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Alzheimer's Disease Reviews: 2001
(571 References)
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(2001). "Alzheimer's disease: recent progress and
prospects--Part III." Harv Ment Health Lett 18(6): 1-4.
(2001). "New tools for taking control of Alzheimer disease." Johns Hopkins
Med Lett Health After 50 13(10): 4-5.
(2001). "Alzheimer's disease: recent progress and prospects--Part I." Harv
Ment Health Lett 18(4): 1-4.
Abdulla, Y. H. (2001). "A plausible function of the prion protein: conjectures
and a hypothesis." Bioessays 23(5): 456-62.
Amyloid beta precursor protein (APP) and prion protein (PrP) are cell membrane
elements implicated in neurodegenerative diseases. Both proteins undergo
endoproteolysis. Evidence is adduced from the literature hinting that the
process in the two proteins could be related, their functions may overlap and
their distributions coincide. It is proposed that PrP catalyses its own
cleavage, the C-terminal fragment functions as an alpha secretase and the
N-terminal segment chaperones the active site; the alpha secretase releases
anticoagulant and neurotrophic ectodomains from APP. The proposals explain some
features of spongiform encephalopathies.
Abe, K. and H. Saito (2001). "Effects of basic fibroblast growth factor on
central nervous system functions." Pharmacol Res 43(4): 307-12.
Basic fibroblast growth factor (bFGF), initially identified as mitogens with
prominent angiogenic properties, is now recognized as multifunctional growth
factors with notable actions on neuronal cells. bFGF promotes the survival and
neurite growth of brain neurons in vitro and in vivo, suggesting that it
functions as a neurotrophic factor. This effect of bFGF could be beneficial for
improving the survival of grafted neurons in transplantation. Furthermore, bFGF
acutely modulates synaptic transmission in the hippocampus, suggesting that it
has a role like a neurotransmitter or neuromodulator. In this article, we make a
brief review of multiple biological activities of bFGF for brain neurons and
discuss its potential usefulness for the treatment of neurodegenerative
disorders including Alzheimer's disease and Parkinson's disease.
Abraham, C. R. (2001). "Reactive astrocytes and alpha1-antichymotrypsin in
Alzheimer's disease." Neurobiol Aging 22(6): 931-6.
There is ample genetic, biochemical, cellular and molecular evidence to show
that the amyloid beta peptide (Abeta), a proteolytic fragment of the amyloid
precursor protein (APP), plays an important, if not causative role in
Alzheimer's disease (AD). An additional hallmark of AD is the neuroinflammatory
response that is associated with the amyloid deposition. We discovered that the
acute phase protein alpha1-antichymotrypsin (ACT) is overexpressed by reactive
astrocytes, and is tightly associated with virtually all amyloid plaques in the
AD brain. It has also been shown that Abeta and ACT bind in vitro. Recently, we
have reported that astrocytic expression of ACT in APP transgenic mice leads to
an increased plaque deposition in ACT/APP doubly transgenic mice compared to the
APP mice alone, suggesting that ACT interferes with Abeta clearance. The main
objective of this review is to summarize the role of astrocytosis and ACT in the
pathogenesis of AD.
Ada, G. (2001). "Vaccines and vaccination." N Engl J Med 345(14):
1042-53.
Adams, L. L., R. J. Gatchel, et al. (2001). "Complementary and alternative
medicine: applications and implications for cognitive functioning in elderly
populations." Altern Ther Health Med 7(2): 52-61.
OBJECTIVE: Aged populations in the United States are growing in numbers, and
stand to be affected most by the changing shape of healthcare delivery. Within
these elderly populations, the problem of decreased cognitive functioning due to
dementing disorders is rising. Recent compelling research on complementary and
alternative medicine interventions targeted at cognitive deficits in the elderly
is reviewed in this survey. DATA SOURCES: A literature review was undertaken to
identify original clinical research studies, review articles, chapters, and
books on treating cognitive deficits in the elderly. Contact with complementary
and alternative medicine researchers provided additional information concerning
developments in this field. STUDY SELECTION: Research studies that were
methodologically sound were selected for review. More purely clinical studies
also were included to provide a thorough overview of the limited amount of
accumulated knowledge in this field. DATA SYNTHESIS: A qualitative synthesis of
the above data was used to comprehensively present all information accumulated
to date in this field. CONCLUSIONS: Although still in the preliminary stages of
development, clinical research exploring the benefits of complementary and
alternative therapies for cognitive deficits among the elderly shows a
significant level of promise that warrants a further investment of resources.
Agostoni, A. and M. Cugno (2001). "[The kinin system: biological mechanisms and
clinical implications]." Recenti Prog Med 92(12): 764-73.
The discovery of the kinin system is not recent, but its study in clinical field
has been done only in the last years. This system is composed by substrates
(kininogens) and plasma and tissue kallikreins are the specific activators of
these substrates producing two vasoactive peptides called bradykinin and
kallidin. The biologic effects of kinins are mediated by specific receptors
called B1 and B2. The activation of this system is particularly important in
blood pressure regulation and in inflammatory reactions. The kinin system is
involved in many clinical situations including respiratory allergic reactions,
septic shock, hypertension and its treatment, hypotensive transfusion reactions,
heart diseases, pancreatitis, hereditary and acquired angioedema, Alzheimer's
disease and liver cirrhosis with ascites. The study of the kinin system in
clinical field, which had been limited by methodological difficulties, has now
received an important stimulus by the recent availability of specific and
sensitive methods of dosage.
Ahmed, M. B. (2001). "Alzheimer's disease: recent advances in etiology,
diagnosis, and management." Tex Med 97(12): 50-8.
Alzheimer's disease is a chronic and progressive neurodegenerative disorder
characterized by cognitive and functional deficit and by behavior disturbance.
This disease presents a major clinical and social challenge. Increasing evidence
suggests that early intervention can delay the progression of the disease and
improve symptoms and cognitive functioning. Recent research focuses on genetic
susceptibility. Genetic testing may eventually prove to be useful in identifying
persons at risk before the onset of symptoms, but at this stage, this testing
plays a limited role in identifying and confirming the diagnosis and in genetic
counseling. The diagnostic work in all suspected cases of dementia should be
started by family physicians; confirmed cases should be treated as soon as
possible by the family physician or referred to a psychiatrist or neurologist
for appropriate treatment. Donepezil, new cholinesterase inhibitors, and vitamin
E have proved effective in delaying progression of Alzheimer's disease.
Albers, D. S. and S. J. Augood (2001). "New insights into progressive
supranuclear palsy." Trends Neurosci 24(6): 347-53.
Increased oxidative damage and mitochondrial dysfunction have been suggested to
play crucial roles in the pathogenesis of several neurodegenerative diseases,
including Parkinson's disease and Alzheimer's disease. In this review, we will
focus on progressive supranuclear palsy (PSP), a rare parkinsonian disorder with
tau pathology. Particular emphasis is placed on the genetic and biochemical data
that has emerged, offering new perspectives into the pathogenesis of this
devastating disease, especially the contributory roles of oxidative damage and
mitochondrial dysfunction.
Alexander, M. (2001). "The charms of music. Step by step prescription for
patients." N C Med J 62(2): 91-4.
Allain, H., S. Schuck, et al. (2001). "Comparative effects of pharmacotherapy on
the maintenance of cognitive function." Eur Psychiatry 16 Suppl 1:
35s-41s.
The quality of human cognitive performance appears today as one of the main
components of quality of life, whatever the age. Ageing by itself and most of
the diseases affecting the central nervous system alter higher brain functions
such as memory, vigilance and attention. Dementia is the most acute example,
with a cascade of behavioral and psychological consequences (BPSD), which are
the main cause of the caregiver's burden and need specific pharmacotherapy. In
this respect, the problem will be the choice of the best drug in situations such
as wandering, agitation, violence, and screaming. The psychotropics, however,
should not deteriorate the already disturbed cognition of the patients. This is
the reason why we propose to establish for each drug, and notably for the
antipsychotics, a precise and exact "cognitive mapping"; in other words, to
measure the effects of drugs on the different components of cognition. The
results of such studies will be predictive of the future phase III clinical
trials and therapeutic responses. As an illustration of this approach we shall
relate two studies, TIATEM (phase I) and TIAGE (phase III/IV), leading to the
determination of a good cognitive safety profile of an atypical neuroleptic
drug, tiapride.
Allison, A. C., R. Cacabelos, et al. (2001). "Celastrol, a potent antioxidant
and anti-inflammatory drug, as a possible treatment for Alzheimer's disease."
Prog Neuropsychopharmacol Biol Psychiatry 25(7): 1341-57.
In the brains of patients with Alzheimer's disease (AD) signs of neuronal
degeneration are accompanied by markers of microglial activation, inflammation,
and oxidant damage. The presence of nitrotyrosine in the cell bodies of neurons
in AD suggests that peroxynitrite contributes to the pathogenesis of the
disease. A drug with antioxidant and anti-inflammatory activity may prevent
neuronal degeneration in AD. Celastrol, a plant-derived triterpene, has these
effects. In low nanomolar concentrations celastrol was found to suppress the
production by human monocytes and macrophages of the pro-inflammatory cytokines
TNF-alpha and IL-1beta. Celastrol also decreased the induced expression of class
II MHC molecules by microglia. In macrophage lineage cells and endothelial cells
celastrol decreased induced but not constitutive NO production. Celastrol
suppressed adjuvant arthritis in the rat, demonstrating in vivo
anti-inflammatory activity. Low doses of celastrol administered to rats
significantly improved their performance in memory, learning and psychomotor
activity tests. The potent antioxidant and anti-inflammatory activities of
celastrol, and its effects on cognitive functions, suggest that the drug may be
useful to treat neurodegenerative diseases accompanied by inflammation, such as
AD.
Allsop, D., L. J. Twyman, et al. (2001). "Modulation of beta-amyloid production
and fibrillization." Biochem Soc Symp(67): 1-14.
Alzheimer's disease (AD) is the most common cause of dementia in old age and
presently affects an estimated 4 million people in the U.S.A. and 0.75 million
people in the U.K. It is a relentless, degenerative brain disease, characterized
by progressive cognitive impairment. In the final stages of the disease,
patients are often bedridden, doubly incontinent and unable to speak or to
recognize close relatives. Pathological changes of Alzheimer's disease include
extensive neuronal loss and the presence of numerous neurofibrillary tangles and
senile plaques in the brain. The senile plaques contain amyloid fibrils derived
from a 39-43-amino-acid peptide referred to as beta-amyloid or A beta. The basic
theory of the so-called 'amyloid hypothesis' is that the deposition of
aggregated forms of A beta in the brain parenchyma triggers a pathological
cascade of events that leads to neurofibrillary tangle formation, neuronal loss
and the associated dementia [1]. Here we discuss progress towards the
identification of inhibitors of A beta production and fibrillization.
Allt, G. and J. G. Lawrenson (2001). "Pericytes: cell biology and pathology."
Cells Tissues Organs 169(1): 1-11.
Pericytes are perivascular cells with multifunctional activities which are now
being elucidated. The functional interaction of pericytes with endothelial cells
(EC) is now being established, using current molecular and cytochemical
techniques. The detailed morphology of the pericyte has been well described.
Pericytes extend long cytoplasmic processes over the surface of the EC, the two
cells making interdigitating contacts. At points of contact, communicating gap
junctions, tight junctions and adhesion plaques are present. Pericytes appear to
show both structural and functional heterogeneity. The coverage of EC by
pericytes varies considerably between different microvessel types and the
location of pericytes on the microvessel is not random but appears to be
functionally determined. Interaction between pericytes and EC is important for
the maturation, remodelling and maintenance of the vascular system via the
secretion of growth factors or modulation of the extracellular matrix. There is
also evidence that pericytes are involved in the transport across the
blood-brain barrier and the regulation of vascular permeability. The
long-standing view that pericytes are the microvessel equivalent of larger
vessel smooth muscle cells and are contractile is being reassessed using current
methods. An important role for pericytes in pathology, and neuropathology in
particular, has been indicated in hypertension, diabetic retinopathy,
Alzheimer's disease, multiple sclerosis and CNS tumour formation.
Amenta, F., L. Parnetti, et al. (2001). "Treatment of cognitive dysfunction
associated with Alzheimer's disease with cholinergic precursors. Ineffective
treatments or inappropriate approaches?" Mech Ageing Dev 122(16):
2025-40.
