroid replacement therapy. Subjects with documented diagnosis of clinical hypothyroidism without any documented thyroid replacement therapy were characterized as having clinically overt hypothyroidism if they had a TSH level ≥10 mIU/L with a free thyroxine level < 1.01 ng/dL10. Subjects were characterized as having subclinical hypothyroidism based on a physician documentation in the medical record, a TSH level <10 mIU/L, free thyroxine level 1.01–1.79 ng/dL and no thyroxine replacement therapy. Participants with hyperthyroidism were excluded from the study; this was based on a physician diagnosis of hyperthyroidism in the medical record and an abnormally low TSH. All the thyroid tests were performed as per Mayo Clinic laboratory protocols.

Ascertainment of potential confounders

Covariates ascertained by personal interview during baseline evalution included sex, age, years of education, depression, diabetes, hypertension, stroke, or transient ischemic attack and coronary artery disease (angina, myocardial infarction, coronary revascularization or bypass graft). Self reported different medical comorbidities were confirmed from Mayo Clinic medical records-linkage system44. Depression was assessed by the interview of participants using the Beck Depression Inventory47. Body mass index (BMI) was calculated from weight and height measured at baseline visit. Apolipoprotein E (APOE) genotyping was done for each participant using validated methods48.

Analysis

Descriptive characteristics for categorical variables were summarized as frequencies and significance differences were tested using chi-square test. Continuous variables were summarized as median and interquartile range (IQR) and comparisons were made using the rank-sum test. A multiple logistic regression model was used to examine the association of clinical and subclinical hypothyroidism with MCI. The association was modeled with and without the pre-identified covariates of interest, and the model was stratified further according to sex and APOE ε4. We generated an overall model adjusted for age, years of education, sex, APOE ε4, depression, diabetes, hypertension, stroke, BMI and coronary artery disease, and also examined including interactions of sex and APOE ε4 with clinical and subclinical hypothyroidism. Linear regression models adjusted for age, years of education, sex, APOE ε4 were also used to evaluate the association of hypothyroidism with the four cognitive domains (memory, language, visual spatial and attention). All the calculated p values were 2-tailed and was considered statistically significant if p <0.05. All the analyses were done by using SAS software (SAS Institute, Cary NC).

Results

Study sample

A total of 2,050 subjects were evaluated in-person by study personnel. Of these, 122 were excluded: 67 had dementia at baseline, 14 had incomplete assessments, and 41 did not provide authorization to use their medical records in research. Of the remaining 1,928 subjects, 24 were excluded because of hyperthyroidism at the time of evaluation.

Characteristics of study subjects

Of the 1,904 subjects included in the analyses, 316 had MCI (58.5% male) and 1,588 (49.9% male 793) had normal cognitive function. Of the 316, 229 had a-MCI and 87 had na-MCI. MCI subjects were older than those with normal cognitive function (82.1 vs 79.6 years respectively, p<0.001), were less educated (13.0 vs 13.8 education years respectively, p<0.001), and had a lower BMI (27.1 vs 27.8 respectively, p=0.03). In addition, MCI subjects had a higher frequency of APOE ε4 allele carriers than subjects with normal cognitive function (30.0% vs 21.9% respectively, p=0.003), with borderline to high frequency of comorbidities including hypertension (83.5% vs 78.5% respectively, p=0.05), coronary artery disease (49.1% vs 40.3% respectively, p=0.005), diabetes mellitus (24.8% vs 12.3% respectively, p=0.05), stroke (19.9% vs 9.8% respectively, p=<0.0001) and depression (14.7% vs 8.0% respectively, p=0.001). A history of ever smoking was similar between the subjects with MCI and normal cognitive function (49.7% vs 49.1% respectively, p=0.90).

Of 1,904 included subjects, 1,450 had normal thyroid funtion, of which 83.7 % had normal cognitive function and 16.3% had MCI. Three hundred and thirteen subjects had clinical hypothyroidism (82.8% with normal cognitive function and 17.2% with MCI), and 141 had subclinical hypothyroidism (82.3% with normal congnitive function and 17.7% with MCI). Most of the participants (96.5%) with clinical hypothyroidism were on thyroid replacement therapy and those with subclinical hypothyroidism were not on any thyroid replacement therapy. Demographic characteristics and distribution of different covariates between the three groups (clinical hypothyroidism, subclinical hypothyroidism, normal thyroid function) are described in Table 1.

