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Cognitive Enhancement Therapy for Alzheimer’s Disease

The Way Forward

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Summary

Although at present there is no definitive treatment or cure for Alzheimer’s disease, different pharmacological strategies are being actively investigated. At present, cholinergic therapy and nootropics and some neuronotrophic agents represent the available approaches to symptomatic treatment of Alzheimer’s disease. The use of cholinesterase inhibitors (ChEI) constitutes the best cholinergic approach to increase acetylcholine levels. Available data suggest that about 15 to 40% of Alzheimer’s disease patients show a varying degree of cognitive improvement while taking these medications; however, haematological complications (neutropenia or agranulocytosis), together with hepatotoxicity, need to be considered carefully. Recent data suggest that long term administration of nootropics may lead to a significant improvement of cognitive functions in Alzheimer’s disease patients compared with untreated individuals, having excellent tolerability. Protocols for the intracerebroventricular administration of neuronotrophic substances are also ongoing.

The most promising approaches for the future currently undergoing investigation involve attempts to slow the production of β-amyloid and/or to inhibit β-amyloid aggregation. Another rational therapeutic approach would be to inhibit the formation of paired helical filaments (PHF) by increasing and/or modulating the activities of protein phosphatases and kinases. Antioxidant therapy should disrupt or prevent the free radical/β-amyloid recirculating cascade and the progressive neurodegeneration. Idebenone, a synthetic compound acting as an ‘electron trapper’ and free radical scavenger, has shown some efficacy in degenerative and vascular dementia; at present, other different molecules having antioxidative properties [lazaroids (21-aminosteroids), pyrrolopyrimidines, nitric oxide blockers, selegiline, some vitamins] are under investigation.

Lowering absorption or brain tissue concentrations of aluminium also offers possible therapeutic opportunities for slowing the rate of clinical progression of the disease; in this sense, some evidence exists using the aluminium chelating agent deferoxamine (desferrioxamine). Inflammation also may play a significant pathogenetic role in Alzheimer’s disease. As shown by several retrospective analyses, there is an inverse association of anti-inflammatory drug use with the frequency of Alzheimer’s disease diagnosis. Consequently, clinical trials using both nonsteroidal and steroidal molecules have been proposed. These lines of pharmacological intervention represent an important premise for future therapeutic strategies capable of counteracting the pathogenesis of Alzheimer’s disease.

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References

  1. Bush TL, Miller SR, Criqui MN, et al. Risk factors for morbidity and mortality in older population: an epidemiological approach. In: Hazzard WR, Bierman EL, Blass JP, et al., editors. Principles of geriatric medicine and gerontology. New York: McGraw Hill, 1994: 153–66

    Google Scholar 

  2. Keefover RW. The clinical epidemiology of Alzheimer’s disease. Neuroepidemiology 1996; 14: 337–51

    CAS  Google Scholar 

  3. Reisberg B, Ferris SH, de Leon MJ, et al. The stage specific temporal course of Alzheimer’s disease: functional and behavioral concomitants based upon cross-sectional and longitudinal observation. In: Iqbal K, Wisniewski HM, Winblad B, editors. Alzheimer’s disease and related disorders. New York: Alan R. Liss Inc., 1991:23–41

    Google Scholar 

  4. Bobinski M, Weigel J, Wisniewski HM, et al. Atrophy of hippocampal formation subdivisions correlates with stage and duration of Alzheimer disease. Dementia 1995; 6: 205–10

    PubMed  CAS  Google Scholar 

  5. Nitsch RM, Rebeck WG, Deng M, et al. Cerebrospinal fluid levels of amyloid beta-protein in Alzheimers disease: inverse correlation with severity of dementia and effect of apolipoprotein E genotype. Ann Neurol 1995; 37: 512–8

    Article  PubMed  CAS  Google Scholar 

  6. Cai X, Golde TE, Younkin SG, et al. Release of excess amyloid β protein from a mutant amyloid β protein precursor. Science 1993; 259: 514–6

    Article  PubMed  CAS  Google Scholar 

  7. Dyrks T, Dyrks E, Hartmann T, et al. Amyloidogenicity of β-A4 and βA4-bearing amyloid protein precursor fragments by metal-catalyzed oxidation. J Biol Chem 1992; 267: 18210–7

    PubMed  CAS  Google Scholar 

  8. Smith CD, Carney JM, Starke-Reed PE, et al. Excess brain protein oxidation and enzyme dysfunction in normal aging and Alzheimer disease. Proc Natl Acad Sci USA 1991; 88: 10540–3

    Article  PubMed  CAS  Google Scholar 

  9. Subbarao KV, Richardson JS, Ang LC. Autopsy samples of Alzheimers cortex show increased peroxidation in vitro. J Neurochem 1990; 55: 342–5

    Article  PubMed  CAS  Google Scholar 

  10. Hajimohammadreza I, Brammer M. Brain membrane fluidity and lipid peroxidation in Alzheimers disease. Neurosci Lett 1990; 112: 333–7

    Article  PubMed  CAS  Google Scholar 

  11. Lovell MA, Ehmann WD, Butler SM, et al. Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimers disease. Neurology 1995; 45: 1594–601

    Article  PubMed  CAS  Google Scholar 

  12. Mecocci P, MacGarvey U, Beal MF. Oxidative damage to mitochondrial DNA is increased in Alzheimers disease. Ann Neurol 1994; 36: 747–51

    Article  PubMed  CAS  Google Scholar 

  13. Kish SJ, Bergeron C, Rajput A, et al. Brain cytochrome oxidase in Alzheimers disease. J Neurochem 1992; 59: 776–9

    Article  PubMed  CAS  Google Scholar 

  14. Mutisya EM, Bowling AC, Beal ME. Cortical cytochrome oxidase activity is reduced in Alzheimers disease. J Neurochem 1994; 63: 2179–84

    Article  PubMed  CAS  Google Scholar 

  15. Benzi G, Moretti A. Are reactive oxygen species involved in Alzheimers disease? Neurobiol Aging 1995; 16: 661–74

    Article  PubMed  CAS  Google Scholar 

  16. Halliwell B, Gutteridge JMC. Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol 1990; 186: 1–85

    Article  PubMed  CAS  Google Scholar 

  17. Saunders RD, Luttman CA, Keith PT, et al. Beta-amyloid protein potentiates H2O2-induced neuron degeneration in vitro [abstract]. Soc Neurosci Abstr 1991; 17: 1447

    Google Scholar 

  18. Rogers J. Inflammation as a pathogenic mechanism in Alzheimers disease. Arztl Forsch 1995; 45: 439–42

    CAS  Google Scholar 

  19. Rogers J, Cooper NR, Webster S, et al. Complement activation by beta-amyloid in Alzheimer’s disease. Proc Natl Acad Sci USA 1992; 89: 10016–20

    Article  PubMed  CAS  Google Scholar 

  20. Snow AD, Sekiguchi R, Nochlin D, et al. An important role of heparan sulfate proteoglycan (Perlecan) in a model system for the deposition and persistence of fibrillar A beta-amyloid in rat brain. Neuron 1994; 12: 219–34

    Article  PubMed  CAS  Google Scholar 

  21. Altstiel L, Sperber K. Cytokines in Alzheimers disease. Prog Neuropsychopharmacol Biol Psychiatry 1991; 15: 481–95

    Article  PubMed  CAS  Google Scholar 

  22. Donnelly RJ, Friedhoff AJ, Beer B, et al. Interleukin-1 stimulates the beta-amyloid precursor protein promoter. Cell Mol Neurobiol 1990; 10: 485–95

    Article  PubMed  CAS  Google Scholar 

  23. Summers KL, Cuadra G, Naritoku D, et al. Effects of nicotine levels on acetylcholine and biogenic amines in rat cortex. Drug Dev Res 1994; 31: 108–19

    Article  CAS  Google Scholar 

  24. Cuadra G, Giacobini E. Effects of cholinesterase inhibitors and clonidine coadministration on rat cortex neurotransmitters in vivo. J Pharmacol Exp Ther 1995; 275: 228–36

    PubMed  CAS  Google Scholar 

  25. Janson AM, Moller A. Chronic nicotine treatment counteracts nigral cell loss induced by a partial mesiodiencephalic hemitransection: an analysis of the total number and mean volume of neurons and glia in substantia nigra of the male rat. Neuroscience 1993; 4: 931–41

    Article  Google Scholar 

  26. Sjak-shie NN, Burks JN, Meyer EM. Long-term actions on nicotinic receptor stimulation in nucleus basalis lesioned rats: blockade of trans-synaptic cell loss. In: Nagatsu T, Fisher A, Yoshida M, editors. Advances in behavioral biology. Vol. 2. New York: Plenum Press, 1990: 471–5

  27. Nitsch RM, Farber SA, Growdon JH, et al. Release of amyloid β-protein precursor derivatives by electrical depolarization of rat hippocampal slices. Proc Natl Acad Sci USA 1993; 90: 5191–3

    Article  PubMed  CAS  Google Scholar 

  28. Buxbaum JD, Oishi M, Chen HI, et al. Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer β/A4 amyloid protein precursor. Proc Natl Acad Sci USA 1992; 89: 10075–8

    Article  PubMed  CAS  Google Scholar 

  29. Lindfors N, Ernfors P, Falkenberg T, et al. Septal cholinergic afferents regulate expression of brain-derived neurotrophic factor and beta-nerve growth factor mRNA in rat hippocampus. Exp Brain Res 1992; 88: 78–90

    Article  Google Scholar 

  30. Berzaghi M, Cooper J, Castren E, et al. Cholinergic regulation of brain-derived neurotrophic factor and nerve growth factor but not neurotrophin-3 mRNA levels in the developing rat hippocampus. J Neurosci 1993; 13: 3818–26

    CAS  Google Scholar 

  31. Kumar V. Introduction to cholinesterase inhibitors used in Alzheimer’s disease therapy. In: Giacobini E, Becker RE, editors. Alzheimer’s disease: therapeutic strategies. Boston: Birkhäuser, 1994: 99–102

    Google Scholar 

  32. Becker RE, Giacobini E. Mechanisms of cholinesterase inhibition in senile dementia of the Alzheimer type: clinical, pharmacological, and therapeutic aspects. Drug Dev Res 1988; 12: 163–95

    Article  CAS  Google Scholar 

  33. Kumar V, Becker RE. Clinical pharmacology of tetra-hydroaminoacridine: a possible therapeutic agent for Alzheimer’s disease. Int J Pharmacol Toxicol 1989; 27: 478–85

    CAS  Google Scholar 

  34. Kumar V, Calache M. Treatment of Alzheimer disease with cholinergic drugs. Int J Clin Pharmacol Ther Toxicol 1991; 29: 25–37

    Google Scholar 

  35. Bierer LM, Aisen PS, Davidson M, et al. A pilot study of oral physostigmine plus yohimbine in patients with Alzheimer’s disease. Alz Dis Assoc Disord 1993; 7: 98–104

    Article  CAS  Google Scholar 

  36. Gauthier S, Bouchard R, Lamontagne A, et al. Tetrahydro-aminoacridine-lecithin combination treatment in patients with intermediate-stage Alzheimer’s disease. N Engl J Med 1990; 322(18): 1272–6

    Article  PubMed  CAS  Google Scholar 

  37. Wurtman RJ, Blusztajn JK, Growdon JH, et al. Cholinesterase inhibitors increase the brain’s need for free choline. In: Giacobini E, Becker R, editors. Current research in Alzheimer’s therapy. New York: Taylor and Francis, 1988: 95–100

    Google Scholar 

  38. Wilcock GK, Harrold PL. Treatment of Alzheimer’s disease: future directions. Acta Neurol Scand 1996; suppl. 165: 128–36

  39. Becker R, Moriearty P, Unni L. The second generation of cholinesterase inhibitors: clinical and pharmacological effects. In: Becker RE, Giacobini E, editors. Cholinergic basis for Alzheimer therapy. Boston: Birkhäuser, 1991: 263–96

    Google Scholar 

  40. Summers WK, Majovski LV, Marsh GM, et al. Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. N Engl J Med 1986; 315: 1241–5

    Article  PubMed  CAS  Google Scholar 

  41. Eagger SA, Levy R, Sahakian BJ. Tacrine in Alzheimer’s disease. Lancet 1991; 337: 989–92

    Article  PubMed  CAS  Google Scholar 

  42. Davis KL, Thal LJ, Gamzu ER, et al. A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer’s disease. N Engl J Med 1992; 327: 1253–9

    Article  PubMed  CAS  Google Scholar 

  43. Farlow M, Gracon SI, Hershey LA, et al. A controlled trial of tacrine in Alzheimer’s disease. JAMA 1992; 268: 2523–9

    Article  PubMed  CAS  Google Scholar 

  44. Wilcock GK, Surmon DJ, Scott M, et al. An evaluation of the efficacy and safety of tetrahydroaminoacridine (THA) without lecithin in the treatment of Alzheimer’s disease. Age Aging 1993; 22: 316–24

    Article  CAS  Google Scholar 

  45. Knapp MJ, Knopman DS, Solomon PR, et al. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. JAMA 1994; 271: 985–91

    Article  PubMed  CAS  Google Scholar 

  46. Eagger SA, Richards M, Levy R. Long-term effects of tacrine in Alzheimers disease: an open study. Int J Geriatr Psychiatry 1994; 9: 643–7

    Article  Google Scholar 

  47. The tacrine experience [editorial]. Eur J Neurol 1996; 3: S1-8

    Google Scholar 

  48. Brufani M, Mara M, Pomponi M. Anticholinesterase activity of a new carbamate, heptylphysostigmine, in view of its use in patients with Alzheimer-type dementia. Eur J Biochem 1986; 157: 115–20

    Article  PubMed  CAS  Google Scholar 

  49. Canal N, Imbimbo B, for the Eptastigmine Study Group. Clinical trial and therapeutics: relationship between pharmacodynamic activity and cognitive effects of eptastigmine in patients with Alzheimer’s disease. Clin Pharmacol Ther 1996; 60: 218–28

    Article  PubMed  CAS  Google Scholar 

  50. Canal N, Franceschi M, Italian Eptastigmine Investigators: Eptastigmine (MF-201). A double-blind, placebo-controlled, clinical trial in Alzheimer disease patients. In: Giacobini E, Becker R, editors. Alzheimer disease: therapeutic strategies. Boston: Birkhäuser, 1994: 108–12

    Google Scholar 

  51. Siegfred K. The pharmacodynamics of velnacrine: results and conclusion from clinical studies in healthy subjects and patients with Alzheimer’s disease. In: Wilcock GK, editor. The management of Alzheimer’s disease. Wrightson Biomedical Publishing, 1993: 189–201

  52. Siegfred K, Civil R. Clinical update of velnacrine research. In: Giacobini E, Becker R, editors. Alzheimer disease: therapeutic strategies. Boston: Birkhäuser, 1994: 150–4

    Google Scholar 

  53. Moore MJ, Clipp EC. Alzheimer’s disease and caregiver time. Lancet 1994; 343: 239–40

    Article  PubMed  CAS  Google Scholar 

  54. Rogers SL, Friedhoff LT. The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US multicenter, randomized, double-blind, placebo-controlled trial. Dementia 1996; 7: 293–303

    PubMed  CAS  Google Scholar 

  55. Enz A, Amstutz R, Boddeke H, et al. Brain selective inhibition of acetylcholinesterase: a novel approach to therapy for Alzheimer’s disease. Progr Brain Res 1993; 98: 431–8

    Article  CAS  Google Scholar 

  56. Croisile B, Trillet M, Fondarai J, et al. Long-term and high-dose piracetam treatment of Alzheimer’s disease. Neurology 1993; 43: 301–5

    Article  PubMed  CAS  Google Scholar 

  57. Senin U, Abate G, Fieschi C, et al. Aniracetam (Ro 13-5057) in the treatment of senile dementia of Alzheimer type (SDAT): results of a placebo controlled multicenter clinical study. Eur Neuropsychopharmacol 1991; 1: 511–7

    Article  PubMed  CAS  Google Scholar 

  58. Sabel BA, Slavin MD, Stein DG. GM1 ganglioside treatment facilitates behavioural recovery from bilateral brain damage. Science 1984; 225: 340–2

    Article  PubMed  CAS  Google Scholar 

  59. Svennerholm L, Gottfries CG. Membrane lipids selectively diminished in Alzheimer brains suggest synapse loss a primary event in early-onset form (Type I) and demyelination in late-onset form (Type II). J Neurochem 1994; 62: 1039–47

    Article  PubMed  CAS  Google Scholar 

  60. Svennerholm L, Gottfries CG, Blennow K, et al. Parenteral administration of GM1 ganglioside to presenile Alzheimers patients. Acta Neurol Scand 1990; 81: 45–53

    Google Scholar 

  61. Augustinsson LE, Blennow K, Blomstrand C, et al. Intracerebroventricular administration of GM 1 ganglioside to presenile Alzheimer patients. Dementia. In press

  62. Schubert D, Jin L-W, Saitoh T, Cole G. The regulation of amyloid beta precursor protein and its modulatory role in cell adhesion. Neuron 1989; 3: 689–94

    Article  PubMed  CAS  Google Scholar 

  63. Milward EA, Papadopoulos R, Fuller SJ, et al. The amyloid protein precursor of Alzheimer’s disease is a mediator of the effects of nerve growth factor on neurite outgrowth. Neuron 1992; 9: 129–37

    Article  PubMed  CAS  Google Scholar 

  64. Mattson MP, Cheng B, Culwell AR, et al. Evidence for excitoprotective and intraneuronal calcium-regulating. Neuron 1993; 10: 243–54

    Article  PubMed  CAS  Google Scholar 

  65. Nitsch RM, Growdon JH. Role of neurotransmission in the regulation of amyloid β-protein precursor processing. Biochem Pharmacol 1994; 47: 1275–84

    Article  PubMed  CAS  Google Scholar 

  66. Morel A, O’Carroll A-M, Brownstein MJ, et al. Molecular cloning and expression of a rat V1a arginine vasopressin receptor. Nature 1992; 356: 523–6

    Article  PubMed  CAS  Google Scholar 

  67. McEachern AE, Shelton ER, Bhaka S, et al. Expression cloning of a rat B2 bradykinin receptor. Proc Natl Acad Sci USA 1991; 88: 7724–8

    Article  PubMed  CAS  Google Scholar 

  68. Nitsch RM, Wurtman RJ, Growdon JH. Regulation of proteolytic processing of the amyloid β-protein precursor by first messengers. A novel potential approach for the treatment of Alzheimer’s disease. Arztl Forsch 1995; 45: 435–8

    CAS  Google Scholar 

  69. Li K. The role of β-amyloid in the development of Alzheimer’s disease. Drugs Aging 1995; 7: 97–109

    Article  Google Scholar 

  70. Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 1993; 90: 1977–81

    Article  PubMed  CAS  Google Scholar 

  71. Mattson MP, Cheng B, David D, et al. Beta-amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 1992; 12: 376–89

    PubMed  CAS  Google Scholar 

  72. Arispe N, Roja E, Pollard HB. Alzheimer’s disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc Natl Acad Sci USA 1993; 90: 567–71

    Article  PubMed  CAS  Google Scholar 

  73. Copani A, Koh JY, Cotman CW. Beta-amyloid increases neuronal susceptibility to injury by glucose deprivation. Neurol Rep 1991; 2: 763–5

    CAS  Google Scholar 

  74. Dickson DW, Rogers J. Neuroimmunology of Alzheimer’s disease: a conference report. Neurobiol Aging 1992; 13: 793–8

    Article  PubMed  CAS  Google Scholar 

  75. Dickson DW, Farlo J, Davies P, et al. Alzheimer’s disease: a double-labeling immunohistochemical study of senile plaques. Am J Pathol 1988; 132: 86–101

    PubMed  CAS  Google Scholar 

  76. Grundke-Iqbal I, Iqbal K, Quinlan M, et al. Microtubule-associated protein tau: a component of Alzheimer paired helical filaments. J Biol Chem 1986; 261: 6084–9

    PubMed  CAS  Google Scholar 

  77. Grundke-Iqbal I, Iqbal K, Tung Y-C, et al. Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986; 83: 4913–7

    Article  PubMed  CAS  Google Scholar 

  78. Iqbal K, Grundke-Iqbal I, Smith AJ, et al. Identification and localization of a tau peptide to paired helical filaments of Alzheimer’s disease. Proc Natl Acad Sci USA 1989; 86: 5646–50

    Article  PubMed  CAS  Google Scholar 

  79. Papasozomenos SCh, Su Y. Rapid dephosphorylation of × in heat-shocked fetal rat cerebral expiants: prevention and hyperphosphorylation by inhibitors of protein phosphatases PP1 and PP2A. J Neurochem 1995; 65: 396–406

    Article  PubMed  CAS  Google Scholar 

  80. Shimohama S, Fujimoto S, Taniguchi T, et al. Reduction of low-molecular-weight acid phosphatase activity in Alzheimer’s brains. Ann Neurol 1993; 33: 616–21

    Article  PubMed  CAS  Google Scholar 

  81. Saito T, Ishiguro K, Uchida T, et al. In situ dephosphorylation of tau by protein phosphatase 2A and 2B in fetal rat primary cultured neurons. FEBS Lett 1995; 376: 238–42

    Article  PubMed  CAS  Google Scholar 

  82. Fleming LM, Johnson GVW. Modulation of the phosphorylation state of tau insitu:the roles of calcium and cyclic AMP. BiochemJ 1995; 309: 41–7

    CAS  Google Scholar 

  83. Jin LW, Saitoh T. Changes in protein kinases in brain aging and Alzheimers disease: implications for drug therapy. Drugs Aging 1995; 6: 136–49

    Article  PubMed  CAS  Google Scholar 

  84. Masliah E, Cole G, Shimohama S, et al. Differential involvement of protein kinase C isozymes in Alzheimers disease. J Neurosci 1990; 10: 2113–24

    PubMed  CAS  Google Scholar 

  85. Greenberg SM, Kosik KS. Secreted β-APP stimulates MAP kinase and phosphorylation of tau in neurons. Neurobiol Aging; 16: 403–8

  86. Richardson JS, Subbarau KV, Ang LC. Autopsy Alzheimer’s brains show increased peroxidation to an in vitro iron challenge. In: Iqbal K, McLachlan DRC, Winblad B, et al., editors. Alzheimer’s disease: basic mechanisms, diagnosis and therapeutic strategies. Chichester: John Wiley and Sons, 1991: 145–52

    Google Scholar 

  87. Gotz ME, Freyberger A, Hauer E, et al. Susceptibility of brains from patients with Alzheimer’s disease to oxygen-stimulated lipid peroxidation and differential scanning colorimetry. Dementia 1992; 3: 213–22

    Google Scholar 

  88. Murakami M, Zs-Nagy I. Superoxide radical scavenging activity of idebenone in vitro studied by ESR spin trapping method and direct ESR measurement at liquid nitrogen temperature. Arch Gerontol Geriatr 1990; 11: 199–214

    Article  PubMed  CAS  Google Scholar 

  89. Zs-Nagy I, Floyd RA. ESR spin trapping studies on the OH free radical reactions of idebenone. Arch Gerontol Geriatr 1990; 11: 215–31

    Article  PubMed  CAS  Google Scholar 

  90. Senin U, Parnetti L, Barbagallo-Sangiorgi G, et al. Idebenone in senile dementia of Alzheimer type: a multicentre study. Arch Gerontol Geriatr 1992; 15: 249–60

    Article  PubMed  CAS  Google Scholar 

  91. Nappi G, Bono G, Merlo P, et al. Long-term idebenone treatment of vascular and degenerative brain disorders of the elderly. Arch Gerontol Geriatr 1992; 15: 261–9

    Article  PubMed  CAS  Google Scholar 

  92. Marigliano V, Abate G, Barbagallo-Sangiorgi G, et al. Randomized, double-blind, placebo-controlled, multicentre study of idebenone in patients suffering from multi-infarct dementia. Arch Gerontol Geriatr 1992; 15: 239–48

    Article  PubMed  CAS  Google Scholar 

  93. Bergamasco B, Villardita C, Coppi R. Idebenone in the treatment of multi-infarct dementia: a randomised, double-blind, placebo controlled multicentre trial. Arch Gerontol Geriatr 1992; 15: 2371–8

    Google Scholar 

  94. Hall ED. Cerebral ischemia, free radicals and antioxidant protection. Biochem Soc Trans 1993; 21: 334–9

    PubMed  CAS  Google Scholar 

  95. Richardson JS, Kumar U, Kala SV, et al. In vitro evidence for the use of antioxidants in Alzheimers disease. In: Giacobini E, Becker R, editors. Alzheimer disease: therapeutic strategies. Boston: Birkhäuser 1994: 334–9

    Google Scholar 

  96. Sethy VH, Wu H, Oostveen JA, et al. Neuroprotective effects of the pyrrolopyrimidine U-104067F in 3-acetylpyridinetreated rats. Exp Neurol 1996; 140: 79–83

    Article  PubMed  CAS  Google Scholar 

  97. Schulz JB, Henshaw DR, Siwek D, et al. Involvement of free radicals in excitotoxicity in vivo. J Neurochem 1995; 64: 2239–47

    Article  PubMed  CAS  Google Scholar 

  98. Schulz JB, Matthews RT, Jenkins BG, et al. Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo. J Neurosci 1995; 15: 8419–29

    PubMed  CAS  Google Scholar 

  99. Morris JC. Treatment of the cognitive symptoms of dementia [abstract]. In: Dementia update. Sec 441. 48th Annual Meeting of the American Academy of Neurology; 1996 Mar 23–30: San Francisco, 63–74

  100. McLachlan DR, Kruck TPA, Smith WL. Aluminum chelation therapy of Alzheimer’s disease. In: Giacobini E, Becker R, editors. Alzheimer disease: therapeutic strategies. Boston: Birkhäuser, 1994: 328–33

    Google Scholar 

  101. McLachlan DR, Smith WL, Kruck TPA. Desferrioxamine and Alzheimer’s disease: video home behavior assessment of clinical course and measures of brain aluminum. Ther Drug Monit 1993; 15: 602–7

    Article  PubMed  CAS  Google Scholar 

  102. Breitner JCS, Gau BA, Welsh KA, et al. Inverse association of anti-inflammatory treatments and Alzheimer’s disease: initial results of a co-twin control study. Neurology 1994; 44: 227–32

    Article  PubMed  CAS  Google Scholar 

  103. Rogers J, Kirby LC, Hempelman SR, et al. Clinical trial of indomethacin in Alzheimer’s disease. Neurology 1993; 43: 1609–11

    Article  PubMed  CAS  Google Scholar 

  104. Rich JB, Rasmusson DX, Folstein MF, et al. Nonsteroidal anti-inflammatory drugs in Alzheimers disease. Neurology 1995; 45: 51–5

    Article  PubMed  CAS  Google Scholar 

  105. Andersen K, Launer LJ, Ott A, et al. Do nonsteiroidal anti-inflammatory drugs decrease the risk for Alzheimers disease? The Rotterdam study. Neurology 1995; 45: 1441–5

    Article  PubMed  CAS  Google Scholar 

  106. Aisen PS, Davis KL. Inflammatory mechanisms in Alzheimers disease: implications for therapy. Am J Psychiatry 1994; 151: 1105–13

    PubMed  CAS  Google Scholar 

  107. Rogers J, Schulz J, Brachova L, et al. Complement activation and β-amyloid mediated neurotoxicity in Alzheimers disease. Res Immunol 1992; 143: 624–30

    Article  PubMed  CAS  Google Scholar 

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  1. Gerontology and Geriatrics, Department of Clinical Medicine, Pathology and Pharmacology, Perugia University, Via Eugubina 42, 06122, Perugia, Italy

    Lucilla Parnetti, Umberto Senin & Patrizia Mecocci

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  1. Lucilla Parnetti
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Parnetti, L., Senin, U. & Mecocci, P. Cognitive Enhancement Therapy for Alzheimer’s Disease. Drugs 53, 752–768 (1997). https://doi.org/10.2165/00003495-199753050-00003

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