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Congeners of
N(alpha)-acetyl-L-cysteine but not aminoguanidine act as
neuroprotectants from the lipid peroxidation product
4-hydroxy-2-nonenal.
Neely MD, Zimmerman L, Picklo MJ, Ou JJ, Morales CR,
Montine KS, Amaranth V, Montine TJ. Departments of
Pathology and Pharmacology, and the Center for Molecular
Neurosciences, Vanderbilt University Medical Center,
Nashville, TN 37232, USA.
Free Radic Biol Med 2000 Nov 15;29(10):1028-36
Increased generation of neurotoxic lipid peroxidation
products is proposed to contribute to the pathogenesis of
Alzheimer's disease (AD). Current antioxidant therapies are
directed at limiting propagation of brain lipid
peroxidation. Another approach would be to scavenge the
reactive aldehyde products of lipid peroxidation.
N(alpha)-acetyl-L-cysteine (NAC) and aminoguanidine (AG)
react rapidly and irreversibly with 4-hydroxy-2-nonenal
(HNE) in vitro, and both have been proposed as potential
scavengers of HNE in biological systems. We have compared
NAC, AG, and a series of congeners as scavengers of HNE and
as neuroprotectants from HNE. Our results showed that while
both NAC and AG had comparable chemical reactivity with
HNE, only NAC and its congeners were able to block
HNE-protein adduct formation in vitro and in neuronal
cultures. Moreover, NAC and its congeners, but not AG,
effectively protected brain mitochondrial respiration and
neuronal microtubule structure from the toxic effects of
HNE. We conclude that NAC and its congeners, but not AG,
may act as neuroprotectants from HNE.
Could diet be one of the
causal factors of Alzheimer's disease?
Newman PE.
Med Hypotheses 1992 Oct;39(2):123-6
Recent developments show that the brains of persons who
have died from Alzheimer's Disease (AD) have a deficiency
of Essential Fatty acids in one of the principal classes of
phospholipids. It is hypothesized that faulty brain cell
membranes resulting from this deficiency may allow passage
of an enzyme into the bilayer membrane space which cuts
beta amyloid precursor proteins attached to such cells at a
critical intramembrane position releasing a complete
sequence of beta amyloid protein into the extracellular
space. Beta amyloid protein appears to be the principal
active constituent of senile plaques thought to be a
probable cause of brain damage resulting in AD. Treatment
of persons suffering from AD with desferrioxamine, a
trivalent ion chelator to remove aluminium has shown
results in slowing the progression of this disease,
implicating aluminium and/or other chelated substances in
its etiology. Both EFA deficiency and aluminium build-up
may be prevented by dietary precautions.
Alzheimer's disease
revisited.
Newman PE. Paris, France.
Med Hypotheses 2000 May;54(5):774-6
In a previous paper, it was suggested that a relative
deficiency of essential fatty acids might play a role in
the etiology of sporadic or non-familial Alzheimer's
disease. A recent article regarding dementia in the
Rotterdam Study reinforces this suggestion. It is also
hypothesized that this relative deficiency could facilitate
passage of aluminum into the brain, aluminum being
increasingly suggested as one of the possible pathogenic
factors in AD. It is further suggested that hypomethylation
caused by a deficiency of S-adenosylmethionine might also
play a role in the etiology of this disease and perhaps
even of Parkinson's disease. Copyright 2000 Harcourt
Publishers Ltd.
Presynaptic nicotinic
acetylcholine receptors as a functional target of
nefiracetam in inducing a long-lasting facilitation of
hippocampal neurotransmission.
Nishizaki T, Matsuoka T, Nomura T, Kondoh T, Watabe S,
Shiotani T, Yoshii M Department of Physiology, Kobe
University School of Medicine, Japan.
Alzheimer Dis Assoc Disord 2000;14 Suppl 1:S82-94
Nefiracetam (1-10 microM), a nootropic (or
cognition-enhancing) agent, persistently potentiated
currents through Torpedo acetylcholine (ACh) receptors
expressed in Xenopus oocytes as a result of interacting
with a protein kinase C pathway and the ensuing protein
kinase C phosphorylation of the receptors. A similar effect
was found in neuronal nicotinic ACh receptors (alpha4beta2
and alpha7). In contrast, the other nootropic agents such
as piracetam and aniracetam had no potentiating action on
the receptors. A sustained enhancement in the activity of
nicotinic ACh receptors induced by nefiracetam caused a
marked increase in the glutamate release, leading to a
long-term potentiation-like facilitation of hippocampal
synaptic transmissions. One of the consistent
neuropathologic features of the Alzheimer brain is a loss
of nicotinic ACh receptors. This fact, together with the
results of our study, raises the possibility that the loss
of nicotinic ACh receptors may be a key factor in the
decline of cognitive function observed in Alzheimer disease
and that agents targeting neuronal nicotinic ACh receptors
like nefiracetam could, therefore, be of great therapeutic
importance.
Oral administration of
idebenone, a stimulator of NGF synthesis, recovers reduced
NGF content in aged rat brain.
Nitta A, Hasegawa T, Nabeshima T. Department of
Neuropsychopharmacology and Hospital Pharmacy, Nagoya
University School of Medicine, Japan.
Neurosci Lett 1993 Dec 12;163(2):219-22
The relationship between nerve growth factor (NGF) and
senile dementia of the Alzheimer type is of interest. We
demonstrate here that the oral administration of idebenone,
a stimulator of NGF synthesis in vitro, produced recovery
of reduced NGF content in aged rat brain. Twenty-one-day
successive administration of idebenone produced significant
recovery of reduced NGF content in the frontal cortex and
parietal cortex of aged rats. These results suggest that
NGF content in the brain is low in aged rats and that oral
administration of idebenone leads to a recovery of this
reduction.
Oral administration of
idebenone induces nerve growth factor in the brain and
improves learning and memory in basal forebrain-lesioned
rats.
Nitta A, Murakami Y, Furukawa Y, Kawatsura W, Hayashi K,
Yamada K, Hasegawa T, Nabeshima T. Department of
Neuropsychopharmacology and Hospital Pharmacy, Nagoya
University School of Medicine, Japan.
Naunyn Schmiedebergs Arch Pharmacol 1994
Apr;349(4):401-7
Nerve growth factor plays an important role in the
survival and maintenance of cholinergic neurons in the
central neuronal system. In senile dementia of the
Alzheimer type, learning and memory are impaired by the
loss of neurons in the magnocellular cholinergic neuronal
system. It is therefore, of interest to investigate the
role of nerve growth factor in this degenerative disorder.
Since nerve growth factor does not cross the blood-brain
barrier and is easily metabolized by peptidases when
administered peripherally, it can be used for medical
treatment only when directly injected into the brain. We
demonstrate here that the oral administration of idebenone,
a potent in vitro nerve growth factors synthesis
stimulator, induced an increase in nerve growth factor
protein and mRNA, and in choline acetyltransferase
activity, in basal forebrain lesioned rats, but not in
intact rats. Idebenone also ameliorated the behavioral
deficits in habituation, water maze, and passive avoidance
tasks in these animals. These results suggest that
idebenone stimulated nerve growth factor synthesis in vivo
and ameliorates the behavioral deficits which were
accompanied with the recovery of the reduced choline
acetyltransferase activity in the basal forebrain-lesioned
rats.
Hydergine for
dementia.