Table 1.

Demographic and Clinical Characteristic of Subjects with Normal and Decreased Thyroid Function

Normal
N = 1450		 Subclinical
Hypothyroidism
N = 141		 Hypothyroidism
N = 313 * 		p-value
Cognition, n (%) 0.86
Normal 1213 (83.66%) 116 (82.27%) 259 (82.75%)
MCI 237 (16.34%) 25 (17.73%) 54 (17.25%)
Age, median (25th–75th) 80.03 (75.10 – 83.81) 81.67 (77.37 – 84.50) 81.20 (76.69 – 85.01) < 0.0001φ
Education, median (25th–75th) 13 (12 – 16) 13 (12 – 16) 13 (12 – 16) 0.61
BMI 27.16 (24.38 – 30.22) 27.16 (24.52 – 29.83) 27.16 (24.23 – 30.30) 0.98
ApoE ε4, n (%) 0.30
No 1079 (77.18%) 107 (79.26%) 222 (73.51%)
Yes 319 (22.82%) 28 (20.74%) 80 (29.49%)
Gender, n (%) <0.0001ψ
Female 636 (43.86%) 70 (49.65%) 220 (70.29%)
Male 814 (56.14%) 71 (50.35%) 93 (29.71%)
Depression, n (%) 0.62
No 1259 (90.71%) 124 (93.23%) 279 (90.58%)
Yes 129 (9.29%) 9 (6.77%) 29 (9.42%)
Diabetes 0.47
No 1185 (81.72%) 121 (85.82%) 255 (81.47%)
Yes 265 (18.28%) 20 (14.18%) 58 (18.53%)
Hypertension 0.79
No 305 (21.03%) 27 (19.15%) 62 (19.81%)
Yes 1145 (78.97%) 114 (80.85%) 251 (80.19%)
Stroke 0.73
No 1287 (88.76%) 122 (86.52%) 277 (55.50%)
Yes 163 (11.24%) 19 (13.48%) 36 (11.50%)
Ever Smoker 0.02¥
No 710 (49.00%) 77 (54.61%) 179 (57.19%)
Yes 739 (51.00%) 64 (45.39%) 134 (42.81%)
CAD 0.38
No 846 (58.34%) 75 (53.19%) 188 (60.06%)
Yes 604 (41.66%) 66 (46.81%) 125 (39.94%)
Memory z-score, median (25th–75th) −0.02 (−0.72, 0.71) 0.07 (−0.77, 0.74) 0.13(−0.68, 0.83) 0.16
Attention z-score, median (25th–75th) 0.12 (−0.60, 0.69) 0.10 (−0.64, 0.66) 0.17 (−0.55, 0.72) 0.64
Visual Spatial z-score, median (25th–75th) 0.05 (−0.62, 0.67) −0.08 (−0.91, 0.66) 0.18 (−0.66, 0.72) 0.43
Language z-score, median (25th–75th) 0.07 (−0.60, 0.66) 0.06 (−0.49, 0.66) 0.10 (−0.47, 0.72) 0.69
Open in a new tab
*

302 participants with clinical hypothyroidism were on thyroid replacement therapy

Φ

Normal vs Subclinical Hypothyroidism: p= 0.003, Normal vs Hypothyroidism: p= 0.73

Ψ

Normal vs Subclinical Hypothyroidism: p= 0.19, Normal vs Hypothyroidism: p= 0.73

¥

Normal vs Subclinical Hypothyroidism: p= 0.22, Normal vs Hypothyroidism: p=0.73

IQR: interquartile range

Association of MCI with clinical and subclinical hypothyroidism

Compared to persons with normal thyroid function, clinical hypothyroidism was not associated with MCI in the model 1 adjusted for age at visit, sex and education (odds ratio [OR] = 1.09, 95% confidence interval [CI], 0.77–1.53). Even after adjusting the model for covariates (age, gender, education, education years, sex, ApoE ε 4, depression, diabetes, hypertension, stroke, BMI and coronary artery disease), we did not find statistically significant association between MCI and clinical hypothyroidism (OR = 0.99, 95%CI, 0.66–1.48) (Table 2).

