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Double-blind randomized
controlled study of phosphatidylserine in senile demented
patients.
Delwaide PJ, Gyselynck-Mambourg AM, Hurlet A, Ylieff
M.
Acta Neurol Scand 1986 Feb;73(2):136-40
A double-blind randomized controlled study was conducted
in 42 hospitalized demented patients to evaluate the
therapeutical effect of phosphatidylserine (BS-PS). Half of
the patients received 3 X 100 mg of this product, and the
other half a placebo of the same appearance. After a
wash-out period, prescription lasted for six weeks. To
evaluate the patients, two distinct rating scales were
used: the Crichton Scale and an original one (Peri Scale)
designed in our geriatric unit (see Appendix). A circle
crossing test was added. Out of the 35 patients who
completed the trial, 18 had received placebo and 17 BC-PS.
The results indicated a trend toward improvement in the
BC-PS treated patients and an analysis of covariance showed
a significant (p less than 0.05) treatment effect on the
Peri Scale. The results at the end of the treatment period
were compared with those obtained three weeks later. Here
again there was a statistically significant difference in
the Peri Scale results, indicating that modifications are
drug-related. The behavioral improvement shown in this
study is in agreement with experimental studies on aged
animals.
Ginkgo biloba extract:
mechanisms and clinical indications.
Diamond BJ, Shiflett SC, Feiwel N, Matheis RJ, Noskin O,
Richards JA, Schoenberger NE Department of Research, Center
for Research in Complementary and Alternative Medicine,
Kessler Medical Rehabilitation Research and Education
Corporation, West Orange, NJ 07052, USA.
Arch Phys Med Rehabil 2000 May;81(5):668-78
OBJECTIVE: Ginkgo biloba may have a role in treating
impairments in memory, cognitive speed, activities of daily
living (ADL), edema, inflammation, and free-radical
toxicity associated with traumatic brain injury (TBI),
Alzheimer's dementia, stroke, vasoocclusive disorders, and
aging. The purpose of this review is to provide a synthesis
of the mechanisms of action, clinical indications, and
safety of Ginkgo biloba extract.
DATA SOURCES: Empirical studies, reviews, chapters, and
conference proceedings were identified in the following
databases: Medline, the Research Council for Complementary
Medicine based on the British Library database, and
Psychlnfo. Ginkgo biloba, EGb 761, Tanakan, Tebonin, Rokan,
and LI 1370 were the principal index terms.
STUDY SELECTION AND DATA EXTRACTION: Controlled clinical
studies with both positive and negative findings are
included, in addition to animals studies illustrating
mechanisms of activity.
DATA SYNTHESIS: Ginkgo has shown activity centrally and
peripherally, affecting electrochemical, physiologic,
neurologic, and vascular systems in animals and humans with
few adverse side effects or drug interactions. Ginkgo shows
promise in patients with dementia, normal aging, and
cerebrovascular-related disorders. Clinical indications
include memory, information processing, and ADL.
CONCLUSIONS: Ginkgo shows promise in treating some of
the neurologic sequelae associated with Alzheimer's
disease, TBI, stroke, normal aging, edema, tinnitus, and
macular degeneration. Mechanisms of action may include
antioxidant, neurotransmitter/receptor modulatory, and
antiplatelet activating factor properties. While safe,
caution is advised when recommending ginkgo to patients
taking anticoagulants. Future studies should examine dose
effects, component activity, mechanisms, and clinical
applications.
Clinical profile of
donepezil in the treatment of Alzheimer's
disease.
Doody RS. Baylor College of Medicine, Department of
Neurology and Alzheimer's Disease Research Center, Houston,
Tex. 77030-3498, USA.
Gerontology 1999;45 Suppl 1:23-32
Although the underlying pathogenesis of Alzheimer's
disease (AD) is not fully understood, one of its key
features is the widespread loss of central cholinergic
innervation, known to be fundamental for cognitive
processes. This finding led to the hypothesis that
pharmacological enhancement of acetylcholine (ACh)
neurotransmission may alleviate the symptoms of AD.
Currently, cholinergic therapy, particularly cholinesterase
(ChE) inhibition, represents the most realistic approach to
the symptomatic treatment of AD. Donepezil HCl, for
example, is a piperidine-based, reversible
acetylcholinesterase (AChE) inhibitor, chemically distinct
from other ChE inhibitors and rationally designed for the
symptomatic treatment of AD. It is highly selective for
centrally acting AChE, with little or no affinity for
butyrylcholinesterase, present predominantly in the
periphery. Phase I and II clinical trials demonstrated
donepezil's favourable pharmacokinetic, pharmacodynamic and
safety profile with no requirement for dose modification in
the elderly or in patients with renal or hepatic
impairment. Furthermore, its long half-life supports a
simple and convenient once-daily dosing regimen. Subsequent
to encouraging phase II clinical trial results, two
pivotal, randomized, double-blind phase III trials (of 15
and 30 weeks' duration) demonstrated highly significant
improvements in cognition and global function in mild to
moderately severe AD patients treated with either 5 or 10
mg/day donepezil compared with placebo. Adverse events in
the phase II and III trials, primarily cholinergic in
nature, were transient and generally mild in severity and
resolved during continued donepezil administration. Thus,
the donepezil clinical trials programme has shown that this
drug is a clinically effective and well-tolerated,
once-daily treatment for the symptoms of mild to moderately
severe AD.
Therapeutic standards in
Alzheimer disease.
Doody RS Baylor College of Medicine, Department of
Neurology, Houston, Texas 77030, USA.
rdoody@bcm.tmc.edu
Alzheimer Dis Assoc Disord 1999 Nov;13 Suppl 2:S20-6
Donepezil is an effective, well-tolerated, and easily
administered symptomatic treatment for mild-to-moderate
Alzheimer disease (AD). Data from Phase III clinical trials
have demonstrated that donepezil improves cognition, global
function, and activities of daily living. In addition,
there were no clinically significant treatment-related
effects on vital signs or laboratory values in any trial.
Adverse events, when present, were generally mild in
intensity, transient, and resolved during continued
treatment with donepezil. This favorable safety profile,
together with its reported clinical benefits established
donepezil as one standard of AD therapy. Vitamin E is one
of two anti-oxidant therapies that may help to slow the
progression of AD over at least a two-year period. One
large-scale clinical trial suggests that it has sufficient
benefit and safety to join donepezil as a current standard
of AD therapy.
Increased effectiveness
of tacrine by deprenyl co-treatment in rats: EEG and
behavioral evidence
Dringenberg HC, Laporte PP, Diavolitsis P Department of
Psychology, Queen's University, Kingston, Ontario,
Canada.
Neuroreport 2000 Nov 9;11(16):3513-6
The acetylcholinesterase inhibitor tacrine and the
monoamine oxidase inhibitor deprenyl are considered useful
pharmacotherapies for Alzheimer's disease (AD). We assessed
whether co-administration of these two compounds increases
their effectiveness against two measures of
cholinergic-monoaminergic hypofunction in rats, cortical
EEG slowing and impaired spatial performance. EEG slowing
induced by cholinergic-monoaminergic blockade was reversed
by both deprenyl (10 - 50 mg/kg) and tacrine (1 - 20
mg/kg), but co-treatment with a subthreshold dose of
deprenyl plus tacrine was markedly more effective. Neither
tacrine (5 mg/kg) nor deprenyl (10 mg/kg) alone reduced
water maze deficits due to cholinergic-monoaminergic
hypofunction, but co-treatment (using these doses) improved
performance. Cholinergic-monoaminergic co-treatment may
constitute a useful pharmacotherapy to correct
physiological and behavioral dysfunction due to
neurotransmitter deficiencies in AD.