Olin J, Schneider L, Novit A, Luczak S Keck School of
Medicine, University of Southern California, 1975 Zonal
Avenue, KAM-400, Los Angeles, CA, 90033, USA.
jolin@hsc.usc.edu
Cochrane Database Syst Rev 2000;(2):CD000359
BACKGROUND: Currently hydergine is used almost
exclusively for treating patients with either dementia, or
'age-related' cognitive symptoms. Since the early eighties
there have been over a dozen more clinical trials, yet
hydergine's efficacy remains uncertain. Although previous
reviews offer generally favorable support for hydergine's
efficacy, they were, however, limited by a bias with
respect to the particular clinical studies chosen (eg, the
inclusion of case reports, and uncontrolled trials), and by
authors' impressionistic assessments of results. Not
surprisingly, there has been a lack of consensus among
reviewers with regard to the efficacy of hydergine. In
1994, a meta-analysis was published by the present
reviewers who reported that overall, hydergine was more
effective than placebo. However they also observed that the
statistical evidence for efficacy in 'possible or probable
Alzheimer's disease' patients was so modest that one
additional statistically non-significant trial would have
reduced the results to non significance.
OBJECTIVES: Because of uncertainty surrounding the
efficacy of hydergine, the goals of this overview were to
assess its overall effect in patients with possible
dementia, and to investigate potential moderators of an
effect.
SEARCH STRATEGY: The Cochrane Dementia Group Register of
Clinical Trials was searched using the terms 'hydergine',
'ergoloids,' 'ergoloid mesylates,' 'dihydroergocristine,'
'dihydroergocryptine,' 'dihydroergotoxine,' and
'dihydroergocornine. MEDLINE, EMBASE, and two proprietary
databases were searched also. Published reviews were
inspected for further sources.
SELECTION CRITERIA: Trials to be included must be
randomized, double-blind, parallel-group, and unconfounded
comparisons of hydergine with placebo for a treatment
duration of greater than 1 week in subjects with dementia
or symptoms consistent with dementia.
DATA COLLECTION AND ANALYSIS: Data were extracted
independently by the reviewers, pooled where appropriate
and possible, and the pooled odds ratios (95%CI) or the
average differences (95%CI) were estimated. Where possible,
intention-to-treat data were used. Outcomes of interest
included clinical global impressions of change and
comprehensive rating scales. Potential moderating variables
of a treatment effect included: inpatient/outpatient
status, trial duration, age, sex, medication dose,
publication year, and diagnostic grouping.
MAIN RESULTS: There were a total of nineteen trials that
met inclusion criteria and that had data sufficient for
analysis. Thirteen trials reported sufficient information
to use a global rating of improvement and nine trials
provided information on a comprehensive rating scale. Three
trials provided both outcome measures. It was not possible
to use many of the published results in a combined analysis
owing to the lack of sufficient data to perform statistical
analyses. For the twelve trials that used global ratings,
there was a significant effect favoring hydergine (OR 3.78,
95%CI, 2.72-5.27). For the nine trials that used
comprehensive ratings, there was a significant mean
difference favoring hydergine (WMD 0.96, 95%CI, 0.
54-1.37). Hydergine was well tolerated in these trials,
with 78% of randomized subjects available for data
analyses. Greater effect sizes on global ratings were
associated with younger age, and possibly higher dose,
although most of the subgroup analyses were statistically
insignificant.
REVIEWER'S CONCLUSIONS: As in an earlier systematic
review, we found hydergine to show significant treatment
effects when assessed by either global ratings or
comprehensive rating scales (based here on a smaller set of
trials than in the earlier published systematic review
because trials were required to have data that could
conform with MetaView, the Cochrane Collaboration
statistics software). The small number of trials available
for analysis, however, limited the ability of subgroup
analyses to identify statistically significant modera
[Analysis of dietary
factors in Alzheimer's disease: clinical use of nutritional
intervention for prevention and treatment of dementia]
[Article in Japanese]
Otsuka M. Department of Neurology, Jichi Medical School,
Omiya Medical Center.
Nippon Ronen Igakkai Zasshi 2000 Dec;37(12):970-3
To determine dietary factors involved in the
pathological process of Alzheimer's disease (AD), we
analyzed food consumption and intake of nutrients using
Self-administered Diet History Questionnaire (DHQ)
developed for Japanese. Sixty four AD patients and 80
age-matched healthy subjects were enrolled in this study.
AD was diagnosed according to the criteria of DSM-IV.
Dietary behaviors of AD patients was markedly deviated from
those of age-matched healthy elderly. AD patients disliked
fish and green-yellow vegetables and took more meats than
controls. Energy-adjusted analysis of nutrients revealed
that AD patients took less vitamin C and carotene. Most
conspicuously, AD patients took significantly smaller
amount of n-3 polyunsaturated fatty acid (PUFA) reflecting
low consumption of fish, and their n-6/n-3 ratio was
significantly increased. These habits started from 3 months
to 44 years before the onset of dementia, suggesting these
dietary abnormalities are not merely the consequence of
dementia. Rather, it implies that AD might be a life
style-related disease such as coronary heart disease,
western style diet-associated cancer and hyperallergy. To
see if cognitive function was improved by correcting the
n-6/n-3 ratio, we prescribed eicossapentaenoic acid (EPA),
one type of n-3 PUFA, for AD patients. Cognitive function
was evaluated using MMSE. Administration of EPA (900
mg/day) improved MMSE significantly with maximal effects at
3 months and the effects lasted 6 months. However, the
score of MMSE decreased after 6 months. The present study
showed that nutritional intervention is useful for the
prevention of AD, and also for the therapy of dementia,
though it has some limitation.
Estrogen deficiency and
risk of Alzheimer's disease in women.
Paganini-Hill A, Henderson VW. Department of Preventive
Medicine, University of Southern California School of
Medicine, Los Angeles 90031.
Am J Epidemiol 1994 Aug 1;140(3):256-61
The authors explored the possibility that estrogen loss
associated with menopause may contribute to the development
of Alzheimer's disease by using a case-control study nested
within a prospective cohort study. The Leisure World Cohort
includes 8,877 female residents of Leisure World Laguna
Hills, a retirement community in southern California, who
were first mailed a health survey in 1981. From the 2,529
female cohort members who died between 1981 and 1992, the
authors identified 138 with Alzheimer's disease or other
dementia diagnoses likely to represent Alzheimer's disease
(senile dementia, dementia, or senility) mentioned on the
death certificate. Four controls were individually matched
by birth date (+/- 1 year) and death date (+1 year) to each
case. The risk of Alzheimer's disease and related dementia
was less in estrogen users relative to nonusers (odds ratio
= 0.69, 95 percent confidence interval 0.46-1.03). The risk
decreased significantly with increasing estrogen dose and
with increasing duration of estrogen use. Risk was also
associated with variables related to endogenous estrogen
levels; it increased with increasing age at menarche and
(although not statistically significant) decreased with
increasing weight. This study suggests that the increased
incidence of Alzheimer's disease in older women may be due
to estrogen deficiency and that estrogen replacement
therapy may be useful for preventing or delaying the onset
of this dementia.
Estrogen replacement
therapy and risk of Alzheimer disease.
Paganini-Hill A, Henderson VW. Department of Preventive
Medicine, University of Southern California School of
Medicine, Los Angeles, USA.