Table 2.

Association of Clinical and Subclinical Hypothyroidism with MCI

Group Thyroid groups P for
trend
Normal
Thyroid
function		 Subclinical
Hypothyroidism		 Clinical
Hypothyroidism
Total sample; n (%) 1450 (76.2%) 141 (7.4%) 313 (16.4%)
Model 1; OR (95% CI)* 1.00 (Reference) 1.03 (0.65, 1.65) 1.09 (0.77, 1.53) 0.89
Model 2; OR (95% CI) ** 1.00 (Reference) 0.88 (0.38, 2.03) 0.99 (0.66, 1.48) 0.96
Men; n (%) 814 (83.2%) 71 (7.3%) 93 (9.5%)
Model 1; OR (95% CI)* 1.00 (Reference) 1.28 (0.71, 2.31) 0.93 (0.53, 1.64) 0.68
Model 2; OR (95% CI)** 1.00 (Reference) 1.29 (0.68, 2.44) 1.02 (0.57, 1.82) 0.73
Women; n, (%) 636 (68.7%) 70 (7.6%) 220 (23.7%)
Model 1; OR (95% CI)* 1.00 (Reference) 0.76 (0.35, 1.65) 1.17 (0.76, 1.80) 0.55
Model 2; OR (95% CI)** 1.00 (Reference) 0.86 (0.37, 2.02) 1.04 (0.66, 1.66) 0.92
APOE ε4 −ve; n (%) 1079 (76.6%) 107 (7.6%) 222 (15.8%)
Model 1; OR (95% CI)* 1.00 (Reference) 1.10 (0.64, 1.89) 0.94 (0.61, 1.44) 0.88
Model 2; OR (95% CI)** 1.00 (Reference) 1.15 (0.66, 2.01) 0.87 (0.55, 1.37) 0.71
APOE ε4 +ve; n (%) 319 (74.7%) 28 (6.6%) 80 (18.7%)
Model 1; OR (95% CI)* 1.00 (Reference) 0.84 (0.30, 2.32) 1.35 (0.74, 2.45) 0.56
Model 2; OR (95% CI)** 1.00 (Reference) 0.88 (0.28, 2.78) 1.47 (0.79, 2.76) 0.45
Open in a new tab
*

Logistic regression models.

*

Model 1 is adjusted for age at visit, sex and education.

**

Model 2 is adjusted for age at visit, years of education, any APOE ε4 allele, Beck Depression Inventory depression, diabetes, hypertension, stroke, body mass index, coronary artery disease, and smoking.

P-value for interaction of sex with hypothyroidism = 0.45

P-value for interaction of APOE ε4 with hypothyroidism = 0.30

Similarly, there was no association of subclinical hypothyroidism with MCI in the model 1; the OR was 1.03 (95%CI, 0.65–1.65) compared to those with normal thyroid function. There was also no association in the model 2; the OR was 0.88 (95%CI 0.38–2.03) after adjustment for covariaates

Since hypothyroidism is more frequent in women49, we did a stratified analysis by sex, to assess possible effect modification by sex on the association between MCI and hypothyroidism. Table 2 presents the 2 models for the association between MCI and thyroid funtion in men and in women. None of the models showed significant associations of MCI with clinical or subclinical hypothyroidism. Stratified analysis by APOE ε4 also showed insignificant association between MCI and thyroid groups (Table 2). The association of a-MCI and na-MCI with clinical and subclinical hypothyroidism were also insignificant. Table 3 describes the associations of clincial and subclincial hypothyroidism with four cognitive domains after controlling for age, years of education, sex, ApoE4.

Table 3.

Association of thyroid group with performance in cognitive domains*

Cognitive domain Thyroid groups
Normal
Thyroid
Function		 Subclinical
hypothyroidism		 Clinical
hypothyroidism
Beta (SE) p-value Beta (SE) p-
value
Memory Reference −0.03 (0.08) 0.67 0.06 (0.06) 0.34
Attention/executive function Reference 0.01 (0.08) 0.85 0.05 (0.06) 0.36
Visual Spatial skills Reference −0.08 (0.08) 0.32 0.13 (0.06) 0.03
Language Reference 0.02 (0.08) 0.82 0.06 (0.06) 0.33
Open in a new tab

SE- standard error

*

Linear regression models, models are adjusted for age, sex, years of education, APOE e4 genotype. Cognitive measures are entered as continuous variables.

