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Differential Diagnosis of Alzheimer Disease With Cerebrospinal Fluid Levels of Tau Protein Phosphorylated at Threonine 231
Katharina Buerger, MD;
Raymond Zinkowski, PhD;
Stefan J. Teipel, MD;
Tero Tapiola, MD;
Hiroyuki Arai, MD, PhD;
Kaj Blennow, MD, PhD;
Niels Andreasen, MD, PhD;
Klaus Hofmann-Kiefer, MD;
John DeBernardis, PhD;
Daniel Kerkman, PhD;
Cheryl McCulloch, BS;
Russell Kohnken, PhD;
Frank Padberg, MD;
Tuula Pirttilä, MD, PhD;
Marc B. Schapiro, MD;
Stanley I. Rapoport, PhD;
Hans-Jürgen Möller, MD;
Peter Davies, PhD;
Harald Hampel, MD
Arch Neurol. 2002;59:1267-1272.
ABSTRACT
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Background Phosphorylation of tau protein at threonine 231 (using full-length tau,
441 amino acids, for the numbering scheme) (p-tau231) occurs specifically
in postmortem brain tissue of patients with Alzheimer disease (AD) and can
be sensitively detected in cerebrospinal fluid (CSF).
Objectives To determine to what extent CSF levels of p-tau231 distinguish
patients with AD from control subjects and from patients with other dementias,
and to investigate whether p-tau231 levels are a better diagnostic
marker than levels of total tau protein (t-tau) in CSF.
Design and Setting Cross-sectional, multicenter, memory clinic–based studies.
Participants One hundred ninety-two patients with a clinical diagnosis of AD, frontotemporal
dementia (FTD), vascular dementia, Lewy body dementia, or other neurological
disorder and healthy controls.
Main Outcome Measures Levels of CSF tau proteins as measured with enzyme-linked immunosorbent
assays.
Results Mean CSF levels of p-tau231 were significantly elevated in
the AD group compared with all other groups. Levels of p-tau231
did not correlate with dementia severity in AD, and discriminated with a sensitivity
of 90.2% and a specificity of 80.0% between AD and all non-AD disorders. Moreover,
p-tau231 levels improved diagnostic accuracy compared with t-tau
levels when patients with AD were compared with healthy controls (P = .03) and demented subjects (P<.001), particularly
those with FTD (P<.001), but not those with vascular and Lewy
body dementias. Sensitivity levels between AD and FTD were raised by p-tau231 compared with t-tau levels from 57.7% to 90.2% at a specificity
level of 92.3% for both markers.
Conclusion Increased levels of CSF p-tau231 may be a useful, clinically
applicable biological marker for the differential diagnosis of AD, particularly
for distinguishing AD from FTD.
INTRODUCTION
ABNORMAL hyperphosphorylation of the microtubule-associated tau protein
and its incorporation into neurofibrillary tangles are major hallmarks of
Alzheimer disease (AD). Until recently, only total tau protein (t-tau) as
a marker of neuronal damage was detectable in cerebrospinal fluid (CSF). Elevated
levels of CSF t-tau have been observed in patients with AD,1
even in those with mild dementia,2 compared
with healthy elderly controls. However, CSF t-tau levels are of limited value
in the differential diagnosis of AD, because they can be increased in other
dementia disorders.3-8
Therefore, it appears likely that t-tau levels reflect neuronal degeneration
rather than AD-specific pathophysiology. The use of antibodies to sites of
tau that are specifically phosphorylated in AD may help to increase diagnostic
accuracy, because the marker would be linked to a neuropathological hallmark
of the disease. Detection of phosphorylated tau protein in the CSF therefore
may provide a useful biomarker as outlined by the consensus report of the
Working Group on Molecular and Biochemical Markers of Alzheimer's Disease.9
Recently, 3 different immunoassays were developed that reliably detect
phosphorylated tau (p-tau) in the CSF.10-12
These assays detect different sites of phosphorylation. Levels of CSF tau
phosphorylated at threonine 181 were elevated in patients with AD compared
with those with other dementias and healthy control subjects.13-14
Itoh and colleagues12 showed that CSF tau phosphorylated
at serine 199 discriminates between subjects with AD and non-AD disorders
with a sensitivity and a specificity of 85%.
