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Aging, Neurodegenerative Disease and the Brain

Published online by Cambridge University Press:  29 November 2010

Edith G. McGeer  and
Patrick L. McGeer
Edith G. McGeer
Affiliation:
University of British Columbia
Patrick L. McGeer
Affiliation:
University of British Columbia
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Abstract

The brain undergoes many changes in chemistry and structure during normal aging. For example, it dries and shrinks. Neurons are lost from some regions and there is also neuronal atrophy and loss of synaptic branching. The extent of such losses remains controversial for all but a few subcortical regions of the brain. Decreases in glucose metabolism and in some pre-and post-synaptic neurotransmitter indices have also been reported. Many systems, however, remain entirely unexplored. The evidence to date also indicates that there is great regional specificity in the effects, and that humans show considerable variability between individuals. Of interest is the fact that some of the changes most clearly demonstrated in normal aging - such as loss of dopaminergic neurons of the substantia nigra and cholinergic neurons of the medial basal forebrain - also occur in a much accentuated form in neurodegenerative diseases such as Parkinson's disease and Alzheimer disease. The small loss of these systems in normal aging may account for the shuffling gait, stooped posture and memory loss in the elderly. A phenomenon seen in neurodegenerative diseases, but not in normal aging, is the appearance of chronic inflammation in the brain. The suggestion that the progress of such diseases might be slowed by treatment with anti-inflammatory agents has, in the case of Alzheimer disease, gained some support from 19 epidemiological studies and one very small clinical trial. Clearly more detailed clinical trials are required, and caution must be used because of the undesirable side effects of currently available anti-inflammatory agents.

Résumé

L'eorganisation anatomique et chimique du cerveau humain subit de nombreux changements au cours du vieillissement. Certains neurons meurent, d'autres s'atrophient et ily a une réduction marquée du nombre de synapses dans des régions spécifiques du cerveau. Des diminutions du métabolisme du glucose et des effets pré- et post-synaptiques des neurotransmetteurs ont aussi été rapportées. À l'exception de certaines structures sous-corticales, il existe cependant une controverse quant à la sévérité des changements dans l'ensemble du cerveau. De plus, les effets du vieillissement sont très variables d'une région du cerveau à l'autre ainsi que d'un individu à l'autre. Certains phénomènes observès dans le vieillissement normal, tels la perte des neurones dopaminergique de la substance noire et celle des neurones cholinergiques du prosencé;phale basal, apparaissent sous une forme grandement exacerbées dans diverses pathologies neurodégénératives comme les maladies de Parkinson et d'Alzeimer. Les faibles altérations qui surviennent au niveau de ces systémes lors du vieillissement normal pourraient étre responsables des troubles d'équilibre, de la pauvreté de mouvement et des pertes de mémoires que l'on observent chez les gens âgés. Cependant, l'inflammation chronique du cerveau semble être une caractéristique typique des individus atteints de maladies neurodégénératives. L'hypothèse voulant que cette inflammation puisse être ralentie par un traitement avec des agents anti-inflammatoires a été supportée par les résultats de 19 études épidémiologiques ainsi que par un essai clinique de moindre envergure. Cependant, d'Autres études cliniques devront ètre réalisées et une attention particulière devra être portée aux effets secondaires de la thérapie anti-inflammatoire conventionnelle afin d'en arriver à une conclusion définitive.