Vitamin B12 deficiency in
dementia and cognitive impairment: the effects of treatment
on neuropsychological function.
Eastley R, Wilcock GK, Bucks RS. Avon and Western
Wiltshire Mental Health Care NHS Trust, Southmead Hospital,
Bristol, UK.
Int J Geriatr Psychiatry 2000 Mar;15(3):226-33
BACKGROUND: Vitamin B12 assay is part of the routine
investigation of dementia, although few studies have
investigated the effects of treatment on cognition. We
examined the effects of B12 treatment on neuropsychological
function and disease progression in patients presenting
with dementia or cognitive impairment.
METHODS: From 1432 patients who were assessed at the
Bristol Memory Disorders Clinic, 125 patients with low
serum B12 were identified. Sixty-six patients presenting
with dementia, and 22 with cognitive impairment were seen
for a second assessment after treatment. Changes in
neuropsychological test scores were compared with those of
patients with normal serum B12, matched by age and
diagnosis.
RESULTS: The majority of patients with low serum B12 had
normal Hb and MCV values. We found no cases of reversible
B12 deficiency dementia. The B12 treatment patients who
presented with dementia showed no significant improvement,
and no less deterioration, in their neuropsychological
function than their matched group. However, a treatment
effect was demonstrated among the patients presenting with
cognitive impairment. These improved significantly compared
to matched patients on the verbal fluency test
(p<0.01).
CONCLUSION: All patients with cognitive impairment
should be investigated for B12 deficiency. Vitamin B12
treatment may improve frontal lobe and language function in
patients with cognitive impairment, but rarely reverses
dementia. Copyright 2000 John Wiley &amp; Sons, Ltd.
Piracetam reverses
hippocampal membrane alterations in Alzheimer's
disease.
Eckert GP, Cairns NJ, Muller WE Department of
Pharmacology, Biocenter, University of Frankfurt, Federal
Republic of Germany.
J Neural Transm 1999;106(7-8):757-61
The in vitro effects of piracetam treatment on the
fluidity of membranes from the hippocampus of Alzheimer's
Disease patients (AD) and non-demented controls were
studied. Hippocampal membranes of AD patients showed a
significant lower hydrocarbon core fluidity compared with
membranes from elderly non-demented controls. Preincubation
with piracetam enhanced the hydrocarbon core fluidity of
hippocampal membranes from AD-patients as well as elderly
controls in a concentration depending fashion, although the
effect was more pronounced for the AD membranes. In the
presence of piracetam, the difference of the membrane
fluidity between AD and control membranes was not longer
apparent.
Immunological mechanisms
and the spectrum of psychiatric syndromes in Alzheimer's
disease.
Eikelenboom P, Hoogendijk WJ, Jonker C, van Tilburg W.
Graduate School Neuroscience, Amsterdam, The
Netherlands
J Psychiatr Res 2002 Sep-Oct;36(5):269-80
Pathological, genetic and epidemiological studies
support the opinion that inflammatory mechanisms are
involved in the pathogenesis of Alzheimer's disease (AD).
Recent pathological and neuroradiological (PET) data show
that activation of microglia is an early pathogenic event
that precedes the process of severe neuropil destruction in
AD brains. In this paper we review the evidence that
inflammatory mediators can play a pathogenic role in some
behavioural disorders frequently encountered during the
clinical course in AD patients. Motivational disturbances
are the most striking of the depressive symptoms in AD and
can be present in a preclinical stage of the disease.
Experimental animal studies and clinical trials in humans
have shown that cytokines can induce similar symptoms which
were described as 'sickness behaviour' or 'depressive-like'
state. Delirious states are frequently observed in more
advanced stages of dementia. Delirium is generally
considered the result of an imbalance in neurotransmitter
systems with severe deficits of the cholinergic systems.
Animal studies show that pro-inflammatory cytokines, such
as interleukin-1, induce a reduced activity of the
cholinergic system. In AD, the release of cytokines would
exacerbate any already existing disturbances in the
cholinergic neurotransmission. This could explain the
susceptibility of demented patients to delirium provoked by
a wide variety of trivial incidents that are accompanied by
an acute phase response. The data reviewed in this paper
suggest that it could be worthwhile employing a
neuroimmunological approach to study at molecular level the
pathogenesis of a broad spectrum of behavioural
disturbances common in the clinical course of AD
patients.
Double-blind cross-over
study of phosphatidylserine vs. placebo in patients with
early dementia of the Alzheimer type . Engel RR,
Satzger W, Gunther W, Kathmann N, Bove D, Gerke S, Munch U,
Hippius H. Psychiatric Hospital, University of Munich,
Germany.
Eur Neuropsychopharmacol 1992 Jun;2(2):149-55
Thirty-three patients with mild primary degenerative
dementia according to DSM-III (MMS between 15 and 27) took
part in a double-blind cross-over study of
phosphatidylserine (Fidia, 300 mg/d) versus placebo. Both
treatment phases lasted for 8 weeks with an 8 week washout
phase in between and a 4 week washout phase before
treatment phase one. Clinical global improvement ratings
showed significantly more patients improving under BC-PS
than under placebo during treatment phase one. The
improvement carried over to the following wash-out and
treatment phases. There were no significant improvements in
GBS dementia rating scale, psychometric tests or
P300-latency. 16-channel EEG mapping findings indicated
that the patients initially showed higher power values in
all frequency bands (except alpha), when compared to a
younger, healthy control group. BC-PS reduced the higher
power values compared to placebo, shifting EEG power more
towards the normal level.
Selegiline in the
treatment of Alzheimer's disease: a long-term randomized
placebo-controlled trial. Czech and Slovak Senile Dementia
of Alzheimer Type Study Group.
Filip V, Kolibas E Department of Psychiatry, Comenius
University, Bratislava, Slovak Republic.
pharmnet@comp.cz
J Psychiatry Neurosci 1999 May;24(3):234-43
OBJECTIVE: To evaluate the efficacy and adverse effects
of the type B monoamine oxidase inhibitor selegiline (also
known as I-deprenyl) in the treatment of Alzheimer's
disease. DESIGN: Long-term, double-blind,
placebo-controlled trial.
SETTING: Seven cities (1 or 2 nursing homes in each
city) in the Czech and Slovak Republics. PATIENTS: A total
of 173 nursing-home residents fulfilling the DSM-III
criteria for mild to moderate Alzheimer's disease.
INTERVENTIONS: Selegiline (10 mg per day) or placebo (both
including 50 mg ascorbic acid) administered for 24
weeks.
OUTCOME MEASURES: Clinical Global Impressions scale and
Nurses Observation Scale for Inpatient Evaluation at
baseline and at weeks 6, 12 and 24; Clock Drawing Test at
baseline and 24 weeks, results of which were evaluated as
normal or pathologic, and quantitatively on a modified
6-point scale; Sternberg's Memory Scanning test at baseline
and at weeks 6, 12 and 24; Mini Mental State Examination,
and electroencephalogram at baseline and 24 weeks;
Structured Adverse Effects Rating Scale; physical,
laboratory, hematological and electrocardiographic
examinations at baseline and weeks 12 and 24.