The observations of the loss of cholinergic function in neocortex and
hippocampus in Alzheimer's disease (AD) developed the hypothesis that
replacement of cholinergic function may be of therapeutic benefit to AD
patients. The different approaches proposed or tested included intervention with
acetylcholine (ACh) precursors, stimulation of ACh release, use of muscarinic or
nicotinic receptor agonists and acetylcholinesterase (AChE) or cholinesterase
(ChE) inhibition. Inhibition of endogenous ACh degradation through ChE
inhibitors and precursor loading were treatments more largely investigated in
clinical trials. Of the numerous compounds in development for the treatment of
AD, AChE and ChE inhibitors are the most clinically advanced, although clinical
trials conducted to date did not always confirm a significant benefit of these
drugs on all symptom domains of AD. The first attempts in the treatment of AD
with cholinergic precursors did not confirm a clinical utility of this class of
compounds in well controlled clinical trials. However, cholinergic precursors
most largely used such as choline and phosphatidylcholine (lecithin) were
probably not suitable for enhancing brain levels of ACh. Other phospholipids
involved in choline biosynthetic pathways such as CDP-choline, choline
alphoscerate and phosphatidylserine clearly enhanced ACh availability or release
and provided a modest improvement of cognitive dysfunction in AD, these effects
being more pronounced with choline alphoscerate. Although some positive results
cannot be generalized due to the small numbers of patients studied, they
probably would justify reconsideration of the most promising molecules in larger
carefully controlled trials.
Andoh, T. (2001). "[Effects of general anesthetics on neuronal nicotinic
acetylcholine receptors and their roles in the mechanism of anesthesia]."
Masui 50(10): 1072-84.
Neuronal nicotinic acetylcholine receptors (nAchRs) are widely expressed in the
central and autonomic nervous systems and have subunit compositions with
biophysical and pharmacological properties distinct from those of the receptors
at the neuromuscular junction. They are thought to modulate synaptic
transmission in the central nervous system (CNS) mainly by regulating the
release of neurotransmitters. Although roles of neuronal nAchRs in the CNS are
poorly understood, these receptors are involved in cognitive performance,
nociception and psychoneurological disorders such as Alzheimer's and Parkinson
disease. It is known that both central and peripheral neuronal nAchRs are
sensitive to various types of anesthetics. Among those, barbiturates, ketamine,
volatile and gaseous anesthetics depress neuronal nAchRs at or below clinical
concentrations. Inhibition of neuronal nAchRs by barbiturates is unlikely to
contribute to the anesthetic action of barbiturates, since this effect does not
correlate with the anesthetic potencies of barbiturate stereoisomers. Relevance
of inhibition of these receptors is controversial for anesthetic effects of
other anesthetics, because conflicting results have been obtained from
comparison of this effect with anesthetic actions of stereoisomers or
structurally related compounds. However, it is possible that inhibition of
central nAchRs contributes to secondary effects attributed to anesthesia such as
impairment in memory and cognitive performance.
Andrews, G. R. (2001). "The priority of basic research on ageing vulnerability
in a comprehensive research agenda on ageing for the 21st century." Novartis
Found Symp 235: 4-9; discussion 9-10.
The prospects for individual and population ageing as we enter a new century
pose some of the greatest social, economic and humanitarian challenges humankind
as a whole has ever faced. The basic biological mechanisms that control human
ageing remain ill understood but it is clear that for many individuals
exhibiting predisposition to risk factors for certain chronic diseases, such as
coronary heart disease, diabetes, osteoporosis, certain cancers and Alzheimer's
disease, such predisposition is mediated through genetic processes that operate
at a most fundamental biomolecular level interacting with nongenetic attributes.
The prospect of improved understanding of the fundamental processes underlying
the pathogenesis of common age-related diseases that may lead to identification
of interventions that are effective in preventing, delaying or ameliorating the
diseases and their consequences is compelling. It is this prospect that provides
the prime justification for giving high priority to research on ageing
vulnerability in a comprehensive research agenda on ageing for the 21st century.
Anthony, M., J. K. Williams, et al. (2001). "What would be the properties of an
ideal SERM?" Ann N Y Acad Sci 949: 261-78.
Selective estrogen receptor modulators (SERMs) are drugs that bind to the
estrogen receptor (ER); in some tissues they act like estrogen (agonists), while
in other tissues they oppose the action of estrogen (antagonists). The SERM
tamoxifen acts as an estrogen antagonist in the breast in that it prevents and
treats breast cancer, but it acts as an estrogen agonist in the endometrium,
where it can induce cancer. Estrogen, and to a lesser extent SERMs, are
effective in preventing and treating osteoporosis. Contrary to the prevalent
hypothesis that estrogen provides benefit to women with regard to secondary
prevention of coronary heart disease (CHD), randomized clinical trials have
demonstrated that estrogen is associated with an increased risk of CHD in this
population of women. Conflicting results have been reported on the effect of
estrogens on cognitive function. The latest and largest randomized clinical
trials have demonstrated a beneficial role in short-term memory in nondemented
women, in contrast to the absence of such benefit in improving symptoms in women
with Alzheimer's disease. Although estrogens have been used successfully to
treat some menopausal symptoms such as hot flashes, the SERMs tamoxifen and
raloxifene actually induce or increase hot flashes. Data on the beneficial and
adverse effects of estrogen and SERMs are reported along with an elaboration of
the constellation of properties that would characterize an ideal SERM working
through the ER.
Apfel, S. C. (2001). "Neurotrophic factor therapy--prospects and problems."
Clin Chem Lab Med 39(4): 351-5.
Over the past 15 years neurotrophic factors have generated considerable
excitement for their potential as therapy for a wide variety of degenerative
neurological disorders, for which there is currently no treatment. The first
part of this period was marked by the discovery, characterization, and cloning
of many new growth factors, and by successful testing of these factors in animal
models of neurological disease. In recent years the biotechnology industry and
pharmaceutical industry have attempted to replicate the success of the animal
studies in clinical trials. Although some studies have demonstrated moderate
efficacy, for the most part the clinical trials have been less successful at
demonstrating the therapeutic efficacy of this new class of drugs. For example,
nerve growth factor appeared to be efficacious in two phase II clinical trials
for peripheral neuropathy, but failed in a large scale phase III trial. Ciliary
neurotrophic factor, brain derived neurotrophic factor and insulin like growth
factor-1 have all been tested in clinical trials for the treatment of
amyotrophic lateral sclerosis, with at best, variable indications of efficacy.
Nevertheless, there are still many reasons to be optimistic that some of these
agents may be useful clinically. Many technical and pharmacological issues
remain to be adequately addressed, before neurotrophic factors can live up to
their potential. Our collective experience with them has re-adjusted previously
wild expectations, so that they are now much more realistic. This is necessary
and beneficial for the maturation of this field of study.
Arendt, T. (2001). "Disturbance of neuronal plasticity is a critical
pathogenetic event in Alzheimer's disease." Int J Dev Neurosci 19(3):
231-45.
Brain areas affected by AD pathology are primarily those structures that are
invovled in the regulation of "higher brain functions". The functions these
areas subserve such as learning, memory, perception, self-awareness, and
consciousness require a life-long re-fittng of synaptic contacts that allows for
the acquistion of new epigenetic information, a process based on a particularly
high degree of structural plasticity. Here, we outline a hypothesis that it is
the "labile state fo differentiation" of a subset of neurons in the adult brain
that allows for ongoing neuroplastic processes after development is completed
but at the same time renders these neurons particularly vulnerable. Mechanisms
of molecular and cellular control of neuronal differentiation and proliferation
might, thus, not only play a role during development but critically involved in
the pathogenesis of neurodegeneration.
Arendt, T. (2001). "Alzheimer's disease as a disorder of mechanisms underlying
structural brain self-organization." Neuroscience 102(4): 723-65.
Mental function has as its cerebral basis a specific dynamic structure. In
particular, cortical and limbic areas involved in "higher brain functions" such
as learning, memory, perception, self-awareness and consciousness continuously
need to be self-adjusted even after development is completed. By this lifelong
self-optimization process, the cognitive, behavioural and emotional reactivity
of an individual is stepwise remodelled to meet the environmental demands. While
the presence of rigid synaptic connections ensures the stability of the
principal characteristics of function, the variable configuration of the
flexible synaptic connections determines the unique, non-repeatable character of
an experienced mental act. With the increasing need during evolution to organize
brain structures of increasing complexity, this process of selective dynamic
stabilization and destabilization of synaptic connections becomes more and more
important. These mechanisms of structural stabilization and labilization
underlying a lifelong synaptic remodelling according to experience, are
accompanied, however, by increasing inherent possibilities of failure and may,
thus, not only allow for the evolutionary acquisition of "higher brain function"
but at the same time provide the basis for a variety of neuropsychiatric
disorders. It is the objective of the present paper to outline the hypothesis
that it might be the disturbance of structural brain self-organization which,
based on both genetic and epigenetic information, constantly "creates" and
"re-creates" the brain throughout life, that is the defect that underlies
Alzheimer's disease (AD). This hypothesis is, in particular, based on the
following lines of evidence. (1) AD is a synaptic disorder. (2) AD is associated
with aberrant sprouting at both the presynaptic (axonal) and postsynaptic
(dendritic) site. (3) The spatial and temporal distribution of AD pathology
follows the pattern of structural neuroplasticity in adulthood, which is a
developmental pattern. (4) AD pathology preferentially involves molecules
critical for the regulation of modifications of synaptic connections, i.e.
"morphoregulatory" molecules that are developmentally controlled, such as
growth-inducing and growth-associated molecules, synaptic molecules, adhesion
molecules, molecules involved in membrane turnover, cytoskeletal proteins, etc.
(5) Life events that place an additional burden on the plastic capacity of the
brain or that require a particularly high plastic capacity of the brain might
trigger the onset of the disease or might stimulate a more rapid progression of
the disease. In other words, they might increase the risk for AD in the sense
that they determine when, not whether, one gets AD. (6) AD is associated with a
reactivation of developmental programmes that are incompatible with a
differentiated cellular background and, therefore, lead to neuronal death. From
this hypothesis, it can be predicted that a therapeutic intervention into these
pathogenetic mechanisms is a particular challenge as it potentially interferes
with those mechanisms that at the same time provide the basis for "higher brain
function".
Armstrong, R. A., N. J. Cairns, et al. (2001). "What does the study of the
spatial patterns of pathological lesions tell us about the pathogenesis of
neurodegenerative disorders?" Neuropathology 21(1): 1-12.
Discrete pathological lesions, which include extracellular protein deposits,
intracellular inclusions and changes in cell morphology, occur in the brain in
the majority of neurodegenerative disorders. These lesions are not randomly
distributed in the brain but exhibit a spatial pattern, that is, a departure
from randomness towards regularity or clustering. The spatial pattern of a
lesion may reflect pathological processes affecting particular neuroanatomical
structures and, therefore, studies of spatial pattern may help to elucidate the
pathogenesis of a lesion and of the disorders themselves. The present article
reviews first, the statistical methods used to detect spatial patterns and
second, the types of spatial patterns exhibited by pathological lesions in a
variety of disorders which include Alzheimer's disease, Down syndrome, dementia
with Lewy bodies, Creutzfeldt-Jakob disease, Pick's disease and corticobasal
degeneration. These studies suggest that despite the morphological and molecular
diversity of brain lesions, they often exhibit a common type of spatial pattern
(i.e. aggregation into clusters that are regularly distributed in the tissue).
The pathogenic implications of spatial pattern analysis are discussed with
reference to the individual disorders and to studies of neurodegeneration as a
whole.
Arnold, S. E. (2001). "Contributions of neuropathology to understanding
schizophrenia in late life." Harv Rev Psychiatry 9(2): 69-76.
The neurobiological basis of cognitive and functional deterioration commonly
observed in elderly persons with schizophrenia is unclear. Despite superficial
similarities in the clinical and neuropsychological profiles of schizophrenia in
late life with neurodegenerative dementias, extensive neuropathological
investigations have failed to find any evidence of neurodegeneration or neural
injury beyond what is typically observed in brains of individuals without
neuropsychiatric illness. In contrast, growing neuropathological data indicate
aberrant brain development and connectivity in schizophrenia (including
abnormalities in cytoarchitecture, innervation, and synaptic integrity) and
abnormal molecular signaling pathways important in the formation of the nervous
system and ongoing plasticity in maturity. These developmental abnormalities may
represent a state of decreased cerebral reserve that causes persons with
schizophrenia to be more vulnerable to the toxic effects of even "normal"
accumulations of age-related neurodegenerative lesions.
Ashe, K. H. (2001). "Learning and memory in transgenic mice modeling Alzheimer's
disease." Learn Mem 8(6): 301-8.
Recent advances in behavioral analyses of transgenic mouse models of Alzheimer's
disease (AD) are discussed, and their impact on our understanding of the
molecular basis of cognitive impairment in AD is considered. Studies of the
relationship between memory and Ass in transgenic mice expressing the amyloid
precursor protein (APP) and its variants suggest that aging promotes the
formation of soluble Ass assemblies mediating negative effects on memory. A
significant component of memory loss in APP transgenic mice is apparently caused
by soluble Ass assemblies, but whether and how much of the dementia within
individuals afflicted with AD is caused by these Ass species is unclear. Future
studies in composite transgenic mice developing amyloid plaques, neurofibrillary
tangles, and other AD pathology may allow for the determination of the relative
contribution of Ass and non-Ass components to dementia.
Askanas, V. and W. K. Engel (2001). "Inclusion-body myositis: newest concepts of
pathogenesis and relation to aging and Alzheimer disease." J Neuropathol Exp
Neurol 60(1): 1-14.
