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Adverse and side effects excluded
- Regina Stroebele (18 March 2002)
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Alzheimer’s anti-amyloid vaccination and statins: two approaches, one dogma. The time for change.
- Alexei R. Koudinov, Natalia V. Koudinova (20 March 2002)
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Bells Palsy-Recent Developments in Neurology
- Philip A Atkin (22 March 2002)
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Amyloid hypothesis, synaptic function, and Alzheimer’s disease, or: Beware: the dogma is revitalized
- Alexei R. Koudinov, Natalia V. Koudinova (15 May 2002)
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Regina Stroebele, (Specialist) GP D-81677 Muenchen
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I am not a Neurologist. But I have seen enough neuro-surgical cases to know how mutilating side effects of surgical interventions in the lobus temporalis can be. In my humble opinion, these side and adverse efects should be named and considered before a surgical intervention occurs just to save costs for drugs in prevention & treatment of aura and "small seizures". |
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Alexei R. Koudinov, senior research scientist Berezov Acad Lab, Russian Acad Med Sci, Moscow; Neurology, P.O.Box 1665, Rehovot 76100, Israel, Natalia V. Koudinova
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A disappointing news come like thunderstorm as this week BMJ article (16 March 2002 Vol.324, 656-660) did not make a note of it. This news is the failure of the first human Alzheimer’s disease vaccination trial [1]. The vaccine made of synthetic amyloid peptide attempted to reduce the amyloid load in the brain of patients by means of the body immune reaction with anti-amyloid antibodies. Instead, it caused the cerebral inflammation in fifteen volunteers of 360 who have been vaccinated [1]. It’s hard to believe that this failure was totally unexpected. It’s hard to accept that the most important issue today is to find out why it happened (see Alzheimer’s forum pre-live discussion commentaries ; also see below). The likely explanation is that those who claim it did not study well in a medical school, did not get proper basic biomedical education, and/or have a competing interest in a decade-long “advancing” the dogma that “amyloid is Alzheimer’s disease” [2]. There were no other way for the vaccine then to die away as the "vaccination" approach was based on a complete ignorance of amyloid beta normal physiological function(s) and as soon as the vaccination basic did not satisfy the key Hippocrates principal of “no harm”. Recent Science magazine New Focus essay on Alzheimer’s disease as well as several other articles in a number of influential journals [3] set the pace for another strategy to tackle brain amyloid by means of lowering cholesterol with statins (also see this week BMJ contribution). Thus, both approaches (i.e. vaccination and statins) despite of their significant differences have a unifying basis. Their proponents aim small in size amyloid beta protein that over the last fifteen years grew into the major dogma of Alzheimer’s research [1,3]. Many grant applications and scientific articles on the subject
make no-reference statement that there is a compelling evidence that accumulation
and aggregation of amyloid beta plays a causal role in the development
of the disease. Top biomedical journals add to the dogma by publishing
redundant editorials and review articles [4] and refusing
to balance the discussion by publshing novel and alternative viewpoints.
The above explains why elucidating normal functional biochemistry of amyloid beta remained an underground priority in Alzheimer’s research since the soluble form of amyloid beta was discovered a decade ago. Despite of this, there is an accumulating evidence that amyloid beta is a functional and essential component of brain metabolism. Thus, it is a structural constituent of high density lipoproteins, is capable to modulate oxidative mechanisms [5] and is involved in lipid metabolism and membrane dynamics as a regulatory element [6,7]. Correspondingly, the role of amyloid beta in lipid (particularly cholesterol) metabolism makes feasible an important possibility ignored in all cited above articles on cholesterol and Alzheimer’s disease [3]. That is the functional need for brain amyloid beta to fix abnormal cholesterol dynamics in Alzheimer’s disease, a welcome (yet far from understanding) cause of neurodegeneration [6,8]. The natural failure of Alzheimer’s “immunoterapy”
in our view must boost the research on physiologically relevant mechanisms
of neural degeneration and Alzheimer’s disease and related disorders [8],
and on normal functional biochemistry of amyloid beta.