RESULTS: A total of 143 subjects completed enough of the
trial to be entered in the analysis. Subjects were analyzed
by 2 subgroups depending on whether they had a normal or
pathologic result of the Clock Drawing Test. Analysis of
variance showed significant improvement with selegiline
versus placebo among those with a normal result of the
Clock Drawing Test on the Mini Mental Status Examination
(total score and orientation-place subscale) and among
those with a pathologic result of the Clock Drawing Test of
Sternberg's Memory Scanning test (for both speed and
accuracy), on the Clinical Global Impressions scale as well
as in terms of the dominant frequency on
electroencephalograms.
CONCLUSION: Selegiline has a long-term beneficial effect
in Alzheimer's disease on memory modalities that reflect
the function of the prefrontal areas of the brain, which
are rich in dopamine receptors. The delayed appearance of
differences between selegiline and placebo supports the
notion that the mechanism of action is through neuronal
rescue or neuroprotection. The differential response of
patients with normal and pathologic results of the Clock
Drawing Test may reflect the fact that the evaluation
methods' sensitivity to change depends on the severity of
dementia.
Treatment of
Alzheimer's disease with short- and long-term oral THA and
lecithin: a double-blind study.
Fitten LJ, Perryman KM, Gross PL, Fine H, Cummins J,
Marshall C. VA Medical Center, Sepulveda, Calif 91343.
Am J Psychiatry 1990 Feb;147(2):239-42
Ten Alzheimer's disease patients underwent a trial of
oral tetrahydroaminoacridine (THA) and lecithin. After 3
inpatient weeks there was no clear therapeutic effect.
Three of six patients able to continue in long-term
treatment showed measurable cognitive improvement, but only
one displayed clinically obvious improvement.
Donepezil.
Pharmacoeconomic implications of therapy.
Foster RH, Plosker GL Adis International Limited,
Auckland, New Zealand. demail@adis.co.nz
Pharmacoeconomics 1999 Jul;16(1):99-114
Donepezil is a specific acetylcholinesterase inhibitor
that can improve symptoms in patients with mild-to-moderate
Alzheimer's disease; cognitive function is maintained above
baseline levels for up to 1 year and normal decline of
cognitive function is slowed. The ability of the patient to
perform daily activities and neuropsychiatric symptoms may
also be improved by donepezil, but data are limited.
Donepezil is not expected to alter the underlying
neurodegenerative process, and the response to the drug
varies between individuals. In the absence of validated
instruments to measure quality of life, it is not clear how
donepezil affects this parameter. In a US survey of
caregivers of patients with Alzheimer's disease who were
being cared for at home at the start of the 6-month study
period, treatment with donepezil did not increase overall
direct medical costs. The acquisition cost of the drug was
balanced by reduced institutionalisation costs. Economic
analyses using Markov models from the US, UK and Canada
suggest that donepezil initiated in the early stages of
disease may be effectively cost neutral as a result of
patients remaining in a nonsevere state of disease for a
longer time.
Neuronal sparing and
behavioral effects of the antiapoptotic drug, (-)deprenyl,
following kainic acid administration.
Gelowitz DL, Paterson IA Department of Psychiatry,
University of Cincinnati, OH 45267-0559, USA.
Pharmacol Biochem Behav 1999 Feb;62(2):255-62
(-)Deprenyl is an irreversible inhibitor of monoamine
oxidase B (MAO-B) frequently used as an adjunct therapy in
the treatment of Parkinson's Disease. Recent evidence,
however, has found that deprenyl's metabolites are
associated with an antiapoptotic action within certain
neuronal populations. Interestingly, deprenyl's
antiapoptotic actions appear not to depend upon the
inhibition of MAO-B. Due to a paucity of information
surrounding (-)deprenyl's ability to spare neurons in vivo,
a series of studies was conducted to further investigate
this phenomenon within an apoptotic neuronal death model:
kainic acid induced excitotoxicity. Results indicated that
(-)deprenyl increased hippocampal neuronal survival
compared to saline-matched controls following kainic acid
insult. Furthermore, it was discovered that (-)deprenyl
treatment could be stopped 14 days following CNS insult by
kainate, with evidence of neuronal sparing still present by
day 28. In open-field locomotor activity testing of
kainate-treated animals, those given subsequent (-)deprenyl
treatment showed habituation curves similar to control
subjects, while saline-treated animals did not. Given
deprenyl's antiapoptotic actions, it is proposed that
(-)deprenyl may be beneficial in the treatment of a variety
of neurodegenerative diseases where evidence of apoptosis
exists, such as Parkinson's and Alzheimer's Disease, by
slowing the disease process itself.
The incidence of
dementia and intake of animal products: preliminary
findings from the Adventist Health Study.
Giem P, Beeson WL, Fraser GE Department of Preventive
Medicine, School of Medicine, Loma Linda University, CA
92350.
Neuroepidemiology 1993;12(1):28-36
We investigated the relationship between animal product
consumption and evidence of dementia in two cohort
substudies. The first enrolled 272 California residents
matched for age, sex, and zip code (1 vegan, 1
lacto-ovo-vegetarian, and 2 'heavy' meat eaters in each of
68 quartets). This design ensured a wide range of dietary
exposure. The second included 2,984 unmatched subjects who
resided within the Loma Linda, California area. All
subjects were enrolled in the Adventist Health Study. The
matched subjects who ate meat (including poultry and fish)
were more than twice as likely to become demented as their
vegetarian counterparts (relative risk 2.18, p = 0.065) and
the discrepancy was further widened (relative risk 2.99, p
= 0.048) when past meat consumption was taken into account.
There was no significant difference in the incidence of
dementia in the vegetarian versus meat-eating unmatched
subjects. There was no obvious explanation for the
difference between the two substudies, although the power
of the unmatched sub-study to detect an effect of 'heavy'
meat consumption was unexpectedly limited. There was a
trend towards delayed onset of dementia in vegetarians in
both substudies.
Abdominal omentum
transfer and the nervous system.
Goldsmith HS.
Lancet 1985 Jun 29;1(8444):1514
No Abstracts Available
Brain vascularization
by intact omentum.
Goldsmith HS, Chen WF, Duckett SW.
Arch Surg 1973 May;106(5):695-8
No Abstracts Available
Lipid angiogenic factor
from omentum.
Goldsmith HS, Griffith AL, Kupferman A, Catsimpoolas
N.
JAMA 1984 Oct 19;252(15):2034-6
Placing the omentum on the brain surface by surgical
transposition or transplantation will result in the
development of numerous neovascular connections between
these two structures. This phenomenon occurs even in the
absence of cerebral ischemia, which raised the question as
to whether an angiogenic factor was causing the response. A
lipid material obtained from the omentum contains a potent
angiogenic factor extractable in a chloroform-methanol
solvent mixture. Angiogenesis created by this material was
observed in the rabbit cornea after only a single injection
of the substance. The angiogenic material obtained from the
omentum is abundant in supply. This important
characteristic offers promise for the purification and
identification of its structure, which should allow for
extensive animal and clinical studies dealing with the
development or inhibition of angiogenesis.
Vascularization of
brain and spinal cord by intact omentum.
Goldsmith HS, Steward E.
Appl Neurophysiol 1984;47(1-2):57-61
No Abstracts Available
Vasoactive
neurochemicals identified in omentum: a preliminary
report.
Goldsmith HS, McIntosh T, Vezina RM, Colton T.
Department of Surgery, Boston University School of
Medicine.
Br J Neurosurg 1987;1(3):359-64
There has been increasing interest in biologic,
immunologic, and chemical activity originating from omental
tissue. Since clinical improvement has been observed in
some patients very shortly after surgically transposing
their omentum to the spinal cord or brain, the question
arose as to whether neurochemicals might be present in
omental tissue; a possible explanation for some of these
neurological changes. This paper reports the presence of
vasoactive neurochemicals in canine omental tissue. It
remains unclear, however, whether the omentum produces or
simply concentrates these and other neurochemicals.