We review the newest advances related to seeking the pathogenic mechanism(s) of
sporadic inclusion-body myositis (s-IBM) and present the pathologic diagnostic
criteria of s-IBM. We discuss the possible pathogenic role of several themes,
such as 1) increased amyloid-beta precursor protein (AbetaPP) and of its
fragment Abeta; 2) phosphorylation of tau protein; 3) oxidative stress; 4)
abnormal a) signal-transduction, b) transcription, and c) RNA accumulation; 5)
"junctionalization" and myogenous" denervation; and 6) lymphocytic inflammation.
Evidence is provided supporting our hypothesis that overexpression of AbetaPP
within the aging muscle fibers is an early upstream event causing the subsequent
pathogenic cascade. The remarkable pathologic similarities between s-IBM muscle
and Alzheimer disease (AD) brain are discussed, and the possible cause and
significance are addressed.
Auchus, A. P. and C. P. Chen (2001). "Asia regional meeting of the International
Working Group for the Harmonization of Dementia Drug Guidelines: meeting
report." Alzheimer Dis Assoc Disord 15(2): 66-8.
This meeting successfully catalyzed the establishment of a new working alliance
between clinical dementia researches in Asia and identified common goals for the
group to attain. The progress toward achieving these goals will be examined at
the next Asia regional meeting, which is being planned for October 2002 in
Beijing, China. This new regional working group will work with the IWG to
overcome the existing methodological and regulatory obstacles impeding dementia
treatment trials in Asia.
Auchus, A. P. and C. P. Chen (2001). "Asia-Pacific Consensus Statement on
dementia." Alzheimer Dis Assoc Disord 15(2): 63-5.
The 12 national Alzheimer's Associations that contributed to this Consensus
Statement will continue to network with one another regionally and will continue
to share relevant expertise and practical resources. It is expected that
regional consensus on dementia will evolve in individual member countries and in
the Asia-Pacific region as a whole. It is the hope of the participating members
of these two consensus conferences that this document will provide the
inspiration, direction, and practical ideas to further advance the goals of
national Alzheimer's Associations and to further advance dementia-related
medical and service activities within the Asia-Pacific region.
Autret, A., B. Lucas, et al. (2001). "Sleep and brain lesions: a critical review
of the literature and additional new cases." Neurophysiol Clin 31(6):
356-75.
We present a comprehensive review of sleep studies performed in patients with
brain lesions complemented by 16 additional personal selected cases and by
discussion of the corresponding animal data. The reader is cautioned about the
risk of establishing an erroneous correlation between abnormal sleep and a given
disorder due to the important inter and intra variability of sleep parameters
among individuals. Salient points are stressed: the high frequency of
post-stroke sleep breathing disorders is becoming increasingly recognised and
may, in the near future, change the way this condition is managed.
Meso-diencephalic bilateral infarcts induce a variable degree of damage to both
waking and non-REM sleep networks producing and abnormal waking and sometimes a
stage 1 hypersomnia reduced by modafinil or bromocriptine, which can be
considered as a syndrome of cathecholaminergic deficiency. Central pontine
lesions induce REM and non-REM sleep insomnia with bilateral lateral gaze
paralysis. Bulbar stroke leads to frequent sleep breathing disorders.
Polysomnography can help define the extent of involvement of various
degenerative diseases. Fragmented sleep in Parkinson's disease may be preceded
by REM sleep behavioural disorders. Multiple system atrophies are characterised
by important sleep disorganization. Sleep waking disorganization and a specific
ocular REM pattern are often seen in supra-nuclear ophtalmoplegia. In Alzheimer
patients, sleep perturbations parallel the mental deterioration and are possibly
related to cholinergic deficiency. Fronto-temporal dementia may be associated
with an important decrease in REM sleep. Few narcoleptic syndromes are reported
to be associated with a tumour of the third ventricle or a multiple sclerosis or
to follow a brain trauma; all these cases raise the question whether this is a
simple coincidence, a revelation of a latent narcolepsy or, as in non-DR16/DQ5
patients, a genuine symptomatic narcolepsy. Trypanosomiasis and the abnormal
prion protein precociously after sleep patterns. Polysomnography is a precious
tool for evaluating brain function provided it is realised under optimal
conditions in stable patients and interpreted with caution. Several unpublished
cases are presented: one case of pseudohypersomnia due to a bilateral thalamic
infarct and corrected by modafinil, four probable late-onset autosomal recessive
cerebellar ataxias without sleep pattern anomalies, six cases of fronto-temporal
dementia with strong reduction in total sleep time and REMS percentage on the
first polysomnographic night, one case of periodic hypersomnia associated with a
Rathke's cleft cyst and four cases of suspected symptomatic narcolepsy with a
DR16-DQ5 haplotype, three of which were post-traumatic without MRI anomalies,
and one associated with multiple sclerosis exhibiting pontine hyper signals on
MRI.
Aviel-Ronen, S., B. Shalmon, et al. (2001). "[Alzheimer disease and
estrogen--the connection, modes of influence and the therapy]." Harefuah
140(2): 139-43.
Bachurin, S. O. (2001). "[Medicinal and chemical approaches to focused search of
agents for treatment and therapy of Alzheimer disease]." Vopr Med Khim
47(2): 155-97.
The analysis and justification of medicinal chemistry approaches for focused
search of novel agents for Alzheimer's disease (AD) and related disorders
treatment and prevention have been reviewed. The systematization of modern
biochemical and structural date related to the action of physiologically active
compounds on the nervous system apparatus engaged in the AD-like disorders
pathogenesis was performed. The major attention was paid to the cholinomimetic,
anti-amyloid and antimetabolic approaches, basing on the results published in
scientific literature in 3-4 last years and results of preclinical and clinical
trials, presented in the internet database in the fall of 2000.
Bajetto, A., R. Bonavia, et al. (2001). "Chemokines and their receptors in the
central nervous system." Front Neuroendocrinol 22(3): 147-84.
Chemokines are a family of proteins associated with the trafficking of
leukocytes in physiological immune surveillance and inflammatory cell
recruitment in host defence. They are classified into four classes based on the
positions of key cystiene residues: C, CC, CXC, and CX3C. Chemokines act through
both specific and shared receptors that all belong to the superfamily of
G-protein-coupled receptors. Besides their well-established role in the immune
system, several recent reports have demonstrated that these proteins also play a
role in the central nervous system (CNS). In the CNS, chemokines are
constitutively expressed by microglial cells, astrocytes, and neurons, and their
expression can be increased after induction with inflammatory mediators.
Constitutive expression of chemokines and chemokine receptors has been observed
in both developing and adult brains, and the role played by these proteins in
the normal brain is the object of intense study by many research groups.
Chemokines are involved in brain development and in the maintenance of normal
brain homeostasis; these proteins play a role in the migration, differentiation,
and proliferation of glial and neuronal cells. The chemokine stromal
cell-derived factor 1 and its receptor, CXCR4, are essential for life during
development, and this ligand-receptor pair has been shown to have a fundamental
role in neuron migration during cerebellar formation. Chemokine and chemokine
receptor expression can be increased by inflammatory mediators, and this has in
turn been associated with several acute and chronic inflammatory conditions. In
the CNS, chemokines play an essential role in neuroinflammation as mediators of
leukocyte infiltration. Their overexpression has been implicated in different
neurological disorders, such as multiple sclerosis, trauma, stroke, Alzheimer's
disease, tumor progression, and acquired immunodeficiency syndrome-associated
dementia. An emerging area of interest for chemokine action is represented by
the communication between the neuroendocrine and the immune system. Chemokines
have hormone-like actions, specifically regulating the key host
physiopathological responses of fever and appetite. It is now evident that
chemokines and their receptors represent a plurifunctional family of proteins
whose actions on the CNS are not restricted to neuroinflammation. These
molecules constitute crucial regulators of cellular communication in
physiological and developmental processes.
Balin, B. J. and D. M. Appelt (2001). "Role of infection in Alzheimer's
disease." J Am Osteopath Assoc 101(12 Suppl Pt 1): S1-6.
Alzheimer's disease (AD) is a chronic condition in which inflammation has been
shown to contribute to neurodegeneration. Current thinking suggests that
deposition of beta-amyloid in the brain promotes inflammation resulting in
neuronal damage/death. Alternatively, our data suggest that chronic inflammation
observed in late-onset sporadic AD may be stimulated by infection with the
obligate, intracellular bacterium, Chlamydia pneumoniae. Our results indicate
that C. pneumoniae is found in high frequency in glial cells in areas of
neuropathology within the brains of patients with AD. Based on our evidence,
nervous system infection with C. pneumoniae should be considered a risk factor
for sporadic AD.
Ball, M. J., R. Mathews, et al. (2001). "Latent HSV 1 virus in trigeminal
ganglia: the optimal site for linking prevention of Alzheimer's disease to
vaccination." Neurobiol Aging 22(5): 705-9; discussion 717-9.
Bamberger, M. E. and G. E. Landreth (2001). "Microglial interaction with
beta-amyloid: implications for the pathogenesis of Alzheimer's disease."
Microsc Res Tech 54(2): 59-70.
The etiology of Alzheimer's disease (AD) involves a significant inflammatory
component as evidenced by the presence of elevated levels of a diverse range of
proinflammatory molecules in the AD brain. These inflammatory molecules are
produced principally by activated microglia, which are found to be clustered
within and adjacent to the senile plaque. Moreover, long-term treatment of
patients with non-steroidal anti-inflammatory drugs has been shown to reduce
risk and incidence of AD and delay disease progression. The microglia respond to
beta-amyloid (Abeta) deposition in the brain through the interaction of
fibrillar forms of amyloid with cell surface receptors, leading to the
activation of intracellular signal transduction cascades. The activation of
multiple independent signaling pathways ultimately leads to the induction of
proinflammatory gene expression and production of reactive oxygen and nitrogen
species. These microglial inflammatory products act in concert to produce
neuronal toxicity and death. Therapeutic approaches focused on inhibition of the
microglial-mediated local inflammatory response in the AD brain offer new
opportunities to intervene in the disease.
Ban, T. A. (2001). "Pharmacotherapy of mental illness--a historical analysis."
Prog Neuropsychopharmacol Biol Psychiatry 25(4): 709-27.
The history of pharmacotherapy of mental illness can be divided into three
periods. Introduction of morphine, potassium bromide, chloral hydrate, hyoscine,
paraldehyde, etc., during the second half of the 19th century (first period),
led to the replacement of physical restraint by pharmacological means in
behavior control. Introduction of nicotinic acid, penicillin, thiamine, etc.,
during the first half of the 20th century (second period), led to significant
changes in the diagnostic distribution of psychiatric patients; psychoses due to
cerebral pellagra, and dementia due to syphilitic general paralysis virtually
disappeared from psychiatric hospitals, and the prevalence of dysmnesias
markedly decreased. Treatment with therapeutically effective drugs of mania,
schizophrenia, depression, bipolar disorder, generalized anxiety disorder, panic
disorder, obsessive compulsive disorder, Alzheimer's disease, etc., during the
second half of the 20th century (third period), brought to attention the
heterogeneity of the populations within the diagnostic categories of
schizophrenia and depression. Introduction of the first set of psychotropics and
the spectrophotofluorimeter during the 1950s triggered the development of
neuropsychopharmacology. Introduction of genetic technology for the separation
of receptor subtypes in the 1980s opened the path for the "tailoring" of
psychotropic drugs by the dawn of the 21st century, to receptor affinities.
Banaclocha, M. M. (2001). "Therapeutic potential of N-acetylcysteine in
age-related mitochondrial neurodegenerative diseases." Med Hypotheses
56(4): 472-7.
Increasing lines of evidence suggest a key role for mitochondrial damage in
neurodegenerative diseases. Brain aging, Parkinson's disease, Alzheimer's
disease, Huntington's disease and Friedreich's ataxia have been associated with
several mitochondrial alterations including impaired oxidative phosphorylation.
Mitochondrial impairment can decrease cellular bioenergetic capacity, which will
then increase the generation of reactive oxygen species resulting in oxidative
damage and programmed cell death. This paper reviews the mechanisms of
N-acetylcysteine action at the cellular level, and the possible usefulness of
this antioxidant for the treatment of age-associated neurodegenerative diseases.
First, this thiol can act as a precursor for glutathione synthesis as well as a
stimulator of the cytosolic enzymes involved in glutathione regeneration.
Second, N-acetylcysteine can act by direct reaction between its reducing thiol
group and reactive oxygen species. Third, it has been shown that
N-acetylcysteine can prevent programmed cell death in cultured neuronal cells.
And finally, N-acetylcysteine also increases mitochondrial complex I and IV
specific activities both in vitro and in vivo in synaptic mitochondrial
preparations from aged mice. In view of the above, and because of the ease of
its administration and lack of toxicity in humans, the potential usefulness of
N-acetylcysteine in the treatment of age-associated mitochondrial
neurodegenerative diseases deserves investigation.
Baranano, D. E. and S. H. Snyder (2001). "Neural roles for heme oxygenase:
contrasts to nitric oxide synthase." Proc Natl Acad Sci U S A 98(20):
10996-1002.
