| Volume 3, Number
3, June 2001:
Guest Editor: David Small, Issue on Biology Markers in AD
Pages 257-260
David H Small
Biomarkers of Alzheimer’s disease: bridging the gap between basic
science and clinical practice
Pages 261-286
Elsdon Storey, Glynda J. Kinsella, Melissa J. Slavin
The neuropsychological diagnosis of Alzheimer's disease
Abstract: Neuropsychological assessment potentially subserves
several functions in subjects in whom Alzheimer’s disease (AD) is
suspected. Such assessment can detect the presence of brain disease
once significant neuronal disruption has occurred. Analysis of the
pattern and evolution of cognitive deficits allows inferences to be
drawn regarding the likely underlying pathology. Neuropsychological
assessment enables delineation of the particular cognitive strengths
and weaknesses of individual patients, facilitating the construction
of individual management programs. Lastly, cognitive testing
provides a cost-effective means of monitoring disease progression
and the effects of treatment. This review describes the typical
pattern and evolution of cognitive deficits in AD, outlines a number
of variant presentations, discusses the differential diagnosis from
other dementias, and addresses the issue of progression to
clinically probable AD in the cognitively impaired, non-demented
elderly. It is anticipated that biomarkers for AD will complement
neuropsychological assessment by enabling disease detection before
unequivocal cognitive deterioration has ensued, and by improving the
accuracy of clinical diagnosis of dementia type. The development of
reliable biomarkers will also enable improvements in the sensitivity
and accuracy of neuropsychological assessment in AD to be made, more
quickly and efficiently than is currently possible using
longitudinal studies.
Pages 287-292
John Growdon
Incorporating biomarkers into clinical drug trials in Alzheimer's
disease
Abstract: Incorporating biomarkers into clinical drug trials
for Alzheimer’s disease (AD) could 1) increase the homogeneity of
patients through improved diagnosis, 2) establish surrogate outcome
measures for drug efficacy, 3) test pharmacogenetic bases of drug
response, and 4) verify proposed mechanisms of drug action. Among
biological correlates of AD, those with the greatest potential to
improve diagnostic accuracy are genetic abnormalities that cause AD
or increase the risk of AD; characteristic changes in amyloid
derivatives and tau and blood in CSF; and neuroimaging detection of
brain atrophy and reduction in brain metabolism and blood flow.
Although there are no AD biological markers that qualify as true
surrogate endpoints in clinical drug trials, indices of brain
atrophy show promise as a technique to track progression of dementia
and as a measure of treatment efficacy. Anti-amyloid strategies for
treatment are the leading candidates for the next generation of
Alzheimer therapies. Predicted changes in amyloid derivative levels
in CSF can help verify drug activity and illuminate the mechanism of
action.
Pages 293-304
Ekaterina Rogaeva, Anurag Tandon, Peter H. St George-Hyslop
Genetic markers in the diagnosis of Alzheimer’s disease
Summary: Alzheimer’s disease (AD) is the most common
neurodegenerative disorder associated with dementia in the elderly
population. Its clinical symptoms are manifest with increasing
prominence during mid- to late stages of adulthood. In the absence
of precise biological indicators that precede or accompany the
cognitive decline, diagnostic confirmation of AD requires postmortem
detection of histopathological characteristics such as amyloid
plaques, neurofibrillary tangles, and extensive cortical atrophy.
While the etiology of AD remains incompletely understood, it was
recognized early on that the observed familial aggregation of AD
implied the presence of one or more inherited susceptibility markers
that could be useful in diagnosis and treatment. To date, genetic
analyses of these pedigrees have resolved four independent genetic
loci linked with inherited susceptibility to AD.
Pages 305-312
Catriona A. McLean, Konrad Beyreuther, Colin L. Masters
Amyloid Aß levels in Alzheimer’s disease – a diagnostic tool and
the key to understanding the natural history of Aß
Abstract: The biogenesis and degradation/clearance of Aß
amyloid lies at the centre of the pathogenesis of Alzheimer’s
disease. Quantification of the various metabolic pools of Aß in the
brains and in the periphery may aid in diagnosis, prognosis and the
elucidation of the natural history of this disorder. Estimation of
the Aß levels using immunoassays (ELISA and the western blots) are
complementary techniques which are now being applied in humans and
experimental models. The various forms of Aß in differing cellular
compartments are now being assayed, and a picture of the natural
history of Alzheimer’s disease is beginning to emerge.
Pages 313-322
Mikio Shoji and Mitsuyasu Kanai
Cerebrospinal fluid Aß40 and Aß42: natural course and clinical
usefulness
Abstract: Amyloid ß protein 40 (Aß40) and 42 Aß42, major
components of senile plaque amyloids, are physiological peptides
present in the brain, cerebrospinal fluid (CSF) and plasma. The
levels of CSF Aß40 and Aß42(43) show a U-shaped natural course in
normal aging. The increase of Aß42(43) over 60 years of age is
inhibited in Alzheimer’s disease (AD). This specific alteration of
CSF Aß42(43) correlates with Aß deposits in the AD brain providing a
biological basis for a biomarker of AD. In the GTT2 study, assays
of the CSF Aß ratio [(Aß40/Aß42(43)] showed a diagnostic sensitivity
(59%) and specificity (88%) compared with non-AD type dementia and
controls. The levels of the Aß ratio increased from early to late
stages of AD. Combination assays of CSF tau and Aß ratio provided
further efficient diagnostic sensitivity (81%) and specificity
(87%). The reliability of the assay may prompt worldwide usage of
these CSF biomarkers for Alzheimer’s patients.
Pages 323-328
Javier Sáez-Valero and David H. Small
Acetylcholinesterase and butyrylcholinesterase glycoforms are
biomarkers of Alzheimer’s disease
Abstract: The identification of a biochemical marker in
cerebrospinal fluid (CSF) that can discriminate between Alzheimer's
disease (AD) and other dementia-causing diseases at would be a major
advance. Our previous studies have shown that the glycosylation of
acetylcholinesterase (AChE) is altered in the post mortem brain and
cerebrospinal fluid of AD patients. We have also found that the
glycosylation of AChE is altered in lumbar CSF collected ante
mortem. The change in glycosylation of AChE is very specific for
AD and is not seen in many other neurological diseases including
other dementias. The sensitivity of detection of AD using AChE
glycosylation (60-80%) is lower than that considered necessary for a
satisfactory diagnostic marker. However, more recently we have
found that the glycosylation of the related enzyme
butyrylcholinesterase (BuChE) is also altered in AD CSF. By
combining the analysis of AChE glycosylation with that of BuChE
glycosylation, improved sensitivity of detection is obtained. We
propose that AChE and BuChE glycosylation may be of diagnostic
value, especially when used in combination with other CSF markers
such as Aß or tau.
Pages 329-338
Gary E. Gibson and Hui Zhang
Abnormalities in oxidative processes in non-neuronal tissues from
patients with Alzheimer’s disease
Abstract: Overwhelming evidence demonstrates that oxidative
stress occurs in brains from patients with Alzheimer’s Disease (AD).
Whether the oxidative stress is secondary to neurodegeneration, or
if it underlies the pathology is not clear. The persistence of
AD-related abnormalities in oxidative processes in non-neuronal
tissues, including cultured cells, infers that an imbalance in
production and removal of reactive oxygen species is an inherent
property of cells from AD patients. These results suggest that
changes in oxidative processes in AD cells could precede and/or
cause AD-related neuropathology. Abnormalities in oxidative
processes may also cause changes in signal transduction systems such
as calcium that occur in cells from AD patients. The ability to
manipulate oxidative processes in peripheral tissues, especially
cultured cells, from AD patients should facilitate a mechanistic
understanding of the changes in oxidative processes in AD brain. The
use of peripheral tissues has the potential to identify both state
and trait dependent diagnostic markers, which could be used as
endpoints for selecting treatments or monitoring therapeutic
effectiveness.
Pages 339-344
Wilfred A. Jefferies, Dara L. Dickstein and Maki Ujiie
Assessing p97 as a Alzheimer’s disease serum biomarker
Abstract: The search is ongoing for a reliable serum
biomarker for AD. The level of iron is elevated in the brain of
Alzheimer’s disease (AD) patients. Our studies have demonstrated
that the level of the iron transport protein, p97, is increased in
the serum of AD patients but not in various control groups. These
results have recently been confirmed by another laboratory who
extended our findings by demonstrating that p97 is not elevated in
other neurodegenerative diseases. This qualifies p97 as a
potentially powerful biomarker for AD. Although the relationship
between increased level of iron and p97 in the AD brain is not well
understood, our research supports the hypothesis that p97
over-expressed by senile plaque associated reactive microglia is
exocytosed and appears in blood. The relationship between elevated
levels of serum p97 and AD, together with the possible future
clinical application of p97 are considered in this report.
Pages 345-353
Suzanne M. de la Monte, Jack R. Wands
The AD7C-NTP neuronal thread protein biomarker for detecting
Alzheimer's disease
Abstract: Dementia in Alzheimer’s disease (AD) is ultimately
due to cell loss mediated by several mechanisms including,
apoptosis, impaired mitochondrial function, and possibly necrosis. A
second major neuroanatomic correlate of dementia is aberrant
cortical neuritic sprouting with abundant proliferation of
dystrophic neurites. Early in vivo detection of AD will
require non-invasive assays of highly sensitive and relatively
specific biomarkers that reflect these fundamental abnormalities in
cellular function. The AD-associated neuronal thread protein
(AD7c-NTP) gene encodes a ~41 kD membrane-spanning phosphoprotein
that causes apoptosis and neuritic sprouting in transfected neuronal
cells. The AD7c-NTP gene is over-expressed in AD beginning early in
the course of disease. In the brain, increased AD7c-NTP
immunoreactivity is associated with phospho-tau-immunoreactive
cytoskeletal lesions, but not with amyloid-ß accumulations. The
levels of AD7c-NTP in postmortem brain tissue correlate with the
levels measured in paired ventricular fluid samples, suggesting that
the protein is secreted or released by dying cells into
cerebrospinal fluid (CSF). In this regard, elevated levels of
AD7c-NTP can be detected in both CSF and urine of patients with
early or moderately severe AD, and the CSF and urinary levels of
AD7c-NTP correlate with the severity of dementia. The newest
configuration of the AD7c-NTP assay, termed “7c Gold”, has greater
than 90% sensitivity and specificity for detecting early AD. The
aggregate results from a number of studies suggest that AD7c-NTP is
an excellent biomarker that could be helpful in the routine clinical
evaluation of elderly patients at risk for AD.
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