Recent developments in neurology
BMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7338.656 (Published 16 March 2002) Cite this as: BMJ 2002;324:656All rapid responses
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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.
Competing interests: No competing interests
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.
direct evidence on the pathogenic primacy or importance of amyloid in the disease. |
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.
the amyloid dogma that retarded Alzheimer’s understanding and cure development for about fifteen years and caused millions of research dollars spent for nothing. |
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
a Colleague] [Send us an email] [Authors Internet Office] [Related eLetters to Editor] [Recent Key Article One] [Recent Key Article Two] [Lay Summary One] [Lay Summary Two] |
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:
Lee VM. Abeta immunization: moving Abeta peptide from
brain to blood. Proc Natl Acad Sci USA. 98, 8931-8932 (2001) [ PubMed
].
St George-Hyslop PH, Westaway DA. Alzheimer's disease.
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].
Barinaga M. An Immunization Against Alzheimer's? Science.
285, 175-177 (1999) [ PubMed
].
Heemels MT. Alzheimer's disease. Plaque removers and
shakers. Nature.406, 465 (2000) [ PubMed
].
Helmuth L. Alzheimer's congress: Further Progress on
a beta-Amyloid Vaccine. Science. 289, 375 (2000) [ PubMed
].
Weiner HL, Lemere CA, Maron R, et al. Nasal administration
of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model
of Alzheimer's disease. Ann Neurol. 48, 567-579 (2000) [ PubMed
].
Frangione B. Alzheimer's forum "Question and Answer session"
transcript, 11 February 2002 [ FullText ].
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,
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]; Haley RW, Dietschy JM. Is there a connection between the concentration
of cholesterol circulating in plasma and the rate of neuritic plaque formation
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[ FullText
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Essential role for cholesterol in synaptic plasticity and neuronal degeneration.
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] [ Authors
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Alzheimer's peptides Ab1-40 and Ab1-28
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[ Article
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Cholesterol and Alzheimer's disease: Is there a link? Neurology. 58,
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].
Q: Is Alzheimer’s amyloid beta bad? A: No. It does not. |
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Competing interests: No competing interests
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".
Competing interests: No competing interests
Amyloid hypothesis, synaptic function, and Alzheimer’s disease, or: Beware: the dogma is revitalized
a Colleague
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].
mentioned once in the above article [2]. This
is despite the accumulating evidence that the peptide and its precursor
are essential for brain function and chemistry. Particularly, amyloid beta
is an antioxidant and a molecular sensor of membrane lipid dynamics [1].
Amyloid beta may also serve an essential role
in synapse and synaptic plasticity that underlie learning and memory.
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].
study by Walsh et al. [2] are several
articles that show that amyloid beta is a structure-functional constituent
of lipoproteins [9], and that lipoproteins potently
inhibit neural toxicity of Abeta [10]. The conceivable
lack of the amyloid beta interaction with lipoproteins in the Nature
study could exacerbate the lack of the in vivo physiological/therapeutic
relevance of the reported neurotoxicity data [2].
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
a Colleague] [Send
us an email]
[Authors
Internet Office]
Search PubMed for:
[ AR
Koudinov | NV
Koudinova ]
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
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416,
535-39 (2002) [ PubMed
] [ Accompanying
commentary ]
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Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like
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[ PubMed
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in synaptic transmission.
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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,
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against A beta(1-42) and apoE toxicity in human SH-SY5Y neuroblastoma cells.
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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
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15 Uniform requirements
for manuscripts submitted to biomedical journals. International Committee
of Medical Journal Editors. Med Educ. 33, 66-78
(1999) [
Full
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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:
(To moderate the unfair discussion
of the Nature article [2] please
also see the supplementary references listed below)
1S Smith MA, Drew KL, Nunomura A et al.
Amyloid-beta, tau alterations and mitochondrial dysfunction in Alzheimer
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plaque (and not diffuse amyloid) is a condition for neuronal dysfunction.
Clin
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[ Full
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home citation
"There are circumstances where
selection of evidence, interpretation of results or emphasis of presentation
might be inadvertently or even deliberately biased by a researcher's other
interests" -P.Campbell (Ref.15)
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Competing interests: No competing interests