The heme oxygenase (HO) and nitric oxide (NO) synthase (NOS) systems display
notable similarities as well as differences. HO and NOS are both oxidative
enzymes using NADPH as an electron donor. The constitutive forms of the enzyme
are differentially activated, with calcium entry stimulating NOS by binding to
calmodulin, whereas calcium entry activates protein kinase C to phosphorylate
and activate HO2. Although both NO and carbon monoxide (CO) stimulate soluble
guanylyl cyclase to form cGMP, NO also S-nitrosylates selected protein targets.
Both involve constitutive and inducible biosynthetic enzymes. However, functions
of the inducible forms are virtual opposites. Macrophage-inducible NOS generates
NO to kill other cells, whereas HO1 generates bilirubin to exert antioxidant
cytoprotective effects and also provides cytoprotection by facilitating iron
extrusion from cells. The neuronal form of HO, HO2, is also cytoprotective.
Normally, neural NO in the brain seems to exert some sort of behavioral
inhibition. However, excess release of NO in response to glutamate's
N-methyl-d-aspartate receptor activation leads to stroke damage. On the other
hand, massive neuronal firing during a stroke presumably activates HO2, leading
to neuroprotective actions of bilirubin. Loss of this neuroprotection after HO
inhibition by mutant forms of amyloid precursor protein may mediate
neurotoxicity in Familial Alzheimer's Disease. NO and CO both appear to be
neurotransmitters in the brain and peripheral autonomic nervous system. They
also are physiologic endothelial-derived relaxing factors for blood vessels. In
the gastrointestinal pathway, NO and CO appear to function as
coneurotransmitters, both stimulating soluble guanylyl cyclase to cause smooth
muscle relaxation.
Barber, R., A. Panikkar, et al. (2001). "Dementia with Lewy bodies: diagnosis
and management." Int J Geriatr Psychiatry 16 Suppl 1: S12-8.
OBJECTIVE: To summarize the clinical, pathological, imaging and treatment
aspects of dementia with Lewy bodies (DLB). METHOD: Review of literature
(MEDLINE). RESULTS: DLB is the second most common form of degenerative dementia,
accounting for up to 20% of cases in the elderly. It is characterized by
fluctuating cognitive impairment, spontaneous parkinsonism and recurrent visual
hallucinations. Consensus clinical criteria have been published and have been
shown to have high specificity, but they may still lack sensitivity.
Pathologically, DLB may be classified as a Lewy body (LB) disorder and/or as an
alpha-synucleinopathy. It is probable that a spectrum of LB disorders exists
with the clinical features reflecting the distribution and severity of
pathology. Although both DLB and Alzheimer's disease (AD) show a reduction in
pre-synaptic cholinergic transmission from the basal forebrain, in DLB there are
also deficits in cholinergic transmission from brain stem nuclei. Post-synaptic
cortical muscarinic receptors are more functionally intact in DLB suggesting
potential responsiveness to cholinergic enhancement. Neuroimaging findings
indicate a relative preservation of medial temporal lobe structures in DLB but
similar distribution of white matter changes on MRI compared with AD. Defects in
nigrostriatal dopamine pathways in DLB have been demonstrated with functional
neuroimaging using ligands highlighting pre- and post-synaptic dopaminergic
systems. Preliminary studies also indicate subtle differences in perfusion
patterns on SPECT with a greater degree of occipital hypoperfusion in DLB
compared with AD. Accurate diagnosis of DLB is clinically important as the
management of psychosis and behavioural disturbances is complicated by
sensitivity to neuroleptic medication. There is accumulating evidence to suggest
that DLB may be particularly amenable to cholinergic enhancers. The clinical
management of DLB is considered using a four step approach: making a diagnosis;
identification of problem symptoms; appropriate non-pharmacological
interventions; and pharmacological interventions. CONCLUSIONS: Consensus
criteria for probable DLB have high specificity-a positive clinical diagnosis is
likely to be correct. Treatment choices must consider effects upon motor,
cognitive and psychiatric symptoms. Non-pharmacological management is an
essential first step, as is reduction or withdrawal of drugs with potential
adverse effects. Neuroleptic sensitivity reactions appear less likely to occur
with the newer atypical antipsychotics. Cholinesterase inhibitors have been
shown in open-label studies and one placebo RCT to be well tolerated and
effective in treating cognitive and psychiatric symptoms in DLB. They may become
first-line treatments.
Barbieri, S., K. Hofele, et al. (2001). "Mouse models of alpha-synucleinopathy
and Lewy pathology. Alpha-synuclein expression in transgenic mice." Adv Exp
Med Biol 487: 147-67.
Barolin, G. S. (2001). "[Psychotherapy in senile dementia?!]." Wien Med
Wochenschr 151(15-17): 342-7.
Psychotherapy for senile demented patients is feasible and should become a
routine. However, it must be integrated psychotherapy that is not school-centred
but patient-centered. Especially in the work with senile demented patients it
must closely cooperate with all health professions that are in the field. These
endeavours must be systematically coordinated. Analytic psychotherapy in the
classical sense is not feasable. However, in old (and demented) patients
sometimes a strong desire persists to tell out of the past. The therapist's task
there is mainly listening and not interpreting. Children, animals,
plush-animals, music and dance-therapy are not so well-known possibilities to
find a psychotherapeutic approach to senile demented persons. The basic
psychotherapy should be known to all health professions. Professional
psychotherapy should be given more attention as to the psychotherapy of old
people.
Baxter, M. G. (2001). "Effects of selective immunotoxic lesions on learning and
memory." Methods Mol Biol 166: 249-65.
Belanoff, J. K., K. Gross, et al. (2001). "Corticosteroids and cognition." J
Psychiatr Res 35(3): 127-45.
The brain is a major target organ for corticosteroids. It has been observed that
excessive circulatory levels of endogenous and exogenous corticosteroids are
frequently associated with cognitive impairment in a wide variety of clinical
disease states. Cognition and low levels of corticosteroids have been less well
studied. In this paper we review the literature on glucocorticosteroid effects
on cognition and delineate specific functions that appear to be causally
affected. We draw a possible connection to specific areas of brain perturbation,
including the hippocampus and frontal lobe regions. The possibility that
cognitive dysfunction caused by glucocorticoids can be pharmacologically managed
is introduced.
Bennett, D. (2001). "Public health importance of vascular dementia and
Alzheimer's disease with cerebrovascular disease." Int J Clin Pract Suppl(120):
41-8.
Vascular dementia (VaD) refers to a heterogeneous group of conditions that
include all dementia syndromes resulting from ischaemic, haemorrhagic, anoxic or
hypoxic brain damage. VaD is the second most common cause of dementia in the
elderly after Alzheimer's disease. Persons with VaD are at greater risk of
morbidity and mortality compared with those without dementia or those with
Alzheimer's disease, and appear to be at greater risk of institutionalisation.
Despite the importance of the problem posed by VaD, few placebo-controlled,
double-blind, randomised clinical trials have been conducted. Although dementia
may result solely from the accumulation of brain damage from cerebrovascular
disease (CVD), recent data suggest that VaD often results from a combination of
both CVD and Alzheimer's disease ('mixed' dementia). This raises the possibility
that persons with VaD may respond to medications that are commonly used to treat
Alzheimer's disease.
Benveniste, E. N., V. T. Nguyen, et al. (2001). "Immunological aspects of
microglia: relevance to Alzheimer's disease." Neurochem Int 39(5-6):
381-91.
Alzheimer's disease (AD) is a progressive dementing neurologic illness, and the
most frequent cause of dementia in the elderly. Neuritic plaques are one of the
main neuropathological findings in AD, and the major protein component is the
beta-amyloid protein (A beta). Another striking feature of neuritic plaques is
the presence of activated microglia, cytokines, and complement components,
suggestive of "inflammatory foci" within AD brain. In this review, we will
examine the mechanisms by which microglia become activated in AD, emphasizing
the role in the A beta protein and proinflammatory cytokines. As well, pathways
for suppression of microglial activation by immunosuppressive cytokines will be
described. Inflammation mediated by activated microglia is an important
component of AD pathophysiology, and strategies to control this response could
provide new therapeutic approaches for the treatment of AD.
Bianchetti, A. and M. Trabucch (2001). "Clinical aspects of Alzheimer's
disease." Aging (Milano) 13(3): 221-30.
Alzheimer's disease (AD) is the most common of the dementing disorders. AD
begins insidiously and progresses gradually; it is characterized clinically not
only by an impairment in cognition, but also by a decline in global function, a
deterioration in the ability to perform activities of daily living, and the
appearance of behavioral disturbances. No definitive tests for the diagnosis are
available, and AD is a diagnosis of inclusion based on patient history, physical
examination, neuropsychological testing, and laboratory studies. Disease
progression is highly variable, and median survival after the onset of dementia
ranges from 5 to 9.3 years. Early recognition of AD allows time to plan for the
future, and to treat patients before marked deterioration occurs.
Bickel, H. (2001). "[Dementia in advanced age: estimating incidence and health
care costs]." Z Gerontol Geriatr 34(2): 108-15.
Based on results from large-scale epidemiological field studies in the western
industrial countries, 930,000 elderly people in Germany were estimated to suffer
from a dementing disorder at the end of 1996. Following the most recent
population projection, a population increase of the number of elderly people (65
yrs. and above) from 12.9 million (mio.) in 1996 to more than 20 mio. in 2030 is
anticipated. Based on the assumption that age-specific prevalence rates of
dementia will remain stable, a steep rise in patient numbers by an average of
20,000 per year can thus be expected, reaching 1.56 mio. in 2030 and more than 2
mio. in 2050. Studies on the cost of illness point to an enormous economic
burden caused by dementia. The unpaid informal care provided by relatives and
the high expenses for long-term institutional care can be considered as the most
significant components of total costs. Currently, the medical costs associated
with diagnosis and treatment, however, appear as an almost negligible fraction
of the total costs.
Bieber, E. J. and D. P. Cohen (2001). "Estrogens and hormone replacement
therapy: is there a role in the preservation of cognitive function?" Int J
Fertil Womens Med 46(4): 206-9.
Alzheimer's disease affects as many as 40% of Americans over the age of 80 and,
as such, is a major public health issue. Interestingly, there is a two- to
threefold greater prevalence in women than in men. It has been estimated that
the prevalence of Alzheimer's disease will quadruple over the next half century.
There have been implications of an effect of estrogen on neurological function
for many years. As long as 50 years ago a study published in the gerontology
literature suggested that the administration of i.m. estrogen in a nursing home
population was associated with improvement in memory and a delay in progression
of memory loss. Most recently there has been great interest in the effect of
estrogen on both neurons and the CNS vasculature. A study evaluating verbal
memory and abstract reasoning in over 700 women without dementia demonstrated
that women who had used estrogen for as little as 1 year had significant
improvements in baseline cognitive testing. The pathogenesis of Alzheimer's
disease and neurodementia is better understood today but remains incompletely
elucidated. It has been suggested that inflammation exists both within the
neurovasculature and the stroma and that beta-amyloid creates an inflammatory
reaction. In Alzheimer's patients there are abnormal deposits of proteins such
as beta-amyloid, presenelin, and apolipoprotein E-4. Estrogen may act as a
protectant against these inflammatory mediating proteins. While a recent trial
demonstrated no impact of estrogen in patients diagnosed with mild to moderate
Alzheimer's, other studies have suggested that estrogen use significantly delays
disease onset. One study followed over 1,100 subjects who were free of disease
at trial initiation over a period of 1 to 5 years. Even short-term use of
estrogen imparted protection, although longer-term estrogen use was associated
with greater protection. Unfortunately, most women are unaware of the potential
beneficial effect of estrogen on cognitive function. Prospective studies are
under way to try to delineate how estrogen impacts Alzheimer's disease.
Bigler, E. D. (2001). "Premorbid brain volume and dementia." Arch Neurol
58(5): 831-3.
Billiard, M. and B. Ondze (2001). "[Disorders of awakening. Second part:
secondary disorders]." Rev Neurol (Paris) 157(5): 480-96.
Secondary disorders of awakening should be distinguished from primary disorders,
narcolepsy, idiopathic hypersomnia, recurrent hypersomnia, the causes of which
are still unknown despite regular progress in the knowledge of the
pathophysiology of narcolepsy. By definition secondary disorders of awakening
are due to clearly identified causes of various origins. Two main types of
secondary disorders of awakening have been distinguished: those depending on
more or less voluntary sleep curtailment or on psychotropic or non psychotropic
medications and those consecutive to different disorders, respiratory,
neurologic, traumatic, psychotropic, infectious, metabolic, endocrinologic, and
insomnia. Some of these disorders, frequent or very frequent, are
polysomnographically investigated, night and day, enabling to assess in each
case the type and severity of sleepiness. Others are only clinically evaluated.
Disorders of awakening secondary to neurologic conditions and to a lesser extent
to infectious conditions offer a special opportunity to study the anatomical
basis of these disorders. They are granted more space.
Birge, S. J., B. S. McEwen, et al. (2001). "Effects of estrogen deficiency on
brain function. Implications for the treatment of postmenopausal women."