Keywords

InflammationAlzheimer DiseaseNeurotransmittersDopamineParkinson's DiseasePick's DiseaseDiffuse Lewy Body DiseaseComplementInflammationmaladie d'Alzheimerneurotransmetteursdopaminemaladie de Parkinsonmaladie de Pickmaladie diffuse du corps de Lewycomplement
Type
Articles
Information
Canadian Journal on Aging / La Revue canadienne du vieillissement , Volume 16 , Issue 2 , Été/Summer 1997 , pp. 218 - 236
Copyright
Copyright © Canadian Association on Gerontology 1997

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References

1.Brayne, C.Research and Alzheimer's disease: an epidemiological perspective. Psychol Med. 1993, 23, 287–296.CrossRefGoogle ScholarPubMed
2.Calne, D.B., Eisen, A., Meneilly, G.Normal aging of the nervous system. Ann Neurol. 1991, 30, 206–207.CrossRefGoogle ScholarPubMed
3.Coffey, C.E., Wilkinson, W.E., Parashos, L.A., Soady, S.A.R., Sullivan, R.J., Patterson, L.J., Figiel, G.S., Webb, M.C., Spritzer, C.E., Djang, W.T.Quantitative cerebral anatomy of the aging human brain: a cross-sectional study using magnetic resonance imaging. Neurology. 1992, 42, 527–536.CrossRefGoogle Scholar
4.Kaye, J.A., DeCarlie, C., Luxenberg, J.S., Rapoport, S.I.The significnace of age-related enlargement of the cerbral ventricles in healthy men and women measured by quantitative computed x-ray tomography. J Am Gertiatric Soc. 1992, 40, 225–231.CrossRefGoogle Scholar
5.Leuchter, A.F., Dunkin, J.J., Lufkin, R.B., Anzai, Y., Cook, I.A., Newton, T.F.Effect of white matter disease on functional connections in the aging brain. J Neurol Neurosurg Psychiat. 1994, 57, 1347–1354.CrossRefGoogle ScholarPubMed
6.Ylikowski, A., Erkinjuntti, T., Raininko, R., Sarna, S., Sulkava, R., Tilvis, R.White matter hyperintensities on MRI in the neurologically nondiseased elderly. Analysis of cohorts of consecutive subjects aged 55 to 85 years living at home. Stroke. 1995, 26, 1171–1177.CrossRefGoogle Scholar
7.DeCarli, C., Haxby, J.V., Gillette, J.A., Teichberg, D., Rapoport, S.I., Schapiro, M.B.Longitudinal changes in lateral ventricular volume in patients with dementia of the Alzheimer type. Neurology. 1992, 42, 2029–2036.Google ScholarPubMed
8.Davis, P.C., Gray, L., Albert, M., Wilkinson, W., Hughes, J., Heyman, A., Gado, M., Kumar, A.J., Destian, S., Lee, C., Duvall, E., Kido, D., Nelson, M.J., Bello, J., Westhers, S., Jolesz, F., Kikinis, R., Brooks, M.The consortium to establish a registry for Alzheimer's disease. Reliability of a standardized MRI evaluation of Alzheimer's disease. Neurology. 1992, 42, 1676–1680.CrossRefGoogle Scholar
9.Jobst, K.A., Smith, A.D., Szatmari, M., Esiri, M.M., Jaskowski, A., Hindley, N., McDonald, B., Molyneux, A.J.Rapidly progressing atrophy of medial temporal lobe in Alzheimer's disease. Lancet. 1994. 343, 829–830.CrossRefGoogle ScholarPubMed
10.Fox, N.C., Freeborough, P.A., Rossor, M.N.Visualization and quantification of rates of atrophy in Alzheimer's disase. Lancet. 1996, 348, 94–97.CrossRefGoogle Scholar
11.Goldman, J.E., Calingasan, N.Y., Gibson, G.E.Aging and the brain. Current Opin Neurol. 1994, 7, 287–293.CrossRefGoogle ScholarPubMed
12.Volkow, N.D., Ding, Y.S., Fowler, J.S., Wang, G.J., Gatley, S.J., Hitzemann, R., Smith, G., Fields, S.D., Gur, R.Dopamine transporters dcrease with age. J Nucl Med. 1996, 37, 554–559.Google Scholar
13.McGeer, P.L., McGeer, E.G., Suzuki, J.S.Aging and extrapyramidal function. Arch Neurol. 1977, 34, 33–35.CrossRefGoogle ScholarPubMed
