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Kaj Blennow, MD, PhD
(1,2) and Douglas Galasko, MD, PhD (3)
1) Dept. of Clinical Neuroscience, Unit of Neurochemistry,
University of G�teborg, Sweden
2) The Medical Research Council, Sweden.
3) Dept. of Neurology, VA Medical Center, Dept. Of Veterans
Affairs, San Diego, California, USA
Corresponding author: Kaj Blennow, MD, Ph.D. Dept. of Clinical
Neuroscience, Unit of Neurochemistry Sahlgren's University
Hospital, M�lndal SE-431 80 Sweden
Tel: + 46 313431791 Fax: + 43 31 3432426 E-mail: KAJ.BLENNOW@MS.SE
 Download as a PDF here
Key words: Alzheimer�s disease (AD), b -amyloid (Ab ),
biochemical markers, cerebrospinal fluid (CSF), diagnosis,
tau.ACKNOWLEDGEMENTS
Supported by grants from the Swedish Medical Research Council
(projects # 11560 and 12103).
ABSTRACT
In view of current (AChE inhibitors) and future (e.g. anti-Ab
aggregators), development and evaluation of cerebrospinal fluid
(CSF) biomarkers for Alzheimer�s disease (AD) has become a rapidly
growing research field. Diagnostic biomarkers for AD would be
especially valuable as aids in the diagnosis early in the course of
the disease, when correct diagnosis is difficult, and when
therapeutic compounds have the greatest potential of being
effective. This paper reviews CSF biomarkers for AD, with emphasis
on their role in the clinical diagnosis, and methodological aspects
of importance for developing such analyses. Today, two biochemical
markers, CSF-tau and CSF-Ab 42, perform satisfactory enough to have
a role in the clinical work-up of patients dementia, if used
together with the cumulative information from clinical information
and brain-imaging techniques. These markers are especially useful
to discriminate early or incipient AD from age-associated memory
impairment, depression, and some secondary dementias.
INTRODUCTION
Alzheimer�s disease (AD) is the major cause of dementia in the
elderly. Although rare genetic (autosomal dominant) forms of AD
exist, most patients have no obvious family history and are
classified as having sporadic AD. The neuropathology of AD shows
neuronal and synaptic degeneration, and an increased number of
senile plaques (SP) and neurofibrillary tangles (NFT) compared to
non-demented individuals of comparable age. Synaptic degeneration
in AD is found in widespread cortical areas (Masliah et al, 1991).
SP are composed of a central core of aggregated b -amyloid (Ab )
(Masters et al, 1985), a breakdown product derived from the amyloid
precursor protein (APP) (Kang et al, 1987). NFT are insoluble
intracellular thread-like structures made up of a
hyperphosphorylated form of the microtubule-associated protein tau,
called phospho-tau (Goedert et al, 1993).
Today, several acetylcholine esterase inhibitors are available
for symptomatic treatment of AD. Drugs that also may have
beneficial effects on the disease process, e.g. compounds affecting
the deposition of Ab , are under development. These possibilities
for therapeutic intervention have heightened awareness of the
importance of early and accurate diagnosis of AD.
However, current clinical criteria for the diagnosis of AD are
relatively vague, and are largely based on the exclusion of other
dementing illnesses (McKhann et al, 1984). A relatively high
accuracy rate with regard to the clinical diagnosis of AD (80-90%)
has been reported (Tierneyet al.1988; Jellinger 1996; Galaskoet
al.1994). However, these reports emanate from expert research
academic centers and are often based on patients in the later
stages of the disease who were followed for several years before
the confirming autopsy. The diagnostic accuracy rate is probably
considerably lower in general hospitals, and especially in the
earlier stages of the disease when the symptoms are often silent or
indistinct and clinical diagnosis is more difficult. This is
unfortunate, as pharmaceutical therapy is probably most effective
early in the course of disease, before neurodegeneration is too
severe and widespread. Thus, there is a great need for biochemical
diagnostic markers (biomarkers) that could aid in the diagnosis of
AD early in the course of the disease.
The cerebrospinal fluid (CSF) is in direct contact with the
extracellular space of the brain, and its constituents reflect many
biochemical changes in the brain. Since AD pathology is restricted
to the brain, CSF is an obvious source of biomarkers for AD. During
the last years, CSF biomarkers for AD have also gained increased
attention. In this paper, we review the two CSF biomarkers that
have been most extensively studied by different research centers
and have proved to have the highest clinical diagnostic potential,
i.e. CSF-tau and CSF-Ab 42 (Fig. 1). We also focus on neurochemical factors
of importance for making these biomarkers useful in clinical
chemistry.
Besides their diagnostic potential, CSF biomarkers may also be
useful to monitor the biochemical effect of therapeutic compounds.
In AD, a drug that slows or arrests neurodegeneration might lower
the level of a marker of active neuronal damage, such as CSF-tau.
Similarly, a drug that acts by decreasing the deposition of Ab
might increase the level of CSF Ab 42 in repeated samples.
CURRENT CSF
biomarkers for ADCSF - (total) tau protein
Tau is a microtubule-associated protein located in the neuronal
axons, while it is not present in dendrites (Goedert, 1993). There
are six different isoforms, and numerous phosphorylation sites, of
tau in the human brain (Goedert 1993).
An increase in CSF-(total)tau in AD has been recorded in
numerous studies (for review see e.g. Andreasenet al.1998; Galasko
1998). The ability of CSF-tau to discriminate between AD and normal
aging has been relatively good, above 80%, in most studies. High
CSF-tau levels are, however, also found in a proportion of cases
with other dementia disorders. This applies particularly to
vascular dementia, in which high CSF-tau levels have been found in
a relatively high proportion of cases in some studies (Blennowet
al.1995; Andreasenet al.1998), while only in occasional cases in
other studies (Tatoet al.1995; Moriet al.1995; Araiet al.1998;
Mecocciet al.1998; Nishimuraet al.1998; Hulstaertet al.1999). It
has been suggested that vascular dementia patients with high
CSF-tau levels may constitute a subgroup with concomitant AD
pathology (Andreasenet al.1998), which implies that CSF-tau might
be of use in identifying vascular dementia cases where AD is a
contributory factor to the dementia.
In contrast, in patients with other types of dementia (e.g.
alcoholic dementia), chronic neurological disorders (e.g.
Parkinson�s disease, progressive supranuclear palsy) and
psychiatric disorders (e.g. depression), elevated CSF-tau levels
are found only in occasional cases (Blennowet al.1995; Molinaet
al.1997; Elliset al.1998; Mitaniet al.1998; Morikawaet al.1999;
Urakamiet al.1999).
The major clinical usefulness of CSF-tau seems to be in the
discrimination of AD from normal aging. It might also be of use in
some other differential diagnoses (e.g. depression, alcoholic
dementia and Parkinson�s disease), which sometimes may be difficult
to differentiate form AD on clinical grounds. The fact that an
increase in CSF-tau can be found in acute destructive conditions,
such as stroke (Arai et al, 1995), does not really reduce the
clinical usefulness of CSF-tau, since these disorders are not
differential diagnoses from AD.
Most likely, the level of CSF-tau reflects the degree of
neuronal/axonal degeneration, regardless of cause. Longitudinal
data on CSF tau shows that levels remain stably elevated over 12�24
months of follow-up (Andreasen et al, 1999a). This would enable
CSF-tau levels to be used as an outcome measure to assess treatment
aimed at neuroprotection.
CSF-Ab 42
The b -amyloid protein (Ab or b /A4 protein) is a
cleavage-product from the amyloid precursor protein (APP), encoded
by a single gene on chromosome 21 (Kang et al, 1987). APP is a
transmembrane protein with a single transmembrane domain, a long
N-terminal segment and a shorter cytoplasmic C-terminus (Fig 2). The Ab part of APP encompasses the
first 28 extracellular and the following 12-14 transmembrane amino
acids (Fig 2). Non-amyloidogenic secretory forms of
APP is normally generated by cleavage within the Ab region by an
unidentified enzyme termed a -secretase, while Ab is produced by an
alternative metabolic pathway, in which two proteases, termed b -
and g -secretase cleave APP on each side of the Ab sequence (Fig 2).
There are two major C-terminal variants of Ab , a shorter form
ending at Val-40 (Ab 40), and a longer form ending at Ala-42 (Ab
42) (Fig 3). Ab 42aggregates more rapidly than Ab 40
and is also the predominating form of amyloid in diffuse plaques
and in SP (for review see Dicksonet al. 1997).
Ab is generated as a soluble peptide during normal cellular
metabolism, and is secreted into the extracellular space and
biological fluids, including CSF (Haass etal.1992). A marked
decrease in CSF-Ab 42 is found in a high percentage of patients
with AD (Motteret al.1995; Galaskoet al.1998; Andreasenet al.1999b;
Hulstaertet al.1999). The sensitivity is above 80-90%, resulting in
a relatively good ability for CSF-Ab 42 to distinguish AD from
normal aging and depression. However, the specificity for CSF-Ab
42for the diagnosis of AD compared to other dementias has been less
extensively studied than for CSF-tau, and needs to be further
evaluated.
Measurement of A� in CSF may reflect cerebral amyloid
deposition. Hypothetically, in AD Ab secreted from neurons, and
possibly other cells in the brain, binds to existing aggregates of
Ab in extracellular SP, with lower levels remaining to circulate in
the CSF (Andreasen et al, 1999b). Longitudinal data show that
CSF-Ab 42 levels remain relatively stable over 12�24 months of
follow-up (Andreasen et al, 1999b). This implies that CSF could be
used to monitor the effects of anti-amyloid drugs in AD.
Combination of
CSF-tau and CSF-Ab 42
The strategy of combining CSF-tau and CSF-Ab 42 as biomarkers
for AD is appealing, since the concentrations of these substances
are believed to reflect two of the central pathogenic processes in
the disorder, and the combination might thus result in increased
sensitivity and specificity. Indeed, some large studies have shown
that both sensitivity and specificity increase for the combination
compared with CSF-tau or CSF-Ab 42 alone (Galasko et al, 1998;
Kanai et al, 1998; Hulstaert et al. 1999, Andreasen et al, 2000).
These studies are summarized in Table 1.
Also when used as routine analyses in clinical chemistry, and
the sensitivity and specificity figures are determined on all
consecutive patients admitted for investigation of cognitive
disturbances during one year in a community-based setting, the
sensitivity to identify AD is above 90% (Andreasen et al,
2000).
Further, the combination of CSF-tau and CSF-Ab 42 also has a
high sensitivity to predict progression to AD in patients with mild
cognitive impairment (Andreasen et al, 1999c). This finding shows
that these CSF markers show abnormal values very early in the
disease process, already before the clinical dementia.
CSF-tau and CSF-Ab
42 in clinical chemistry
As for all other test in clinical chemistry, methodological
factors have to be evaluated when developing CSF biomarkers. CSF
sampling, handling and storage can influence levels of many
analytes. It has to be evaluated whether a molecule passes from
serum to CSF across the blood-brain barrier, which occurs for many
proteins that have higher levels in serum than in CSF (Tibblin et
al, 1977). If so, the CSF levels will reflect the periphery more
than the CNS. Neither CSF-tau nor CSF-Ab 42 are affected by this
problem (Blennow et al, 1995; Vanderstichele et al, 1998). Further,
CSF-tau or Ab 42 do not show concentration gradients in lumbar CSF
(Vanderstichele et al, 1998), which, if present, complicates the
interpretation of lumbar CSF levels, since these will vary with the
volume and portion of CSF analyzed (Blennow et al, 1993).
However, the hydrophobic Ab peptide may absorb to some types of
test tubes commonly used for lumbar puncture or for centrifugation
in the laboratory (Andreasen et al, 1999b). The level of Ab 42
decreases to about 65% in polystyrene or in glass tubes, as
compared with polypropylene tubes (Andreasen et al, 1999b).
Therefore, polypropylene tubes must be used both for CSF sampling
and for centrifugation and storage.
Both CSF-tau and CSF-Ab 42 are determined using sandwich ELISA
techniques, using antibodies directed against different epitopes of
the proteins, making the analyses very sensitive and specific.
Current ELISA assays for CSF-tau use monoclonal antibodies that
detect all isoforms of tau independent of phosphorylation, and thus
measure the "total" CSF-tau level (Blennow et al, 1995), while Ab
ELISA assays are specific to Ab 42, with minimal cross-reactivity
against peptides ending at residues 43 or 40 (Motteret al.1995;
Vandersticheleet al.1998).
The biological variation is low for both CSF-tau (Andreasen et
al, 1998) and CSF-Ab 42 (Andreasen et al, 1999b), i.e. very similar
CSF levels are found when longitudinal CSF samples are analyzed
from individual patients. Also the analytical variation is low, the
coefficient of variance (CV) for internal control samples when
CSF-tau and CSF-Ab 42 are run as a routine clinical neurochemical
analyses during one year is approximately 10% (Andreasen et al,
2000).
Finally, it is also of importance to consider clinical
confounding factors when evaluating CSF biomarkers for AD. One
problematic issue is that studies are most often performed on
clinically diagnosed patients, and data on neuropathologically
confirmed cases are scarce. Although the positive predictive value
for the clinical diagnosis of AD (i.e. the probability that AD is
present when the criteria are met) has been relatively high, about
85%, the negative predictive value (i.e. the probability that AD is
not present when the diagnostic criteria are not met) has been
considerably lower (Tierneyet al.1988; Jellinger 1996; Galaskoet
al.1994). This is especially troublesome for some of the non-AD
dementias (e.g. vascular dementia and fronto-temporal dementia). In
fact, neuropathological studies have found that a high proportion
(40-80%) of clinically diagnosed patients with vascular dementia
have notable concomitant AD pathology (Jellinger 1996; Kosunenet
al.1996). The fact that current clinical diagnostic criteria cannot
be considered to be of 'gold standard' quality results in that it
is difficult to get high sensitivity and specificity figures for
CSF biomarkers. Further, even if they are asymptomatic, age-matched
control subjects may harbor presymptomatic AD lesions in their
brains (Tomlinson & Henderson 1976; Davies et al. 1988; Price
& Morris 1999), which also reduces the specificity figures of
CSF biomarkers for AD.
THE CLINICAL use of
CSF biomarkers for AD
Much effort has focused on finding a single neurochemical marker
for AD. This may be elusive unless the marker is related to a
pathogenic step that is unique to AD. For example, neuronal and
synaptic degeneration is not only found in AD but also in most
chronic degenerative disorders of the brain. Similarly, deposition
of Ab is not specific to AD, but is also found in normal aging,
dementia pugilistica, Lewy body dementia, and after acute brain
trauma, while deposition of PHF to in inclusions such as tangles
may form in normal aging, dementia pugilistica, myotonic dystrophy,
and other forms of tau are found in inclusions in progressive
supranuclear palsy and fronto-temporal dementia(Davies et al, 1988;
Roberts et al, 1994; Mc Kenzie et al, 1996). Thus, since the
central neuropathological findings in AD are not specific for AD,
it is unlikely that one single biochemical marker will absolutely
discriminate between AD and other dementia disorders.
Instead, the combination of several CSF biochemical markers
(e.g. CSF-tau, CSF-Ab 42 and possibly other like phospho-tau and a
/b -secretase cleaved APP) could be used in conjunction with other
diagnostic methods. The overall accuracy of the clinical diagnosis
of AD may increase if the diagnosis is based on cumulative
information gained from the clinical examination, brain-imaging
techniques (e.g. SPECT and MRT scans), and CSF biochemical markers.
As an analogy, the clinical diagnosis of myocardial infarction is
based on the combination of clinical symptomatology,
electrocardiogram, and biochemical markers (e.g. creatine kinase).
Today, the CSF markers tau and Ab 42, when used as an adjunct to
clinical diagnosis, have the potential to help to differentiate AD
from some problematic differential diagnoses, especially
age-associated memory impairment, depressive pseudo-dementia,
Parkinson�s disease, progressive supranuclear palsy and alcoholic
dementia.
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