It will also hopefully caution all that bias and unacceptable ignorance of “non-mainstream” facts may lead one day to ground zero of Alzheimer’s research and its’ social impact [ 2 ]. Competing interests: none
References: 1. Check E. Nerve inflammation halts trial for Alzheimer's drug. Nature.s 415, 462 (2002) [ PubMed ] [Alzheimer forum Drug News report] [Alzheimer forum live discussion transcript] For additional historical reading on vaccination approach
see the following articles:
2. Smith R. Beyond conflict of interest. BMJ. 317, 291-292 (1998) [ FullText ]; Smith R. Medical editor lambasts journals and editors. BMJ. 323, 651 (2001) [ FullText ]; Smith R. Measuring the social impact of research. BMJ. 323, 528 (2001) [ FullText ]. 3. Marx J. Alzheimer's disease: bad for the heart, bad for the mind? Science. 294, 508-509 (2001) [ PubMed ] [ FullText ]; Simons M, Keller P, Dichgans J, Schulz JB. Cholesterol and Alzheimer’s disease: Is there a link? Neurology. 57, 1089-1093 (2001) [ PubMed ] [ FullText ] [ Reply on Letter to the Editor ]; Wolozin B. A fluid connection: Cholesterol and Ab. Proc Natl Acad Sci USA. 98, 5371-5373 (2001) [ PubMed ] [ FullText ]; Haley RW, Dietschy JM. Is there a connection between the concentration of cholesterol circulating in plasma and the rate of neuritic plaque formation in Alzheimer disease? Arch Neurol. 57, 1410-1412, (2000) [ PubMed ]; Golde TE, Eckman CB. Cholesterol modulation as an emerging strategy for the treatment of Alzheimer's disease. Drug Discovery Today. 6, 1049-1055 (2001) [ PubMed ] [ FullText ]; Refolo LM, Pappolla MA, LaFrancois J, et al. A cholesterol-lowering drug reduces b-amyloid pathology in a transgenic mouse model of Alzheimer's disease. Neurobiol Dis. 8, 890-899 (2001) [ PubMed ] [ FullText ]; Puglielli L, Konopka G, Pack-Chung E, et al. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nature Cell Biol. 10, 905-912 (2001) [ PubMed ] [ FullText ] [ Letter to the Editor ]; Hartmann T. Cholesterol, Abeta and Alzheimer's disease. TINS. 24, S45-48 (2001) [ PubMed ]. 4. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 81, 741-66 (2001) [ PubMed ]; Selkoe DJ. Toward a comprehensive theory for Alzheimer's disease. Hypothesis: Alzheimer's disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci. 924, 17-25 (2000) [ PubMed ]; Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer's disease Nature. Neurological disorders. 399 (Supplement), A23-A31; Selkoe D. The origins of Alzheimer disease: a is for amyloid. JAMA. 283, 1615-1617 (2000) [ PubMed ] [ Full Text ]. 5. Kontush A. Amyloid-beta: an antioxidant that becomes a pro-oxidant and critically contributes to Alzheimer's disease. Free Radic Biol Med. 31, 1120-1131 (2001) [ PubMed ]; Bush A. Response: '...and C is for Clioquinol' -- the AbetaCs of Alzheimer's disease. TINS. 25, 123-124 (2002) [ PubMed ]. 6. Koudinov AR, Koudinova NV. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. 15, 1858-1860 (2001), originally published online June 27, 2001, 10.1096/fj.00-0815fje [ Article Preface at the authors WEB site ] [ Abstract and Full text at FASEB J ] [ PubMed ] [ Authors related eLetters to editor ]; Koudinov AR, Koudinova NV, Berezov TT. Alzheimer's peptides Ab1-40 and Ab1-28 inhibit the plasma cholesterol esterification rate. Biochem Mol Biol Inter. 38, 747-752 (1996) [ PubMed ] [ Reprint Order ]; Liu Y, Peterson DA, Schubert D. Amyloid beta peptide alters intracellular vesicle trafficking and cholesterol homeostasis. Proc Natl Acad Sci USA. 95, 13266-13271 (1998) [ PubMed ] [ FullText ]. 7. Chochina SV, Avdulov NA, Igbavboa U, Cleary JP, O'Hare EO, Wood WG. Amyloid beta-peptide(1-40) increases neuronal membrane fluidity. Role of cholesterol and brain region. J Lipid Res. 42, 1292-1297 (2001) [ PubMed ] [ Full Text ]; Muller WE, Kirsch C, Eckert GP. Membrane-disordering effects of beta-amyloid peptides. Biochem Soc Trans. 29, 617-623 (2001) [ PubMed ]. 8. Koudinov AR, Koudinova NV.