Early diagnosis of
cognitive impairment in the elderly with the focus on
Alzheimer's disease.
Gottfries CG, Lehmann W, Regland B. Department of
Psychiatry and Neurochemistry, Institute of Clinical
Neuroscience, Goteborg University, Molndal, Sweden.
J Neural Transm 1998;105(8-9):773-86
In dementia disorders, it can be assumed that the
pathological process in the brain has been present for a
long time. It is therefore of importance to have a
preclinical or an early clinical diagnosis. Obviously,
vulnerability genes, such as ApoE-4, can be diagnosed
preclinically. As we have no treatment to offer patients
with genetic risk factors, genotyping for ApoE-4 is at
present of no clinical use. Trained neuropsychologists have
today access to sensitive tests which reveal cognitive
impairment before the disturbances reach the level of
dementia. Laboratory investigations of cerebrospinal fluid
have so far yielded no great results. Tau protein appears
to be the most sensitive marker, but it is unspecific.
Chromogranin A separates early onset from late onset
Alzheimer's disease and seems to be a marker for synaptic
degeneration. Synaptotagmin was also found to be reduced in
patients with early onset Alzheimer's disease. Still we do
not know, however, whether these proteins are early markers
for degenerative processes in the brain. Laboratory
investigations of blood have not yielded markers of use in
early or differential diagnosis of dementia disorders. In a
study at our own institute, however, we found
serum-homocysteine (S-HCY) to be an early and sensitive
marker for cognitive impairment. In patients with dysmentia
(mild cognitive impairment), no less than 39% had
pathological S-HCY levels, indicating insufficient 1-carbon
metabolism.
Nuclear
factor-kappaB/Rel proteins: a point of convergence of
signalling pathways relevant in neuronal function and
dysfunction.
Grilli M, Memo M. Schering-Plough Research Institute,
San Raffaele Science Park, Milan, Italy.
mariagrazia.grilli@spcorp.com
Biochem Pharmacol 1999 Jan 1;57(1):1-7
Nuclear factor-kappaB (NF-kappaB)/Rel designates a
family of transcription factors participating in the
activation of a wide range of genes crucially involved in
immune and inflammatory function. NF-kappaB/Rel proteins
have been demonstrated recently in primary neurons and in
several brain areas. Functional significance of these
proteins is still not understood completely, but since
certain subsets of neurons appear to contain constitutively
active DNA-binding activity, it seems likely that they may
participate in normal brain function. A growing body of
evidence is accumulating for a specific activation of
NF-kappaB/Rel proteins in the CNS, and in particular in
neuronal cells, during neurodegenerative processes
associated to etiologically unrelated conditions. Whether
NF-kappaB activation is part of the neurodegenerative
process or of protective mechanisms is a matter of debate.
This issue will be reviewed here with particular attention
to the available reports on the activity of NF-kappaB/Rel
proteins in both experimental paradigms of
neurodegeneration and post-mortem brain tissue of patients
affected by various neurological diseases. We hypothesize
that NF-kappaB/Rel proteins may represent the point of
convergence of several signalling pathways relevant for
initiating or accelerating the process of neuronal
dysfunction and degeneration in many neurological diseases,
including Parkinson's disease, Alzheimer's disease, CNS
viral infections, and possibly others. If NF-kappaB/Rel
proteins represent an integrating point of several pathways
potentially contributing to neuronal degeneration,
molecules that finely modulate their activity could
represent a novel pharmacological approach to several
neurological diseases.
Evidence that nerve
growth factor influences recent memory through structural
changes in septohippocampal cholinergic
neurons.
Gustilo MC, Markowska AL, Breckler SJ, Fleischman CA,
Price DL, Koliatsos VE Department of Pathology, The Johns
Hopkins University School of Medicine, Baltimore, Maryland
21205, USA.
J Comp Neurol 1999 Mar 22;405(4):491-507
We compared, in 4- and 23-month-old Fischer-344 rats,
the effects of nerve growth factor (NGF) on basal forebrain
cholinergic neurons with behavioral performance in
acetylcholine-dependent memory tasks (recent and reference
memory). Noncholinergic monoamine markers in target fields
of cholinergic neurons were also investigated. We found
that NGF has contrasting effects on recent memory in the
two age groups in causing improvement in aged rats and
deterioration in young rats. In addition, NGF caused
significant increase in the size of cholinergic perikarya
in all sectors of the basal nucleus complex (BNC). Higher
doses of NGF were required to produce hypertrophy in aged
animals, a pattern consistent with a lower sensitivity to
NGF of aged cholinergic neurons. Analysis of covariance
showed that the behavioral effects of NGF were eliminated
after covarying out the hypertrophy of cholinergic
perikarya. Therefore, NGF causes hypertrophy of cholinergic
perikarya regardless of age, and this neurobiological
measure correlates with the effects of NGF on recent
memory. Reference memory improved moderately only in old
rats. This mild effect covaried with an increase in choline
acetyltransferase activity in neocortex. Cortical terminal
fields of noradrenergic and serotoninergic pathways were
not affected by NGF. Taken together, our results indicate
that NGF influences recent memory in an age- and
transmitter-specific fashion. We postulate that the direct
cause of the effects of NGF on memory is not perikaryal
hypertrophy per se but rather an increased density of
terminals, which always accompanies perikaryal hypertrophy.
Although these results continue to support the use of NGF
for the treatment of Alzheimer's disease, they raise
questions regarding the therapeutic role of NGF for
degeneration of BNC neurons occurring in young age.
Clinical aspects of
nimodipine.
Grobe-Einsler R
Pharma Research Center, Wuppertal, Germany.
Clin Neuropharmacol 1993;16 Suppl 1:S39-45
This overview describes the result of the clinical
development program in organic brain syndrome (impaired
brain function in old age), where efficacy was proven in 11
double-blind, placebo-controlled studies. Another study
within this development program showed nimodipine not only
to be superior to placebo but also to hydergine.
Furthermore, in a placebo-controlled clinical trial,
nimodipine caused further improvement in performance
compared to regular mental exercise at home. Due to the
results in the organic brain syndrome program, registration
was granted in 23 countries worldwide for this indication.
In one clinical trial in the dementia development program,
patients with dementia were carefully allocated either to
primary degenerative dementia (PDD) or multi-infarct
dementia (MID) stratum; nimodipine was shown to be superior
to placebo independent of the etiology. Other clinical
trials conducted in this indication supported the evidence
for efficacy and showed that nimodipine-treated patients
performed better than placebo patients. The safety profile
of the drug is well established and substantiated by
extensive postmarketing surveillance. In general,
nimodipine was well tolerated, showing few adverse events.
Finally, topics for future research are covered such as
developing new instruments to assess more severe patients,
expanding the patient collective to secondary dementias
such as AIDS and Parkinson dementia, implementation of
cost/utility elements in the development program, and the
issue of nimodipine's potential role in the prevention of
disease.
Vitamin E and Alzheimer
disease: the basis for additional clinical
trials.
Grundman M. Alzheimer's Disease Cooperative Study, 9500
Gilman Drive 0949, La Jolla, CA, 92093-0949, USA.
mgrundman@ucsd.edu.
Am J Clin Nutr 2000 Feb;71(2):630S-636S
Many lines of evidence suggest that oxidative stress is
important in the pathogenesis of Alzheimer disease. In
particular, beta-amyloid, which is found abundantly in the
brains of Alzheimer disease patients, is toxic in neuronal
cell cultures through a mechanism involving free radicals.
Vitamin E prevents the oxidative damage induced by
beta-amyloid in cell culture and delays memory deficits in
animal models. A placebo-controlled, clinical trial of
vitamin E in patients with moderately advanced Alzheimer
disease was conducted by the Alzheimer's Disease
Cooperative Study. Subjects in the vitamin E group were
treated with 2000 IU (1342 alpha-tocopherol equivalents)
vitamin E/d. The results indicated that vitamin E may slow
functional deterioration leading to nursing home placement.
A new clinical trial is planned that will examine whether
vitamin E can delay or prevent a clinical diagnosis of
Alzheimer disease in elderly persons with mild cognitive
impairment.
The effect of
tetrahydrofolate on tetrahydrobiopterin
metabolism.
Hamon CG, Blair JA, Barford PA.
J Ment Defic Res 1986 Jun;30 ( Pt 2):179-83
5-Methyltetrahydrofolate and vitamin B12 appear to be
required for the biosynthesis of tetrahydrobiopterin. A
deficiency of either could be sufficient to bring about
neurological change which can be corrected by reversing the
deficiency. Patients with senile dementia could possibly be
benefited by the administration of
5-methyltetrahydrofolate.
Long-term effects of
phosphatidylserine, pyritinol, and cognitive training in
Alzheimer's disease. A neuropsychological, EEG, and PET
investigation
Heiss WD, Kessler J, Mielke R, Szelies B, Herholz K
Max-Planck-Institut fur neurologische Forschung.
Dementia 1994 Mar-Apr;5(2):88-98
70 patients with probable Alzheimer's disease were
randomly allocated to four groups: 17 patients received
only social support. 18 cognitive training twice a week, in
17 cognitive training was combined with pyritinol 2 x 600
mg/day and in 18 cognitive training was combined with
phosphatidylserine 2 x 200 mg/day. Treatment duration was 6
months. Before and after treatment, the patients underwent
neuropsychological testing as well as measurement of the
regional cerebral metabolic rate for glucose using positron
emission tomography and 18F-2-fluoro-2-deoxy-D-glucose.
Before treatment the groups were comparable in respect to
resting and activated glucose pattern achieved by a visual
recognition task. Electrophysiological changes were
assessed as EEG power, globally and in 4 frequency bands.
This 6-month study in four groups of patients with
Alzheimer's disease indicated that phosphatidylserine
treatment has an effect on different measures of brain
function. Since neuropsychological improvements were best
documented after 8 and 16 weeks and faded towards the end
of the treatment period, it must be concluded that this
symptomatic therapy is mainly of short-term benefit and was
overcome by the progressive pathological changes at the end
of the treatment period.
JC virus infection and
Alzheimer's disease: reappraisal of an in situ
hybridization approach.
Heinonen O, Syrjanen S, Mantyjarvi R, Syrjanen K,
Riekkinen P. Department of Neurology, University of Kuopio,
Finland.
Ann Neurol 1992 Apr;31(4):439-41
To assess the validity of the recently reported data on
frequent occurrence of latent JC virus (JCV) infections in
the brains of patients with Alzheimer's disease, we used in
situ hybridization with biotinylated whole genomic JCV
probes and the streptavidin-biotinylated alkaline
phosphatase method to examine brain sections of such
patients. We did not find any signs of JCV either in the
brains of the patients with Alzheimer's disease or in those
of nondemented, elderly control patients. Non-specific
staining of corpora amylacea-like bodies, however, was
invariably detected with in situ hybridization using JCV
probes.
Lecithin for dementia
and cognitive impairment (Cochrane Review).
Higgins JP, Flicker L MRC Biostatistics Unit, Institute
of Public Health, Robinson Way, Cambridge, Cambridgeshire,
UK, CB2 2SR. julian.higgins@mrc-bsu.cam.ac.uk [Record
supplied by publisher]
Cochrane Database Syst Rev 2000;4:CD001015
BACKGROUND: Alzheimer's disease sufferers have been
found to have a lack of the enzyme responsible for
converting choline into acetylcholine within the brain.
Lecithin is a major dietary source of choline, so extra
consumption may reduce the progression of dementia.
OBJECTIVES: To determine the efficacy of lecithin in the
treatment of dementia or cognitive impairment.
SEARCH STRATEGY: The Cochrane Dementia and Cognitive
Impairment Group Register of Clinical Trials has been
searched, as have the electronic databases MEDLINE, EMBASE,
Psychlit, ISI and Current Contents. Reference lists and
relevant books have been examined.
SELECTION CRITERIA: All unconfounded, randomized trials
comparing lecithin with placebo in a treatment period
longer than one day, in patients with dementia of the
Alzheimer type, vascular dementia, mixed vascular and
Alzheimer's disease, unclassified or other dementia or
unclassified cognitive impairment not fulfilling the
criteria for dementia are eligible for inclusion.
DATA COLLECTION AND ANALYSIS: Data were extracted by two
independent reviewers and cross-checked. Meta-analyses were
performed when more than one trial provided data on a
comparable outcome on sufficiently similar patients. Random
effects analyses were performed whenever heterogeneity
between results appeared to be present. Standardised mean
difference were used due do the use of different scales and
periods of treatment. Odds ratios for dichotomous data were
pooled using the Mantel-Haenszel or DerSimonian and Laird
methods.
MAIN RESULTS: Twelve randomized trials have been
identified involving patients with Alzheimer's disease (265
patients), Parkinsonian dementia (21 patients) and
subjective memory problems (90 patients). No trials
reported any clear clinical benefit of lecithin for
Alzheimer's disease or Parkinsonian dementia. Few trials
contributed data to meta-analyses. The only statistically
significant result was in favour of placebo for adverse
events, based on one trial, which appears likely to be a
spurious result. A dramatic result in favour of lecithin
was obtained in a trial of subjects with subjective memory
problems.
REVIEWER'S CONCLUSIONS: Evidence from randomized trials
does not support the use of lecithin in the treatment of
patients with dementia. A moderate effect cannot be ruled
out, but results from the small trials to date do not
indicate priority for a large randomized trial.
DHEA-S plasma levels
and incidence of Alzheimer's disease.
Hillen T, Lun A, Reischies FM, Borchelt M,
Steinhagen-Thiessen E, Schaub RT Department of Internal
Medicine-Geriatrics, Medical Faculty, Humboldt University
Berlin/Charite, Germany.
Biol Psychiatry 2000 Jan 15;47(2):161-3
BACKGROUND: Cross-sectional studies controlling for age
and gender reported a relationship between Alzheimer's
disease and low dehydroepiandrosterone sulphate (DHEA-S)
plasma levels. Prospective data with sufficient control for
confounding factors are lacking.
METHODS: A nested case-control study examined baseline
DHEA-S in participants of the Berlin Aging Study. Cases (n
= 14) developed dementia of the Alzheimer type within 3
years. Control group A (n = 14) was matched for gender,
age, multimorbidity, and immobility. Control group B (n =
13) was matched for gender and age and comprised
participants free from multimorbidity, immobility,
multimedication, need of help, incontinence, visual
impairment, hearing impairment, and depression.
RESULTS: The mean plasma DHEA-S concentration of case
subjects was 1.02 0.61 mumol/L. Both control groups had
higher mean DEHA-S levels, in control group A, it was 1.89
1.24 mumol/L (p = .012) and in control group B 1.70 1.38
mumol/L (p = .093).