14.Brody, H. An examination of cerebral cortex and brain stem in aging. In: Terry, AD & Gershon, S (eds), Neurobiology of Aging, vol. 3. New York: Raven Press, 1976, 177–181.Google Scholar
15.Palmer, A.M., DeKosky, S.T.Monamine neurons in aging and Alzheimer's disease. J Neural Transmiss Gen Sect. 1993, 91, 135–159.CrossRefGoogle Scholar
16.Hsu, H.K., Peng, M.T.Hypothalamic neuron number of old female rats. Gerontology. 1978, 24, 434–440.CrossRefGoogle ScholarPubMed
17.Vijayashankar, N., Brody, H.Aging in the human brainstem: a study of the nucleus of the trochlear nerve. Acta Anat. 1977, 99, 169–172.CrossRefGoogle ScholarPubMed
18.Bugiani, O., Salvarani, S., Perdelli, F., Mancardi, G.L., Leonardi, A.Nerve cell loss with aging in the putamen. Eur Neurol. 1978, 17, 286–293.CrossRefGoogle ScholarPubMed
19.McGeer, P.L.Aging, Alzheimer's disease and the cholinergic system. Can J Physiol Pharmacol. 1984, 62, 741–754.CrossRefGoogle ScholarPubMed
20.Bartus, R.T., Dean, R.L., Beer, B., Lippa, A.S.The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982, 217, 408–417.CrossRefGoogle ScholarPubMed
21.Finch, C.Neuron atrophy during aging: programmed or sporadic? Trends Neurosci. 1993, 16, 104–110.CrossRefGoogle ScholarPubMed
22.Masliah, E., Mallory, M., Hansen, L., DeTeresa, R., Terry, R.D.Quantitative synaptic alterations in the human neocortex during normal aging. Neurology. 1993, 43, 192–197.CrossRefGoogle ScholarPubMed
23.Eastwood, S.L., Burnet, P.W., McDonald, B., Clinton, J., Harrison, P.J.Synaptophysin gene expression in human brain: a quantitative in situ hybridization and immunocytochemical study. Neuroscience. 1994, 59, 881–892.CrossRefGoogle Scholar
24.McGeer, E.G., McGeer, P.L. Neurotransmitters in normal aging. In: Platt, D (ed), Geriatrics I. Berlin, Heidelberg, New York: Springer-Verlag. 1982, 263–282.CrossRefGoogle Scholar
25.Fulop, T. Jr., Seres, I.Age-related changes in signal transduction. Implications for neuronal transmission and potential for drug intervention. Drugs & Aging. 1994, 5, 366–390.CrossRefGoogle ScholarPubMed
26.Roth, G.S., Joseph, J.A.Cellular and molecular mechanisms of impaired dopaminergic function during aging. Ann NY Acad Sci. 1994, 719, 129–135.CrossRefGoogle ScholarPubMed
27.Waldemar, G.Functional brain imaging with SPECT in normal aging and dementia, methodological, pathophysiological and diagnostic aspects. Cerebrovas & Brain Metab Rev. 1995, 7, 89–130.Google ScholarPubMed
28.McGeer, R.G., Peppard, R.P., McGeer, P.L., Tuokko, T., Crockett, D., Parks, R., Akiyama, H., Calne, D.B., Beattie, B.L., Harrop, R.18 Fluorodeoxyglucose positron emission tomography studies in presumed Alzheimer cases, including 13 serial scans. Can J Neurol Sci. 1990, 17, 1–11.CrossRefGoogle Scholar
29.McGeer, E.G., McGeer, P.L., Harrop, R., Akiyama, H., Kamo, H.Correlations of regional postmortem enzyme activities with premortem local metabolic rates in Alzheimer's disease. J Neurosci. Res. 1990, 27, 6, 210–218.CrossRefGoogle ScholarPubMed
30.Hoyer, S.Age-related changes in cerebral oxidative metabolis. Implications for therapy. Drugs & Aging. 1995, 6, 136–149.CrossRefGoogle Scholar
31.Jin, L.W., Saitoh, T.Changes in protein kinases in brain aging and Alzheimer's disease. Implications for drug therapy. Drugs & Aging. 1995, 6, 136–149.CrossRefGoogle ScholarPubMed
32.Roth, G.S., Joseph, J.A., Mason, R.P.Membrane alterations as causes of impaired signal transduction in Alzheimer's disease and aging. Trends Neurosci. 1995, 18, 203–206.CrossRefGoogle Scholar