Discussion

In this population based cross-sectional study in elderly persons, we did not find any significant association of MCI with clinical and subclinical hypothyroidsm, after accounting for the possible confounding factors and interactions. Our findings are consistent with previous studies that reported a lack of association between thyroid dysfunction and cognitive decline9–15, 20–24. Gussekloo et al. found no association between thyroid status and cognitive performance in either cross-sectional and prospective study designs in a population based cohort of individuals aged 85 year or more10. Similary, other investigators were unable to find any significant association of cognitive decline with subclinical hypothyroidism9–15 and clinical hypothyroidism20–24. However they did not specifically look for the association of hypothyroidism with MCI, a well-defined, earliest detectable clinical stage of cognitive impairment.

On the other hand, many studies have found positive association of cognitive decline with clinical hypothyroidism16–18, 50 and subclinical hypothyroidism3, 5–7. However, unlike the present study, none of the previous studies have evaluated the association of hypothyroidism with MCI.

Cognitive decline and thyroid dysfunction, are both common in the elderly10, and a widely held view is that hypothyroidism is a reversible risk factor for cognitive impairment, even though several studies have shown no such association. Our population based findings also argue against an association and suggest that neither clinical nor subclinical hypothyroidism is a risk factor for MCI. Similarly, we did not find any significant association with individual cognitive domains except for the borderline association of clinical hypothyroidism with reduced performance in the visuospatial skills domain, but the clinical significance of this is unknown. This raises questions about the need for routine testing of thyroid function as a part of the diagnostic work-up in patients with MCI. Since patients with dementia were excluded from our analysis, we are unable to comment on the association of clinicial and subclinical hypothyroidism with dementia. We found no significant interaction of hypothyroidism (clinical and subclinical) with sex and APOE ε4..

Our study have several strengths. It is a large population-based study representing an upper midwest population and may be generalizable to other populations represented in our study, or to the United States white population51. Since participants were randomly selected from the population, the risk of selection bias is reduced in comparison to studies that enrolled subjets from hospitals or referral settings. We validated the self report of different co-morbidities using the medical record system of REP. The ascertainment of MCI was done by using a comprehensive and the diagnosis was made by a consensus process resulting in a reliable approach for the detection of MCI26.

Potential weaknesses of our study include the cross-sectional study design, which prevents us from making causal inferences, and our inability to confirm that hypothyroidism preceded MCI.

In conclusion, we found that clinical and subclinical hypothyroidism are not associated with MCI in an elderly population. Our findings need to be validated in a separate settings using the standard criteria for MCI and also validated in a longitudinal study. This study contributes to the growing body of evidence that suggests that hypothyroidism is not associated with mild cognitive impairment.

Acknowledgement

We thank study participants for their participation, and the Mayo Clinic Study of Aging team (coordinators, psychometrists, psychologists, program management team and physicians) for their help in conducting this study. The study was funded by NIH-NIA grants P50 AG016574 (PI: R.C.P.), U01 AG006786 (PI: R.C.P.), and K01 AG028573 (PI: R.O.R.); by NIH-NIAMS grant R01 AR030582 (PI: W.A.R.); the NIH-NIMH grant K01 MH068351 (PI: Y.E.G.), and by Robert H. and Clarice Smith and Abigail van Buren Alzheimer’s Disease Research Program. Ajay K Parsaik had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Shane Pankratz and Kelly K. Edwards conducted the data analysis.

Footnotes

Conflict of interest: None of the authors has any disclosures or conflict of interest.