Phosphorylation of tau protein at threonine 231 (p-tau231)
appears very early in AD and precedes paired helical filament assembly.15 A bioassay of p-tau231 demonstrated a
sensitivity of 85% and a specificity of 97% in distinguishing AD from other
neurological disorders (OND).10 These preliminary
data suggest that CSF p-tau231 may be a good biochemical marker
for AD. The assay detects early features of pathophysiology, might be used
to track disease progression in individual patients,16
and accurately discriminates patients with AD from neurological control subjects.10
In the present study, we investigated in an independent patient and
control sample to what extent CSF p-tau231 levels discriminate
between patients with AD and those with other common causes of dementia (fronto-temporal
dementia [FTD], vascular dementia [VD], and Lewy body dementia [LBD]) and
between patients with AD and healthy controls (HC). To our knowledge, the
potential of p-tau231 in CSF to differentiate AD from other dementias
has not been studied. The discriminative power of p-tau231 measurements
was compared with that of measurements of t-tau, which has been studied as
a diagnostic marker for AD.
SUBJECTS, MATERIALS, AND METHODS
SUBJECT SELECTION
We enrolled a total of 192 subjects. Of these, 82 had probable AD (defined
by criteria of the National Institute of Neurological and Communicative Disorders
and Stroke–Alzheimer's Disease and Related Disorders
Association)17; 26, FTD18;
17, LBD19; and 20, VD.20 These
patients had structural and functional imaging findings consistent with the
diagnoses. Twenty-six patients with OND were diagnosed as having amyotrophic
lateral sclerosis (n = 2), human immunodeficiency virus infection (n = 1),
systemic lupus erythematosus (n = 1), stroke syndrome (n = 3), hereditary
motor and sensory neuropathy type I (n = 1), Lyme borreliosis (n = 3), rheumatoid
arthritis (n = 1), polyneuropathy (n = 2), sarcoidosis (n = 1), Huntington
disease (n = 1), progressive spasticity of unknown etiology (n = 1), bulbar
syndrome of unknown etiology (n = 2), other psychiatric disorder (n = 2),
myopathy (n = 1), diplopia and nystagmus (n = 1), palsy of the sixth cranial
nerve (n = 1), essential tremor (n = 1), and extrapyramidal symptoms of unknown
etiology (n = 1). We also included 21 HC subjects. Study subjects were recruited
at the following 5 academic expert centers: the Dementia Research Section
and Memory Clinic, Alzheimer Memorial Center, Department of Psychiatry, Ludwig-Maximilian
University, Munich, Germany (38 AD, 6 FTD, 10 VD, 9 LBD, 19 OND, and 13 HC
subjects); the Department of Neuroscience and Neurology, University of Kuopio,
Kuopio, Finland (7 AD, 4 FTD, 6 VD, 5 LBD, and 7 OND subjects); the Department
of Geriatric Medicine, Tohoku University School of Medicine, Sendai, Japan
(12 AD, 7 FTD, 4 VD, and 3 LBD subjects); the Department of Rehabilitation,
Pitea River Valley Hospital, Pitea, Sweden (5 FTD subjects); and the Brain
Physiology and Metabolism Section,National Institute on Aging, National Institutes
of Health, Bethesda, Md (25 AD, 4 FTD, and 8 HC subjects). Characteristics
of the patients and controls are given in Table 1. The protocol was approved by the local ethical committees
and the institutional review boards of the participating centers. Informed
consent was obtained from all subjects.
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Table 1. Characteristics of Patients and Control Subjects*
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Eight of the 21 HC subjects were volunteers without any medical, neurological,
or psychiatric disorder. Thirteen HC subjects were cognitively normal according
to results of the battery of the Consortium to Establish a Registry for Alzheimer's
Diease21 (results within ±1 SD in all
subtests). The CSF was collected while the subjects underwent spinal anesthesia
for surgery of the urinary tract or lower extremities. Three of these subjects
had diabetes mellitus as a substantial somatic comorbidity.
CSF SAMPLING AND ANALYSES OF TAU PROTEINS
The CSF samples were obtained by means of lumbar puncture, and aliquots
were stored at -80°C until analysis. Mean ± SD length of
CSF storage was 4.1 ± 4.4 years. Levels of p-tau231 were
measured using an enzyme-linked immunosorbent assay (Molecular Geriatrics
Corporation, Vernon Hills, Ill) that is specific for p-tau231.10 Results of experiments describing the specificity
of the detection antibody CP9 for p-tau231 have been reported.10 The coefficients of variation calculated from the
raw data were 13.6% (interassay) and 6.8% (intra-assay). For each patient,
80 µL of CSF was analyzed per well in duplicates. Repeated cycles of
freezing and thawing of CSF samples did not affect the level of p-tau231 (data not shown). Length of CSF storage did not affect p-tau231 levels in any group ( , –0.15 to 0.30; P>.20).
A pool of AD CSF was made from samples of 40 individuals with clinically
diagnosed AD who were unrelated to the study population. This AD CSF pool
was used to produce a standard curve. Levels of p-tau231 in our
subjects were expressed in terms of the volume of the AD CSF pool that gave
an equivalent signal, termed microliters of CSF equivalents. The plot of the standard curve produced with the AD CSF pool did
not pass through the origin, and consequently, extremely low p-tau231 signals produced negative values in terms of microliters of CSF equivalents.
