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Cognitive Dysfunction, Hippocampal Atrophy and Glucocorticoid Feedback in Alzheimer’s Disease

      Background

      The hippocampal formation is damaged early in Alzheimer’s disease (AD). An association between temporal lobe volume and cognitive function has been shown in several studies. Increased limbic-hypothalamic-pituitary-adrenal (LHPA) axis function has been suggested to be related to hippocampal atrophy and cognitive impairment. Our hypothesis was that there is a clear link between hippocampal volume – notably of the CA1 region - memory (episodic and visuospatial) and decreased feedback sensitivity in the LHPA axis in AD.

      Methods

      Sixteen medication-free outpatients with mild to moderate AD were included. Hippocampal volume was measured with magnetic resonance imaging. Dexamethasone suppression tests were performed using .5 mg and .25 mg dexamethasone. Three different components in the neuropsychological battery – Rey 15 item memory test, Alzheimer’s Disease Assessment Scale (ADAS) word recall and spatial span from Wechsler Adult Intelligence Scale – Revised neuropsychological instrument (WAIS-R NI) – were found to represent episodic and visuospatial memory.

      Results

      Low hippocampal CA1 volume and high post-dexamethasone cortisol levels in combination were significantly associated with Rey 15 item memory and spatial span test outcomes. No association was found between LHPA feedback and hippocampal volume.

      Conclusions

      Low hippocampal volume and a disturbed negative feedback in the LHPA axis link to specific cognitive impairments in Alzheimer’s disease.