Arch Intern Med 1996 Oct 28;156(19):2213-7
BACKGROUND: With Alzheimer disease emerging as a major
public health problem, the identification of factors that
might prevent this disease are important. Estrogen loss
associated with menopause may contribute to the development
of Alzheimer disease.
OBJECTIVE: To evaluate the effects of different estrogen
preparations, varying dosages of estrogen, and duration of
estrogen replacement therapy on the risk of Alzheimer
disease in postmenopausal women.
STUDY DESIGN AND METHODS: A case-control study nested
within a prospective cohort study of residents of Leisure
World Laguna Hills, a retirement community in Southern
California. The cohort comprised 8877 women who were first
mailed a health survey in 1981. Of the 3760 female cohort
members who died between 1981 and 1995, 248 women with
Alzheimer disease or other dementia diagnoses likely to
represent Alzheimer disease (senile dementia, dementia, or
senility) mentioned on the death certificate were
identified. Five controls were individually matched to each
case according to year of death and year of birth (+/- 1
year).
RESULTS: The risk of Alzheimer disease and related
dementia was significantly reduced in estrogen users
compared with nonusers (odds ratio, 0.65; 95% confidence
interval, 0.49-0.88). The risk was reduced for both oral
and nonoral (i.e., injections and/or creams) routes of
administration. The risk decreased significantly with both
increasing dosages (P = .01) and increasing duration (P =
.01) of oral therapy with conjugated equine estrogen, the
most commonly used estrogen preparation. Within each dose
category, the risk decreased with increasing duration of
therapy, with the lowest observed risk in long-term users
who received high doses (odds ratio, 0.48; 95% confidence
interval, 0.19-1.17).
CONCLUSION: This study suggests that estrogen
replacement therapy may be useful for preventing or
delaying the onset of Alzheimer disease in postmenopausal
women.
Alzheimer beta protein
mediated oxidative damage of mitochondrial DNA: prevention
by melatonin.
Pappolla MA, Chyan YJ, Poeggeler B, Bozner P, Ghiso J,
LeDoux SP, Wilson GL. University of South Alabama Medical
Center, Department of Pathology and Neurology, Mobile
36617, USA. mpappoll@usamail.usouthal.edu
J Pineal Res 1999 Nov;27(4):226-9
Most contemporary progress in Alzheimer's disease (AD)
stems from the study of a 42 43 amino acid peptide. called
the amyloid beta protein (Abeta), as the main
neuropathologic marker of the disorder. It has been
demonstrated that Abeta has neurotoxic properties and that
such effects are mediated by free-radicals. Exposure of
neuronal cells to Abeta results in a spectrum of oxidative
lesions that are profoundly harmful to neuronal
homeostasis. We had previously shown that Abeta25-35
induces oxidative damage to mitochondrial DNA (mtDNA) and
that this modality of injury is prevented by melatonin.
Because Abeta25 35 does not occur in AD and because the
mode of toxicity by Abeta25-35 may be different from that
of Abeta1-42 (the physiologically relevant form of Abeta),
we extended our initial observations to determine whether
oxidative damage to mtDNA could also be induced by
Abeta1-42 and whether this type of injury is prevented by
melatonin. Exposure of human neuroblastoma cells to
Abeta1-42 resulted in marked oxidative damage to mtDNA as
determined by a quantitative polymerase chain reaction
method. Addition of melatonin to cell cultures along with
Abeta completely prevented the damage. This study supports
previous findings with Abeta25-35, including a causative
role for Abeta in the mitochondrial oxidative lesions
present in AD brains. Most important, the data confirms the
neuroprotective role of melatonin in Abeta-mediated
oxidative injury. Because melatonin also inhibits amyloid
aggregation, lacks toxicity, and efficiently crosses the
blood-brain barrier, this hormone appears superior to other
available antioxidants as a candidate for pharmacologic
intervention in AD.
A concise synthetic
pathway for trans-metanicotine analogues.
Park H, Jang J, Sin KS. College of Pharmacy, Kangwon
National University, Chunchon, Korea.
haeilp@cc.kangwon.ac.kr
Arch Pharm Res 2000 Jun;23(3):202-5
A convenient pathway for synthesis of trans-metanicotine
analogues was developed. trans-Metanicotine, a subtype
(alpha4beta2)-selective ligand for neuronal nicotinic
acetylcholine receptor, is under clinical phase for
Alzheimer's disease. Zn-mediated allylation of allyl
bromide and acetaldehyde followed by Heck reaction with
3-bromopyridine gave 5-pyridin-3-yl-pent-4-en-3-ol (2).
Tosylation of 5-pyridin-3-yl-pent-4-en-3-ol followed by
substitution reaction with methylamine in sealed tube gave
methyl-(1-methyl-4-pyridin-3-yl-but-3-enyl)-amine (4) in
good yields. Thus, trans-metanicotine analogues modified at
the alpha-position of the methylamino group with various
functional groups can be obtained in 4 steps.
Acetylcholine in mind:
a neurotransmitter correlate of consciousness?
Perry E, Walker M, Grace J, Perry R. MRC Neurochemical
Pathology Unit, Newcastle General Hospital, Westgate Road,
Newcastle upon Tyne, UK NE4 6BE.
Trends Neurosci 1999 Jun;22(6):273-80
The cholinergic system is one of the most important
modulatory neurotransmitter systems in the brain and
controls activities that depend on selective attention,
which are an essential component of conscious awareness.
Psychopharmacological and pathological evidence supports
the concept of a 'cholinergic component' of conscious
awareness. Drugs that antagonize muscarinic receptors
induce hallucinations and reduce the level of
consciousness, while the nicotinic receptor is implicated
as being involved in the mechanism of action of general
(inhalational) anaesthetics. In degenerative diseases of
the brain, alterations in consciousness are associated with
regional deficits in the cholinergic system. In Alzheimer's
disease (AD), there is a loss of explicit (more than
implicit) memory and hypoactivity of cholinergic
projections to the hippocampus and cortex, while the visual
hallucinations experienced by subjects with Dementia with
Lewy bodies (DLB) are associated with reductions in
neocortical ACh-related activity. In Parkinson's disease,
the additional loss of pedunculopontine cholinergic
neurones, which control REM (rapid eye movement) sleep or
dreaming, is likely to contribute to REM abnormalities,
which also occur in DLB. Widespread basal-forebrain and
rostral brainstem cholinergic pathways, which include
converging projections to the thalamus, appear to be
located strategically for generating and integrating
conscious awareness. Alleviation of a range of cognitive
and non-cognitive symptoms by drugs that modulate the
cholinergic system, which are being developed for the
treatment of AD and related disorders, could be caused by
changes in consciousness.
Effects of
physostigmine and lecithin on memory in Alzheimer
disease.
Peters BH, Levin HS.
Ann Neurol 1979 Sep;6(3):219-21
Because there is evidence that central cholinergic
mechanisms are depleted in dementia, we studied the effects
of central cholinergic augmentation on the memory of 5
patients with Alzheimer disease. Patients received placebo,
lecithin, physostigmine, or lecithin plus physostigmine in
a double-blind study using titrated doses of the
acetylcholinesterase inhibitor physostigmine. Memory was
evaluated with alternate forms of the selective reminding
procedure. Compared with lecithin alone, the combination of
physostigmine and lecithin consistently enhanced memory
storage and retrieval; physostigmine without lecithin
produced no memory facilitation. The strategy of combining
a cholinergic agonist and precursor holds promise, although
a larger clinical trial is needed.