References

  • 1.Tan ZS, Beiser A, Vasan RS, et al. Thyroid function and the risk of Alzheimer disease: the Framingham Study. Archives of internal medicine. 2008 Jul 28;168(14):1514–1520. doi: 10.1001/archinte.168.14.1514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001 May 8;56(9):1143–1153. doi: 10.1212/wnl.56.9.1143. [DOI] [PubMed] [Google Scholar]
  • 3.Baldini IM, Vita A, Mauri MC, et al. Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry. 1997 Aug;21(6):925–935. doi: 10.1016/s0278-5846(97)00089-4. [DOI] [PubMed] [Google Scholar]
  • 4.Haggerty JJ, Jr, Garbutt JC, Evans DL, et al. Subclinical hypothyroidism: a review of neuropsychiatric aspects. International journal of psychiatry in medicine. 1990;20(2):193–208. doi: 10.2190/ADLY-1UU0-1A8L-HPXY. [DOI] [PubMed] [Google Scholar]
  • 5.Jensovsky J, Ruzicka E, Spackova N, Hejdukova B. Changes of event related potential and cognitive processes in patients with subclinical hypothyroidism after thyroxine treatment. Endocrine regulations. 2002 Sep;36(3):115–122. [PubMed] [Google Scholar]
  • 6.Monzani F, Del Guerra P, Caraccio N, et al. Subclinical hypothyroidism: neurobehavioral features and beneficial effect of L-thyroxine treatment. The Clinical investigator. 1993 May;71(5):367–371. doi: 10.1007/BF00186625. [DOI] [PubMed] [Google Scholar]
  • 7.Resta F, Triggiani V, Barile G, et al. Subclinical hypothyroidism and cognitive dysfunction in the elderly. Endocrine, metabolic & immune disorders drug targets. 2012 Sep;12(3):260–267. doi: 10.2174/187153012802002875. [DOI] [PubMed] [Google Scholar]
  • 8.Wu T, Flowers JW, Tudiver F, Wilson JL, Punyasavatsut N. Subclinical thyroid disorders and cognitive performance among adolescents in the United States. BMC pediatrics. 2006;6:12. doi: 10.1186/1471-2431-6-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.de Jongh RT, Lips P, van Schoor NM, et al. Endogenous subclinical thyroid disorders, physical and cognitive function, depression, and mortality in older individuals. European journal of endocrinology/European Federation of Endocrine Societies. 2011 Oct;165(4):545–554. doi: 10.1530/EJE-11-0430. [DOI] [PubMed] [Google Scholar]
  • 10.Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frolich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age. JAMA : the journal of the American Medical Association. 2004 Dec 1;292(21):2591–2599. doi: 10.1001/jama.292.21.2591. [DOI] [PubMed] [Google Scholar]
  • 11.Jorde R, Waterloo K, Storhaug H, Nyrnes A, Sundsfjord J, Jenssen TG. Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. The Journal of clinical endocrinology and metabolism. 2006 Jan;91(1):145–153. doi: 10.1210/jc.2005-1775. [DOI] [PubMed] [Google Scholar]
  • 12.Lindeman RD, Schade DS, LaRue A, et al. Subclinical hypothyroidism in a biethnic, urban community. Journal of the American Geriatrics Society. 1999 Jun;47(6):703–709. doi: 10.1111/j.1532-5415.1999.tb01593.x. [DOI] [PubMed] [Google Scholar]
  • 13.Luboshitzky R, Oberman AS, Kaufman N, Reichman N, Flatau E. Prevalence of cognitive dysfunction and hypothyroidism in an elderly community population. Israel journal of medical sciences. 1996 Jan;32(1):60–65. [PubMed] [Google Scholar]
  • 14.Park YJ, Lee EJ, Lee YJ, et al. Subclinical hypothyroidism (SCH) is not associated with metabolic derangement, cognitive impairment, depression or poor quality of life (QoL) in elderly subjects. Archives of gerontology and geriatrics. 2010 May-Jun;50(3):e68–e73. doi: 10.1016/j.archger.2009.05.015. [DOI] [PubMed] [Google Scholar]
  • 15.Roberts LM, Pattison H, Roalfe A, et al. Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction? Ann Intern Med. 2006 Oct 17;145(8):573–581. doi: 10.7326/0003-4819-145-8-200610170-00006. [DOI] [PubMed] [Google Scholar]
