Edinburgh Explorer 11-hydroxysteroid dehydrogenase type 1, brain atrophy and cognitive decline

Excess cortisol levels are linked with brain atrophy and cognitive decline in older people. 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) potently amplifies intracellular glucocorticoid action by converting inert cortisone to active cortisol, but any causal importance in brain ageing is unexplored. We tested the hypotheses that higher systemic 11ß-HSD1 activity predicts brain atrophy and cognitive decline in older men. In a longitudinal study of 41 men (65-70y at baseline) we measured baseline systemic 11ß-HSD1 activity, the urinary 5alpha- and 5beta-tetrahydrocortisol to tetrahydrocortisone ratio (THFs/THE), and assessed change in brain atrophy, white matter lesions and cognitive function over six years. Baseline THFs/THE correlated negatively with baseline hippocampal volumes (left: r=-0.37; right: r=-0.34; p<0.05) and positively with ventricular volumes (r=0.43, p=0.006) and periventricular white matter lesions (rho=0.31, p=0.047). Importantly, baseline THFs/THE but not cortisol predicted increase in ventricular volumes (r=0.33, p=0.037) and decline in processing speed (r=-0.55, p=0.0002) over six years. The predictive link between systemic 11 β -HSD1 activity and progressive brain atrophy and cognitive decline suggests 11 β -HSD1 inhibition as a plausible therapy for brain ageing.

[1]  J. Seckl,et al.  11β-Hydroxysteroid Dehydrogenase Type 1 Expression Is Increased in the Aged Mouse Hippocampus and Parietal Cortex and Causes Memory Impairments , 2010, The Journal of Neuroscience.

[2]  Karen J. Ferguson,et al.  Quantitative and Qualitative Measures of Hippocampal Atrophy Are Not Correlated in Healthy Older Men , 2010, Journal of neuroimaging : official journal of the American Society of Neuroimaging.

[3]  Carol Brayne,et al.  Age, neuropathology, and dementia. , 2009, The New England journal of medicine.

[4]  Manuel Desco,et al.  Assessment of the increase in variability when combining volumetric data from different scanners , 2009, Human brain mapping.

[5]  J. Im,et al.  Behavioral stress accelerates plaque pathogenesis in the brain of Tg2576 mice via generation of metabolic oxidative stress , 2009, Journal of Neurochemistry.

[6]  Nuno Sousa,et al.  Effects of altered corticosteroid milieu on rat hippocampal neurochemistry and structure--an in vivo magnetic resonance spectroscopy and imaging study. , 2008, Journal of psychiatric research.

[7]  A. Hofman,et al.  Glucocorticoid receptor variant and risk of dementia and white matter lesions , 2008, Neurobiology of Aging.

[8]  Owen Carmichael,et al.  Trajectories of brain loss in aging and the development of cognitive impairment , 2008, Neurology.

[9]  B. Walker.  Glucocorticoids and cardiovascular disease. , 2007, European journal of endocrinology.

[10]  R. Morris,et al.  Enhanced Hippocampal Long-Term Potentiation and Spatial Learning in Aged 11β-Hydroxysteroid Dehydrogenase Type 1 Knock-Out Mice , 2007, The Journal of Neuroscience.

[11]  N. Pedersen,et al.  Age changes in processing speed as a leading indicator of cognitive aging. , 2007, Psychology and aging.

[12]  F. Labrie,et al.  Localization and glucocorticoid regulation of 11β-hydroxysteroid dehydrogenase type 1 mRNA in the male mouse forebrain , 2007, Neuroscience.

[13]  J. Seckl,et al.  Liver-selective transgene rescue of hypothalamic-pituitary-adrenal axis dysfunction in 11beta-hydroxysteroid dehydrogenase type 1-deficient mice. , 2007, Endocrinology.

[14]  Sharon E. Lee,et al.  Ventricular volume and dementia progression in the Cardiovascular Health Study , 2007, Neurobiology of Aging.

[15]  T. Olsson,et al.  Cognitive Dysfunction, Hippocampal Atrophy and Glucocorticoid Feedback in Alzheimer’s Disease , 2006, Biological Psychiatry.

[16]  B. Singer,et al.  Urinary cortisol excretion as a predictor of incident cognitive impairment , 2005, Neurobiology of Aging.

[17]  Joanna M. Wardlaw,et al.  Plasma cortisol levels, brain volumes and cognition in healthy elderly men , 2005, Psychoneuroendocrinology.

[18]  B. Walker,et al.  The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans. , 2005, Diabetes.

[19]  D. Mohr,et al.  A meta-analysis of cortisol response to challenge in human aging: importance of gender , 2004, Psychoneuroendocrinology.