Medicinal plants and
Alzheimer's disease: from ethnobotany to
phytotherapy.
Perry EK, Pickering AT, Wang WW, Houghton PJ, Perry NS
Medical Research Council, Newcastle General Hospital,
Newcastle upon Tyne. e.k.perry@ncl.ac.uk
J Pharm Pharmacol 1999 May;51(5):527-34
The use of complementary medicines, such as plant
extracts, in dementia therapy varies according to the
different cultural traditions. In orthodox Western
medicine, contrasting with that in China and the Far East
for example, pharmacological properties of traditional
cognitive- or memory-enhancing plants have not been widely
investigated in the context of current models of
Alzheimer's disease. An exception is Gingko biloba in which
the gingkolides have antioxidant, neuroprotective and
cholinergic activities relevant to Alzheimer's disease
mechanisms. The therapeutic efficacy of Ginkgo extracts in
Alzheimer's disease in placebo controlled clinical trials
is reportedly similar to currently prescribed drugs such as
tacrine or donepezil and, importantly, undesirable side
effects of Gingko are minimal. Old European reference
books, such as those on medicinal herbs, document a variety
of other plants such as Salvia officinalis (sage) and
Melissa officinalis (balm) with memory-improving
properties, and cholinergic activities have recently been
identified in extracts of these plants. Precedents for
modern discovery of clinically relevant pharmacological
activity in plants with long-established medicinal use
include, for example, the interaction of alkaloid opioids
in Papaver somniferum (opium poppy) with endogenous opiate
receptors in the brain. With recent major advances in
understanding the neurobiology of Alzheimer's disease, and
as yet limited efficacy of so-called rationally designed
therapies, it may be timely to re-explore historical
archives for new directions in drug development. This
article considers not only the value of an integrative
traditional and modern scientific approach to developing
new treatments for dementia, but also in the understanding
of disease mechanisms. Long before the current
biologically-based hypothesis of cholinergic derangement in
Alzheimer' s disease emerged, plants now known to contain
cholinergic antagonists were recorded for their amnesia-
and dementia-inducing properties.
Acetyl-L-carnitine
physical-chemical, metabolic, and therapeutic properties:
relevance for its mode of action in Alzheimer's disease and
geriatric depression.
Pettegrew JW, Levine J, McClure RJ Department of
Psychiatry, School of Medicine, University of Pittsburgh,
PA 15213, USA. pettegre+@pitt.edu
Mol Psychiatry 2000 Nov;5(6):616-32
Acetyl-L-carnitine (ALCAR) contains carnitine and acetyl
moieties, both of which have neurobiological properties.
Carnitine is important in the beta-oxidation of fatty acids
and the acetyl moiety can be used to maintain acetyl-CoA
levels. Other reported neurobiological effects of ALCAR
include modulation of: (1) brain energy and phospholipid
metabolism; (2) cellular macromolecules, including
neurotrophic factors and neurohormones; (3) synaptic
morphology; and (4) synaptic transmission of multiple
neurotransmitters. Potential molecular mechanisms of ALCAR
activity include: (1) acetylation of -NH2 and -OH
functional groups in amino acids and N terminal amino acids
in peptides and proteins resulting in modification of their
structure, dynamics, function and turnover; and (2) acting
as a molecular chaperone to larger molecules resulting in a
change in the structure, molecular dynamics, and function
of the larger molecule. ALCAR is reported in double-blind
controlled studies to have beneficial effects in major
depressive disorders and Alzheimer's disease (AD), both of
which are highly prevalent in the geriatric population.
In-vivo glutathione
elevation protects against hydroxyl free radical-induced
protein oxidation in rat brain.
Pocernich CB, La Fontaine M, Butterfield DA. Department
of Chemistry, University of Kentucky, Lexington 40506,
USA.
Neurochem Int 2000 Mar;36(3):185-91
Glutathione deficiency has been associated with a number
of neurodegenerative diseases including Lou Gehrig's
disease, Parkinson's disease, and HIV. A crucial role for
glutathione is as a free radical scavenger. Alzheimer's
disease (AD) brain is characterized by oxidative stress,
manifested by protein oxidation, lipid oxidation, oxidized
glutathione, and decreased activity of glutathione
S-transferase, among others. Reasoning that elevated levels
of endogenous glutathione would offer protection against
free radical-induced oxidative stress, rodents were given
in vivo injections of N-acetylcysteine (NAC), a known
precursor of glutathione, to study the vulnerability of
isolated synaptosomal membranes treated with Fe2+/H2O2, a
known hydroxyl free radical producer. Protein carbonyls, a
marker of protein oxidation, were measured. NAC
significantly increased endogenous glutathione levels in
cortical synaptosome cytosol (P < 0.01). As reported
previously, protein carbonyl levels of the
Fe2+/H2O2-treated synaptosomes were significantly higher
compared to that of non-treated controls (P < 0.01),
consistent with increased oxidative stress. In contrast,
protein carbonyl levels in Fe2+/H2O2-treated synaptosomes
isolated from NAC-injected animals were not significantly
different from saline-injected non-treated controls,
demonstrating protection against hydroxyl radical induced
oxidative stress. These results are consistent with the
notion that methods to increase endogenous glutathione
levels in neurodegenerative diseases associated with
oxidative stress, including AD, may be promising.
Cognitive deficit
induced by acute tryptophan depletion in patients with
Alzheimer's disease.
Porter RJ, Lunn BS, Walker LL, Gray JM, Ballard CG,
O'Brien JT. Academic Department of Psychiatry, University
of Newcastle upon Tyne, England.
Am J Psychiatry 2000 Apr;157(4):638-40
OBJECTIVE: The study assessed the effects on global
cognitive function and mood of a reduction of brain
serotonin by means of acute tryptophan depletion in 16
patients with dementia of the Alzheimer type and in 16
cognitively intact comparison subjects.
METHOD: In a double-blind, crossover design, subjects
received a tryptophan-free amino acid drink to induce acute
tryptophan depletion and, on a separate occasion, a placebo
drink containing a balanced mixture of amino acids. On each
occasion, ratings of depressed mood were made at baseline
and 4 and 7 hours later, and the Modified Mini-Mental State
was administered at baseline and 4 hours later.
RESULTS: Patients with dementia of the Alzheimer type
had a significantly lower mean score on the Modified
Mini-Mental State after acute tryptophan depletion than
after receiving placebo. The comparison group showed no
difference in mean score on the Modified Mini-Mental State
after acute tryptophan depletion and after receiving
placebo. No significant changes in mood were found in
either group.
CONCLUSIONS: Acute tryptophan depletion significantly
impaired cognitive function in patients with dementia of
the Alzheimer type. Compromised serotonergic function, in
combination with cholinergic deficit, may make an important
contribution to cognitive decline in dementia of the
Alzheimer type.
Toxic effects of
beta-amyloid(25-35) on immortalised rat brain endothelial
cell: protection by carnosine, homocarnosine and
beta-alanine.
Preston JE, Hipkiss AR, Himsworth DT, Romero IA, Abbott
JN. Institute of Gerontology, King's College London, UK.
j.preston@kcl.ac.uk
Neurosci Lett 1998 Feb 13;242(2):105-8
The effect of a truncated form of the neurotoxin
beta-amyloid peptide (A beta25-35) on rat brain vascular
endothelial cells (RBE4 cells) was studied in cell culture.