Brain Cholesterol Pathology is the Cause of Alzheimer's Disease. Clin.
Med. Health Res. published online November 27, 2001, clinmed/2001100005
[ Article
Preface at the authors WEB site ] [ Abstract
and FullText at Clin Med J ] [ Authors
related eLetters to editor ]; Koudinov AR, Berezov TT, Koudinova NV.
Cholesterol and Alzheimer's disease: Is there a link? Neurology. 58,
1135 (2002) [ Neurology
online edition ]; Naguib M, Flood P, McArdle JJ, Brenner HR. Advances
in neurobiology of the neuromuscular junction: implications for the anesthesiologist.
Anesthesiology.
96,
202-231 (2002) [ PubMed
] [ FullText
]; Koudinov AR, Koudinova NV, Beisiegel U. Cholesterol homeostasis failure
at neuromuscular junctions and CNS synapses: a unifying cause of synaptic
degeneration? Neurology online. 26 February 2002 [ FullText
].
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Philip A Atkin, SpR Hon. Clinical Lecturer in Oral Medicine Royal London Hospital Dental Institute, New Road, London E1 1BB
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Editor, I was interested to read the recent Clinical Review, 'Recent Developments in Neurology' (BMJ. 2002 Mar 16;324(7338):656-60) and in particular the discussion of the use of corticosteroids in the treatment of Bell's palsy. In the section concerned with Bell's palsy the authors conclude that the early use of corticosteroids is probably justified. This is repeated in the text box summary. I would suggest that this view is not supported by the best evidence available. In support of this statement the authors cite an evidence-based paper by Grogan and Gronseth. However, in this review the authors state that the benefit from steroids has not definitely been established. (Grogan PM, Gronseth GS. Practice parameter:steroids, acyclovir, and surgery for Bell's palsy (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56:830- 6). Two excellent sources of evidence based medicine which should be used to guide clinicians decisions are the Cochrane Library, and Clinical Evidence. A recent Cochrane review (Salinas RA et al,Corticosteroids for Bell's palsy (idiopathic facial paralysis) (Cochrane Review). Cochrane Database Syst Rev. 2002;(1):CD001942.), concluded that 'the available evidence from randomised controlled trials does not show significant benefit from treating Bell's palsy with corticosteroids'. Salinas, again, in the most recent edition of Clinical Evidence (Salinas R, Bell's palsy, Clinical Evidence 2001;6:961-4)concludes that 'two systematic reviews of RCT's and one subsequent RCT found no good evidence that steroids provide long term benefit compared with placebo'. Thus, taking only the best evidence available, the use of corticosteroids in the treatment of Bell's palsy suggested by the authors should only be proposed as part of a large randomised controlled trial to determine the truth (or otherwise) of this hypothesis. |
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Alexei R. Koudinov, neuroscientist and editor Berezov Academic Laboratory, c/o PO Box 1665, Rehovot 76100 Israel; NeurobiologyOfLipids.org, Natalia V. Koudinova
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To add to the discussion on the role of amyloid beta protein in Alzheimer’s disease [1] we would like to bring readers attention to recent Nature article [2], that attempted to revitalize the amyloid hypothesis. Over the past decade this hypothesis grew up into the major dogma of Alzheimer’s research. The key claim of the amyloid dogma is that amyloid beta (Abeta) represents
a bad neurotoxic molecule that has to be removed from the brain. The inability
of the toxic concept to advance the ‘transgenic mice cure’ [3]
with patients’ treatment become apparent earlier this year when anti-amyloid
vaccination was halted [1].