      Key Words

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      References

        • Almkvist O.
        Neuropsychological features of early Alzheimer’s disease.
        Acta Neurol Scand Suppl. 1996; 165: 63-71
        • Almkvist O.
        • Backman L.
        Detection and staging of early clinical dementia.
        Acta Neurol Scand. 1993; 88: 10-15
        • Bernard L.C.
        • Fowler W.
        Assessing the validity of memory complaints.
        J Clin Psychol. 1990; 46: 432-436
        • Bobinski M.
        • de Leon M.J.
        • Tarnawski M.
        • Wegiel J.
        • Reisberg B.
        • Miller D.C.
        • et al.
        Neuronal and volume loss in CA1 of the hippocampal formation uniquely predicts duration and severity of Alzheimer disease.
        Brain Res. 1998; 805: 267-269
        • Burgess N.
        • Maguire E.A.
        • O’Keefe J.
        The human hippocampus and spatial and episodic memory.
        Neuron. 2002; 35: 625-641
        • de Leon M.J.
        • McRae T.
        • Tsai J.R.
        • George A.E.
        • Marcus D.L.
        • Freedman M.
        • et al.
        Abnormal cortisol response in Alzheimer’s disease linked to hippocampal atrophy.
        Lancet. 1988; 2: 391-392
        • Folstein M.F.
        • Folstein S.E.
        • McHugh P.R.
        “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician.
        J Psychiatr Res. 1975; 12: 189-198
        • Fratiglioni L.
        • Launer L.J.
        • Andersen K.
        • Breteler M.M.
        • Copeland J.R.
        • Dartigues J.F.
        • et al.
        Incidence of dementia and major subtypes in Europe.
        Neurology. 2000; 54: S10-S15
        • Hodges J.
        The amnestic prodrome of Alzheimer’s disease.
        Brain. 1998; 121: 1601-1602
        • Hughes C.P.
        • Berg L.
        • Danziger W.L.
        • Coben L.A.
        • Martin R.L.
        A new clinical scale for the staging of dementia.
        Br J Psychiatry. 1982; 140: 566-572
        • Huizenga N.A.
        • Koper J.W.
        • de Lange P.
        • Pols H.A.
        • Stolk R.P.
        • Grobbee D.E.
        • et al.
        Interperson variability but intraperson stability of baseline plasma cortisol concentrations, and its relation to feedback sensitivity of the hypothalamo-pituitary-adrenal axis to a low dose of dexamethasone in elderly individuals.
        J Clin Endocrinol Metab. 1998; 83: 47-54
        • Ivnik R.J.
        • Malec J.F.
        • Tangalos E.G.
        • Petersen R.C.
        • Kokmen E.
        • Kurland L.
        The Auditory-Verbal Learning Test (AVLT).
        Psychological Assessment. 1990; 2: 304-312
        • Jack Jr, C.R.
        • Petersen R.C.
        • Xu Y.
        • O’Brien P.C.
        • Smith G.E.
        • Ivnik R.J.
        • et al.
        Rates of hippocampal atrophy correlate with change in clinical status in aging and AD.
        Neurology. 2000; 55: 484-489
        • Kaplan E.
        • Berg L.
        • Danziger W.L.
        • Coben L.A.
        • Martin R.L.
        WAIS-R, manual. WAIS-R as a neuropsychological instrument. 1991; (San Antonio, TX.)
        • Kier E.L.
        • Kim J.H.
        • Fulbright R.K.
        • Bronen R.A.
        Embryology of the human fetal hippocampus.
        AJNR Am J Neuroradiol. 1997; 18: 525-532
        • Lezak M.
        Neuropsychological assessment. 3rd ed. Oxford University Press, New York1995
        • Lupien S.J.
        • de Leon M.
        • de Santi S.
        • Convit A.
        • Tarshish C.
        • Nair N.P.V.
        • et al.
        Cortisol levels during human aging predict hippocampal atrophy and memory deficits.
        Nature Neurosci. 1998; 1: 69-73
        • Lupien S.J.
        • Lepage M.
        Stress, memory, and the hippocampus.
        Behav Brain Res. 2001; 127: 137-158
        • McEwen B.S.
        Stress and the aging hippocampus.
        Front Neuroendocrinol. 1999; 20: 49-70
        • McEwen B.S.
        The neurobiology of stress.
        Brain Res. 2000; 886: 172-189
        • McEwen B.S.
        • de Leon M.J.
        • Lupien S.J.
        • Meaney M.J.
        Corticosteroids, the Aging Brain and Cognition.
        Trends in Endocrinology and Metabolism. 1999; : 92-96
        • McKann G.
        • Drachman D.
        • Folstein M.
        • Katzman R.
        • Price D.
        • Stadlan E.M.
        Clinical diagnosis of Alzheimer’s disease.
        Neurology. 1984; 34: 939-944
        • Montgomery S.A.
        • Asberg M.
        A new depression scale designed to be sensitive to change.
        Br J Psychiatry. 1979; 134: 382-389
        • Newcomer J.W.
        • Craft S.
        • Hershey T.
        • Askin K.
        • Bardgett M.E.