Toxic effects of the peptide were seen at 200 microg/ml A
beta using a mitochondrial dehydrogenase activity (MTT)
reduction assay, lactate dehydrogenase release and glucose
consumption. Cell damage could be prevented completely at
200 microg/ml A beta and partially at 300 microg/ml A beta,
by the dipeptide carnosine. Carnosine is a naturally
occurring dipeptide found at high levels in brain tissue
and innervated muscle of mammals including humans. Agents
which share properties similar to carnosine, such as
beta-alanine, homocarnosine, the anti-glycating agent
aminoguanidine, and the antioxidant superoxide dismutase
(SOD), also partially rescued cells, although not as
effectively as carnosine. We postulate that the mechanism
of carnosine protection lies in its anti-glycating and
antioxidant activities, both of which are implicated in
neuronal and endothelial cell damage during Alzheimer's
disease. Carnosine may therefore be a useful therapeutic
agent.
An overview of
carbohydrate-protein interactions with specific reference
to myosin and ageing.
Ramamurthy B, H]o]ok P, Larsson L. Noll Physiological
Research Center, The Pennsylvania State University,
University Park, PA 16802, USA.
Acta Physiol Scand 1999 Dec;167(4):327-9
Non-enzymatic glycosylation (glycation), a
post-translational modification of proteins, results from
the reaction of proteins with reducing sugars. Glycation is
implicated in various pathologies like diabetes,
Alzheimer's disease and it has been suggested to play an
important role in the ageing process. Research on protein
glycation has primarily studied extracellular proteins such
as albumin, haemoglobin and collagen. However, there is
increasing evidence that intracellular proteins may also be
affected by glycation, and glycation of myosin is reported
to decrease myosin ATPase activity. Glycated adducts are
detected by various techniques such as chromatography,
electrophoresis, fluorescence and immunochemistry.
Inhibition or removal of these adducts has been achieved by
chemical compounds such as aminoguanidine (amG),
beta-mercaptoethanol (bME) and N-phenacylthiazolium bromide
(PTB). In the present pilot study, using a novel in vitro
motility assay, we have observed an attenuation in the
motility speed of actin (approximately 13%) on myosin
extracted from single muscle fibre segments after 15-min
glucose incubation. Addition of bME to the incubation
medium maintained actin motility speed.
Education, occupation,
and prevalence of dementia: findings from the Conselice
study.
Ravaglia G, Forti P, Maioli F, Sacchetti L, Mariani E,
Nativio V, Talerico T, Vettori C, Macini PL. Department of
Internal Medicine, Cardioangiology, and Hepatology,
University Hospital S. Orsola-Malpighi, Bologna, Italy.
ravaglia@almadns.unibo.it
Dement Geriatr Cogn Disord 2002;14(2):90-100
Information about the epidemiology of dementia in Italy
is still limited, although this cognitive disorder
represents a serious public health concern. We estimated
the prevalence of dementia and dementia subtypes in the
elderly population of a Northern Italian municipality,
Conselice, in the Emilia Romagna region (n = 1,016 subjects
aged 65-97 years). The associations of dementia with two
modifiable risk factors, education and occupation, were
also evaluated. Overall dementia prevalence was 5.9% (95%
confidence interval 4.3-7.8), exponentially increased with
age, and was higher among women. Of the dementia cases, 50%
were Alzheimer's disease (AD), but an unusually high
prevalence (45%) was found for vascular dementia (VD).
After adjustment for age and gender, education but not
occupation was associated with both AD and VD. This
association could not be explained by occupation, life
habits, and previous history of hypertension or
cardiovascular disease. Copyright 2002 S. Karger AG,
Basel
The role of the
polymorphic genes apolipoprotein E and methylene-
tetrahydrofolate reductase in the development of dementia
of the Alzheimer type.
Regland B, Blennow K, Germgard T, Koch-Schmidt AC,
Gottfries CG. Institute of Clinical Neuroscience, Goteborg
University, Goteborg, Sweden.
Dement Geriatr Cogn Disord 1999 Jul-Aug;10(4):245-51
The gene for apolipoprotein E (APOE) is polymorphic, and
its variant APOE4 is a major risk factor for the
development of Alzheimer-type dementia (AD). Another risk
factor for AD appears to be negative cobalamin balance,
which is very common in elderly people. Cobalamin and
folate are interdependent and essential components of the
one-carbon metabolism. Another important component is
methylenetetrahydrofolate reductase (MTHFR), the gene for
which is also polymorphic. Thermolabile MTHFR (tMTHFR), a
gene variant that reduces the activity of its enzyme, is
common in the general population. In the present study, 75%
of 140 AD patients had at least one APOE4 allele. The
numbers of APOE4 and tMTHFR alleles correlated
significantly with the serum folate levels, however, in
opposite directions. The significance of this was augmented
by an inverse correlation between APOE4 and tMTHFR. Thus,
not only MTHFR but also APOE appears to be related to the
one-carbon metabolism, suggesting that APOE4 and
insufficient one-carbon metabolism may be synergistic risk
factors for AD.
Melatonin as a
pharmacological agent against neuronal loss in experimental
models of Huntington's disease, Alzheimer's disease and
parkinsonism.
Reiter RJ, Cabrera J, Sainz RM, Mayo JC, Manchester LC,
Tan DX. Department of Cellular and Structural Biology,
University of Texas Health Science Center, San Antonio
78229-3900, USA. Reiter@uthscsa.edu
Ann N Y Acad Sci 1999;890:471-85
This review summarizes the experimental findings related
to the neuroprotective role of melatonin. In particular, it
focuses on research directed at models of Huntington's
disease, Alzheimer's disease and Parkinsonism. Melatonin
has been shown to be highly effective in reducing oxidative
damage in the central nervous system; this efficacy derives
from its ability to directly scavenge a number of free
radicals and to function as an indirect antioxidant. In
particular, melatonin detoxifies the highly toxic hydroxyl
radical as well as the peroxyl radical, peroxynitrite
anion, nitric oxide, and singlet oxygen, all of which can
damage macromolecules in brain cells. Additionally,
melatonin stimulates a variety of antioxidative enzymes
including superoxide dismutase, glutathione peroxidase and
glutathione reductase. One additional advantage melatonin
has in reducing oxidative damage in the central nervous
system is the ease with which to crosses the blood-brain
barrier. This combination of actions makes melatonin a
highly effective pharmacological agent against free radical
damage. The role of physiological levels of melatonin in
forestalling oxidative damage in the brain is currently
being tested.
Nutritional status of
free-living Alzheimer's patients.
Renvall MJ, Spindler AA, Ramsdell JW, Paskvan M.
Department of Medicine, University of California Medical
Center, San Diego 92103-1990.
