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Concentrations of amyloid protein in cerebrospinal fluid of patients with alzheimer's disease.

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Am J Hum Genet 1994;54:852-863
Concentrations of Amyloid
p Protein in Cerebrospinal
Fluid of Patients with
Alzheimer's Disease
W. A. van Gool," M. A. Kuiper,t G. J. M. Walstra,"
E. Ch. Welters,? and P. A. Bolhuis"
Deposition of fibrillar amyloid P protein (AP) is increased in brains of patients with Alzheimer's disease.
Concentrations of AD were measured in cerebrospinal
fluid with an enzyme-linked immunosorbent assay in 10
neurological patients free from neurodegenerative disease, 28 patients with Parkinson's disease, and 18 patients with probable Alzheimer's disease. Levels of AP
in cerebrospinal fluid were not significantly different
among these groups. This observation suggests that concentrations of soluble A P in cerebrospinal fluid as measured in this study do not reflect the amount of fibrillar,
aggregated A P i n the brain of patients with Alzheimer's
van Goo1 WA, Kuiper MA, Walstra GJM, Wolrers ECh,
Bolhuis PA. Concentrations of amyloid p protein in
cerebrospinal fluid of patients with Alzheimer's
disease. Ann Neurol 1995;37:277-279
Fibrillar aggregates of amyloid P protein (AP) in the
brain are an invariant feature of Alzheimer's disease
(AD). The identification of missense mutations in the
P amyloid precursor protein (APP) gene causing the
disease in some families with the autosomal dominant
form of familial A D (FAD) f l ] is the strongest evidence that APP (mis)metabolism is a central event in
the pathogenetic process. In apparent contradiction,
AP has been identified in media of cell cultures under
normal conditions and in plasma and cerebrospinal
fluid (CSF) of various species including humans, suggesting that the AP peptide can be a normal product
of APP metabolism [2-41. Cells transfected with the
APP gene mutation causing FAD in a Swedish pedigree produced a fivefold to eightfold increase of AP
secretion in the culture medium, establishing a link
between increased secretion of AP and clinical manifestations of A D [4, 51. These observations suggested
that measurements of AP in CSF may be useful in
diagnosing AD. Here we report on the concentration
of the AP peptide in CSF (CSF-AP) of patients
with AD.
Materials and Methods
All patients were at least 5 5 years old. Control patients were
selected from the daily routine in a large academic hospital.
This group comprised 10 patients without clinical signs of
dementia or other evidence of neurodegenerative disease.
Final diagnoses in this group were, for example, polyneuropathy of undetermined origin or spondylotic caudal radiculopathy. Along with a group of younger patients, these patients
were included in a report on age effects on CSF-AP 162.
Patients with idiopathic Parkinson's disease (PD) ( N = 28)
were selected according to the criteria of the Parkinson's
Disease Brain Bank {7]. Absence of cognitive deficits was
verified on clinical examination and on follow-up, which
varied from 1 to 2 years. A D patients ( N = 18) fulfilled
National Institute of Neurological and Communicative Disorders and Stroke- Alzheimer's Disease and Related Disorders Association (NINCDSIADRDA) criteria for probable
AD, including a 6-month follow-up 181. None of the AD
patients was institutionalized.
CSF was obtained by lumbar puncture between 9 A M and
5 PM. Samples were frozen ( - 70°C) until the time of AP
measurement using the monoclonal antibody 266 as a capture and lOD5 as a biotinylated reporter antibody. Immunoreactivity was visualized by the addition of streptavidinalkaline phosphatase (Boehringer Mannheim) and addition
of 4-methyl-umbellipheryl phosphate and quantitated in a
Millipore Cytofluor 2350 fluorometer [2].
The study protocol, including informed consent from all
subjects, was approved by the institutional ethical committee.
From the "Department of Neurology, Academic Medical Center,
University of Amsterdam, and the ?Departmentof Neurology, Acadernisch Ziekenhuis der Vrije Universiteit, Amsterdam, The Netherlands.
Received Aug 5 , 1994, and revised form Oct 18. Accepted for publication Oct 2 5 , 1994.
Address correspondence to Dr van God, Department of Neurology,
Academic Medical Center, Universiry of Amsterdam, PO Box
22700, 1100 DE Amsterdam, The Netherlands.
The Table contains patient characteristics and the mean
AP concentrations in CSF. CSF-AP concentration and
its ratio to total CSF protein were not significantly different in the three groups.
Several explanations may account for the absence of
gross changes in CSF-AP concentrations in AD. Firstly,
Copyright 0 1995 by the American Neurological Associatior,
Cerebrwpinal Fliiid tCSFi Amyloid p Protein (APi and CSF-AP t o Protein Ratio in Control Subjects
avd Patients uith Parkinson’s DiseaJ.e or Alzbeinier’s DiJease
Alzheimer’s Disease
72.0 ( 27.2)
68.4 ( 27.7)
74.2 ( k 9 . 0 )
Age (yr)
Male-female rdtio
($ with mild dementiab
CSF-AP (ng/ml)
8.0 ( t 3.8)
2.3-1 7.6
9.9 ( c 4.0)
4.6- 14.6
23.3 ( ? 12.0)
21.5 ( 2 1 3 . 6 )
25.5 ( 2 9 . 6 )
7.1-4 3 .?
10.3 ( 4 _ 3.9)
CSF-APiprotein (ngimg)
3.0- 17.4
”Standard deviaions are shown in parentheses.
hClassiticarion ‘LS “mild” dementia was made according to CAMDEX criteria [ 171. The remainder of AD parients were classified as suffering
from dementia of “moderate” severity.
in a study lacking neuropathological confirmation, diagnostic misclassification of AD or control subjects may
have affected the results. The accuracy of the diagnostic criteria for A D used in the present study ranges
from 80 to 100% in most studies on clinicopathological correlations “91. Although misclassification of some
of the patients with probable A D can not be excluded
with certainty, it is improbable that this factor alone
accounts for the complete overlap of CSF-AP values.
False-negative classification of P D patients or other
control patients is not likely to have occurred either,
because incipient A D at the time of lumbar puncture
was excluded by a careful clinical examination and a
follow-up after 1 to 2 years in PD patients.
Secondly, complex interactions between changes in
CSF production rate, CSF volume, and AP clearance
from CSF may have resulted in relatively normal concentrations despite increased AP production rates in
AD. However, a large increase of CSF volume due to
severe cerebral atrophy is not likely to explain our
findings because the A D patients were in the early
stages of the disease and because normalizing CSF-AP
for total CSF protein made no difference. Future studies expressing AP concentrations as a ratio relative to
measures of total APP production may resolve this
possibility. Although our findings are consistent with
results reported by others using a semiquantitative
method [l0}, it is possible that studying larger groups
of patients would result in small but significant differences between AD and control patients. Also the possibility remains that CSF-AP levels in optimally
healthy, elderly control subjects are different from
those in our patient groups, who all had some form of
neurological disease. Considering the overlap of
CSF-AP values found in this study, it is not likely that
such a difference will be useful for diagnostic purposes,
Annals of Neurology
Vol 37
No 2
February 1995
in analogy to many other CSF constituents that have
been studied in A D [ 111.
Concentrations of AP in lumbar CSF relative to
plasma are almost a factor three higher in CSF, supporting the notion that most of the AP in CSF originates from the brain [2] The amount of AP in the
brain is clearly increased in AD patients 112). These
observations may appear difficult to reconcile with the
absence of appreciable changes of CSF-AP as measured
by the enzyme-linked immunosorbent assay under
study. However, AP in AD brains is found in the form
of fibrillar aggregates and it may be this specific physical property that mediates its neurotoxic effects [ 131.
The concentration of AP in CSF could reflect only the
fraction of soluble AP and it is not necessarily correlated with the amount of the fibrillar protein in the
pool of aggregated, hydrophobic AP as found in senile
plaques [ 1, 12). Moreover, we measured total CSF-AP,
whereas specifically “long” forms of AP (1-42, 1-43)
may be important in seeding aggregation of AP and
this “long” AP recently was shown to be increased in
PAPP mutants causing A D [14, 151. Increased
amounts of soluble AP extending to amino acid residue
42 in A D brain, without a concomitant increase of
these forms of AP in CSF [16], suggest that CSF may
not be an appropriate medium to monitor APP or AP
mecabolism in the brain. It is possible that the dominant AP species in CSF originate from other sources
than the brain such as the meninges or choroid plexus.
Direct comparisons of quantified cerebral fibrillar and
soluble forms of AP with the various forms of soluble
AP in postmortem CSF in individual patients may resolve this issue in future studies.
In conclusion, the absence of gross changes in
CSF-AP levels in A D suggests that measurement of
total CSF-AP as performed in this study might not be
useful in diagnosing AD. The many factors that may
influence CSF-AP require further study in order to
clarify the potential role for adapted methods of
CSF-A@ measurements in studying the pathophysiology of AD or in diagnosing this condition.
We thank Dr C Vigo-PeIfrey dt Athena Neurosciences for performing the AP assays and Dr D. B. Schenk for critical discussions.
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Proton Magnetic
Resonance SDeCtrOSCO~iC
Imaging in Pitients wr’th
Frontal Lobe Epilepsy
Paul A. Garcia, MD,’ Kenneth D. Laxer, MD,*
Jrroen van der Grond, PhD,t James W. H u g , PhD,iii
Gerald B. Matson, PhDJ and Michael W. Weiner, MD?#
Proton magnetic resonance spectroscopic imaging (‘H
MRSI) has demonstrated decreased N-acetyl compounds
(NA) in the epileptogenic hippocampus in patients with
temporal lobe epilepsy. We studied 8 patients with frontal Iobe epilepsy and found mean NA/creatine (Cr) in
the epileptogenic frontal lobe decreased by 27% compared with that of the contralateral homologous region
(1.81 f 0.36 vs 2.49 2 0 . 6 0 , ~< 0.008). In every patient,
N A G was decreased in the epileptogenic region by at
least 5%>. These findings suggest that ’H MRSI may be
useful in the presurgical evaluation of patients with
frontal lobe epilepsy.
Garcia PA, Laxer KD, van der Grond J, H u g JW,
Matson GB, Weiner MW. Proton magnetic
resonance specrroscopic imaging in patients wirh
frontal lobe epilepsy.
Ann Neurol 199537279-281
Magnetic resonance spectroscopic imaging (MRSI) utilizes phase encoding to allow spectral acquisition simultaneously from multiple cerebral regions [ 11. Proton
(‘H)MRSI permits analysis of choline (Cho), creatine
(Cr), and N-acetyl compounds (NA), which are preJominantly N-acetylasparrate (NAA). NAA has received considerable interest due to the fact that it is
distributed in the brain primarily in neurons [Z]. ‘H
MRSI has consistently demonstrated decreased NA in
diseases characterized by neuronal loss such as glial
tumors [ 3 ] and infarctions [ 4 ] . Recently, patients with
temporal lobe epilepsy (TLE) have been shown to have
reduced NA in the epileptogenic hippocampus, suggesting that ‘H MRSI may be a useful presurgical localizing tool in patients with TLE [ 5 , 61.
While modern imaging techniques including mag-
From the Departments of ‘Neurology, <-Radiology,$Pharmaceutical
Chemistry, and $Medicine, University of California, San Francisco,
CA, and the Department of “Neurology, University of Alabama,
Birmingham, AL.
Received Jul 22, 1904, and in revised form Oct 14. Accepted for
publication Oct 28, 1994.
Address correspondence to D r Garcia, Northern California Comprehensive Epilepsy Center, University of California, San Francisco,
Room A-889, Box 01 38, 400 Parnassus Ave, San Francisco, C A
94 143.
Copyright G 1995 by the American Neurological Association
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patients, concentrations, protein, amyloid, disease, alzheimers, fluid, cerebrospinal
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