  • 16.Breteler MM, van Duijn CM, Chandra V, et al. Medical history and the risk of Alzheimer's disease: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group. International journal of epidemiology. 1991;20(Suppl 2):S36–S42. doi: 10.1093/ije/20.supplement_2.s36. [DOI] [PubMed] [Google Scholar]
  • 17.Erlanger DM, Kutner KC, Jacobs AR. Hormones and cognition: current concepts and issues in neuropsychology. Neuropsychology review. 1999 Dec;9(4):175–207. doi: 10.1023/a:1021634622577. [DOI] [PubMed] [Google Scholar]
  • 18.Osterweil D, Syndulko K, Cohen SN, et al. Cognitive function in non-demented older adults with hypothyroidism. Journal of the American Geriatrics Society. 1992 Apr;40(4):325–335. doi: 10.1111/j.1532-5415.1992.tb02130.x. [DOI] [PubMed] [Google Scholar]
  • 19.van Boxtel MP, Menheere PP, Bekers O, Hogervorst E, Jolles J. Thyroid function, depressed mood, and cognitive performance in older individuals: the Maastricht Aging Study. Psychoneuroendocrinology. 2004 Aug;29(7):891–898. doi: 10.1016/j.psyneuen.2003.08.002. [DOI] [PubMed] [Google Scholar]
  • 20.Kim JM, Stewart R, Kim SY, et al. Thyroid stimulating hormone, cognitive impairment and depression in an older korean population. Psychiatry investigation. 2010 Dec;7(4):264–269. doi: 10.4306/pi.2010.7.4.264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Kramer CK, von Muhlen D, Kritz-Silverstein D, Barrett-Connor E. Treated hypothyroidism, cognitive function, and depressed mood in old age: the Rancho Bernardo Study. European journal of endocrinology/European Federation of Endocrine Societies. 2009 Dec;161(6):917–921. doi: 10.1530/EJE-09-0606. [DOI] [PubMed] [Google Scholar]
  • 22.Lopez O, Huff FJ, Martinez AJ, Bedetti CD. Prevalence of thyroid abnormalities is not increased in Alzheimer's disease. Neurobiology of aging. 1989 May-Jun;10(3):247–251. doi: 10.1016/0197-4580(89)90058-4. [DOI] [PubMed] [Google Scholar]
  • 23.Shalat SL, Seltzer B, Pidcock C, Baker EL., Jr Risk factors for Alzheimer's disease: a case-control study. Neurology. 1987 Oct;37(10):1630–1633. doi: 10.1212/wnl.37.10.1630. [DOI] [PubMed] [Google Scholar]
  • 24.Small GW, Matsuyama SS, Komanduri R, Kumar V, Jarvik LF. Thyroid disease in patients with dementia of the Alzheimer type. Journal of the American Geriatrics Society. 1985 Aug;33(8):538–539. doi: 10.1111/j.1532-5415.1985.tb04617.x. [DOI] [PubMed] [Google Scholar]
  • 25.Gauthier S, Reisberg B, Zaudig M, et al. Mild cognitive impairment. Lancet. 2006 Apr 15;367(9518):1262–1270. doi: 10.1016/S0140-6736(06)68542-5. [DOI] [PubMed] [Google Scholar]
  • 26.Petersen RC. Clinical practice. Mild cognitive impairment. The New England journal of medicine. 2011 Jun 9;364(23):2227–2234. doi: 10.1056/NEJMcp0910237. [DOI] [PubMed] [Google Scholar]
  • 27.Petersen RC, Roberts RO, Knopman DS, et al. Mild cognitive impairment: ten years later. Archives of neurology. 2009 Dec;66(12):1447–1455. doi: 10.1001/archneurol.2009.266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Archives of neurology. 1999 Mar;56(3):303–308. doi: 10.1001/archneur.56.3.303. [DOI] [PubMed] [Google Scholar]
  • 29.Petersen RC, Stevens JC, Ganguli M, Tangalos EG, Cummings JL, DeKosky ST. Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001 May 8;56(9):1133–1142. doi: 10.1212/wnl.56.9.1133. [DOI] [PubMed] [Google Scholar]
  • 30.Roberts RO, Geda YE, Knopman DS, et al. The Mayo Clinic Study of Aging: design and sampling, participation, baseline measures and sample characteristics. Neuroepidemiology. 2008;30(1):58–69. doi: 10.1159/000115751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993 Nov;43(11):2412–2414. doi: 10.1212/wnl.43.11.2412-a. [DOI] [PubMed] [Google Scholar]