Am J Med Sci 1989 Jul;298(1):20-7
Self-reported, dietary intake and biochemical estimates
of thiamine, riboflavin, folate, vitamin B-12, protein, and
iron were compared in 22, free-living elders by individuals
who had senile dementia of the Alzheimer's type (SDAT) and
in 41 who were cognitively normal (CN). The two groups did
not differ significantly in their intake of these nutrients
or the number of deficiency states for intake (less than
67% RDA). Low serum transketolase (thiamin; p less than
0.055), red blood cell (RBC) folate (p less than 0.06), and
serum vitamin B-12 (p less than 0.05) levels occurred more
often in SDAT patients than in CN subjects. Individuals in
both groups who used multivitamin supplements had
significantly higher biochemical values for thiamine (p
less than 0.03), riboflavin (p less than 0.01), and vitamin
B-12 (p less than 0.003) than nonsupplement users. Because
of the differences in vitamin B-12 and RBC folate levels
between groups, a retrospective analysis was performed on a
larger group of subjects drawn from a geriatric assessment
clinic. Patients with SDAT had significantly lower serum
vitamin B-12 (p less than 0.01) and lower RBC folate (p
less than 0.03) values than CN subjects. Which mean values
for vitamin B-12 and RBC folate were grouped by degree of
impairment in SDAT subjects, vitamin B-12 was significantly
lower in mildly and moderately impaired subjects than in
those with normal cognition. Mean values for both nutrients
did not differ significantly between severely impaired and
CN subjects. There was a significant quadratic relationship
between cognitive impairment and biochemical values for
vitamin B-12.(ABSTRACT TRUNCATED AT 250 WORDS)
Low plasma vitamin C in
Alzheimer patients despite an adequate diet.
Riviere S, Birlouez-Aragon I, Nourhashemi F, Vellas B.
Hopital La Grave-Casselar, Toulouse, France.
Int J Geriatr Psychiatry 1998 Nov;13(11):749-54
OBJECTIVE: To compare the vitamin C and E plasma levels
in patients with Alzheimer's disease (AD) and to assess the
vitamin C intake and nutritional status.
DESIGN: Case-control study. Four groups of sex- and
age-matched subjects were compared: severe AD and moderate
AD, in patients with moderate AD and controls.
SETTING: Community and hospitalized patients in the
region of Toulouse, France.
PARTICIPANTS: Patients with dementia who fulfilled
criteria for Alzheimer's disease: severe Alzheimer group (N
= 20), Mini-Mental State Examination (MMSE) score range
0-9; moderate Alzheimer group (N = 24), MMSE 10-23;
hospitalized Alzheimer group (N = 9), MMSE 10-23. Control
group (N = 19), MMSE 24-30.
MEASURES: Plasma vitamin E and C were quantified by
HPLC-fluorescence. Consumption of raw and cooked fruit and
vegetables was evaluated in order to determine the mean
vitamin C intakes. Mini Nutritional Assessment (MNA) and
plasma albumin were used to measure nutritional status.
RESULTS: Institutionalized and community subjects were
analysed separately. MNA scores were normal in home-living
Alzheimer subjects with moderate dementia and significantly
lower in those with severe disease, despite normal plasma
albumin levels. In the home-living Alzheimer subjects,
vitamin C plasma levels decreased in proportion to the
severity of the cognitive impairment despite similar
vitamin C intakes, whereas vitamin E remained stable. The
hospitalized Alzheimer subjects had lower MNA scores and
albumin levels but normal vitamin C intakes, but their
plasma vitamin C was lower than that of community-living
subjects. Institutionalized Alzheimer subjects had
significantly lower MNA scores but normal vitamin C and
albumin levels and vitamin C intakes compared with
community-dwelling subjects of similar degree of cognitive
impairment.
CONCLUSION: Plasma vitamin C is lower in AD in
proportion to the degree of cognitive impairment and is not
explained by lower vitamin C intake. These results support
the hypothesis that oxygen-free radicals may cause
damage.
[Cholinergic hypothesis
and Alzheimer's disease: the place of donepezil
(Aricept)]. [Article in French]
Robert PH, Gokalsing E, Bertogliati C Centre Memoire,
Clinique Universitaire de Psychiatrie, Pavillon J, Hopital
Pasteur, Nice.
Encephale 1999 Nov;25 Spec No 5:23-7; discussion
28-9
This presentation has two objectives: 1) presenting the
relationships between the clinical symptoms of Alzheimer's
disease and cholinergic deficiency, 2) presenting the
results obtained with Aricept (proprietary name of
donepezil hydrochloride), one of the most recent drugs
developed in the context of the cholinergic hypothesis. One
of the earliest pathological events in Alzheimer's disease
consists in the degeneration of cholinergic neurons in the
subcortical regions and, more particularly, in Meynert's
nucleus basalis which projects, in a topographically
organized manner, to the cortical regions and hippocampus.
Some of those regions less affected by the degenerative
process nonetheless retain active post-junctional
receptors. The disappearance of cholinergic neurons from
the nucleus basalis induces disactivation of the cortical
and limbic cells and is responsible for the clinical
symptoms, such as attention, memory and behavioral
disorders. The marketing authorization application for
Aricept is based on various studies designed to enable
preliminary dose determination and assess efficacy and
safety. The first large-scale study designed to evaluate
the efficacy of Aricept administered at a daily dosage of 5
to 10 mg was conducted over 14 weeks. The results show a
significant improvement in cognitive function in the
treatment groups, compared to the placebo groups. The
difference emerged after 3 weeks of treatment, lasted
throughout the 12 weeks of the study and was still very
marked 3 weeks post-treatment discontinuation. The results
of a second study conducted over 30 weeks were similar to
the foregoing results. Compared to placebo, Aricept at a
daily dosage of 5 to 10 mg induces a significant
improvement in cognitive function and overall function. At
week 24, the patients still showed performances that were
superior to their baseline performances. In parallel with
its cognitive effects, Aricept was also shown to improve
the activities of everyday life and alleviate the distress
of caregivers directly confronted with the behavioral
disorders of patients suffering from Alzheimer's
disease.
A controlled trial of
selegiline, alpha-tocopherol, or both as treatment for
Alzheimer ' s disease. The Alzheimer' s Disease Cooperative
Study
Sano M; Ernesto C; Thomas RG; Klauber MR; Schafer K;
Grundman M; Woodbury P; Growdon J; Cotman CW; Pfeiffer E;
Schneider LS; Thal LJ Department of Neurology, Columbia
University College of Physicians and Surgeons, New York,
USA.
N Engl J Med (United States) Apr 24 1997, 336 (17)
p1216-22
BACKGROUND: There is evidence that medications or
vitamins that increase the levels of brain catecholamines
and protect against oxidative damage may reduce the
neuronal damage and slow the progression of Alzheimer's
disease.
METHODS: We conducted a double-blind,
placebo-controlled, randomized, multicenter trial in
patients with Alzheimer's disease of moderate severity. A
total of 341 patients received the selective monoamine
oxidase inhibitor selegiline (10 mg a day),
alpha-tocopherol (vitamin E, 2000 IU a day), both
selegiline and alpha-tocopherol, or placebo for two years.
The primary outcome was the time to the occurrence of any
of the following: death, institutionalization, loss of the
ability to perform basic activities of daily living, or
severe dementia (defined as a Clinical Dementia Rating of
3).
RESULTS: Despite random assignment, the baseline score
on the Mini-Mental State Examination was higher in the
placebo group than in the other three groups, and this
riable was highly predictive of the primary outcome
(P<0.001). In the unadjusted analyses, there was no
statistically significant difference in the outcomes among
the four groups. In analyses that included the base-line
score on the Mini-Mental State Examination as a covariate,
there were significant delays in the time to the primary
outcome for the patients treated with selegiline (median
time, 655 days; P=0.012), alpha-tocopherol (670 days,
P=0.001) or combination therapy (585 days, P=0.049), as
compared with the placebo group (440 days).