[20]  C. Cobelli,et al.  Splanchnic cortisol production occurs in humans: evidence for conversion of cortisone to cortisol via the 11-beta hydroxysteroid dehydrogenase (11beta-hsd) type 1 pathway. , 2004, Diabetes.

[21]  I. Deary,et al.  Glycosylated Hemoglobin Levels in Healthy Elderly Nondiabetic Men are Negatively Associated with Verbal Memory , 2004, Journal of the American Geriatrics Society.

[22]  L J Whalley,et al.  Pronunciation of irregular words is preserved in dementia, validating premorbid IQ estimation , 2004, Neurology.

[23]  B. McEwen,et al.  Sex, stress and the hippocampus: allostasis, allostatic load and the aging process , 2002, Neurobiology of Aging.

[24]  Karen J. Ferguson,et al.  Intracranial capacity and brain volumes are associated with cognition in healthy elderly men , 2002, Neurology.

[25]  S. Berent,et al.  Elevated Cortisol Levels in Cushing’s Disease Are Associated With Cognitive Decrements , 2001, Psychosomatic medicine.

[26]  J. Seckl,et al.  Lack of tissue glucocorticoid reactivation in 11β-hydroxysteroid dehydrogenase type 1 knockout mice ameliorates age-related learning impairments , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[27]  T. Olsson,et al.  Increased glucocorticoid production and altered cortisol metabolism in women with mild to moderate Alzheimer’s disease , 2001, Biological Psychiatry.

[28]  D. M. Lyons,et al.  Glucocorticoid and mineralocorticoid receptor mRNA expression in squirrel monkey brain. , 2000, Journal of psychiatric research.

[29]  T. Salthouse.  Aging and measures of processing speed , 2000, Biological Psychology.

[30]  Nick Bryan,et al.  Clinical Correlates of Ventricular and Sulcal Size on Cranial Magnetic Resonance Imaging of 3,301 Elderly People , 1999, Neuroepidemiology.

[31]  B. Walker,et al.  Obesity and gender influence cortisol secretion and metabolism in man. , 1998, The Journal of clinical endocrinology and metabolism.

[32]  A. Convit,et al.  Cortisol levels during human aging predict hippocampal atrophy and memory deficits , 1998, Nature Neuroscience.

[33]  B. Walker,et al.  Additional value of measurement of urinary cortisone and unconjugated cortisol metabolites in assessing the activity of 11β‐hydroxysteroid dehydrogenase in vivo , 1997, Clinical endocrinology.

[34]  W. Rosen,et al.  Neuropsychological Assessment, 3rd Edition , 1996 .

[35]  C. Edwards,et al.  Glucocorticoids Regulate Hippocampal 11β‐Hydroxysteroid Dehydrogenase Activity and Gene Expression in vivo in the Rat , 1994, Journal of neuroendocrinology.

[36]  F. Fazekas,et al.  Pathologic correlates of incidental MRI white matter signal hyperintensities , 1993, Neurology.

[37]  Robert M. Sapolsky,et al.  Glucocorticoid endangerment of hippocampal neurons is NMDA-receptor dependent , 1990, Brain Research.

[38]  S. Gauthier,et al.  Hypothalamic-pituitary-adrenal activity in aged, cognitively impaired and cognitively unimpaired rats , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[39]  C. Catania,et al.  The amyloidogenic potential and behavioral correlates of stress , 2009, Molecular Psychiatry.

[40]  J. Seckl,et al.  The role of 11beta-hydroxysteroid dehydrogenases in the brain. , 2006, Molecular and cellular endocrinology.

[41]  Karen J. Ferguson,et al.  Intracranial area: a validated method for estimating intracranial volume. , 2005, Journal of neuroimaging : official journal of the American Society of Neuroimaging.

[42]  E. D. de Kloet,et al.  Hormones and the stressed brain. , 2004, Annals of the New York Academy of Sciences.

[43]  J. Seckl,et al.  11 P-Hydroxysteroid Dehydrogenase in Cultured Hippocampal Cells Reactivates Inert 11 -Dehydrocorticosterone, Potentiating Neurotoxicity , 2003 .

[44]  Sterling C. Johnson,et al.  The Word Selective Reminding Subtest of the Test of Memory and Learning (TOMAL): A Concurrent and Construct Validity Study Using the Rey Auditory Verbal Learning Test (RAVLT) and the Wechsler Memory Scale-Revised (WMS-R) , 1995 .

[45]  J. Raven,et al.  Manual for Raven's progressive matrices and vocabulary scales , 1962 .