33.Ames, B.N., Sigenaga, M.K., Hagen, T.M.Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci U.S.A. 1993, 90, 7915–7922.CrossRefGoogle ScholarPubMed
34.Eze, M.O.Membrane fluidity, reactive oxygen species, and cell-mediated immunity: implications in nutrition and disease. Med Hypotheses. 1992, 37, 220–224.CrossRefGoogle ScholarPubMed
35.Tooyama, I., McGeer, E.G., Kawamata, T., Kimura, H., McGeer, P.L.Retention of bFGF immunoreactivity in dopaminergic neurons of the substantia nigra during normal aging in humans contrasts with loss in Parkinson's disease. Brain Res. 1994, 656, 165–168.CrossRefGoogle ScholarPubMed
36.Sutcliffe, J.G., Milner, R.J.Brain specific gene expression. Trends Biochem Sci. 1984, 9, 95–99.Google Scholar
37.McGeer, P.L., McGeer, E.G.The inflammatory response system of brain: Implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res. 1995, 21, 195–218.CrossRefGoogle ScholarPubMed
38.Haass, C.The molecular significance of amyloid beta-peptide for Alzheimer's disease. Eur Arch Psychiatry & Clin Neurosci. 1996, 246, 118–123.CrossRefGoogle ScholarPubMed
39.Selkoe, D.J.Amyloid beta-protein and the genetics of Alzheimer's disease. J Biol Chem. 1996, 271, 18295–18298.CrossRefGoogle ScholarPubMed
40.Goedert, M.Tau protein and the neurofibrillary pathology of Alzheimer's disease. Ann NY Acad Sci. 1996, 777, 121–131.CrossRefGoogle ScholarPubMed
41.Iqbal, K., Grundke-Iqbal, I.Molecular mechanism of Alzheimer's neurofibrillary degeneration and therapeutic intervention. Ann NY Acad Sci. 1996, 777, 132–138.CrossRefGoogle ScholarPubMed
42.McGeer, E.G., McGeer, P.L. Neurodegeneration and the immune system. In: Cable, DB (ed.), Neurodegenerative Disorders. Philadelphia: WB Saunders, 1994, 277–300.Google Scholar
43.McGeer, P.L., Rogers, J., McGeer, E.G.Neuroimmune mechanisms in Alzheimer disease pathogenesis. Alz Dis Assocd Disord. 1984, 8, 149–165.CrossRefGoogle Scholar
44.McGeer, P.L., Rogers, J.Anti-inflammatory agents as a therapeutic approach to Alzheimer's disease. Neurology. 1992, 42, 447–449.CrossRefGoogle ScholarPubMed
45.Ohm, T.G., Muller, H., Braak, H., Bohl, J.Close-meshed prevalance rates of different stages as a tool to uncover the rate of Alzheimer's disease-related neurofibrillary changes. Neuroscience. 1995, 64, 209–217.CrossRefGoogle ScholarPubMed
46.Helmes, E., Merskey, H., Fox, H., Fry, R.N., Bowler, J.V., Hachinski, V.C.Patterns of deterioration in senile dementia of the Alzheimer type. Arch Neurol. 1995, 52, 306–310.CrossRefGoogle ScholarPubMed
47.Schellenberg, G.D.Progress in Alzheimer's disease genetics. Curr Opin Neurol. 1995, 8, 262–267.CrossRefGoogle ScholarPubMed
48.Wisniewski, T., Frangione, B.Molecular biology of brain aging and neurodegenerative disorders. Acta Neurobiol Experiment. 1996, 56, 267–279.CrossRefGoogle ScholarPubMed
49.Rother, K., Till, G.O. (eds.). The Complement System. Berlin, Heidelberg: Springer-Verlag.Google Scholar
50.Eikelenboom, P., Hack, C.E., Rozemuller, J.M., Stam, F.C.Complement activation in amyloid plaques in Alzheimer's dementia. Virchows Archiv B Cell Pathol. 1989, 56, 259–262.CrossRefGoogle ScholarPubMed
51.Ishii, T., Haga, S.Immuno-electron-microscopic localization of complements in amyloid fibrils of senile plaques. Acta Neuropathol. 1984, 63, 296–300.CrossRefGoogle ScholarPubMed
52.McGeer, P.L., Akiyama, H., Itagaki, S., McGeer, E.G.Immune system response in Alzheimer's disease. Can J Neurol Sci. 1989, 16, 516–527.CrossRefGoogle ScholarPubMed