Postgrad Med Spec No: 11-6.
A growing body of evidence suggests that postmenopausal estrogen deficiency
accelerates brain aging and increases the risk of various neurodegenerative
processes, including Alzheimer's disease. Recent preclinical and clinical
studies have indicated that estrogen has positive effects on brain homeostasis
by preserving neural plasticity and the neurotransmitter pathways involved in
learning, memory, and balance. In this article, Dr Birge and his coauthors
address the effects of estrogen on brain function and discuss their implications
for the use of selective estrogen receptor modulators, particularly tamoxifen
and raloxifene, in postmenopausal women.
Birkenhager, W. H., F. Forette, et al. (2001). "Blood pressure, cognitive
functions, and prevention of dementias in older patients with hypertension."
Arch Intern Med 161(2): 152-6.
The prevalence and incidence of degenerative and vascular dementias increase
exponentially with age, from 70 years onward. In view of the increasing
longevity of humans, both varieties are bound to evolve into a major problem
worldwide. According to several longitudinal studies, hypertension appears to
predispose individuals to the development of cognitive impairment and ensuing
dementia, after a period varying from a few years to several decades.
Antihypertensive drug treatment, according to preliminary evidence, may serve to
reduce the rates of such events. Such findings await to be confirmed by formal
therapeutic trials against a backdrop of "historical" observational sources.
Black, S. E., C. Patterson, et al. (2001). "Preventing dementia." Can J
Neurol Sci 28 Suppl 1: S56-66.
Primary prevention will become increasingly important as dementia prevalence
increases and effective retardive therapies are developed. To date, only one
randomized controlled trial (involving treatment of systolic hypertension) has
demonstrated that the incidence of dementia can be reduced. Physicians should
remain alert to possible secondary causes of dementia and correct these whenever
possible. Primary and secondary prevention of stroke should reduce dementia
related to cerebrovascular disease either directly or as a comorbid factor in
Alzheimer's disease (AD). Epidemiological studies have revealed a number of risk
factors for AD including genetic mutation, susceptibility genes, positive family
history, Down's syndrome, age, sex, years of education, head trauma and
neurotoxins. In case-control studies non-steroidal anti-inflammatory medication
and estrogen replacement therapy appear to decrease the relative risk of
developing AD. Further research to develop and test preventative therapies in AD
and other dementias should be strongly encouraged.
Blasko, I., G. Ransmayr, et al. (2001). "Does IFNgamma play a role in
neurodegeneration?" J Neuroimmunol 116(1): 1-4.
Blass, J. P. (2001). "Brain metabolism and brain disease: is metabolic
deficiency the proximate cause of Alzheimer dementia?" J Neurosci Res
66(5): 851-6.
The potential of impairments in oxidative/energy metabolism to cause diseases of
the brain had been proposed even before the major pathways of oxidative/energy
metabolism were described. Deficiencies associated with disease are known in all
the pathways of oxidative/energy metabolism and are associated with some of the
most common disorders of the nervous system, including Alzheimer's disease (AD)
and Parkinson's disease. A common mechanism in these conditions appears to be a
downward mitochondrial spiral, involving abnormalities in energy metabolism,
calcium metabolism, and free radicals (reactive oxygen and nitrogen species). In
AD, the spiral appears to interact with abnormalities in the metabolism of the
Alzheimer amyloid precursor protein (APP) and its Abeta fragment. Several lines
of evidence indicate that the mitochondrial spiral may be a proximate cause of
the clinical disabilities in AD. Decreases in cerebral metabolic rate (CMR)
characteristically occur in AD and in other dementias. Inducing decreases in CMR
leads to clinical disabilities characteristically associated with AD and with
analogous problems in experimental animals. Treatments directed toward
normalizing CMR appear to help at least some patients. Further studies of this
possibility and of treatments designed to ameliorate the mitochondrial spiral
may prove useful for treating AD and perhaps some other dementing disorders.
Bleys, R. L. and T. Cowen (2001). "Innervation of cerebral blood vessels:
morphology, plasticity, age-related, and Alzheimer's disease-related
neurodegeneration." Microsc Res Tech 53(2): 106-18.
The light microscopical and ultrastructural morphology of the innervation of the
major cerebral arteries and pial vessels is described, including the origins of
the different groups of nerve fibres and their characteristic neurotransmitter
phenotype. Species and region specific variations are described and novel data
regarding the parasympathetic innervation of cerebral vessels are presented. The
dynamic nature, or plasticity, of cerebrovascular innervation is emphasized in
describing changes affecting particular subpopulations of neurons during normal
ageing and in Alzheimer's disease. The molecular controls on plasticity are
discussed with particular reference to target-associated factors such as the
neurotrophins and their neuronal receptors, as well as extracellular matrix
related factors such as laminin. Hypotheses are presented regarding the
principal extrinsic and intrinsic influences on plasticity of the
cerebrovascular innervation.
Boada Rovira, M. (2001). "[Strategies for the treatment of Alzheimer's disease.
The 'ad continuum' concept]." Rev Neurol 32(11): 1074-84.
The patient with dementia suffers a chronic disorder, with no specific treatment
and little therapeutic response, which is accompanied by high co morbidity and
additional complications which cause multiple symptoms which limit the patient s
autonomy still further, modify the environment and create progressive
dependence. Thus, from all angles, approach is very difficult both in seeking
the cause and in prevention and also for treatment. The objective of this review
is to establish the guidelines for treatment in view of the long term course of
the disorder, in accordance with the specific weight and intensity of symptoms
from the onset of the illness by means of precise diagnosis of the deficits and
control of the commonest disorders which occur over time, such as psycho
affective, psychotic, sleep disorders or treatment of a state of confusion and
control of the diseases which are most frequent in this population. Finally, we
briefly analyze the health care and social requirements of these patients and
suggest general recommendations for carers to improve management, classifying
the states of dementia into three degrees of severity.
Boddeke, E. W. (2001). "Involvement of chemokines in pain." Eur J Pharmacol
429(1-3): 115-9.
It is well established that neuroinflammation plays an important role in
neurodegenerative diseases like Alzheimer's disease, stroke, traumatic brain-
and spinal cord injury and demyelinating diseases. Likewise, it has been
suggested that neuroinflammation plays an important role in nociception and
hyperalgesia. Most research concerning inflammatory aspects of pain has
concerned the effects of proinflammatory cytokines, prostaglandins and growth
factors. Recently, it has been suggested that chemokines play a role in
inflammatory pain. Chemokines do not only attract blood leukocytes to the site
of injury but also contribute directly to nociception.
Boller, F. and G. D. Barba (2001). "Neuropsychological tests in Alzheimer's
disease." Aging (Milano) 13(3): 210-20.
The recent development of symptomatic pharmacological treatment for Alzheimer's
disease (AD) and the probable introduction of new therapies in a near future
make the assessment of dementia at its different stages an even greater
scientific and public health challenge. Neuropsychological tests, together with
clinical data, are at present the only in vivo non-invasive screening and
diagnostic tools for AD and related disorders. This chapter reviews the
application to AD of standard batteries and short screening tests. It also
analyzes the tests to be applied to detect and assess the specific deficits of
the disease, and discusses the advantages and flaws of current screening and
diagnostic tests of dementia. Emphasis is placed on the need to devise and use
tests developed in a rational manner, with high sensitivity and specificity, not
only in the moderate stages of the disease, but also in the very early and even
"preclinical" stages, as well as during the late stages (severe dementia). It is
known that neuropsychological tests allow one to determine various patients'
profiles. Future research should determine the possible predictive value of
these profiles. This has important implications for therapeutic trials. The
current implicit assumption that all patients with AD tend to evolve and decline
in a similar fashion needs to be critically re-examined.
Borek, C. (2001). "Antioxidant health effects of aged garlic extract." J Nutr
131(3s): 1010S-5S.
Oxidative modification of DNA, proteins and lipids by reactive oxygen species
(ROS) plays a role in aging and disease, including cardiovascular,
neurodegenerative and inflammatory diseases and cancer. Extracts of fresh garlic
that are aged over a prolonged period to produce aged garlic extract (AGE)
contain antioxidant phytochemicals that prevent oxidant damage. These include
unique water-soluble organosulfur compounds, lipid-soluble organosulfur
components and flavonoids, notably allixin and selenium. Long-term extraction of
garlic (up to 20 mo) ages the extract, creating antioxidant properties by
modifying unstable molecules with antioxidant activity, such as allicin, and
increasing stable and highly bioavailable water-soluble organosulfur compounds,
such as S-allylcysteine and S-allylmercaptocysteine. AGE exerts antioxidant
action by scavenging ROS, enhancing the cellular antioxidant enzymes superoxide
dismutase, catalase and glutathione peroxidase, and increasing glutathione in
the cells. AGE inhibits lipid peroxidation, reducing ischemic/reperfusion damage
and inhibiting oxidative modification of LDL, thus protecting endothelial cells
from the injury by the oxidized molecules, which contributes to atherosclerosis.
AGE inhibits the activation of the oxidant-induced transcription factor, nuclear
factor (NF)-kappa B, which has clinical significance in human immunodeficiency
virus gene expression and atherogenesis. AGE protects DNA against free
radical--mediated damage and mutations, inhibits multistep carcinogenesis and
defends against ionizing radiation and UV-induced damage, including protection
against some forms of UV-induced immunosuppression. AGE may have a role in
protecting against loss of brain function in aging and possess other antiaging
effects, as suggested by its ability to increase cognitive functions, memory and
longevity in a senescence-accelerated mouse model. AGE has been shown to protect
against the cardiotoxic effects of doxorubicin, an antineoplastic agent used in
cancer therapy and against liver toxicity caused by carbon tetrachloride (an
industrial chemical) and acetaminophen, an analgesic. Substantial experimental
evidence shows the ability of AGE to protect against oxidant-induced disease,
acute damage from aging, radiation and chemical exposure, and long-term toxic
damage. Although additional observations are warranted in humans, compelling
evidence supports the beneficial health effects attributed to AGE, i.e.,
reducing the risk of cardiovascular disease, stroke, cancer and aging, including
the oxidant-mediated brain cell damage that is implicated in Alzheimer's
disease.
Brandt, R. (2001). "Cytoskeletal mechanisms of neuronal degeneration." Cell
Tissue Res 305(2): 255-65.
The cytoskeleton is the major intracellular determinant of neuronal morphology
and is required for fundamental processes during the development and maintenance
of a neuron. Thus, it is not surprising that many neurodegenerative diseases
including Alzheimer's disease and amyotrophic lateral sclerosis (motor neuron
disease) are characterized by typical abnormalities in the organization of the
cytoskeleton. However, the role of the cytoskeletal changes during the
development of the disease, e.g., whether they have a causative role during
neuronal degeneration or represent an epiphenomenon of neurons that degenerate
by other means, is still disputed. In this review, recent results on the
development and the role of cytoskeletal abnormalities during neurodegenerative
diseases are discussed and a mechanistic framework for the involvement of
cytoskeletal changes during neurodegenerative processes is presented.
Brandt, J. (2001). "Mild cognitive impairment in the elderly." Am Fam
Physician 63(4): 620, 622, 625-6.
Brinton, R. D. (2001). "Cellular and molecular mechanisms of estrogen regulation
of memory function and neuroprotection against Alzheimer's disease: recent
insights and remaining challenges." Learn Mem 8(3): 121-33.
This review focuses on recent advances in our knowledge of estrogen action in
the brain. The greatest amount of attention was devoted to those studies that
impact our understanding of estrogen regulation of memory function and
prevention of degenerative diseases associated with memory systems, such as
Alzheimer's disease. A review of recent advances in our understanding of
estrogen receptors, both nuclear and membrane, is also presented. Finally, these
data are considered in regard to their relevancy to the use of estrogen
replacement therapy for cognitive health throughout menopause and the
development of an estrogen replacement therapy designed for the unique
requirements of the brain.
Brodaty, H., D. Ames, et al. (2001). "Pharmacological treatment of cognitive
deficits in Alzheimer's disease." Med J Aust 175(6): 324-9.
Clinical trials and independent reviews support the use of cholinesterase
inhibitors for treating the symptoms of patients with mild to moderate
Alzheimer's disease (AD). Before initiating cholinesterase inhibitor therapy,
patients should be thoroughly assessed, and the diagnosis confirmed, preferably
by a specialist. Compliance with cholinesterase inhibitor therapy should be
monitored and the response (in global, cognitive, functional and behavioural
domains) reassessed after 2-3 months of treatment. Vitamin E may be protective
against AD, and therapy with 1000 IU twice daily may be considered. There is
insufficient evidence to support the use of other antioxidant agents,
anti-inflammatory agents, monoamine oxidase B inhibitors, folate/homocysteine or
antihypertensive drugs in patients with AD, or hormone replacement therapy in
affected women.
Brody, J. A. and M. D. Grant (2001). "Age-associated diseases and conditions:
implications for decreasing late life morbidity." Aging (Milano) 13(2):
64-7.