CONCLUSIONS: In patients with moderately severe
impairment from Alzheimer's disease, treatment with
selegiline or alpha-tocopherol slows the progression of
disease.
Tyrosine hydroxylase,
tryptophan hydroxylase, biopterin, and neopterin in the
brains of normal controls and patients with senile dementia
of Alzheimer type.
Sawada M, Hirata Y, Arai H, Iizuka R, Nagatsu T.
J Neurochem 1987 Mar;48(3):760-4
The activities of tyrosine hydroxylase and tryptophan
hydroxylase, and the concentrations of the biopterin
cofactor and the precursor neopterin were measured in 14
regions of postmortem brains from four histologically
verified patients of senile dementia of the Alzheimer type
(SDAT) and eight histologically normal controls. Neopterin
concentrations were measured in the human brain for the
first time. The activities of tyrosine hydroxylase and
tryptophan hydroxylase in the brains of patients with SDAT
were significantly reduced in the substantia nigra and in
the lateral segment of the globus pallidus, locus ceruleus,
and substantia nigra, respectively. The concentrations of
total biopterin in the brains of patients with SDAT were
significantly reduced in the putamen and substantia nigra,
but the total neopterin concentrations did not change
significantly. These results suggest that the reduction in
biogenic amines in SDAT might be related to reductions in
biosynthetic enzymes associated with biogenic amines, due
to destruction of monoaminergic neurons.
Brain inflammatory
reaction in an animal model of neuronal degeneration and
its modulation by an anti-inflammatory drug: implication in
Alzheimer's disease.
Scali C, Prosperi C, Vannucchi MG, Pepeu G, Casamenti F
Department of Pharmacology, University of Florence, Viale
Pieraccini, 6, 50139 Florence, Italy.
Eur J Neurosci 2000 Jun;12(6):1900-12
Brain inflammatory processes underlie the pathogenesis
of Alzheimer's disease, and nonsteroidal anti-inflammatory
drugs have a protective effect in the disease. The aim of
this study was to characterize in vivo in the rat brain the
inflammatory reaction in response to excitotoxic insult and
to investigate the efficacy of nimesulide treatment.
Quisqualic acid was injected into the right nucleus basalis
of rats. The excitotoxin induced cholinergic degeneration,
an intense glial reaction and the production of
inflammatory mediators. Three hours after injection, a
five-fold elevation in the concentration of
interleukin-1beta in the injected area was observed. This
elevation was reduced by 50% by nimesulide (10 mg/kg, i.m.)
pretreatment. Electron microscope examination and
immunocytochemical staining revealed an intense activation
of microglia and astrocytes at both 24 h and 7 days after
injection. Cyclooxygenase-2-immunoreactivity was induced in
the blood vessels of the injected hemisphere in
perivascular microglial and endothelial cells 24 h after
injection. Seven days postinjection, a
cyclooxygenase-2-positive signal was induced in the
parenchymal microglia and large amounts of prostaglandin-E2
were measured in the injected area. Twenty-four hours and 7
days after injection, many inducible nitric oxide
synthase-positive cells and a high level of nitrite were
detected at the injection site. Seven days of nimesulide
(10 mg/kg/day, i.m.) treatment strongly attenuated the
microglial reaction, reduced the number of inducible nitric
oxide synthase-positive cells and completely abolished the
increase in prostaglandin-E2 formation. These data provide
valuable support in vivo for the potential efficacy of
cyclooxygenase-2 inhibitors in Alzheimer's disease
therapy.
Alzheimer's disease
after remote head injury: an incidence study.
Schofield PW, Tang M, Marder K, Bell K, Dooneief G, Chun
M, Sano M, Stern Y, Mayeux R. Gertrude H Sergievsky Center,
Columbia University, New York City 10032, USA.
J Neurol Neurosurg Psychiatry 1997 Feb;62(2):119-24
OBJECTIVE: To evaluate a history of remote head injury
as a risk factor for subsequent dementia due to Alzheimer's
disease.
METHODS: 271 participants of a community based
longitudinal study of aging in north Manhattan without
evidence of significant cognitive impairment were
interrogated for a history of head injury on two occasions
at entry into the study. The examining physician sought a
history of head injury with loss of conciousness.
Independently, a risk factor interviewer inquired about a
history of head injury with loss of consiousness or
amnesia, the duration of any loss of consiousness, and the
date of the head injury. Patients were followed up with
standardised annual evaluations for up to five years to
determine the first occurrence of dementia.
RESULTS: Over the course of the study incident dementia
due to probable or possible Alzheimer's disease was
diagnosed in 39 patients. Cox proportional hazards
modelling showed that a history of head injury with loss of
consiousness reported to the physician was associated with
earlier onset of dementia due to Alzheimer's disease
(relative risk (RR) = 4.1, 95% confidence interval (95% CI)
1.3-12.7). head injury with loss of consiousness or amnesia
reported to the risk factor interviewer was not
significantly associated with earlier onset of Alzheimer's
disease overall (RR 2.0, 95% CI 0.7-6.2), but those who
reported loss of consiousness exceeding five minutes were
at significantly increased risk (RR 11.2, 95% CI 2.3-59.8).
Incident Alzheimer's disease was significantly associated
with head injury which occurred within the preceding 30
years (RR 5.4, 95% CI 1.5-19.5).
CONCLUSION: The results of this cohort study are
consistent with the findings of several case-control
studies suggesting that head injury may be a risk factor
for Alzheimer's disease.
Phenolic antioxidants
attenuate neuronal cell death following uptake of oxidized
low-density lipoprotein.
Schroeter H, Williams RJ, Matin R, Iversen L, Rice-Evans
CA. Wolfson Centre for Age-Related Diseases, Guy's, King's,
and St. Thomas's School of Biomedical Sciences, King's
College, Guy's Campus, London, England.
Free Radic Biol Med 2000 Dec 15;29(12):1222-33
Oxidative stress is implicated in neuronal loss
associated with neurodegeneration such as in Parkinson's
disease, Alzheimer's disease and age-related cognitive
decline. Recent reports indicate that the consumption of
flavonoid-rich fruits partly reverses the age-related
neuronal and cognitive decline. In this study, cultured
striatal neurons were exposed to oxidized lipids in the
form of low-density lipoprotein (oxLDL) as a model for the
induction of oxidative injury, and the abilities of
phenolic antioxidants, flavonoids and hydroxycinnamic acid
derivatives, to attenuate this neuronal damage were
examined. OxLDL was demonstrated to enter neuronal cells
and to be capable of eliciting neurotoxicity in a dose- and
time-dependent manner, inducing DNA fragmentation and cell
lysis. Flavonoids exert protective effects, which appear to
be related to specific structural characteristics,
particularly relevant being those defining their reduction
potentials and partition coefficients. In summary, these
data suggest a possible role for flavonoids in reducing
neurodegeneration associated with chronic disorders in
which oxidative stress is implicated.
CSF-folate levels are
decreased in late-onset AD patients.
Serot JM, Christmann D, Dubost T, Bene MC, Faure GC.
Laboratoire d'Immunologie, GRIP, JE DRED 251, Faculte de
Medecine, UHP, Nancy, France. faure@grip.u-nancy.fr
J Neural Transm 2001;108(1):93-9
Folates are involved in the cerebral metabolism of
cobalamine, methionine, L-tyrosine and acetylcholine.
