Thyroid dysfunction and the risk of dementia and cognitive decline : Systematic review , meta-analysis and clinical implications

37 Context: While both overt hyperand hypothyroidism are known to lead to cognitive impairment, data on 38 the association between subclinical thyroid dysfunction and cognitive function are conflicting. 39 Objective: To determine the risk of dementia and cognitive decline associated with subclinical thyroid 40 dysfunction among prospective cohort studies. 41 Data Sources: Search in MEDLINE and EMBASE (inception until November 2014) and reference lists of 42 key articles without language restrictions. 43 Study Selection: Two physicians identified prospective cohorts that assessed thyroid function at baseline 44 and cognitive outcomes (dementia; Mini-Mental State Examination, MMSE). 45 Data Extraction: Data were extracted by one reviewer following standardized protocols and verified by a 46 second reviewer. Both reviewers independently assessed study quality. The primary outcomes were de47 mentia and decline in cognitive function measured by MMSE. We calculated risk ratios and 95% confi48 dence intervals using random-effects models. 49 Data Synthesis: Eleven prospective cohorts followed 16,805 participants during a median follow-up of 50 44.4 months. Five studies analyzed the risk of dementia in subclinical hyperthyroidism (n=6410), six in 51 subclinical hypothyroidism (n=7401). Five studies analyzed MMSE decline in subclinical hyperthyroid52 ism (n=7895), seven in subclinical hypothyroidism (n=8960). In random-effects models, the pooled ad53 justed RR for dementia in subclinical hyperthyroidism was 1.67 (95% confidence interval [CI] 1.04-2.69) 54 and 1.14 (95%CI 0.84-1.55) in subclinical hypothyroidism versus euthyroidism, both without evidence of 55 significant heterogeneity (I2=0.0%). Sensitivity analyses pooling only studies with formal outcome adjudi56 cation or population-based studies yielded similar results. The pooled mean MMSE decline from baseline 57 to follow-up (mean 32 months) did not significantly differ between subclinical hyperor hypothyroidism 58 versus euthyroidism. 59 Conclusions: Subclinical hyperthyroidism might be associated with an elevated risk for dementia, while 60 subclinical hypothyroidism is not, and both conditions are not associated with faster decline in MMSE 61 over time. Available data are limited, and additional large, high-quality studies are needed. 62 63 Formatted: Highlight

[1]  Andrew J. Saykin,et al.  Relationship between the Montreal Cognitive Assessment and Mini-mental State Examination for assessment of mild cognitive impairment in older adults , 2015, BMC Geriatrics.

[2]  N. Ferrara,et al.  Subclinical Hypothyroidism and Cognitive Impairment: Systematic Review and Meta-Analysis. , 2015, The Journal of clinical endocrinology and metabolism.

[3]  A. D. de Craen,et al.  Subclinical hypothyroidism and cognitive function in people over 60 years: a systematic review and meta-analysis , 2015, Front. Aging Neurosci..

[4]  R. Chou,et al.  Screening and Treatment of Thyroid Dysfunction: An Evidence Review for the U.S. Preventive Services Task Force , 2015, Annals of Internal Medicine.

[5]  Peter Jüni,et al.  Systematic reviews and meta-analyses of randomized trials: principles and pitfalls , 2014 .

[6]  M. Ikram,et al.  Cardiovascular risk factors and future risk of Alzheimer’s disease , 2014, BMC Medicine.

[7]  D. Schlessinger,et al.  Prevalence of unknown thyroid disorders in a Sardinian cohort. , 2014, European journal of endocrinology.

[8]  T. Kim,et al.  Lower-but-normal serum TSH level is associated with the development or progression of cognitive impairment in elderly: Korean Longitudinal Study on Health and Aging (KLoSHA). , 2014, The Journal of clinical endocrinology and metabolism.

[9]  A. D. de Craen,et al.  Subclinical Thyroid Dysfunction and Cognitive Decline in Old Age , 2013, PloS one.

[10]  G. Hankey,et al.  Higher free thyroxine levels predict increased incidence of dementia in older men: the Health in Men Study. , 2012, The Journal of clinical endocrinology and metabolism.

[11]  Bart Sheehan,et al.  Assessment scales in dementia , 2012, Therapeutic advances in neurological disorders.

[12]  E. Vittinghoff,et al.  Subclinical Thyroid Dysfunction and the Risk of Heart Failure Events: An Individual Participant Data Analysis From 6 Prospective Cohorts , 2012, Circulation.

[13]  S. Pearce,et al.  The Thyroid in Mind: Cognitive Function and Low Thyrotropin in Older People , 2012, The Journal of clinical endocrinology and metabolism.

[14]  N. Rodondi,et al.  Subclinical thyroid disorders , 2012, The Lancet.

[15]  J. Franklyn,et al.  Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. , 2012, Archives of internal medicine.

[16]  C. Sadowsky,et al.  Practical Guidelines for the Recognition and Diagnosis of Dementia , 2012, The Journal of the American Board of Family Medicine.

[17]  B. Biondi,et al.  Subclinical thyroid disease , 2012, The Lancet.

[18]  K. Otsuka,et al.  Cognitive function with subclinical hypothyroidism in elderly people without dementia: One year follow up , 2012, Geriatrics & gerontology international.

[19]  A. Larner,et al.  Test Your Memory test: diagnostic utility in a memory clinic population , 2011, International journal of geriatric psychiatry.

[20]  P. Donnan,et al.  Morbidity in patients with endogenous subclinical hyperthyroidism , 2011 .

[21]  G. Ravaglia,et al.  Serum Thyroid-Stimulating Hormone as a Predictor of Cognitive Impairment in an Elderly Cohort , 2011, Gerontology.