We discuss two types of age-associated diseases; aging-dependent such as
Alzheimer's disease and congestive heart failure which increase logarithmically
with age, versus age-dependent such as multiple sclerosis and amyotrophic
lateral sclerosis which occur at proscribed ages, and then occurrence of new
cases ceases or diminishes with further aging. Prevention strategies with both
types emphasize postponement or delay of onset. The non-fatal aging-dependent
diseases and conditions are an accumulating burden as we age, and increase
overall morbidity in late years. These include Alzheimer's disease and other
dementias, Parkinson's disease, loss of vision and hearing, incontinence,
osteoporosis and hip fracture, osteoarthritis and depression. With mortality
postponed, we will be living for many years at old and vulnerable ages. Life's
quality will be reasonable for most. Still, increasing the chance that all will
experience this desirable outcome requires pursuing the means to delay the onset
of the physical and social events which we categorize as the non-fatal
aging-dependent diseases and conditions. We must recognize that each added year
occurs at the tip of an exponential curve where risk is maximal.
Bruno, V., G. Battaglia, et al. (2001). "Metabotropic glutamate receptor
subtypes as targets for neuroprotective drugs." J Cereb Blood Flow Metab
21(9): 1013-33.
Metabotropic glutamate (mGlu) receptors have been considered as potential
targets for neuroprotective drugs, but the lack of specific drugs has limited
the development of neuroprotective strategies in experimental models of acute or
chronic central nervous system (CNS) disorders. The advent of potent and
centrally available subtype-selective ligands has overcome this limitation,
leading to an extensive investigation of the role of mGlu receptor subtypes in
neurodegeneration during the last 2 years. Examples of these drugs are the
noncompetitive mGlu1 receptor antagonists, CPCCOEt and BAY-36-7620; the
noncompetitive mGlu5 receptor antagonists, 2-methyl-6-(phenylethynyl)pyridine,
SIB-1893, and SIB-1757; and the potent mGlu2/3 receptor agonists, LY354740 and
LY379268. Pharmacologic blockade of mGlu1 or mGlu5 receptors or pharmacologic
activation of mGlu2/3 or mGlu4/7/8 receptors produces neuroprotection in a
variety of in vitro or in vivo models. MGlu1 receptor antagonists are promising
drugs for the treatment of brain ischemia or for the prophylaxis of neuronal
damage induced by synaptic hyperactivity. MGlu5 receptor antagonists may limit
neuronal damage induced by a hyperactivity of N-methyl-d-aspartate (NMDA)
receptors, because mGlu5 and NMDA receptors are physically and functionally
connected in neuronal membranes. A series of observations suggest a potential
application of mGlu5 receptor antagonists in chronic neurodegenerative
disorders, such as amyotrophic lateral sclerosis and Alzheimer disease. MGlu2/3
receptor agonists inhibit glutamate release, but also promote the synthesis and
release of neurotrophic factors in astrocytes. These drugs may therefore have a
broad application as neuroprotective agents in a variety of CNS disorders.
Finally, mGlu4/7/8 receptor agonists potently inhibit glutamate release and have
a potential application in seizure disorders. The advantage of all these drugs
with respect to NMDA or AMPA receptor agonists derives from the evidence that
mGlu receptors do not "mediate," but rather "modulate" excitatory synaptic
transmission. Therefore, it can be expected that mGlu receptor ligands are
devoid of the undesirable effects resulting from the inhibition of excitatory
synaptic transmission, such as sedation or an impairment of learning and memory.
Bruunsgaard, H., M. Pedersen, et al. (2001). "Aging and proinflammatory
cytokines." Curr Opin Hematol 8(3): 131-6.
Aging is associated with increased inflammatory activity reflected by increased
circulating levels of TNF-alpha, IL-6, cytokine antagonists and acute phase
proteins in vivo. Epidemiologic studies suggest that chronic low-grade
inflammation in aging promotes an atherogenic profile and is related to
age-associated disorders (eg, Alzheimer disease, atherosclerosis, type 2
diabetes, etc.) and enhanced mortality risk. Accordingly, a dysregulated
production of inflammatory cytokines has an important role in the process of
aging. Studies of age-related differences in the production of proinflammatory
cytokines in response to acute stimulations in vitro have yielded inconsistent
results. However, in vivo infectious models show delayed termination of
inflammatory activity and a prolonged fever response in elderly humans,
suggesting that the acute phase response is altered in aging. However, a causal
relation between the acute phase response and the increased mortality because of
bacterial infections in older patients remains to be demonstrated.
Bryant, J., A. Clegg, et al. (2001). "Clinical and cost-effectiveness of
donepezil, rivastigmine and galantamine for Alzheimer's disease: a rapid and
systematic review." Health Technol Assess 5(1): 1-137.
BACKGROUND: Alzheimer's disease is the most common cause of dementia and is
characterised by an insidious onset and slow deterioration. The estimated
prevalence of Alzheimer's disease for a standard health authority (500,000
people) is about 3330. Current service involves a wide range of agencies, and
drug therapy for some patients. OBJECTIVES: To provide a rapid and systematic
review of the clinical effectiveness and cost-effectiveness of donepezil,
rivastigmine and galantamine in the symptomatic treatment of people suffering
from Alzheimer's disease. METHODS: A systematic review of the literature was
undertaken. METHODS - DATA SOURCES: Searches were made of electronic databases,
including MEDLINE, EMBASE, The Cochrane Library, Database of Abstracts of
Reviews of Effectiveness, NHS Economic Evaluation Database, National Research
Register, Science Citation Index, BIOSIS, EconLit, MRC Trials database, Early
Warning System, Current Controlled Trials, TOXLINE, Index of Scientific and
Technical Proceedings, and Getting Easier Access to Reviews. All sources were
searched over the period covered by the databases up to March/July 2000.
Bibliographies of related papers were assessed for relevant studies and experts
were contacted for advice and peer review, and to identify additional published
and unpublished references. Manufacturer submissions to the National Institute
for Clinical Excellence (NICE) were reviewed. METHODS - STUDY SELECTION: Studies
were included if they fulfilled the following criteria: (1) Intervention:
donepezil, rivastigmine or galantamine used to treat Alzheimer's disease. (2)
Participants: people diagnosed with Alzheimer's disease who meet the criteria
for treatment with donepezil, rivastigmine and galantamine. (3) Outcomes:
measures assessing changes in cognition, function, behaviour and mood, quality
of life (including studies assessing carer well-being and carer-input), and time
to institutionalisation. (4) Design: systematic reviews of randomised controlled
trials (RCTs) and RCTs comparing donepezil, rivastigmine or galantamine with
placebo or each other or non-drug comparators were included in the review of
effectiveness. Economic studies of donepezil, rivastigmine or galantamine used
to treat Alzheimer's disease that included a comparator (or placebo) and both
the costs and consequence (outcomes) of treatment were included in the review of
cost-effectiveness. Studies in non-English language, and abstracts and
conference poster presentations of systematic reviews, RCTs and economic
evaluations were excluded. Two reviewers identified studies by independently
screening study titles and abstracts, and then by examining the full text of
selected studies to decide inclusion. METHODS - DATA EXTRACTION AND QUALITY
ASSESSMENT: Data extraction and quality assessment were undertaken by one
reviewer and checked by a second reviewer, with any disagreements resolved
through discussion. The quality of RCTs was assessed using the Jadad scale and
the quality of systematic reviews was assessed using criteria developed by the
NHS Centre for Reviews and Dissemination. The quality of economic evaluation
studies was assessed by their internal validity (i.e. the methods used) using a
standard checklist, and external validity (i.e. the generalisability of the
economic study to the population of interest) using a series of relevant
questions. METHODS - DATA SYNTHESIS: The clinical effectiveness and
cost-effectiveness of donepezil, rivastigmine and galantamine were synthesised
through a narrative review with full tabulation of results of all included
studies. In the economic evaluation, the reviewers assessed whether adjustments
could be made to existing models to reflect the current situation in England and
Wales. RESULTS - CLINICAL EFFECTIVENESS: (1) Donepezil--three systematic reviews
and five RCTs (plus four studies from industry (unpublished data, submitted as
commercial in confidence)) were found. Results suggest that donepezil is
beneficial when assessed using global and cognitive outcome measures. (2)
Rivastigmine--three systematic reviews and five RCTs (plus two studies from
industry (unpublished data, submitted as commercial in confidence)) were found.
Results suggest that rivastigmine is beneficial in terms of global outcome
measures. (3) Galantamine--one systematic review and three RCTs (plus three
studies from industry (unpublished data, submitted as commercial in confidence))
were found. Results suggest that galantamine is beneficial in terms of global,
cognitive and functional scales. RESULTS - SUMMARY OF BENEFITS: It is difficult
to quantify benefits from the evidence available in the literature.
Statistically significant improvements in tests such as ADAS-cog (Alzheimer's
Disease Assessment Scale cognitive subscale) may not be reflected in changes in
daily life. (ABSTRACT TRUNCATED)
Bu, G. (2001). "The roles of receptor-associated protein (RAP) as a molecular
chaperone for members of the LDL receptor family." Int Rev Cytol 209:
79-116.
Members of the LDL receptor family mediate endocytosis and signal transduction
of many extracellular ligands which participate in lipoprotein metabolism,
protease regulation, embryonic development, and the pathogenesis of disease
(e.g., Alzheimer's disease). Structurally, these receptors share common motifs
and modules that are highlighted with clusters of cysteine-rich ligand-binding
repeats. Perhaps, the most significant feature that is shared by members of the
LDL receptor family is the ability of a 39-kDa receptor-associated protein (RAP)
to universally inhibit ligand interaction with these receptors. Under
physiological conditions, RAP serves as a molecular chaperone/escort protein for
these receptors to prevent premature interaction of ligands with the receptors
and thereby ensures their safe passage through the secretory pathway. In
addition, RAP promotes the proper folding of these receptors, a function that is
likely independent from its ability to inhibit ligand binding. The molecular
mechanisms underlying these functions of RAP, as well as the molecular
determinants that contribute to RAP-receptor interaction will be discussed in
this review. Elucidation of these mechanisms should help to clarify how a
specialized chaperone promotes the biogenesis of LDL receptor family members,
and may provide insights into how the expression and function of these receptors
can be regulated via the expression of RAP under pathological states.
Burkman, R. T., J. A. Collins, et al. (2001). "Current perspectives on benefits
and risks of hormone replacement therapy." Am J Obstet Gynecol 185(2
Suppl): S13-23.
Hormone replacement therapy with estrogen alone or with added progestin relieves
menopausal symptoms and physical changes associated with depleted endogenous
estrogen levels. Estrogen replacement has also demonstrated a clear benefit in
the prevention of osteoporosis. Hormone replacement therapy with added progestin
maintains spinal bone density, protects against postmenopausal hip fractures,
and provides these benefits even when therapy is started after age 60. More
recently, additional benefits have emerged. Current estrogen and hormone
replacement therapy users have a 34% reduction in the risk of colorectal cancer
and a 20% to 60% reduction in the risk of Alzheimer's disease. Until recently,
the body of evidence indicated that hormone replacement therapy with estrogen
only reduced cardiovascular disease risk by 40% to 50% in healthy patients;
whether the findings of 3 ongoing trials will change this conclusion is pending
availability of the final results. The many benefits of estrogen and hormone
replacement therapy must be weighed against a slight increase in the risk of
breast cancer diagnosis with use for 5 or more years, but which disappears
following cessation of therapy. Overall, estrogen and hormone replacement
therapy improves the quality of life and increases life expectancy for most
menopausal women.
Bush, A. I. and L. E. Goldstein (2001). "Specific metal-catalysed protein
oxidation reactions in chronic degenerative disorders of ageing: focus on
Alzheimer's disease and age-related cataracts." Novartis Found Symp
235: 26-38; discussion 38-43.
Abnormalities of protein aggregation and deposition may play an important role
in the pathophysiology of a diverse set of chronically progressive degenerative
disorders including Alzheimer's disease, amyotrophic lateral sclerosis,
Parkinson's disease and age-related cataracts. We propose that aberrant
metalloprotein reactions may be a common denominator in these diseases. In these
instances, an abnormal reaction between a protein and redox active metal ions
(especially copper or iron) promotes the generation of reactive oxygen species,
and possibly, protein radicalization. These products then lead to chemical
modification of the protein, alterations in protein structure and solubility,
and oxidative damage to surrounding tissue. In this review, we explore these
ideas by focusing on two common diseases of ageing, Alzheimer's disease and
age-related cataracts. Understanding the metalloprotein biochemistry in both
diseases may lead to a better understanding of the underlying pathophysiology in
both disorders and suggest novel targets for therapeutic agents.
Butterfield, D. A., J. Drake, et al. (2001). "Evidence of oxidative damage in
Alzheimer's disease brain: central role for amyloid beta-peptide." Trends Mol
Med 7(12): 548-54.