  • 32.Pfeffer RI, Kurosaki TT, Harrah CH, Jr, Chance JM, Filos S. Measurement of functional activities in older adults in the community. Journal of gerontology. 1982 May;37(3):323–329. doi: 10.1093/geronj/37.3.323. [DOI] [PubMed] [Google Scholar]
  • 33.Wechsler D. Manual for the Wechsler Memory Scale-Revised. New York: The Psychological Corporation; 1987. [Google Scholar]
  • 34.Rey A. L'examen clinique en psychologie. Paris: Presses Universitaires de France; 1964. [Google Scholar]
  • 35.R R. Validity of the Trail-making test as an indication of organic brain damage. Percept Mot Skills. 1958;8:271–276. [Google Scholar]
  • 36.Wechsler D. Wechsler Adult Intelligence Scale-Revised. San Antonio, TX: The Psychological Corporation; 1981. [Google Scholar]
  • 37.Kaplan EGH, Weintraub S. The Boston Naming Test. 2nd ed. Boston, MA: Lea & Fabiger; 1978. [Google Scholar]
  • 38.Strauss ESE, Spreen O. A Compendium of Neuropsychological Tests. New York: Oxford University Press; 2006. [Google Scholar]
  • 39.Ivnik RJMJ, Smith GE, et al. Mayo’s Older Americans Normative Studies: WAIS-R, WMS-R and AVLT norms for ages 56 through 97. Clin Neuropsychol. 1992;6:1–104. [Google Scholar]
  • 40.Kokmen E, Smith GE, Petersen RC, Tangalos E, Ivnik RC. The short test of mental status. Correlations with standardized psychometric testing. Archives of neurology. 1991 Jul;48(7):725–728. doi: 10.1001/archneur.1991.00530190071018. [DOI] [PubMed] [Google Scholar]
  • 41.Petersen RC, Roberts RO, Knopman DS, et al. Prevalence of mild cognitive impairment is higher in men. The Mayo Clinic Study of Aging. Neurology. 2010 Sep 7;75(10):889–897. doi: 10.1212/WNL.0b013e3181f11d85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Petersen RC. Mild cognitive impairment as a diagnostic entity. Journal of internal medicine. 2004 Sep;256(3):183–194. doi: 10.1111/j.1365-2796.2004.01388.x. [DOI] [PubMed] [Google Scholar]
  • 43.Association AP. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. Washington, DC: American Psychiatric Association; 1994. [Google Scholar]
  • 44.Melton LJ., 3rd History of the Rochester Epidemiology Project. Mayo Clinic proceedings. Mayo Clinic. 1996 Mar;71(3):266–274. doi: 10.4065/71.3.266. [DOI] [PubMed] [Google Scholar]
  • 45.H-ICDA. Hospital Adaptation of ICDA. 2nd ed. Ann Arbor, MI: Commission on Professional and Hospital Activities; 1973. [Google Scholar]
  • 46.Organization WH. International Classification of Diseases, Ninth Revision (ICD-9) Geneva: Switzerland World Health Organization; 1977. [Google Scholar]
  • 47.Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients. Journal of personality assessment. 1996 Dec;67(3):588–597. doi: 10.1207/s15327752jpa6703_13. [DOI] [PubMed] [Google Scholar]
  • 48.Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. Journal of lipid research. 1990 Mar;31(3):545–548. [PubMed] [Google Scholar]
  • 49.MPJTunbridge V. WMG The epidemiology of thyroid disease. In: Braverman LEUtiger RD, editor. The Thyroid 9th ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1996. pp. 474–482. [Google Scholar]
  • 50.van der Cammen TJ, Mattace-Raso F, van Harskamp F, de Jager MC. Lack of association between thyroid disorders and Alzheimer's disease in older persons: a cross-sectional observational study in a geriatric outpatient population. Journal of the American Geriatrics Society. 2003 Jun;51(6):884. doi: 10.1046/j.1365-2389.2003.51278.x. [DOI] [PubMed] [Google Scholar]
  • 51.St Sauver JL, Grossardt BR, Leibson CL, Yawn BP, Melton LJ, 3rd, Rocca WA. Generalizability of epidemiological findings and public health decisions: an illustration from the Rochester Epidemiology Project. Mayo Clinic proceedings. Mayo Clinic. 2012 Feb;87(2):151–160. doi: 10.1016/j.mayocp.2011.11.009. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES