Advertisement

Oxidative injury in diseases of the central nervous system: focus on alzheimer’s disease

  • Domenico Praticò
    Affiliations
    Department of Pharmacology and Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Search for articles by this author
  • Norman Delanty
    Correspondence
    Requests for reprints should be addressed to Norman Delanty, MB, MRCPI, Department of Clinical Neurological Sciences, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland
    Affiliations
    Department of Clinical Neurological Sciences, Royal College of Surgeons in Ireland, and Division of Neurology, Beaumont Hospital, Dublin, Ireland
    Search for articles by this author

      Abstract

      Alzheimer’s disease is one of the most challenging brain disorders and has profound medical and social consequences. It affects approximately 15 million persons worldwide, and many more family members and care givers are touched by the disease. The initiating molecular event(s) is not known, and its pathophysiology is highly complex. However, free radical injury appears to be a fundamental process contributing to the neuronal death seen in the disorder, and this hypothesis is supported by many (although not all) studies using surrogate markers of oxidative damage. In vitro and animal studies suggest that various compounds with antioxidant ability can attenuate the oxidative stress induced by beta-amyloid. Recently, clinical trials have demonstrated potential benefits from treatment with the antioxidants, vitamin E, selegiline, extract of Gingko biloba, and idebenone. Further studies are warranted to confirm these findings and explore the optimum timing and antioxidant combination of such treatments in this therapeutically frustrating disease.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Geldmacher D.S.
        • Whitehouse P.J.
        Evaluation of dementia.
        N Engl J Med. 1996; 335: 330-336
        • Mayeux R.
        • Sano M.
        Treatment of Alzheimer’s disease.
        N Engl J Med. 1999; 341: 1670-1679
        • Hofman A.
        • Ott A.
        • Breteler M.M.B.
        • et al.
        Atherosclerosis, apolipoprotein E, and prevelance of dementia, and Alzheimer’s disease in the Rotterdam study.
        Lancet. 1997; 349: 151-154
        • Martin J.B.
        Molecular basis of the neurodegenerative disorders.
        N Engl J Med. 1999; 340: 1970-1980
        • Roses A.D.
        A model for susceptibility polymorphisms for complex diseases.
        Neurogenetics. 1997; 1: 3-11
        • Lovestone S.
        Early diagnosis and the clinical genetics of Alzheimer’s disease.
        J Neurol. 1999; 246: 69-72
        • Selkoe D.J.
        Alzheimer’s disease.
        Science. 1997; 275: 630-631
        • Ojaimi J.
        • Masters C.L.
        • McLean C.
        • et al.
        Irregular distribution of cytochrome c oxidase protein subunits in aging and Alzheimer’s disease.
        Ann Neurol. 1999; 46: 656-660
        • Wolozin B.
        • Iwasaki K.
        • Vito P.
        • et al.
        Participation of presenelin 2 in apoptosis.
        Science. 1996; 274: 1710-1713
        • Itzhaki R.F.
        • Lin W.-R.
        • Shang D.
        • et al.
        Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease.
        Lancet. 1997; 349: 241-244
        • De Silva H.A.
        • Aronson J.K.
        • Grahame-Smith D.G.
        • et al.
        Abnormal function of potassium channels in platelets of patients with Alzheimer’s disease.
        Lancet. 1998; 352: 1590-1593
        • Delanty N.
        • Dichter M.A.
        Oxidative injury in the nervous system.
        Acta Neurol Scand. 1998; 98: 145-153
        • Jenner P.
        Oxidative damage in neurodegenerative disease.
        Lancet. 1994; 344: 796-798
        • Halliwell B.
        Free radicals, antioxidants, and human disease.
        Lancet. 1994; 344: 721-724
        • Floyd R.A.
        Antioxidants, oxidative stress, and degenerative neurological disorders.
        Proc Soc Exper Biol Med. 1999; 222: 236-245
        • Harman D.
        Free radical theory of aging.
        Mutat Res. 1992; 275: 257-266
        • Ames B.N.
        • Shigenda M.K.
        • Hagen T.M.
        Oxidants, antioxidants, and the degenerative diseases of aging.
        Proc Natl Acad Sci USA. 1993; 90: 7915-7922
        • Beal M.F.
        Aging, energy, and oxidative stress in neurodegenerative disease.
        Ann Neurol. 1995; 38: 357-366
        • Reiter R.J.
        Oxidative processes and antioxidant defense mechanisms in the aging brain.
        FASEB J. 1995; 9: 526-533
        • Okabe T.
        • Hamaguchi K.
        • Inafuku T.
        • Hara M.
        Aging and superoxide dismutase activity in cerebrospinal fluid.
        J Neurol Sci. 1996; 141: 100-104
        • van Leeuwen F.W.
        • Hol E.M.
        Molecular misreading of genes in Down syndrome as a model for the Alzheimer type of neurodegeneration.
        J Neural Transm Suppl. 1999; 57: 137-159
        • Stewart R.
        Cardiovascular factors in Alzheimer’s disease.
        J Neurol Neurosurg Psychiatry. 1998; 65: 143-147
        • Nemetz P.N.
        • Leibson C.
        • Naessens J.M.
        • et al.
        Traumatic brain injury and time to onset of Alzheimer’s disease.
        Am J Epidemiol. 1999; 149: 32-40
        • Ott A.
        • Slooter A.J.
        • Hofman A.
        • et al.
        Smoking and risk of dementia and Alzheimer’s disease in a population-based cohort study.
        Lancet. 1998; 351: 1840-1843
        • Merchant C.
        • Tang M.X.
        • Albert S.
        • et al.
        The influence of smoking on the risk of Alzheimer’s disease.
        Neurology. 1999; 52: 1408-1412
        • Leibson C.L.
        • Rocca W.A.
        • Hanson V.A.
        • et al.
        Risk of dementia among persons with diabetes mellitus.
        Am J Epidemiol. 1997; 145: 301-308
        • Busciglio J.
        • Yankner B.A.
        Apoptosis and increased generation of reactive oxygen species in Down’s syndrome neurons in vitro.
        Nature. 1995; 378: 776-779
        • Ruef J.
        • Peter K.
        • Nordt T.K.
        • et al.
        Oxidative stress and atherosclerosis.
        Thromb Haemost. 1999; 82: 32-37
        • Shohami E.
        • Beit-Yannai E.
        • Horowitz M.
        • Kohen R.
        Oxidative stress in closed-head injury.
        J Cereb Blood Flow Metab. 1997; 17: 1007-1019
        • Reilly M.P.
        • Delanty N.
        • Lawson J.A.
        • FitzGerald G.A.
        Modulation of oxidant stress in vivo in chronic cigarette smokers.
        Circulation. 1996; 94: 19-25
        • Fukagawa N.K.
        • Li M.
        • Liang P.
        • et al.
        Aging and high concentrations of glucose potentiate injury to mitochondrial DNA.
        Free Radic Biol Med. 1999; 27: 1437-1443
        • Gutteridge J.
        Lipid peroxidation and antioxidants as biomarkers of tissue damage.
        Clin Chem. 1995; 41: 1819-1828
        • Moore K.
        • Roberts L.I.
        Measurement of lipid peroxidation.
        Free Rad Res. 1998; 28: 659-671
        • Subbarao K.V.
        • Richardson J.S.
        • Ang L.C.
        Autopsy samples of Alzheimer’s cortex show increased peroxidation in vitro.
        J Neurochem. 1990; 55: 342-345
        • Balazs L.
        • Leon M.
        Evidence of an oxidative challenge in the Alzheimer’s brain.
        Neurochem Res. 1994; 19: 1131-1137
        • Lovell M.A.
        • Ehmann W.D.
        • Butler S.M.
        • Markesbery W.R.
        Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease.
        Neurology. 1995; 45: 1594-1601
        • Marcus D.L.
        • Thomas C.
        • Rodriguez C.
        • et al.
        Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer’s disease.
        Exp Neurol. 1998; 150: 40-44
        • Hajimohammadreza I.
        • Brammer M.
        Brain membrane fluidity and lipid peroxidation in Alzheimer’s disease.
        Neurosc Letters. 1990; 112: 333-337
        • Palmer A.M.
        • Burns M.A.
        Selective increase in lipid peroxidation in the inferior temporal cortex in Alzheimer’s disease.
        Brain Res. 1994; 645: 338-342
        • Ramassamy C.
        • Averill D.
        • Beffert U.
        • et al.
        Oxidative damage and protection by antioxidants in the frontal cortex of Alzheimer’s disease is related to the apolipoprotein E genotype.
        Free Rad Biol Med. 1999; 27: 544-553
        • McIntosh L.J.
        • Trush M.A.
        • Troncoso J.C.
        Increased susceptibility of Alzheimer’s disease temporal cortex to oxygen free radical–mediated processes.
        Free Rad Biol Med. 1997; 23: 183-190
        • Yeo H.C.
        • Helbock H.J.
        • Chyu D.W.
        • Ames B.N.
        Assay of malondialdehyde in biological fluids by gas chromatography-mass spectrometry.
        Anal Biochem. 1994; 220: 391-396
        • Hayn M.
        • Kremser K.
        • Singewald N.
        • et al.
        Evidence against the involvement of reactive oxygen species in the pathogenesis of neuronal death in Down’s syndrome and Alzheimer’s disease.
        Life Sciences. 1996; 59: 537-544
        • Lyras L.
        • Cairns N.J.
        • Jenner A.
        • Jenner P.
        • Halliwell B.
        An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer’s disease.
        J Neurochem. 1997; 68: 2061-2069
        • Esterbauer H.
        • Schaur R.J.
        • Zollner H.
        Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes.
        Free Rad Biol Med. 1991; 11: 81-128
        • Markesbery W.R.
        • Lovell M.A.
        Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease.
        Neurobiol Ag. 1998; 19: 33-36
        • Lovell M.A.
        • Ehmann W.D.
        • Mattson M.P.
        • Markesbery W.R.
        Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer’s disease.
        Neurobiol Ag. 1997; 18: 457-461
        • Pratico D.
        F2-isoprostanes.
        Atherosclerosis. 1999; 147: 1-10
        • Pratico D.
        • Lee V.M.Y.
        • Trojanowski J.Q.
        • et al.
        Increased F2-isoprostanes in Alzheimer’s disease.
        evidence for enhanced lipid peroxidation in vivo. FASEB J. 1998; 12: 1777-1783
        • Montine T.J.
        • Markesbery W.R.
        • Morrow J.D.
        • Roberts L.J.
        Cerebrospinal fluid F2-isoprostane levels are increased in Alzheimer’s disease.
        Ann Neurol. 1998; 44: 410-413
        • Montine T.J.
        • Markesbery W.R.
        • Zackert W.
        • et al.
        The magnitude of brain lipid peroxidation correlates with the extent of degeneration but not with density of neuritic plaques or neurofibrillary tangles or with APOE genotype in Alzheimer’s disease patients.
        Am J Pathol. 1999; 155: 863-868
        • Roberts L.J.
        • Montine T.J.
        • Markesbery W.R.
        • et al.
        Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid.
        J Biol Chem. 1998; 273: 13605-13612
        • Nourooz-Zadeh J.
        • Liu E.H.
        • Yhlen B.
        • et al.
        F4-isoprostanes as specific marker of docosahexaenoic acid peroxidation in Alzheimer’s disease.
        J Neurochem. 1999; 72: 734-740
        • Montine K.S.
        • Olson S.J.
        • Amarnath V.
        • et al.
        Immunohistochemical detection of 4-hydroxy-2-nonenal adducts in Alzheimer’s disease is associated with inheritance of APOE4.
        Am J Pathol. 1997; 150: 437-443
        • Montine K.S.
        • Kim P.J.
        • Olson S.J.
        • et al.
        4-Hydroxy-2-nonenal pyrrole adducts in human neurodegenerative disease.
        J Neuropathol Exper Neurol. 1997; 56: 866-871
        • Montine K.S.
        • Reich E.
        • Neely M.D.
        • et al.
        Distribution of reducible 4-hydroxynonenal adduct immunoreactivity in Alzheimer disease is associated with APOE genotype.
        J Neuropathol Exper Neurol. 1998; 57: 415-425
        • Sayre L.M.
        • Zelasko D.A.
        • Harris P.L.
        • et al.
        4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer’s disease.
        J Neurochem. 1997; 68: 2092-2097
        • Jeandel C.
        • Nicolas M.B.
        • Dubois F.
        • et al.
        Lipid peroxidation and free radical scavengers in Alzheimer’s disease.
        Gerontology. 1989; 35: 275-282
        • Kalman J.
        • Kudchodkar B.J.
        • Murray K.
        • et al.
        Evaluation of serum-lipid-related cardiovascular risk factors in Alzheimer’s disease.
        Dem Geri Cogni Dis. 1999; 10: 488-493
        • Ahlskog J.E.
        • Uitti R.J.
        • Low P.A.
        • et al.
        No evidence for systemic oxidant stress in Parkinson’s or Alzheimer’s disease.
        Movement Disorders. 1995; 10: 566-573
        • Hajimohammadreza I.
        • Brammer M.J.
        • Eagger S.
        • et al.
        Platelet and erythrocyte membrane changes in Alzheimer’s disease.
        Biochim Biophys Acta. 1990; 1025: 208-214
        • Kalman J.
        • Dey I.
        • Ilona S.V.
        • et al.
        Platelet membrane fluidity and plasma malondialdehyde levels in Alzheimer’s demented patients with and without family history of dementia.
        Biol Psych. 1994; 35: 190-194
        • Montine T.J.
        • Beal M.F.
        • Cudkowicz M.E.
        • et al.
        Increased CSF F2-isoprostane concentration in probable AD.
        Neurology. 1999; 52: 562-565
        • Feillet-Coudray C.
        • Tourtauchaux R.
        • Niculescu M.
        • et al.
        Plasma levels of 8-epiPGF2-α, an in vivo marker of oxidative stress, are not affected by aging or Alzheimer’s disease.
        Free Rad Biol Med. 1999; 27: 463-469
      1. Waddington E, Croft K, Clarnette R, et al. Plasma F2-isoprostane levels are increased in Alzheimer’s disease: evidence of increased oxidative stress in vivo. Alzheimer’s Report. 1999;2:277–282.

      2. Pratico D, Clark CM, Lee VMY, Trojanowski JQ, Rokach J, Fitzgerald GA. Increased 8,12–iso-iPF2alpha-VI in Alzheimer’s Disease: Correlation of a non-invasive index of lipid peroxidation with disease severity. Ann Neurol. (In Press).

        • Reznick A.Z.
        • Packer L.
        Oxidative damage to proteins.
        Methods Enzymol. 1994; 233: 357-363
        • Smith C.D.
        • Carney J.M.
        • Starke-Reed P.E.
        • et al.
        Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease.
        Proc Nat Acad Sci USA. 1991; 88: 10540-10543
        • Hensley K.
        • Hall N.
        • Subramaniam R.
        • et al.
        Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation.
        J Neurochem. 1995; 65: 2146-2156
        • Hensley K.
        • Maidt M.L.
        • Yu Z.
        • et al.
        Electrochemical analysis of protein nitrotyrosine and dityrosine in the Alzheimer brain indicates region-specific accumulation.
        J Neurosc. 1998; 18: 8126-8132
        • Smith M.A.
        • Perry G.
        • Richey P.L.
        • et al.
        Oxidative damage in Alzheimer’s.
        Nature. 1996; 382: 120-121
        • Good P.F.
        • Werner P.
        • Hsu A.
        • et al.
        Evidence of neuronal oxidative damage in Alzheimer’s disease.
        Am J Pathol. 1996; 149: 21-28
      3. Smith MA, Richey Harris PL, Sayre LM, et al. Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J Neurosc. 1997;17:2653–2657.

        • Su J.H.
        • Deng G.
        • Cotman C.W.
        Neuronal DNA damage precedes tangle formation and is associated with up-regulation of nitrotyrosine in Alzheimer’s disease brain.
        Brain Res. 1997; 774: 193-199
        • Mullaart E.
        • Boerrigter M.E.
        • Brouwer A.
        • et al.
        Age-dependent accumulation of alkali-labile sites in DNA of post-mitotic but not in that of mitotic rat liver cells.
        Mechan Age Devel. 1988; 45: 41-49
        • Gavrieli Y.
        • Sherman Y.
        • Ben-Sasson S.A.
        Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation.
        J Cell Biol. 1992; 119: 493-501
        • Shigenaga M.K.
        • Ames B.N.
        Assays for 8-hydroxy-2′-deoxyguanosine.
        Free Rad Biol Med. 1991; 10: 211-216
        • Shigenaga M.K.
        • Aboujaoude E.N.
        • Chen Q.
        • Ames B.N.
        Assays of oxidative DNA damage biomarkers 8-oxo-2′-deoxyguanosine and 8-oxoguanine in nuclear DNA and biological fluids by high-performance liquid chromatography with electrochemical detection.
        Methods Enzymol. 1994; 234: 16-33
        • Mullaart E.
        • Boerrigter M.E.
        • Ravid R.
        • et al.
        Increased levels of DNA breaks in cerebral cortex of Alzheimer’s disease patients.
        Neurobiol Ag. 1990; 11: 169-173
        • Mecocci P.
        • MacGarvey U.
        • Beal M.F.
        Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease.
        Ann Neurol. 1994; 36: 747-751
        • Koppele J.M.
        • Lucassen P.J.
        • Sakkee A.N.
        • et al.
        8OHdG levels in brain do not indicate oxidative DNA damage in Alzheimer’s disease.
        Neurobiol Ag. 1996; 17: 819-826
        • Gabbita S.P.
        • Lovell M.A.
        • Markesbery W.R.
        Increased nuclear DNA oxidation in the brain in Alzheimer’s disease.
        J Neurochem. 1998; 71: 2034-2040
        • Lovell M.A.
        • Gabbita S.P.
        • Markesbery W.R.
        Increased DNA oxidation and decreased levels of repair products in Alzheimer’s disease ventricular CSF.
        J Neurochem. 1999; 72: 771-776
        • Wade R.
        • Hirai K.
        • Perry G.
        • Smith M.A.
        Accumulation of 8-hydroxy-guanosine in neuronal cytoplasm indicates mitochondrial damage and radical production are early features of Alzheimer’s disease.
        J Neuropathol Exp Neurol. 1998; 57: 511
        • Mecocci P.
        • Polidori M.C.
        • Ingegni T.
        • et al.
        Oxidative damage to DNA in lymphocytes from AD patients.
        Neurology. 1998; 51: 1014-1017
        • Monnier V.M.
        • Cerami A.
        Nonenzymatic browning in vivo.
        Science. 1981; 211: 491-493
        • Smith M.A.
        • Sayre L.M.
        • Monnier V.M.
        • Perry G.
        Radical AGEing in Alzheimer’s disease.
        Trend Neurosci. 1995; 18: 172-176
        • Vitek M.P.
        • Bhattacharya K.
        • Glendening J.M.
        • et al.
        Advanced glycation end products contribute to amyloidosis in Alzheimer disease.
        Proc Nat Acad Sci USA. 1994; 91: 4766-4770
      4. Yan SD, Chen X, Schmidt AM, et al. Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. Proc Nat Acad Sci USA. 1994:7787–7791.

        • Smith M.A.
        • Taneda S.
        • Richey P.L.
        • et al.
        Advanced Maillard reaction end products are associated with Alzheimer disease pathology.
        Proc Nat Acad Sci USA. 1994; 91 ([published erratum appears in Proc Natl Acad Sci USA. 1995;92:2016]): 5710-5714
        • Ledesma M.D.
        • Bonay P.
        • Colaco C.
        • Avila J.
        Analysis of microtubule-associated protein tau glycation in paired helical filaments.
        J Biol Chem. 1994; 269: 21614-21619
        • Guevara J.
        • Espinosa B.
        • Zenteno E.
        • et al.
        Altered glycosylation pattern of proteins in Alzheimer disease.
        J Neuropathol Exper Neurol. 1998; 57: 905-914
        • Guenette S.Y.
        • Tanzi R.E.
        Progress toward valid transgenic mouse models for Alzheimer’s disease.
        Neurobiol Ag. 1999; 20: 201-211
        • Pappolla M.A.
        • Chyan Y.J.
        • Omar R.A.
        • et al.
        Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer’s disease.
        Am J Pathol. 1998; 152: 871-877
        • Smith M.A.
        • Hirai K.
        • Hsiao K.
        • et al.
        Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress.
        J Neurochem. 1998; 70: 2212-2215
      5. Emilien G, Malateaux J-M, Beyreuther K, Masters Cl. Alzheimer disease. Mouse models pave the way for therapeutic opportunities. Arch Neurol. 2000; 57:176–181.

      6. Delanty N, Dichter MA. Antioxidant therapy in neurologic disease. Arch Neurol. 2000 (in press).

        • Hall E.D.
        • Andrus P.K.
        • Smith S.L.
        • et al.
        Pyrrolopyrimidines.
        novel brain-penetrating antioxidants with neuroprotective activity in brain injury and ischemia models. J Pharmacol Exp Ther. 1997; 281: 895-904
        • Oyama Y.
        • Chikahisa L.
        • Ueha T.
        • et al.
        Ginkgo biloba extract protects brain neurons against oxidative stress induced by hydrogen peroxide.
        Brain Res. 1996; 712: 349-352
        • Talley A.K.
        • Dewhurst S.
        • Perry S.
        • et al.
        Tumor necrosis factor alpha-induced apoptosis in human neuronal cells.
        Moll Cell Biol. 1995; 15: 2359-2366
        • Behl C.
        • Davis J.
        • Cole G.M.
        • Schubert D.
        Vitamin E protects nerve cells from amyloid-beta protein toxicity.
        Biochem Biophys Res Commun. 1992; 186: 944-950
        • Pereira C.
        • Santos M.S.
        • Oliveira C.
        Involvement of oxidative stress on the impairment of energy metabolism induced by A beta peptides on PC12 cells.
        Neurobiol Dis. 1999; 6: 209-219
        • Pappolla M.A.
        • Chyan Y.J.
        • Poeggeler B.
        • et al.
        Alzheimer beta protein mediated oxidative damage of mitochondrial DNA.
        J Pineal Res. 1999; 27: 226-229
        • Yamada K.
        • Tanaka T.
        • Han D.
        • et al.
        Protective effects of idebenone and alpha-tocopherol on beta-amyloid-(1–42)-induced learning and memory deficits in rats.
        Eur J Neurosci. 1999; 11: 83-90
      7. Sano M, Ernesto C, Thomas RG, et al, and the Alzheimer’s Disease Cooperative Study. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med. 1997;336:1216–1222.

        • Pincus M.M.
        Alpha-tocopherol and Alzheimer’s disease.
        N Engl J Med. 1997; 337 ([letter]): 572
        • Grundman M.
        Vitamin E, and Alzheimer disease.
        Am J Clin Nutr. 2000; 71: 630S-636S
      8. Le Bars PL, Katz MM, Berman N, et al, for the North American EGb Study Group. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. JAMA. 1997;278:1327–1332.

        • Gutzmann H.
        • Hadler D.
        Sustained efficacy and safety of idebenone in the treatment of Alzheimer’s disease.
        J Neural Transmission. 1998; 54: 301-310