Amyloid beta-peptide (Abeta) is heavily deposited in the brains of Alzheimer's
disease (AD) patients. Free-radical oxidative stress, particularly of neuronal
lipids, proteins and DNA, is extensive in those AD brain areas in which Abeta is
abundant. Recent research suggests that these observations might be linked, and
it is postulated that Abeta-induced oxidative stress leads to neurodegeneration
in AD brain. Consonant with this postulate, Abeta leads to neuronal lipid
peroxidation, protein oxidation and DNA oxidation by means that are inhibited by
free-radical antioxidants. Here, we summarize current research on phospholipid
peroxidation, as well as protein and DNA oxidation, in AD brain, and discuss the
potential role of Abeta in this oxidative stress.
Butterfield, D. A., B. J. Howard, et al. (2001). "Brain oxidative stress in
animal models of accelerated aging and the age-related neurodegenerative
disorders, Alzheimer's disease and Huntington's disease." Curr Med Chem
8(7): 815-28.
Oxidative stress in brain is emerging as a potential causal factor in aging and
age-related neurodegenerative disorders. Brain tissue from living patients is
difficult to acquire; hence, animal models of aging and age-related
neurodegenerative disorders, though not perfect models, have provided tissue to
study the role of oxidative stress in these disorders. In this review, the
central role of oxidative damage in brain in models of accelerated aging
(progeria and Werner's syndrome) and the age-related neurodegenerative
disorders, Alzheimer's disease and Huntington's disease, will be presented and
evaluated. To the extent that the animal models faithfully mirror their
respective disorders, and based on the totality of the studies, it is apparent
that oxidative stress, the excess of free radicals over the means of scavenging
these harmful agents, may play critical roles in the molecular basis of
accelerated aging, Alzheimer's disease, and Huntington's disease.
Butterfield, D. A. and J. Kanski (2001). "Brain protein oxidation in age-related
neurodegenerative disorders that are associated with aggregated proteins."
Mech Ageing Dev 122(9): 945-62.
Protein oxidation, one of a number of brain biomarkers of oxidative stress, is
increased in several age-related neurodegenerative disorders or animal models
thereof, including Alzheimer's disease, Huntington's disease, prion disorders,
such as Creutzfeld-Jakob disease, and alpha-synuclein disorders, such as
Parkinson's disease and frontotemporal dementia. Each of these neurodegenerative
disorders is associated with aggregated proteins in brain. However, the
relationship among protein oxidation, protein aggregation, and neurodegeneration
remain unclear. The current rapid progress in elucidation of mechanisms of
protein oxidation in neuronal loss should provide further insight into the
importance of free radical oxidative stress in these neurodegenerative
disorders.
Byerly, M. J., M. T. Weber, et al. (2001). "Antipsychotic medications and the
elderly: effects on cognition and implications for use." Drugs Aging
18(1): 45-61.
Despite being frequently prescribed in the elderly, antipsychotic medications
are commonly associated with adverse effects in this population, including
sedative, orthostatic and extrapyramidal adverse effects. Growing evidence
suggests that antipsychotics can also cause deleterious cognitive effects in
some elderly patients. Preclinical and growing clinical evidence indicates that
inhibitory effects on dopaminergic, cholinergic and histaminergic neurochemical
systems may account for antipsychotic-associated cognitive impairment in the
elderly. A review of published reports of the cognitive effects of
antipsychotics in the elderly suggests that newer antipsychotic medications may
possess a more favourable cognitive profile than that of traditional agents in
this population. The cognitive effect that a specific antipsychotic will have in
the elderly, however, is likely better predicted by considering the
pharmacodynamic action of an individual agent in combination with the
pathophysiology of the condition being treated. Agents with relatively weak
dopamine inhibiting effects (e.g. clozapine and quetiapine), for example, would
theoretically have a cognitive profile superior to that of agents with higher
degrees of dopaminergic inhibition (all traditional agents, risperidone,
olanzapine and ziprasidone) when used for conditions associated with diminished
dopamine function (e.g. idiopathic Parkinson's disease). Drugs with weak
anticholinergic effects (high-potency traditional agents, risperidone,
quetiapine and ziprasidone) would theoretically be less likely to cause
cognitive impairment than agents with high degrees of cholinergic receptor
blocking actions (clozapine and olanzapine) when treating patients with impaired
cholinergic function (e.g. Alzheimer's disease). Cholinergic agonist effects of
clozapine and olanzapine may, however, mitigate potential adverse cognitive
effects associated with the cholinergic blocking actions of these agents. Large,
rigorous trials comparing the cognitive effects of antipsychotics with diverse
pharmacodynamic actions are lacking in the elderly and are needed.
Calabrese, V., G. Scapagnini, et al. (2001). "Mitochondrial involvement in brain
function and dysfunction: relevance to aging, neurodegenerative disorders and
longevity." Neurochem Res 26(6): 739-64.
It is becoming increasingly evident that the mitochondrial genome may play a key
role in neurodegenerative diseases. Mitochondrial dysfunction is characteristic
of several neurodegenerative disorders, and evidence for mitochondria being a
site of damage in neurodegenerative disorders is partially based on decreases in
respiratory chain complex activities in Parkinson's disease, Alzheimer's
disease, and Huntington's disease. Such defects in respiratory complex
activities, possibly associated with oxidant/antioxidant balance perturbation,
are thought to underlie defects in energy metabolism and induce cellular
degeneration. Efficient functioning of maintenance and repair process seems to
be crucial for both survival and physical quality of life. This is accomplished
by a complex network of the so-called longevity assurance processes, which are
composed of genes termed vitagenes. A promising approach for the identification
of critical gerontogenic processes is represented by the hormesis-like positive
effect of stress. In the present review, we discuss the role of energy
thresholds in brain mitochondria and their implications in neurodegeneration. We
then review the evidence for the role of oxidative stress in modulating the
effects of mitochondrial DNA mutations on brain age-related disorders and also
discuss new approaches for investigating the mechanisms of lifetime survival and
longevity.
Calabrese, E. J. (2001). "Amyloid beta-peptide: biphasic dose responses."
Crit Rev Toxicol 31(4-5): 605-6.
This article summarizes recent findings indicating that amyloid beta-peptide
displays neurotoxic and neurotrophic effects, depending on concentration.
Mechanistic findings revealed that reactive oxygen species mediate both the
toxic and neurotropic responses as a function of concentration with low doses
being neutotrophic, while higher doses were toxic. The data reveal a potential
biological function for amyloid beta-peptide within an optimal concentration
zone. These findings suggest the critical role of dose in understanding disease
causation and clinical therapeutics for Alzheimer's disease.
Canales, J. J., R. Corbalan, et al. (2001). "Aluminium impairs the
glutamate-nitric oxide-cGMP pathway in cultured neurons and in rat brain in
vivo: molecular mechanisms and implications for neuropathology." J Inorg
Biochem 87(1-2): 63-9.
Aluminium (Al) is a neurotoxicant and appears as a possible etiological factor
in Alzheimer's disease and other neurological disorders. The mechanisms of Al
neurotoxicity are presently unclear but evidence has emerged suggesting that Al
accumulation in the brain can alter neuronal signal transduction pathways
associated with glutamate receptors. In cerebellar neurons in culture, long
term-exposure to Al added 'in vitro' impaired the glutamate-nitric oxide
(NO)-cyclic GMP (cGMP) pathway, reducing glutamate-induced activation of NO
synthase and NO-induced activation of the cGMP generating enzyme, guanylate
cyclase. Prenatal exposure to Al also affected strongly the function of the
glutamate-NO-cGMP pathway. In cultured neurons from rats prenatally exposed to
Al, we found reduced content of NO synthase and of guanylate cyclase, and a
dramatic decrease in the ability of glutamate to increase cGMP formation.
Activation of the glutamate-NO-cGMP pathway was also strongly impaired in
cerebellum of rats chronically treated with Al, as assessed by in vivo brain
microdialysis in freely moving rats. These findings suggest that the impairment
of the Glu-NO-cGMP pathway in the brain may be responsible for some of the
neurological alterations induced by Al.
Capone, G. T. (2001). "Down syndrome: advances in molecular biology and the
neurosciences." J Dev Behav Pediatr 22(1): 40-59.
The entire DNA sequence for human chromosome 21 is now complete, and it is
predicted to contain only about 225 genes, which is approximately three-fold
fewer than the number initially predicted just 10 years ago. Despite this
remarkable achievement, very little is known about the mechanism(s) whereby
increased gene copy number (gene dosage) results in the characteristic phenotype
of Down syndrome. Although many of the phenotypic traits show large individual
variation, neuromotor dysfunction and cognitive and language impairment are
observed in virtually all individuals. Currently, there are no efficacious
biomedical treatments for these central nervous system-associated impairments.
To develop novel therapeutic strategies, the effects of gene dosage imbalance
need to be understood within the framework of those critical biological events
that regulate brain organization and function.
Carlson, L. A. and B. Winblad (2001). "[Reduced prevalence of dementia in
patients treated with antilipemic agents. An overview of cholesterol metabolism
in the brain and actions]." Lakartidningen 98(36): 3795-7.
Carpenter, D. O. (2001). "Effects of metals on the nervous system of humans and
animals." Int J Occup Med Environ Health 14(3): 209-18.
Several metals have toxic actions on nerve cells and neurobehavorial
functioning. These toxic actions can be expressed either as developmental
effects or as an increased risk of neurodegenerative diseases in old age. The
major metals causing neurobehavioral effects after developmental exposure are
lead and methylmercury. Lead exposure in young children results in a permanent
loss of IQ of approximately 5 to 7 IQ points, and also results in a shortened
attention span and expression of anti-social behaviors. There is a critical time
period (<2 years of age) for development of these effects, after which the
effects do not appear to be reversible even if blood lead levels are lowered
with chelation. Methylmercury has also been found to have effects on cognition
at low doses, and prenatal exposure at higher levels can disrupt brain
development. Metals have also been implicated in neurodegenerative diseases,
although it is unlikely that they are the sole cause for any of them. Elevated
aluminum levels in blood, usually resulting from kidney dialysis at home with
well water containing high aluminum, result in dementia that is similar to but
probably different from that of Alzheimer's disease. However, there is some
epidemiological evidence for elevated risk of Alzheimer's in areas where there
is high concentration of aluminum in drinking water. Other metals, especially
lead, mercury, manganese and copper, have been implicated in amvotrophic lateral
sclerosis and Parkinson's disease.
Castellano, C., V. Cestari, et al. (2001). "NMDA receptors and learning and
memory processes." Curr Drug Targets 2(3): 273-83.
In the first part of this review studies are considered in which pre- or
post-training peripheral or intracerebroventricular administrations of
competitive or noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists
were carried out in a variety of animal species tested in different experimental
conditions, in order to investigate the effects of these drugs on acquisition
and memory processes. In particular, post-training treatments, which are known
to affect memory consolidation, ruling out the possible "aspecific effects"
linked to the pre-training administrations, show that the NMDA receptor
antagonists impair memory in animals tested in various tasks. Memory impairments
are also evident when the NMDA antagonists (in particular AP5) are injected into
different brain structures, including amygdala and hippocampus. In a second part
of this review some recent studies are considered showing the existence of: a)
cholinergic-glutamatergic interactions; b) interactions between NMDA receptors
and opioid system, and c) interactions between NMDA receptor antagonists
(MK-801) and cocaine, in the modulation of memory processes of laboratory
animals. The results of some studies showing the involvement of glutamatergic
mechanisms in Alzheimer's disease are finally reported, and the therapeutic
efficacy of glutamatergic drugs in the treatment of this disease is considered.
Cechetto, D. F. (2001). "Role of nuclear factor kappa B in neuropathological
mechanisms." Prog Brain Res 132: 391-404.
Chadha, S. and J. Young (2001). "Key developments in geriatric medicine."
Practitioner 245(1626): 698-700, 702, 704-5 passim.
Chan, P. L. and N. H. Holford (2001). "Drug treatment effects on disease
progression." Annu Rev Pharmacol Toxicol 41: 625-59.
Degenerative diseases are characterized by a worsening of disease status over
time. The rate of deterioration is determined by the natural rate of progression
of the disease and by the effect of drug treatments. A goal of drug treatment is
to slow disease progression. Drug treatments can be categorized as symptomatic
or protective. Symptomatic treatments do not affect the rate of disease
progression whereas protective treatments have the ability to slow disease
progression down. Many current methods for describing disease progression have
two common drawbacks: a linear relationship between time and disease status is
assumed, and within- and between-subject variability is ignored. Disease
progress models combined with pharmacokinetic pharmacodynamic models and
hierarchical random effects statistical models provide insights into
understanding the time course and management of degenerative disease.
Chapman, P. F., A. M. Falinska, et al. (2001). "Genes, models and Alzheimer's
disease." Trends Genet 17(5): 254-61.
Alzheimer's disease (AD) is a neurodegenerative disorder that is claiming an
increasing number of victims as the world population ages. The identification of
gene mutations and polymorphisms that either cause AD or significantly increase
the risk for developing it enabled the creation of a whole generation of
realistic rodent models of the disease. Animals expressing mutated human amyloid
precursor protein and presenilin 1 show dramatic parallels to AD, although none
of the models appear to capture the full range of pathologies that characterize
the human disease. Increased refinement of these models will enhance the already
tantalizing possibility of treatment.