Thus it was shown that whereas acute treatment of rat hippocampal slices with low concentrations of bath applied peptide Abeta1-40 did not change basal synaptic transmission, there was an increase in tetanus induced long-term potentiation (LTP) [4], a synaptic plasticity measure. Moreover, Abeta1-40 triggered the slow onset long-term potentiation of the NMDA receptor-mediated synaptic currents [5] in the hippocampal slices from young rats, but did not affect the basal AMPA receptor-mediated transmission, resting membrane potential or input resistance of the granule cells. Similar results were presented by Schulz, who showed no effect of Abeta1-42 on AMPA currents, and demonstrated the increase of NMDA currents by the peptide [6]. This report proposed that Abeta peptides (Abeta1-42, Abeta1-28 and Abeta1-40) increase the probability of LTP under the paradigm that induced little LTP in control slices [6]. The above studies [4, 5, 6] favor neuronal synaptic function for amyloid beta rather then synaptotoxicity of amyloid beta claimed in Nature report [2]. The synaptic function for amyloid beta is additionally supported by
several studies by others, particularly, by an increase of synaptic amyloid
precursor protein with learning capacity in rats [7],
and by neuronal activity dependent secretion of natural Abeta [8,
also see Supplementary References].
Last sentence of the article by Walsh et al. [2] states that "the authors declare that they have no competing financial interests." However, several freely available articles and online documents disclose that Dennis Selkoe, the senior author, "was the principal founding scientist of Athena Neurosciences" [11], "a firm that had licensed research findings from academic institutions and companies" [11A], is "an Elan consultant" [12] and is a co-inventor of several related patents [13]. The above [11, 11A, 12, 13], and the identity of Alzheimer’s therapeutic perspective drawn in the Nature article [2] and in the publications of D.Selkoe co-inventors [3, 13, 14], the members of the pharmaceutical industry, indicate the competing interest of the senior author as it is defined [15] by the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, the Nature [16], BMJ, and by the Society for Neuroscience, the major professional society of neuroscientists. Competing interests: none
References: 1 Koudinov AR, Koudinova NV. Alzheimer’s anti-amyloid vaccination and statins: two approaches, one dogma. The time for change. BMJ. Published online 20 March, 2002. Available at: http://bmj.com/cgi/eletters/324/7338/656#20681 2 Walsh DM, Klyubin I, Fadeevam JV, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 416, 535-39 (2002) [ PubMed ] [ Accompanying commentary ] 3 Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 400, 173-77 (1999) [ PubMed ] [ 2002 account ] 4 Wu J, Anwyl R, Rowan MJ. b-amyloid-(1-40) increases long-term potentiation in rat hippocampus in vitro. Europ J Pharm. 284, R1-R3 (1995) [ PubMed ] 5 Wu J, Anwyl R, Rowan MJ. b-amyloid selectively augments NMDA receptor-mediated synaptic transmission in rat hippocampus. NeuroReport. 6, 2409-13 (1995) [ PubMed ] 6 Schulz PE. b-peptides enhance the magnitude and probability of long term potentiation. Soc Neurosci Abstr. 22, 2111 (1996) 7 Huber G, Bailly Y, Martin JR, Mariani J, Brugg B. Synaptic b-amyloid precursor proteins increase with learning capacity in rats. Neurosci. 80, 313-20 (1997) [ PubMed ]. 8 Kamenetz FR, Tomita T, Borchelt DR, Sisodia SS, Iwatsubo T, Malinow R. Activity dependent secretion of b-amyloid: roles of b-amyloid in synaptic transmission. Soc Neurosci Abstr. 26, 491 (2000) [ Abstract at ScholarOne ]. 9 Koudinov AR, Berezov TT, Koudinova NV. The levels of soluble amyloid beta in different high density lipoprotein subfractions distinguish Alzheimer’s and normal aging CSF: implication for brain cholesterol pathology? Neurosci Lett. 314, 115-18 (2001) [ Full Text ] [ PubMed ] [ Reprint Order ] ; Koudinov AR, Koudinova NV. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. 15, 1858-60 (2001), originally published online June 27, 2001, 10.1096/fj.00-0815fje [ Article Preface at the authors WEB site ] [ Post-publication account in Science ] [ Abstract and Full text at FASEB J ] [ PubMed ] [ Authors related eLetters to editor ] 10 Farhangrazi ZS, Ying H, Bu G, et al. High density lipoprotein decreases beta-amyloid toxicity in cortical cell culture. NeuroReport. 8, 1127-30 (1997) [ PubMed ] ; Cedazo-Minguez A, Huttinger M, Cowburn RF. Beta-VLDL protects against A beta(1-42) and apoE toxicity in human SH-SY5Y neuroblastoma cells. NeuroReport.12, 201-6 (2001) [ PubMed ] ; Koldamova RP, Lefterov IM, Lefterova MI, Lazo JS. Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits A beta aggregation and toxicity. Biochemistry. 40, 3553-60 (2001) [ PubMed ] 11 Biography of Selkoe, D. Web site of Partners Program of Excellence in Alzheimer's and Other Neurodegenerative Diseases [ Full text ] ; 11A Dalton R. Researchers caught in dispute over transgenic mice patents. Nature . 404, 319-20 (2000) [ FullText ] [ Related other item in Nature ] (Ref. 11A also discloses the Elan/Athena relation) 12 Steinberg D. Companies halt first Alzheimer vaccine trial. At issue: what inflamed patients' brains? The Scientist. 16, 22 (2002) [ Full text ]. 13 Schenk DB, Schlossmacher MG, Selkoe DJ, Seubert PA, Vigo-Pelfrey C, inventors; Elan Pharmaceuticals, Inc., Eli Lilly and Company, Brigham and Women's Hospital, Inc., assignees. Method for identifying .beta.-amyloid peptide production inhibitors. US Patent 6,284,221. Sept. 4, 2001 [ Full text at USPTO ] ; Schenk DB, Schlossmacher MG, Selkoe DJ, Seubert PA, Vigo-Pelfrey C, inventors; Athena Neurosciences, Inc., Eli Lilly and Company, Brigham and Women's Hospital, assignees. Methods and compositions for the detection of soluble .beta.-amyloid peptide. US Patent 5,837,672. Nov. 17, 1998 [ Full text at USPTO ] ; Schlossmacher MG, Selkoe DJ, inventors; Athena Neurosciences, Eli Lilly and Company, assignees. Methods of screening for compounds which inhibit soluble .beta.-amyloid peptide production. US Patent 5,766,846. June 16, 1998 [ Full text at USPTO ] ; Selkoe, Dennis, J. Biography. ISI HighlyCited.com. Last updated August 15, 2001. [ Research Funding/Grants ] [ ISI Patent List ] ; Also see Ref.2 (section 'Synthesis of gamma-secretase inhibitors') for two patent applications related to the study conclusion. 14 Schenk D, Games D, Seubert P. Potential treatment opportunities for Alzheimer's disease through inhibition of secretases and Abeta immunization. J Mol Neurosci. 17, 259-67 (2001) [ PubMed ] ; Schenk D, Seubert P, Ciccarelli RB. Immunotherapy with beta-amyloid for Alzheimer's disease: a new frontier. DNA Cell Biol. 20, 679-81 (2001) [ PubMed ]. 15 Uniform requirements for manuscripts submitted to biomedical journals. International Committee of Medical Journal Editors. Med Educ. 33, 66-78 (1999) [ Full text ] ; Campbell, P. Competing financial interests: Statement of policy on competing financial interests. Nature. Published 23 August 2001 [ Full text ] [ Take home citation ]; Society for Neuroscience. Rules for Submission and Presentation of Abstracts. SFN web site 2002 edition. [ Full text ] [ Full text at ScholarOne ]; Smith R. Beyond conflict of interest. BMJ. 317, 291-92 (1998) [ Full text ]. 16 Two earlier versions of this letter (commenting on the paper by Walsh et al. [2]) were submitted to Nature and then were rejected. Supplementary references:
1S Smith MA, Drew KL, Nunomura A et al.
Amyloid-beta, tau alterations and mitochondrial dysfunction in Alzheimer
disease: the chickens or the eggs? Neurochem Int. 40, 527-31
(2002) [ PubMed
]
5S Heese K, Nagai Y, Sawada T. Identification of
a new synaptic vesicle protein 2B mRNA transcript which is up-regulated
in neurons by amyloid beta peptide fragment (1-42). Biochem Biophys
Res Commun. 289, 924-28 (2001) [ PubMed
]
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