CONCLUSIONS: This population-based prospective study
supports the role of DHEA-S as a risk factor for
Alzheimer's disease.
Carnosine, a
protective, anti-ageing peptide?
Hipkiss AR. Molecular Biology and Biophysics Group,
King's College London, Strand, UK.
Int J Biochem Cell Biol 1998 Aug;30(8):863-8
Carnosine (beta-alanyl-L-histidine) has protective
functions additional to anti-oxidant and free-radical
scavenging roles. It extends cultured human fibroblast
life-span, kills transformed cells, protects cells against
aldehydes and an amyloid peptide fragment and inhibits, in
vitro, protein glycation (formation of cross-links,
carbonyl groups and AGEs) and DNA/protein cross-linking.
Carnosine is an aldehyde scavenger, a likely lipofuscin
(age pigment) precursor and possible modulator of diabetic
complications, atherosclerosis and Alzheimer's disease.
Pluripotent protective
effects of carnosine, a naturally occurring
dipeptide.
Hipkiss AR, Preston JE, Himsworth DT, Worthington VC,
Keown M, Michaelis J, Lawrence J, Mateen A, Allende L,
Eagles PA, Abbott NJ. Molecular Biology and Biophysics
Group, King's College London, Strand, United Kingdom.
alan.hipkiss@kcl.ac.uk
Ann N Y Acad Sci 1998 Nov 20;854:37-53
Carnosine is a naturally occurring dipeptide
(beta-alanyl-L-histidine) found in brain, innervated
tissues, and the lens at concentrations up to 20 mM in
humans. In 1994 it was shown that carnosine could delay
senescence of cultured human fibroblasts. Evidence will be
presented to suggest that carnosine, in addition to
antioxidant and oxygen free-radical scavenging activities,
also reacts with deleterious aldehydes to protect
susceptible macromolecules. Our studies show that, in
vitro, carnosine inhibits nonenzymic glycosylation and
cross-linking of proteins induced by reactive aldehydes
(aldose and ketose sugars, certain triose glycolytic
intermediates and malondialdehyde (MDA), a lipid
peroxidation product). Additionally we show that carnosine
inhibits formation of MDA-induced protein-associated
advanced glycosylation end products (AGEs) and formation of
DNA-protein cross-links induced by acetaldehyde and
formaldehyde. At the cellular level 20 mM carnosine
protected cultured human fibroblasts and lymphocytes, CHO
cells, and cultured rat brain endothelial cells against the
toxic effects of formaldehyde, acetaldehyde and MDA, and
AGEs formed by a lysine/deoxyribose mixture. Interestingly,
carnosine protected cultured rat brain endothelial cells
against amyloid peptide toxicity. We propose that carnosine
(which is remarkably nontoxic) or related structures should
be explored for possible intervention in pathologies that
involve deleterious aldehydes, for example, secondary
diabetic complications, inflammatory phenomena, alcoholic
liver disease, and possibly Alzheimer's disease.
Endogenous mechanisms
of neuroprotection: role of zinc, copper, and
carnosine.
Horning MS, Blakemore LJ, Trombley PQ. Biomedical
Research Facility, Department of Biological Science,
Florida State University, Tallahassee 32306-4340, USA.
horning@neuro.fsu.edu
Brain Res 2000 Jan 3;852(1):56-61
Zinc and copper are endogenous transition metals that
can be synaptically released during neuronal activity.
Synaptically released zinc and copper probably function to
modulate neuronal excitability under normal conditions.
However, zinc and copper also can be neurotoxic, and it has
been proposed that they may contribute to the
neuropathology associated with a variety of conditions,
such as Alzheimer's disease, stroke, and seizures.
Recently, we demonstrated that carnosine, a dipeptide
expressed in glial cells throughout the brain as well as in
neuronal pathways of the visual and olfactory systems, can
modulate the effects of zinc and copper on neuronal
excitability. This result led us to hypothesize that
carnosine may modulate the neurotoxic effects of zinc and
copper as well. Our results demonstrate that carnosine can
rescue neurons from zinc- and copper-mediated neurotoxicity
and suggest that one function of carnosine may be as an
endogenous neuroprotective agent.
Health benefits of
docosahexaenoic acid.
Horrocks LA, Yeo YK Docosa Foods Ltd, 1275 Kinnear Road,
Columbus, OH 43212-1155, USA,
Pharmacol Res 1999 Sep;40(3):211-25
Docosahexaenoic acid (DHA) is essential for the growth
and functional development of the brain in infants. DHA is
also required for maintenance of normal brain function in
adults. The inclusion of plentiful DHA in the diet improves
learning ability, whereas deficiencies of DHA are
associated with deficits in learning. DHA is taken up by
the brain in preference to other fatty acids. The turnover
of DHA in the brain is very fast, more so than is generally
realized. The visual acuity of healthy, full-term,
formula-fed infants is increased when their formula
includes DHA. During the last 50 years, many infants have
been fed formula diets lacking DHA and other omega-3 fatty
acids. DHA deficiencies are associated with foetal alcohol
syndrome, attention deficit hyperactivity disorder, cystic
fibrosis, phenylketonuria, unipolar depression, aggressive
hostility, and adrenoleukodystrophy. Decreases in DHA in
the brain are associated with cognitive decline during
aging and with onset of sporadic Alzheimer disease. The
leading cause of death in western nations is cardiovascular
disease. Epidemiological studies have shown a strong
correlation between fish consumption and reduction in
sudden death from myocardial infarction. The reduction is
approximately 50% with 200 mg day(-1)of DHA from fish. DHA
is the active component in fish. Not only does fish oil
reduce triglycerides in the blood and decrease thrombosis,
but it also prevents cardiac arrhythmias. The association
of DHA deficiency with depression is the reason for the
robust positive correlation between depression and
myocardial infarction. Patients with cardiovascular disease
or Type II diabetes are often advised to adopt a low-fat
diet with a high proportion of carbohydrate. A study with
women shows that this type of diet increases plasma
triglycerides and the severity of Type II diabetes and
coronary heart disease. DHA is present in fatty fish
(salmon, tuna, mackerel) and mother's milk. DHA is present
at low levels in meat and eggs, but is not usually present
in infant formulas. EPA, another long-chain n-3 fatty acid,
is also present in fatty fish. The shorter chain n-3 fatty
acid, alpha-linolenic acid, is not converted very well to
DHA in man. These longchain n-3 fatty acids (also known as
omega-3 fatty acids) are now becoming available in some
foods, especially infant formula and eggs in Europe and
Japan. Fish oil decreases the proliferation of tumour
cells, whereas arachidonic acid, a longchain n-6 fatty
acid, increases their proliferation. These opposite effects
are also seen with inflammation, particularly with
rheumatoid arthritis, and with asthma. DHA has a positive
effect on diseases such as hypertension, arthritis,
atherosclerosis, depression, adult-onset diabetes mellitus,
myocardial infarction, thrombosis, and some cancers.
Copyright 1999 Academic Press.
High brain myo-inositol
levels in the predementia phase of Alzheimer's disease in
adults with Down's syndrome: a 1H MRS study.
Huang W, Alexander GE, Daly EM, Shetty HU, Krasuski JS,
Rapoport SI, Schapiro MB Laboratory of Neurosciences,
National Institute on Aging, Clinical Center, NIH,
Bethesda, MD, USA. whuang@clio.rad.sunysb.edu
Am J Psychiatry 1999 Dec;156(12):1879-86
OBJECTIVE: An extra portion of chromosome 21 in Down's
syndrome leads to a dementia in later life that is
phenotypically similar to Alzheimer's disease. Down's
syndrome therefore represents a model for studying
preclinical stages of Alzheimer's disease. Markers that
have been investigated in symptomatic Alzheimer's disease
are myoinositol and N-acetyl-aspartate. The authors
investigated whether abnormal brain levels of myo-inositol
and other metabolites occur in the preclinical stages of
Alzheimer's disease associated with Down's syndrome.
METHOD: The authors used 1H magnetic resonance
spectroscopy (MRS) with external standards to measure
absolute brain metabolite concentrations in 19 nondemented
adults with Down's syndrome and 17 age- and sex-matched
healthy comparison subjects.
RESULTS: Concentrations of myoinositol and
choline-containing compounds were significantly higher in
the occipital and parietal regions of the adults with
Down's syndrome than in the comparison subjects. Within the
Down's syndrome group, older subjects (42-62 years, N = 11)
had higher myo-inositol levels than younger subjects (28-39
years, N = 8). Older subjects in both groups had lower
N-acetylaspartate levels than the respective younger
subjects, although this old-young difference was not
greater in the Down's syndrome group.
CONCLUSIONS: The approximately 50% higher level of
myo-inositol in Down's syndrome suggests a gene dose effect
of the extra chromosome 21, where the human osmoregulatory
sodium/myo-inositol cotransporter gene is located. The even
higher myoinositol level in older adults with Down's
syndrome extends to the predementia phase earlier findings
of high myoinositol levels in symptomatic Alzheimer's
disease.
Inflammatory mechanisms
in Alzheimer's disease
Hull M.; Strauss S.; Berger M.; Volk B.; Bauer J.
Department of Psychiatry, Freiburg University Medical
School,D-79104 Freiburg Germany
European Archives of Psychiatry and Clinical
Neuroscience (Germany) 1996, 246/3 (124-128)
In recent years many studies have indicated an
involvement of inflammatory mechanisms in Alzheimer's
disease (AD). Acute-phase proteins such as
alpha1-antichymotrypsin and c-reactive protein, elements of
the complement system, and activated microglial and
astroglial cells are consistently found in brains of AD
patients. Most importantly, also cytokines such as
interleukin-6 (IL-6) have been detected in the cortices of
AD patients, indicating a local activation of components of
the unspecific inflammatory system. Up to now it has
remained unclear whether inflammatory mechanisms represent
a primary event or only an unspecific reaction to brain
tissue damage. Therefore, we investigated whether IL-6
immunoreactivity could be found in plaques prior to the
onset of neuritic changes, or whether the presence of this
cytokine is restricted to later stages of plaque pathology.
We confirmed our previous observation that IL-6 is
detectable in a significant proportion of plaques in the
brains of demented patients. In AD patients IL-6 was found
in diffuse plaques in a significant higher ratio as would
have been expected from a random distribution of IL-6 among
all plaque types. This observation suggests that IL-6 may
precede neuritic changes, and that immunological mechanism
may be involved both in the transformation from diffuse to
neuritic plaques in AD and in the development of
dementia.
Herpes simplex virus
type 1 in brain and risk of Alzheimer's
disease.
Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B,
Jamieson GA. Molecular Neurobiology Laboratory, Department
of Optometry and Vision Sciences, UMIST, Manchester.
Lancet 1997 Jan 25;349(9047):241-4
BACKGROUND: The apolipoprotein E epsilon 4 (APOE-epsilon
4) allele is a risk factor for Alzheimer's disease (AD),
but it is neither essential nor sufficient for development
of the disease. Other factors-genetic or environmental-must
therefore have a role. By means of a PCR we have detected
herpes simplex virus type 1 (HSV1) in latent form in brains
of elderly people with and without AD. We have postulated
that limited reactivation of the virus causes more damage
in AD patients than in elderly people without AD because of
a difference in the hosts. We now report the APOE genotypes
of AD patients and non-AD sufferers with and without HSV1
in brain.
METHODS: DNA was extracted from 84 samples of brain from
46 AD patients (39 temporal lobe, 39 frontal lobe, three
hippocampus) and from 75 samples of brain from 44 non-AD
elderly people (33 temporal lobe, 36 frontal lobe, six
hippocampus). PCR amplification was used to detect HSV1
thymidine kinase gene and the host APOE gene.
FINDINGS: By multiple logistic regression, the
APOE-epsilon 4 allele frequency was significantly higher in
the patients positive for HSV1 in brain than in the
HSV1-negative AD group, the HSV1-positive non-AD group, or
the HSV1-negative non-AD group (52.8% vs 10.0%, 3.6%, and
6.3%, respectively). The odds ratio for APOE-epsilon 4 in
the HSV1-positive AD group compared with HSV1-negative
non-AD group was 16.8 (95% CI 3.61-77.8) and in the
HSV1-negative AD group, 1.67 (0.21-13.4). We also compared
APOE genotypes of 40 people who had recurrent cold sores
and 33 non-sufferers; the APOE-epsilon 4 allele frequencies
were 36% and 9%, respectively (p < 0.0001).
INTERPRETATION: These findings suggest that the
combination of HSV1 in brain and carriage of an
APOE-epsilon 4 allele is a strong risk factor for AD,
whereas either of these features alone does not increase
the risk of AD. The findings in people with cold sores
support our hypothesis that APOE-epsilon 4 and HSV1
together are damaging in the nervous system.
Demonstration of CRP
immunoreactivity in brains of Alzheimer's disease:
Immunohistochemical study using formic acid pretreatment of
tissue sections
Iwamoto N.; Nishiyama E.; Ohwada J.; Arai H. Department
of Psychiatry, Juntendo University, School of Medicine,
2-1-1 Hongo,Bunkyo-ku, Tokyo 113 Japan
Neuroscience Letters (Ireland) 1994, 177/1-2 (23-26)
C-reactive protein (CRP) is a well-known serum protein
which increases during inflammation and deposits in
destructed tissues. To establish whether CRP appears in
brain of Alzheimer's disease (AD), we immunohistochemically
investigated tissue sections which were pretreated with
formic acid. Positive immunostainings by anti-CRP
antibodies were clearly recognized in senile plaques (SP)
in the pretreated tissue sections whereas very weak
immunostainings in non-treated sections. These findings may
suggest that the formation process of SP contains an acute
phase of inflammatory state.
Evaluation of memantine
for neuroprotection in dementia.
Jain KK. Jain PharmaBiotech, Blasiring 7, CH-4057 Basel,
Switzerland. jain@pharmabiotech.ch.
Expert Opin Investig Drugs 2000 Jun;9(6):1397-406
Memantine, a non-competitive NMDA antagonist, has been
approved for use in the treatment of dementia in Germany
for over ten years. The rationale for use is excitotoxicity
as a pathomechanism of neurodegenerative disorders.