Checler, F. (2001). "The multiple paradoxes of presenilins." J Neurochem
76(6): 1621-7.
Chen, M. and H. L. Fernandez (2001). "Alzheimer movement re-examined 25 years
later: is it a "disease" or a senile condition in medical nature?" Front
Biosci 6: E30-40.
Dementia in the elderly used to be rare, but why has it become a major social
threat today? There can be many potential answers, but an ultimate one is clear:
the longer life expectancy today. This knowledge indicates that "advanced aging"
is a primary suspect in the origin of senile dementia. If so, then why can many
elderly remain healthy at the same old age? We know, for example, that elderly
people commonly have a certain degree of atherosclerosis and osteoporosis, but
only some of them develop severe clinical symptoms at the same age. These
different outcomes generally can be explained by "risk factors" in life
(exercise, diet, individual background, etc). It thus appears to be a general
pattern that advanced aging (after age 80) will set the stage for various senile
disorders, but risk factors largely determine the onset age as well as
individual specificity of their clinical manifestations. In this context, senile
disorders including senile dementia would differ fundamentally from the
pathogen-caused conventional diseases (AIDS, polio, cancer, Down's, etc.) by
origin, incidence, and intervention strategy. This view would call into question
the current definition of senile dementia as a conventional "disease"
(Alzheimer's). The term "Alzheimer's disease" originally referred to "midlife"
dementia, but it is defined today to be the same medical entity as senile
dementia on the basis that they both display the same hallmarks and symptoms
despite their onset age difference. Now, after in-depth scrutiny, we finally
come to realize that they are not the same disease, but as different as heart
failure at midlife versus the "same" failure at advanced age (i.e., a
conventional disease versus a senile condition). Thus, by eliminating the age
difference, the new definition has converted a senile condition into a
conventional "disease", thereby changing the course of its scientific inquiry to
miss the main targets. This may be why after extensive studies for 25 years, the
origin of senile dementia has remained an enigma.
Chen, M. and H. L. Fernandez (2001). "Where do Alzheimer's plaques and tangles
come from? Aging-induced protein degradation inefficiency." Front Biosci
6: E1-E11.
Amyloid plaques and neurofibrillary tangles are prominent lesions in the aging
brain and they may be responsible for cell death in Alzheimer's disease. But a
basic question has not been answered: why and how are plaques and tangles formed
during aging? In this study, we approach this question by first examining what
happens in the aging body. Plaques and tangles do not come alone, but together
with many other aging markers in the body (cholesterol deposition, gallstones,
hair graying, and bone loss, etc.). Because these aging markers occur to a
certain extent in all elderly and at about the same time in life, it is
reasonable to conceive that they originate from a common cause, that is,
aging-induced metabolic inefficiency. If cholesterol and gallstone depositions
are the results of inefficient degradation/clearance of lipids and minerals,
then similarly plaque and tangle formation in most people would be the results
of inefficient normal degradation of ?-amyloid precursor protein (APP) and tau,
respectively. By this view, our studies should focus on the enzymes responsible
for APP and tau normal degradation and their natural changes in aging, rather
than on presumed pathological factors. Whatever precise mechanisms underlying
their depositions, plaques and tangles are the natural products of aging, thus
fundamentally different from pathological events such as cancer growth in
concept.
Chertkow, H., H. Bergman, et al. (2001). "Assessment of suspected dementia."
Can J Neurol Sci 28 Suppl 1: S28-41.
At the Second Canadian Consensus Conference on Dementia (CCCD) (February, 1998),
a group of neurologists, geriatricians, and psychiatrists met to consider
guidelines for evaluation of dementia in Canada. This review paper formed a
background paper for their discussion of dementia diagnosis. These experts from
across the country concluded that diagnosis of suspected dementia cases
continued to rest on skilled clinical assessment. Mental status exam, preferably
in some quantifiable form, has become an essential part of the assessment.
Selected laboratory tests are advisable in all cases (CBC, TSH, electrolytes,
calcium, and glucose), but the CCCD continued to advise that CT scanning was
mandatory only in selected cases where clinical findings pointed to another
possibility besides Alzheimer's disease. The growing list of other diagnostic
measures with potential usefulness in diagnosis of Alzheimer's disease or
dementia in general was reviewed, but the evidence was judged as insufficient to
support routine use of these tests by physicians. As new treatments for
Alzheimer's disease become available, neurologists face new diagnostic
challenges--differentiating Mild Cognitive Impairment, Frontotemporal dementias
and Mixed dementias, and Lewy Body Dementia. Guidelines to aid in differential
diagnosis are presented.
Chodobski, A. and J. Szmydynger-Chodobska (2001). "Choroid plexus: target for
polypeptides and site of their synthesis." Microsc Res Tech 52(1):
65-82.
Choroid plexus (CP) is an important target organ for polypeptides. The
fenestrated phenotype of choroidal endothelium facilitates the penetration of
blood-borne polypeptides across the capillary walls. Thus, both circulating and
cerebrospinal fluid (CSF)-borne polypeptides can reach their receptors on
choroidal epithelium. Several polypeptides have been demonstrated to regulate
CSF formation by controlling blood flow to choroid plexus and/or the activity of
ion transport in choroidal epithelium. However, many ligand-receptor
interactions occurring in the CP are not involved in the regulation of fluid
secretion. Increasing evidence suggests that the choroidal epithelium plays an
important role in hormonal signaling via a receptor-mediated transport into the
brain (e.g., leptin) and helps to clear certain CSF-borne polypeptides (e.g.,
soluble amyloid beta-protein). Thus, impaired choroidal transport or
insufficient clearance of polypeptides may contribute to pathogenesis of
systemic or central nervous system (CNS) disorders, such as obesity or
Alzheimer's disease. CP epithelium is not only a target but is also a source of
neuropeptides, growth factors, and cytokines in the CNS. These polypeptides
following their release into the CSF may exert distal, endocrine-like effects on
target cells in the brain due to bulk flow of this fluid. Distinct temporal
patterns of choroidal expression of several polypeptides are observed during
brain development and in various CNS disorders, including traumatic brain injury
and ischemia. Therefore, it is proposed that the CP plays an integral role not
only in normal brain functioning, but also in the recovery from the injury. This
review attempts to critically analyze the available data to support the above
hypothesis.
Chorsky, R. L., F. Yaghmai, et al. (2001). "Alzheimer's disease: a review
concerning immune response and microischemia." Med Hypotheses 56(1):
124-7.
Alzheimer's disease (AD), as we think of it today, is the idiopathic progressive
loss of cognitive function over a period of several years. The risk of late
onset dementia increases significantly with each decade of life such that half
of the population over the age of 80 is vulnerable to this disease (1). We know
that proper functioning of the central nervous system is dependent on adequate
blood flow to remove harmful metabolic products and supply nutrients such as
glucose and oxygen to the brain. It has been suggested that cerebral
hypoperfusion causes AD (2). Mean cerebral blood flow decreases with age and
with sclerosis of cerebral blood vessels. Blood flow appears to increase in
stimulated areas of the brain during different activities. However, there is a
derangement of blood flow in disease states; this has been documented in the
temporal lobes of AD patients, (3,4). English language journal articles located
by a MEDLINE search (1960-1999) were reviewed with consideration to the
hypothesis that Alzheimer's disease is an autoimmune disease initiated by low
oxygen tension and microischemia. Inflammation is thought to be a known
contributor to the pathology of AD (5,6). Recent reports support the concept of
autoimmunity as a final common pathway of neuron death, particularly for
cholinergic in Alzheimer's disease (6). A model of Alzheimer's disease is
proposed and related research and treatment modalities are discussed.
Chui, H. (2001). "Dementia due to subcortical ischemic vascular disease."
Clin Cornerstone 3(4): 40-51.
Ischemic vascular disease (IVD) is the second most common cause of dementia in
the Western world. This article focuses on dementia resulting from subcortical
ischemic vascular disease (SIVD), a subtype of IVD, which in many cases may be
prevented. Hypertension and diabetes are the leading causes of small-artery
disease, subcortical brain ischemia, and stepwise or slowing progressive decline
in cognitive function. The pattern of cognitive impairment in SIVD, as compared
with Alzheimer's disease, is characterized by greater impairment of executive
function but better preservation of recognition memory. Structural neuroimaging
studies, such as computed tomography and especially magnetic resonance imaging,
are more sensitive than the clinical examination and can enable detection of
subcortical lacunes and deep white matter changes that are clinically silent.
Often the brain can be protected against SIVD by early diagnosis and management
of risk factors. Once end-organ damage has occurred, however, treatment outcome
is less satisfactory. The most common risk factors for SIVD--hypertension and
diabetes mellitus--are best detected and managed in primary care settings.
Clippingdale, A. B., J. D. Wade, et al. (2001). "The amyloid-beta peptide and
its role in Alzheimer's disease." J Pept Sci 7(5): 227-49.
Amyloid formation plays a central role in the cause and progression of
Alzheimer's disease. The major component of this amyloid is the amyloid-beta (A
beta) peptide, which is currently the subject of intense study. This review
discusses some recent studies in the area of A beta synthesis, purification and
structural analysis. Also discussed are proposed mechanisms for A beta-induced
neurotoxicity and some recent advances in the development of A beta-related
therapeutic strategies.
Clostre, F. (2001). "[Mitochondria: recent pathophysiological discoveries and
new therapeutic perspectives]." Ann Pharm Fr 59(1): 3-21.
Until about a decade ago, few researchers in clinical or evolutionary biology
paid much attention to mitochondria. But over the years, as technological
advances in molecular biology made nuclear functions more accessible to them,
interest in mitochondria began to revive. First, geneticists started tracing
certain rare inherited disorders to mutations in the mitochondria's circular
genome. More recently, other researchers have speculated that mitochondria might
contribute to aging, either by releasing tissue-damaging reactive oxygen
molecules or by impairing and depriving the cell of the energy it needs to
function. One the most important recent developments has been the recognition
that mitochondria play a central role in the regulation of programmed cell
death, or apoptosis. Now, we know that mitochondria play a decisive role in
life-death decisions for the cell and may choose between the apoptotic and
necrotic pathways. Mitochondria can trigger cell death in a number of ways: by
disrupting electron transport and energy metabolism, by activating the
mitochondrial permeability transition, by releasing and/or activating proteins
that mediate apoptosis. Any or all of these mechanisms may help to explain how
mitochondrial defects contribute to the pathogenesis of neuronal death or
dysfunction in ischemia/reperfusion injury as well as in human degenerative
diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis and Huntington's disease. This has opened up new avenues for
understanding the pathogenesis of neurodegeneration and may lead to new and more
effective therapeutic approaches to these diseases.
Coelho, F. and J. Birks (2001). "Physostigmine for Alzheimer's disease."
Cochrane Database Syst Rev(2): CD001499.
BACKGROUND: The main pharmacological approach for the treatment of Alzheimer's
disease (AD) has been based on the use of agents potentiating cholinergic
transmission, particularly by inhibiting acetylcholinesterase (AChE), the enzyme
that destroys acetylcholine after it has been secreted into the synaptic clefts.
Physostigmine is an AChE inhibitor originally extracted from calabar beans. It
is licensed in many countries as an agent for reversing the effect of drugs and
poisons causing the anticholinergic syndrome. Studies conducted more than 20
years ago suggested that physostigmine could improve memory in people with or
without dementia. Investigation of this property has been limited by the very
short half-life of physostigmine. Various forms of administering the drug have
been tried to overcome this problem, most recently a controlled-release (CR)
oral formulation, and a skin patch. It has been proposed as a potential drug for
the symptomatic treatment of AD. OBJECTIVES: To determine whether there is
evidence of beneficial effects for the use of physostigmine in Alzheimer's
disease. To assess the incidence and severity of adverse effects. SEARCH
STRATEGY: The Cochrane Controlled Trials Register was searched using the
following terms: 'physostigmine', 'physostigmine salicylate', 'Synapton' and
'Antilirium' in accordance with the Cochrane Dementia and Cognitive Improvement
Group's search strategy. The pharmaceutical company was contacted. SELECTION
CRITERIA: All relevant unconfounded, double-blind, randomized,
placebo-controlled trials in which physostigmine was administered for more than
one day to patients with dementia of Alzheimer type. Trials in which the
allocation to the treatment was not randomized, or in which the allocation to
the treatment was not concealed were excluded. DATA COLLECTION AND ANALYSIS:
Data were extracted independently by two reviewers (JMC & JB), pooled where
appropriate and possible, and the weighted or standardized mean differences or
Peto odds ratios (95% CI) were estimated. Where possible, intention-to-treat
analysis was used. MAIN RESULTS: Fifteen studies were included using four
different methods of administration of physostigmine. Four studies, involving 29
people in total, used intravenous infusion; seven, involving 131 people, used a
conventional oral form; four, involving 1456 participants, used a
controlled-release oral form, and one study of 181 people used a verum skin
patch. There are no usable results from the intravenous infusion trials, and the
few results from the conventional oral form showed no benefit of physostigmine
compared with placebo. The results from two of the four studies of the
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