        Glucocorticoid-induced impairment in declarative memory performance in adult humans.
        J Neurosci. 1994; 14: 2047-2053
        • Näsman B.
        • Olsson T.
        • Viitanen M.
        • Carlstrom K.
        A subtle disturbance in the feedback regulation of the hypothalamic-pituitary-adrenal axis in the early phase of Alzheimer’s disease.
        Psychoneuroendocrinology. 1995; 20: 211-220
        • O’Brien J.T.
        • Ames D.
        • Schweitzer I.
        • Colman P.
        • Desmond P.
        • Tress B.
        Clinical and magnetic resonance imaging correlates of hypothalamic-pituitary-adrenal axis function in depression and Alzheimer’s disease.
        Br J Psychiatry. 1996; 168: 679-687
        • Rasmuson S.
        • Andrew R.
        • Nasman B.
        • Seckl J.R.
        • Walker B.R.
        • Olsson T.
        Increased glucocorticoid production and altered cortisol metabolism in women with mild to moderate Alzheimer’s disease.
        Biol Psychiatry. 2001; 49: 547-552
        • Reagan L.P.
        • McEwen B.S.
        Controversies surrounding glucocorticoid-mediated cell death in the hippocampus.
        J Chem Neuroanat. 1997; 13: 149-167
        • Rey A.
        L’examen clinique en psychologie. Presses Universitaires de France, Paris1964
        • Rosen W.G.
        • Mohs R.C.
        • Davis K.L.
        A new rating scale for Alzheimer’s disease.
        Am J Psychiatry. 1984; 141: 1356-1364
        • Sanchez M.M.
        • Young L.J.
        • Plotsky P.M.
        • Insel T.R.
        Distribution of corticosteroid receptors in the rhesus brain.
        J Neurosci. 2000; 20: 4657-4668
        • Sapolsky R.M.
        • Krey L.C.
        • McEwen B.S.
        The neuroendocrinology of stress and aging.
        Endocr Rev. 1986; 7: 284-301
        • Sapolsky R.M.
        • Uno H.
        • Rebert C.S.
        • Finch C.E.
        Hippocampal damage associated with prolonged glucocorticoid exposure in primates.
        J Neurosci. 1990; 10: 2897-2902
        • Scheltens P.
        • Fox N.
        • Barkhof F.
        • De Carli C.
        Structural magnetic resonance imaging in the practical assessment of dementia.
        Lancet Neurol. 2002; 1: 13-21
        • Seckl J.R.
        • Olsson T.
        Glucocorticoid hypersecretion and the age-impaired hippocampus.
        J Endocrinol. 1995; 145: 201-211
        • Squire L.R.
        • Knowlton B.
        • Musen G.
        The structure and organisation of memory.
        Annu Rev Psychol. 1993; 44: 453-495
        • Starkman M.N.
        • Gebarski S.S.
        • Berent S.
        • Schteingart D.E.
        Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing’s syndrome.
        Biol Psychiatry. 1992; 32: 756-765
        • Starkman M.N.
        • Giordani B.
        • Berent S.
        • Schork M.A.
        • Schteingart D.E.
        Elevated cortisol levels in Cushing’s disease are associated with cognitive decrements.
        Psychosom Med. 2001; 63: 985-993
        • Starkman M.N.
        • Giordani B.
        • Gebarski S.S.
        • Schteingart D.E.
        Improvement in learning associated with increase in hippocampal formation volume.
        Biol Psychiatry. 2003; 53: 233-238
        • Swanwick G.R.
        • Kirby M.
        • Bruce I.
        • Buggy F.
        • Coen R.F.
        • Coakley D.
        • et al.
        Hypothalamic-pituitary-adrenal axis dysfunction in Alzheimer’s disease.
        Am J Psychiatry. 1998; 155: 286-289
        • Tulving E.
        Human memory.
        in: Andersen P. H.O. Paulsen O. Hökfelt B. Memory concept - 1993. Basic and clinical aspects. Elsevier, Amsterdam1993: 27-45
        • Tuvnes F.A.
        • Steffenach H.A.
        • Murison R.
        • Moser M.B.
        • Moser E.I.
        Selective hippocampal lesions do not increase adrenocortical activity.
        J Neurosci. 2003; 23: 4345-4354
        • Wechsler D.
        Wechsler adult intelligence scale - revised (WAIS-R). 1981; (New York.)
        • Wechsler D.
        Wechsler Memory Scale - Revised manual. 1987; (San Antonio, TX.)
        • West M.J.
        • Coleman P.D.
        • Flood D.G.
        • Troncoso J.C.
        Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer’s disease.
        Lancet. 1994; 344: 769-772
        • Vogels O.J.
        • Zijlmans J.C.
        • van’t Hof M.A.
        • Thijssen H.O.
        • Horstink M.W.
        MR volume estimation of subcortical brain lesions and ventricular cerebrospinal fluid.
        AJNR Am J Neuroradiol. 1995; 16: 1441-1445
        • Wolkowitz O.M.
        • Reus V.I.
        • Weingartner H.
        • Thompson K.
        • Breier A.
        • Doran A.
        • et al.
        Cognitive effects of corticosteroids.
        Am J Psychiatry. 1990; 147: 1297-1303