Remarkably CSF-folate levels are 3 to 4 times higher than
blood-folate levels. To reach the brain, folates are
actively transported by choroid plexus (CP) as well as
vitamins B6, B12, C and E. Epithelial atrophy having been
reported in aging and in Alzheimer's disease (AD), we
measured the CSF folate-levels of 126 patients, including
30 AD consecutive patients to evaluate whether CP functions
of folate-transport were impaired. CSF-folate
concentrations did not vary with age (10.47 +/- 1.93ng/ml
between 20 and 60 years; 9.96 +/- 2.01 ng/ml in elderly
control patients older than 60 years of age, p > 0.05)
while late-onset AD patients had significantly lower
CSF-folate levels (8.26 +/- 1.82 ng/ml, p < 0.001).
These data support a specific alteration of CP transport
function in AD patients.
Chronic (-) deprenyl
administration alters dendritic morphology of layer III
pyramidal neurons in the prefrontal cortex of adult Bonnett
monkeys.
Shankaranarayana Rao BS, Lakshmana MK, Meti BL, Raju TR
Department of Neurophysiology, National Institute of Mental
Health and Neurosciences, P.B. #2900, Hosur Road, Bangalore
560 029, India.
Brain Res 1999 Mar 6;821(1):218-23
Chronic (-) deprenyl (0.2 mg/kg, b.wt; for 25 days)
treatment induced alterations in the dendritic morphology
of prefrontal cortical neurons in adult Bonnett monkeys
were evaluated in the present study. The branching points
and intersections in apical and basal dendrites were
studied up to a distance of 400 and 200 micrometers,
respectively, in Golgi impregnated layer III pyramidal
neurons of the prefrontal cortex. Our results revealed a
significant (p<0.001) increase in the number of
branching points and intersections in both apical and basal
dendrites in (-) deprenyl treated monkeys compared to
controls. Such an enriched dendritic arborization in
prefrontal cortical neurons may be responsible for the
enhancement of cognitive functions in Alzheimer disease
patients following (-) deprenyl treatment.
The pathogenesis of
Alzheimer's disease.
Small GW. Department of Psychiatry and Biobehavioral
Sciences, University of California at Los Angeles School of
Medicine, and the Veterans Affairs Medical Center, USA.
J Clin Psychiatry 1998;59 Suppl 9:7-14
Despite consensus on clinical and neuropathologic
definitions of Alzheimer's disease, limited information is
available on its causes and pathogenesis. Current data
suggest interactions among the various possible biological
and environmental influences that result in a common
pathway leading to the disease. Biological influences
include genetic mutations causing the disease phenotype and
polymorphisms contributing to disease risk. Alterations in
immune or inflammatory responses may also represent
biological influences. Various environmental influences
that may interact with endogenous biological factors
include education, traumatic injury, oxidative stress,
drugs, and hormone replacement. The author describes some
recent findings that suggest possible pathogenic
mechanisms, which may eventually have important treatment
implications.
Should the guidelines
for monitoring serum cholesterol levels in the elderly be
re-evaluated?
Sparks DL, Connor DJ, Browne P, Sabbagh MN; AD
Cholesterol-Lowering Treatment Trial Team. Laboratory of
Neurodegenerative Disease Research, Sun Health Research
Institute, Sun City, AZ 85351, USA.
Larry.Sparks@SunHealth.org
J Mol Neurosci 2002 Aug-Oct;19(1-2):209-12
Elevated circulating cholesterol can have profound
effects on the health of an individual. Such excess
cholesterol can promote coronary artery disease, production
and accumulation of beta-amyloid in the brain, and possibly
Alzheimer's disease (AD). In a clinical trial evaluating
the benefit of a cholesterol-lowering drug in the treatment
of AD, mean cholesterol levels at baseline among
individuals participating in the trial were found to be
relatively high. Based on this observation we suggest that
cholesterol levels should be actively monitored in the
elderly, as many individuals with AD are over 65 years of
age and therefore excluded by currently accepted
guidelines.
Influence of education
and occupation on the incidence of Alzheimer's
disease.
Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D,
Mayeux R. Department of Neurology, Columbia University
College of Physicians and Surgeons, Gertrude H. Sergievsky
Center, New York, NY 10032.
JAMA 1994 Apr 6;271(13):1004-10
OBJECTIVE--Several cross-sectional studies have found an
association between Alzheimer's disease (AD) and limited
educational experience. It has been difficult to establish
whether educational experience is a risk factor for AD
because educational attainment can influence performance on
diagnostic tests. This study was designed to determine
whether limited educational level and occupational
attainment are risk factors for incident dementia.
DESIGN--Cohort incidence study.
SETTING--General community.
PARTICIPANTS-A total of 593 nondemented individuals aged
60 years or older who were listed in a registry of
individuals at risk for dementia in North Manhattan, NY,
were identified and followed up.
INTERVENTIONS--We reexamined subjects 1 to 4 years later
with the identical standardized neurological and
neuropsychological measures.
MAIN OUTCOME MEASURES-Incident dementia.
RESULTS--We used Cox proportional hazards models,
adjusting for age and gender, to estimate the relative risk
(RR) of incident dementia associated with low educational
and occupational attainment. Of the 593 subjects, 106
became demented; all but five of these met research
criteria for AD. The risk of dementia was increased in
subjects with either low education (RR, 2.02; 95%
confidence interval [Cl], 1.33 to 3.06) or low lifetime
occupational attainment (RR, 2.25; 95% Cl, 1.32 to 3.84).
Risk was greatest for subjects with both low education and
low life-time occupational attainment (RR, 2.87; 95% Cl,
1.32 to 3.84).
CONCLUSIONS--The data suggest that increased educational
and occupational attainment may reduce the risk of incident
AD, either by decreasing ease of clinical detection of AD
or by imparting a reserve that delays the onset of clinical
manifestations.
Risk of Alzheimer's
disease and duration of NSAID use.
Stewart WF, Kawas C, Corrada M, Metter EJ Department of
Epidemiology, Johns Hopkins School of Public Health,
Baltimore, MD 21205, USA.
Neurology 1997 Mar;48(3):626-32
In a longitudinal study of 1,686 participants in the
Baltimore Longitudinal Study of Aging, we examined whether
the risk of Alzheimer's disease (AD) was reduced among
reported users of aspirin or other nonsteroidal
anti-inflammatory drugs (NSAIDs). In addition, we examined
use of acetaminophen, a pain-relief medication with little
or no anti-inflammatory activity, to assess the specificity
of the association between AD risk and self-reported
medications. Information on use of medications was
collected during each biennial examination between 1980 and
1995. The relative risk (RR) for AD decreased with
increasing duration of NSAID use. Among those with 2 or
more years of reported NSAID use, the RR was 0.40 (95%
confidence interval [CI]: 0.19-0.84) compared with 0.65
(95% CI: 0.33-1.29) for those with less than 2 years of
NSAID use. The overall RR for AD among aspirin users was
0.74 (95% CI: 0.46-1.18), and no trend of decreasing risk
of AD was observed with increasing duration of aspirin use.
No association was found between AD risk and use of
acetaminophen (RR = 1.35; 95% CI: 0.79-2.30), and there was
no trend of decreasing risk with increasing duration of
use. These findings are consistent with evidence from
cross-sectional studies indicating protection against AD
risk among NSAID users and with evidence suggesting that
one stage of the pathophysiology leading to AD is
characterized by an inflammatory process.
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