Memantine acts as a neuroprotective agent against this
pathomechanism, which is also implicated in vascular
dementia. HIV-1 proteins Tat and gp120 have been implicated
in the pathogenesis of dementia associated with HIV
infection and the neurotoxicity caused by HIV-1 proteins
can be blocked completely by memantine. Memantine has been
investigated extensively in animal studies and following
this, its efficacy and safety has been established and
confirmed by clinical experience in humans. It exhibits
none of the undesirable effects associated with competitive
NMDA antagonists such as dizocilpine. The efficacy of
memantine in a variety of dementias has been shown in
clinical trials. Memantine is considered to be a promising
neuroprotective drug for the treatment of dementias,
particularly Alzheimer's disease for which there is no
neuroprotective therapy available currently. It can be
combined with acetylcholinesterase inhibitors which are the
mainstay of current symptomatic treatment of Alzheimer's
disease. Memantine has a therapeutic potential in numerous
CNS disorders besides dementias which include stroke, CNS
trauma, Parkinson's disease (PD), amyotrophic lateral
sclerosis (ALS), epilepsy, drug dependence and chronic
pain. If memantine is approved by the FDA for some of these
indications by the year 2005, it can become a blockbuster
drug by crossing the US$1 billion mark in annual sales.
Cerebrospinal fluid
levels of alpha-tocopherol (vitamin E) in Alzheimer' s
disease.
Jimenez-Jimenez FJ; de Bustos F; Molina JA; Benito-Leon
J; Tallon-Barranco A; Gasalla T; Orti-Pareja M; Guillamon
F; Rubio JC; Arenas J; Enriquez-de-Salamanca R. Department
of Neurology, Hospital Universitario Principe de Asturias,
Alcala de Henares, Spain.
J Neural Transm (Austria) 1997, 104 (6-7) p703-10
We compared CSF and serum levels, and the CST/serum
ratio of alpha-tocopherol (vitamin E), measured by HPLC, in
44 apparently well-nourished patients with Alzheimer's
disease (AD) and 37 matched controls. CSF and serum vitamin
E levels were correlated, both in AD patients and in
controls. The mean CSF and serum vitamin E levels were
significantly lower in AD patients, and the CSF/serum ratio
of AD patients did not differ significantly between the 2
study groups. CSF vitamin E levels did not correlate with
age, age at onset, duration of the disease and score of the
Minimental State Examination in the AD group. Weight and
body mass index were significantly lower in AD patients
than in controls. These results suggest that low CSF and
serum vitamin E concentrations in AD patients could be
related with a deficiency of dietary intake of vitamin
E.
Serum levels of
beta-carotene, alpha-carotene and vitamin A in patients
with Alzheimer's disease.
Jimenez-Jimenez FJ, Molina JA, de Bustos F, Orti-Pareja
M, Benito-Leon J, Tallon-Barranco A, Gasalla T, Porta J,
Arenas J. Department of Neurology of Hospital 'Principe de
Asturias', University of Alcala de Henares, Madrid,
Spain.
Eur J Neurol 1999 Jul;6(4):495-7
To elucidate the possible role of carotenoids and
vitamin A as risk factors for Alzheimer's disease (AD), we
compared serum levels of beta-carotene and alpha-carotene,
and vitamin A, measured by isocratic high performance
liquid chromatography, of 38 AD patients and 42 controls.
The serum levels of alpha-carotene did not differ
significantly between AD patients and control groups.
However, the serum levels of beta-carotene and vitamin A
were significantly lower in the AD-patient group. These
values did not correlate to age, age at onset or score on
the MiniMental State Examination. Weight and body mass
index were significantly lower in AD patients than in
controls. These results suggest that low serum
beta-carotene concentrations in AD patients could be
related to a deficiency in dietary intake of this
provitamin, although its possible relationship with risk
for AD could not be excluded. Copyright 1999 Lippincott
Williams & Wilkins
Effect of curcumin and
capsaicin on arachidonic acid metabolism and lysosomal
enzyme secretion by rat peritoneal macrophages
Joe B.; Lokesh B.R. B.R. Lokesh, Dept. of Biochemistry
and Nutrition, Centr. Food Technol. Res. Institute,
Mysore-570 013 India sambaiah@nicfos.ernet.in
Lipids (United States) 1997, 32/11 (1173-1180)
The inflammatory mediators secreted by macrophages play
an-important role in autoimmune diseases. Spice components,
such as curcumin from turmeric and capsaicin from red
pepper, are shown to exhibit antiinflammatory properties.
The influence of these spice components on arachidonic acid
metabolism and secretion of lysosomal enzymes by
macrophages was investigated. Rat peritoneal macrophages
preincubated with 10 muM curcumin or capsaicin for 1 h
inhibited the incorporation of arachidonic acid into
membrane lipids by 82 and 76%: prostaglandin Einf 2 by 45
and 48%; leukotriene Binf 4 by 61 and 46%, and leukotriene
Cinf 4 by 34 and 48%, respectively, but did not affect the
release of arachidonic acid from macrophages stimulated by
phorbol myristate acetate. However, the secretion of 6-keto
PG F(1alpha) was enhanced by 40 and 29% from macrophages
preincubated with 10 muM curcumin or capsaicin,
respectively, as compared to those produced by control
cells. Curcumin and capsaicin also inhibited the secretion
of collagenase, elastase, and hyaluronidase to the maximum
extent of 57, 61, 66%, and 46, 69, 67%, respectively. These
results demonstrated that curcumin and capsaicin can
control the release of inflammatory mediators such as
eicosanoids and hydrolytic enzymes secreted by macrophages
and thereby may exhibit antiinflammatory properties.
Is metabolic evidence
for vitamin B-12 and folate deficiency more frequent in
elderly patients with Alzheimer' s disease?
Joosten E; Lesaffre E; Riezler R; Ghekiere V;
Dereymaeker L; Pelemans W; Dejaeger E Department of
Pathophysiology, University Hospitals K. U. Leuven,
Belgium.
J Gerontol A Biol Sci Med Sci (United States) Mar 1997,
52 (2) M76-9.
BACKGROUND: It is still unclear whether there is an
association between Alzheimer's disease and vitamin B-12 or
folate deficiency. This study was designed to investigate
whether patients with Alzheimer's disease are particularly
prone to metabolically significant cobalamin or folate
deficiency as compared to nondemented hospitalized controls
and healthy elderly controls living at home.
METHODS: Evaluation for the diagnosis of Alzheimer's
disease, routine laboratory tests, serum folate and vitamin
B-12, serum methylmalonic acid (MMA), total homocysteine
(tHcy), and radiological tests was performed in 52 patients
with Alzheimer's disease (AD), 50 nondemented hospitalized
controls, and 49 healthy elderly subjects living at
home.
RESULTS: Serum vitamin B-12 and folate levels are
comparable between patients with AD, hospitalized control
patients, and subjects living at home. Patients with AD
have the highest serum MMA and tHcy levels. The MMA levels
of patients with AD and hospitalized controls are not
different, but the mean tHcy level is significantly higher
in patients with AD as compared to nondemented patients or
subjects living at home.
CONCLUSION: The interpretation of the vitamin B-12 and
folate status in patients with AD depends largely on the
methodology (i.e., serum vitamin vs metabolite levels) and
the selection of the control group. Although patients with
AD have the highest tHcy and MMA levels, metabolically
significant vitamin B-12 and folate deficiency is also a
substantial problem in nondemented elderly patients.
Alzheimer's disease:
risk and protection.
Jorm AF. National Health and Medical Research Centre
Psychiatric Epidemiology Research Centre, Australian
National University, Canberra, ACT.
Anthony.Jorm@anu.edu.au
Med J Aust 1997 Oct 20;167(8):443-6
Only four risk factors for Alzheimer's disease can be
regarded as confirmed--old age, family history of dementia,
apo-E genotype and Down syndrome. Other disputed risk
factors with some supporting evidence include ethnic group,
head trauma and aluminium in drinking water. Possible
protection factors, such as anti-inflammatory drugs,
oestrogen replacement therapy and a high education level,
are of great interest because they suggest possible
preventive action.
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