53.Akiyama, H., McGeer, P.L.Brain microglia constitutively express β 2 integrins. J Neuroimmunol. 1990, 30, 81–93.CrossRefGoogle ScholarPubMed
54.Rozemuller, J.M., Eikelenboom, P., Pals, S.T., Stam, F.C.Microglial cells around amyloid plaqes in Alzheimer's disease express leucocyte adhesion molecules of the LFA-1 family. Neurosci Lett. 1989, 101, 288–292.CrossRefGoogle Scholar
55.Yasuhara, O., Aimi, Y., McGeer, E.G., McGeer, P.L.Expression of the complement membrane attack complex and its inhibitors in Pick disease brain. Brain Res. 1994, 652, 346–349.CrossRefGoogle ScholarPubMed
56.Bellavite, P.The superoxide-forming enzymatic system of phagocytes. Free Radical Biol & Med. 1988, 4, 225–261.CrossRefGoogle ScholarPubMed
57.Klegeris, A., Walker, D.G., McGeer, P.L.Activation of macrophages by Alzheimer β-Amyloid peptide. Biochem Biophys Res Commun. 1994, 199, 984–991.CrossRefGoogle ScholarPubMed
58.Akiyama, H., Tooyama, I., Kondo, H., Ikeda, K., Kimura, H., McGeer, E.G., McGeer, P.L.Early response of brain resident microglia to kainic acid-induced hippocampal lesions. Brain Res. 1994, 635, 257–268.CrossRefGoogle ScholarPubMed
59.Pasinetti, G.M., Johnson, S.A., Rozovsky, I., Lampert-Etchells, M., Morgan, D.G., Gordon, M.N., Morgan, T.E, Willoughby, D., Finch, C.E.Complement C1qB and C4 mRNAs responses to lesioning in rat brain. Exp Neurol. 1992, 118, 117–125.CrossRefGoogle ScholarPubMed
60.Rogers, J., Cooper, N.R., Webster, S., Schultz, J., McGeer, P.L., Styren, S., Civin, W.H., Brachova, L., Bradt, B., Ward, P., Leibeburg, I.Complement activation by β-amyloid in Alzheimer disease. Proc Natl Acad Sci USA. 1992, 89 10016–10020.CrossRefGoogle ScholarPubMed
61.Jiang, H., Burdick, D., Glabe, C.G., Cotman, C.W., Tenner, A.J.β-Amyloid activates complement by ninding to a specific region of the collagen-like domain of the C1q A chain. J Immunol. 1994, 152, 5050–5059.CrossRefGoogle ScholarPubMed
62.McGeer, P.L., Walker, D.G., Pitas, R.E., Mahley, R.W., McGeer, E.G.Apolipoprotein E4 (ApoE4) but not ApoE3 or ApoE2 potentiates beta-amyloid protein activation of complement in vitro. Brain Res. 1997, 749, 135–138.CrossRefGoogle ScholarPubMed
63.McGeer, P.L., McGeer, E.G., Rogers, J., Sibley, J.Anti-inflammatory drugs and Alzheimer disease. Lancet. 1990, 335, 1037.CrossRefGoogle ScholarPubMed
64.Heyman, A., Wilkinson, W.E., Stafford, J.A., Helms, M.J., Sigmon, A.H., Weinberg, T.Alzheimer's disease: a study of epidemiological aspects. Ann Neurol. 1984, 15, 335–341.CrossRefGoogle ScholarPubMed
65.French, L.R., Schuman, L.M., Mortimer, J.A., Hutton, J.T., Boatman, R.A., Chrimstians, B.A case-control study of dementia of the Alzheimer's type. Am J Epidemiol. 1985, 121, 414–421.CrossRefGoogle Scholar
66.Broe, G.A., Henderson, A.S., Creasey, H., McCusker, E., Korten, H.E., Jorm, A.F., Longley, W., Anthony, J.C.A case-control study of Alzheimer's disease in Australia. Neurology. 1990, 40, 1698–1707.CrossRefGoogle ScholarPubMed
67.Li, G., Shen, Y.C., Chen, C.H., Zhau, Y.W., Silverman, J.M.A case-control study of Alzheimer's disease in China. Neurology. 1992, 42, 1481–1482.CrossRefGoogle ScholarPubMed
68.Anon. Canadian Study of Health and Aging. Risk factors for Alzheimer's disease in Canada. Neurology. 1994, 44, 2073–2080.CrossRefGoogle Scholar
69.Breitner, J.C.S., Gau, B.A., Welsh, K.A., Plassman, B.L., McDonald, W.M., Helmas, M.J., Anthony, J.C.Inverse association of anti-inflammatory treatments and Alzheimer's disease. Neurology, 1994, 44, 227–232.CrossRefGoogle ScholarPubMed