[22]  M. Surks,et al.  An approach for development of age-, gender-, and ethnicity-specific thyrotropin reference limits. , 2011, Thyroid : official journal of the American Thyroid Association.

[23]  J. Franklyn,et al.  Subclinical hypothyroidism and the risk of coronary heart disease and mortality. , 2010, JAMA.

[24]  J. Franklyn,et al.  A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: the Birmingham Elderly Thyroid study. , 2010, The Journal of clinical endocrinology and metabolism.

[25]  M. Pittler.  Systematic Reviews in Health Care: Meta‐analysis in Context , 2010 .

[26]  I. Benseñor,et al.  Subclinical hyperthyroidism and dementia: the Sao Paulo Ageing & Health Study (SPAH) , 2010, BMC public health.

[27]  J. Park,et al.  Subclinical hypothyroidism (SCH) is not associated with metabolic derangement, cognitive impairment, depression or poor quality of life (QoL) in elderly subjects. , 2010, Archives of gerontology and geriatrics.

[28]  R. Luben,et al.  Initial thyroid status and cardiovascular risk factors: The EPIC‐Norfolk prospective population study , 2010, Clinical endocrinology.

[29]  C. Jack,et al.  Mild cognitive impairment: ten years later. , 2009, Archives of neurology.

[30]  M. Breteler,et al.  Thyroid function, the risk of dementia and neuropathologic changes: The Honolulu–Asia Aging Study , 2009, Neurobiology of Aging.

[31]  C. Brayne,et al.  Thyroid function and cognitive decline in the MRC Cognitive Function and Ageing Study , 2008, Psychoneuroendocrinology.

[32]  B. Biondi,et al.  The clinical significance of subclinical thyroid dysfunction. , 2008, Endocrine reviews.

[33]  P. Scheltens,et al.  Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline , 2007, European journal of neurology.

[34]  Sheng He,et al.  fMRI revealed neural substrate for reversible working memory dysfunction in subclinical hypothyroidism. , 2006, Brain : a journal of neurology.

[35]  Roger M Harbord,et al.  A modified test for small‐study effects in meta‐analyses of controlled trials with binary endpoints , 2006, Statistics in medicine.

[36]  A. Hofman,et al.  Thyroid hormones, dementia, and atrophy of the medial temporal lobe. , 2006, The Journal of clinical endocrinology and metabolism.

[37]  L. Wahlund,et al.  The Significance of Thyroid-Stimulating Hormone and Homocysteine in the Development of Alzheimer’s Disease in Mild Cognitive Impairment , 2006, American journal of Alzheimer's disease and other dementias.

[38]  D. Bunce,et al.  Longitudinal evidence of the impact of normal thyroid stimulating hormone variations on cognitive functioning in very old age , 2005, Psychoneuroendocrinology.

[39]  A. D. de Craen,et al.  Thyroid status, disability and cognitive function, and survival in old age. , 2004, JAMA.

[40]  A. Smith,et al.  Low thyroid-stimulating hormone as an independent risk factor for Alzheimer disease , 2004, Neurology.

[41]  M. Helfand.  Screening for Subclinical Thyroid Dysfunction in Nonpregnant Adults: A Summary of the Evidence for the U.S. Preventive Services Task Force , 2004, Annals of Internal Medicine.

[42]  J. Franklyn,et al.  Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. , 2004, JAMA.

[43]  B. Vellas,et al.  Mild cognitive impairment: a nosological entity? , 2003, Current opinion in neurology.

[44]  L. Fried,et al.  Serum thyroxine level and cognitive decline in euthyroid older women , 2002, Neurology.

[45]  D. Petitti,et al.  Approaches to heterogeneity in meta‐analysis , 2001, Statistics in medicine.

[46]  Douglas G Altman,et al.  Systematic reviews of evaluations of prognostic variables , 2001, BMJ : British Medical Journal.

[47]  Jonathan A C Sterne,et al.  Systematic reviews in health care: Investigating and dealing with publication and other biases in meta-analysis. , 2001, BMJ.

[48]  A Hofman,et al.  Subclinical hyperthyroidism and the risk of dementia. The Rotterdam study , 2000, Clinical endocrinology.

[49]  Domenico Inzitari,et al.  Cognitive Impairment Without Dementia in Older People: Prevalence, Vascular Risk Factors, Impact on Disability. The Italian Longitudinal Study on Aging , 2000, Journal of the American Geriatrics Society.

[50]  G. Smith,et al.  Bias in meta-analysis detected by a simple, graphical test , 1997, BMJ.

[51]  A. Vita,et al.  Psychopathological and cognitive features in subclinical hypothyroidism , 1997, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[52]  C. Begg,et al.  Operating characteristics of a rank correlation test for publication bias. , 1994, Biometrics.

[53]  D. Hogan,et al.  Prevalence and types of dementia in the very old , 1994, Neurology.

[54]  F. Formiga,et al.  Thyroid status and functional and cognitive status at baseline and survival after 3 years of follow-up: the OCTABAIX study. , 2014, European journal of endocrinology.

[55]  D. Bauer,et al.  Subclinical Thyroid Dysfunction and the Risk for Fractures , 2014, Annals of Internal Medicine.

[56]  D. Kiel,et al.  Thyroid Function and the Risk of Alzheimer Disease , 2008 .

[57]  E. Mazzaferri.  Thyroid Status, Cardiovascular Risk, and Mortality in Older Adults , 2007 .

[58]  J. Sundsfjord,et al.  Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. , 2006, The Journal of clinical endocrinology and metabolism.

[59]  S. DeKosky,et al.  Association between A Community-Based Dementia and Study Elevated TSH: , 1996 .