70.Breitner, J.C.S., Welsh, K.A., Helms, M.J., Gaskell, P.C., Gau, B.A., Roses, A.D., Pericak-Vance, M.A., Saunders, A.M.Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Neurobiol Aging. 1995, 16, 523–530.CrossRefGoogle ScholarPubMed
71.Graves, A.B., White, E., Koepsell, T.D., Reifler, B.V., van Belle, G., Larson, E.B., Raskind, M.A case-control study of Alzheimer's disease. Ann Neurol. 1990, 28, 766–774.CrossRefGoogle ScholarPubMed
72.Jenkinson, M.I., Bliss, M.R., Brain, A.T., Scott, D.L.Rheumatoid arthritis and senile dementia of the Alzheimer's type. Brit J Rheumatol. 1989, 28, 86–87.CrossRefGoogle ScholarPubMed
73.Beard, CM., Kokmen, E., Kurland, L.T.Rheumatoid arthritis and susceptibility to Alzheimer's disease. Lancet. 1991, 337, 1426.CrossRefGoogle ScholarPubMed
74.Myllykangas-Luosuarvi, R., Isomaki, H.Alzheimer's disease and rheumatoid arthritis. Brit J Rheumatol. 1994, 33, 501–502.CrossRefGoogle Scholar
75.Lucca, U., Tettamanti, M., Forloni, G., Spagnoli, A.Nonsteroidal anti-inflammatory drug use in Alzheimer's disease. Biol Psychiatry. 1994, 36, 854–856.CrossRefGoogle ScholarPubMed
76.Andersen, K., Launer, L.J., Ott, A., Hoes, A.W., Breteler, M.M.B., Hofman, A.Do nonsteroidal antiinflammatory drugs decrease the risk of Alzheimer's disease? Neurology. 1995, 45, 1441–1445.CrossRefGoogle Scholar
77.McGeer, P.L., Harada, N., Kimura, H., McGeer, E.G., Schulzer, M.Prevalence of dementia amongst elderly Japanese with leprosy: apparent effect of chronic drug therapy. Dementia. 1992, 3, 146–149.Google Scholar
78.Anon. Canadian Study of Health and Aging: study methods and prevalence of dementia. Can Med Assoc J. 1994, 150, 899–913.Google Scholar
79.Corrada, M., Stewart, W., Kawas, C.Nonsteroidal anti-inflammatory drugs and the risk of Alzheimer's disease. Neurology Abstract. 1996, P06 015.Google Scholar
80.McGeer, P.L., Schulzer, M., McGeer, E.G.Arthritis and antiinflammatory agents as possible protective factors for Alzheimer disease: A review of seventeen epidemiological studies. Neurology. 1996, 47, 425–432.CrossRefGoogle Scholar
81.Roses, A.D.Apolipoprotein E alleles as risk factors in Alzheimer's disease. Ann Rev Med. 1996, 47, 387–400.CrossRefGoogle ScholarPubMed
82.Rich, J.B., Rasmusson, D.X., Folstein, M.F., Carson, K.A., Kawas, C., Brandt, J.Nonsteroidal anti-inflammatory drugs in Alzheimer's disease. Neurology. 1995, 45, 51–55.CrossRefGoogle ScholarPubMed
83.Doraiswamy, P.M., Krishen, A., Stallone, F., Martin, W.L., Potts, N.L.S., Metz, A., DeVeaugh-Geiss, J.NSAIDs and cognition in Alzheimer's disease. Neurology. 1996, 46.Google ScholarPubMed
84.Rogers, J., Kirby, L.C., Hempelman, S.R., Berry, D.L., McGeer, P.L., Kaszniak, A.W., Zalinski, J., Cofield, M., Mansukhani, L., Willson, P., Kogan, F.Clinical trial of indomethacin in Alzheimer's disease. Neurology. 1993, 43, 1609–1611.CrossRefGoogle ScholarPubMed
85.Landfield, P.W., Eldridge, J.C.Increased affinity of type II corticosteroid binding in aged rat hippocampus. Exp Neurol. 1989, 106, 110–113.CrossRefGoogle ScholarPubMed
86.Lewis, D.A., Smith, R.E.Steroid-induced psychiatric syndromes. J Affect Disord. 1983, 5, 319–332.CrossRefGoogle ScholarPubMed
87.Fries, J.F.NSAID gastropathy: the second most deadly rheumatic disease? Epidemiology and risk appraisal. J Rheumatol. 1991, 18 (supp. 28), 6–10.Google Scholar
88.Graham, D.Y., Agrawal, N.M., Roth, S.H.Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial. Lancet. 1988, ii, 1277–1280.CrossRefGoogle Scholar