Levels of t-tau protein were measured in duplicate using a commercially available
enzyme-linked immunosorbent assay (Innotest hTau, Art K-1032; Innogenetics,
Gent, Belgium) according to the manufacturer's instructions. The coefficients
of variation were less than 13% (interassay) and 11% (intra-assay). Assay
operators (R.Z. and C.M.) were masked to the diagnostic category of the samples.
STATISTICAL ANALYSES
Values for p-tau231 and t-tau differed significantly from
a normal distribution by the Kolmogorov-Smirnov test. Differences in mean
levels of CSF p-tau231 and t-tau across all groups were assessed
with the Kruskal-Wallis nonparametric 1-way analysis of variance. Pairwise
comparisons between the AD and the other groups were performed with the Mann-Whitney
test. For p-tau231 and t-tau levels, sensitivity and specificity
levels and numbers of correctly allocated cases were derived from receiver
operating characteristic (ROC) curve analysis when the sum of specificity
and sensitivity was maximized. Areas under the ROC curves (AUC) as measures
of diagnostic accuracy were compared between p-tau231 and t-tau
levels using the algorithm of Hanley and McNeil.22-23
Correlations between p-tau231 and t-tau levels and group characteristics
were assessed with the Spearman rank correlation. Differences between groups
with regard to age were assessed with the Mann-Whitney test, and with regard
to sex distribution with the  2 test.
RESULTS
CSF p-TAU231 AND t-TAU LEVELS
As illustrated in Figure 1,
levels of p-tau231 and t-tau were significantly increased in the
AD group compared with all other groups. Because the HC group was significantly
younger than the AD group, we repeated our analysis on a subgroup of 21 patients
with AD and 21 HC subjects matched for age (P = .69)
and sex (P>.99). Differences between the AD and HC
subgroups remained highly significant (P<.001)
for p-tau231 and t-tau levels. Therefore, we included all patients
with AD in our analyses. Levels of CSF p-tau231 and t-tau correlated
significantly with each other in subjects with AD (Spearman = 0.82; P<.001), VD (Spearman = 0.78; P<.001), and LBD (Spearman = 0.77; P<.001).
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Figure 1. Levels of tau protein phosphorylated
at threonine 231 (p-tau231) (A) and total tau protein (t-tau) (B)
in the cerebrospinal fluid (CSF) of patients and control subjects. Dashed
lines represent the cutoff level yielding the best sensitivity and specificity
for discriminating patients with Alzheimer disease (AD) from those with non-AD
disease and healthy control (HC) subjects (by means of receiver operating
characteristic curves). Horizontal solid lines indicate means; FTD, frontotemporal
dementia; VD, vascular dementia; LBD, Lewy body dementia; OND, other neurological
disorders; asterisk, P<.05; dagger, P<.005;
and double dagger, P<.001. All comparisons are with the AD
group.
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CSF p-TAU231 LEVELS ACCORDING TO AGE, SEX, MINI-MENTAL STATE
EXAMINATION SCORE, AND CENTER IN THE AD GROUP
We found no significant effect of sex (P =
.86) or age ( = 0.05; P = .67) on levels of
p-tau231. Levels of CSF p-tau231 did not correlate with
the Mini-Mental State Examination score (Figure 2) ( = 0.02; P = .85). Levels
of p-tau231 levels did not differ significantly between participating
centers (Figure 3) (2 = 1.75; P = .63).
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Figure 2. Correlation between CSF p-tau231 levels and Mini-Mental State Examination (MMSE) scores in patients
with AD ( = 0.02; P = .85). Horizontal line indicates the
correlation line. Other abbreviations are explained in the legend to Figure
1.
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Figure 3. Comparison of CSF p-tau231 levels in patients with AD between participating centers (2 = 1.75; P = .63). Center 1 indicates the Dementia Research
Section and Memory Clinic, Alzheimer Memorial Center, Department of Psychiatry,
Ludwig-Maximilian University, Munich, Germany; center 2, the Brain Physiology
and Metabolism Section, National Institute on Aging, National Institutes of
Health, Bethesda, Md; center 3, the Department of Geriatric Medicine, Tohoku
University School of Medicine, Sendai, Japan; and center 4, the Department
of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland. Short
horizontal lines indicate the means. Other abbreviations are explained in
the legend to Figure 1.
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ROC ANALYSIS
Sensitivity and specificity levels as well as percentage and absolute
numbers of correctly allocated cases are given in Table 2. Levels of p-tau231 discriminated with a high
accuracy between AD and non-AD groups. At a specificity level of 80.0% (88/110),
the p-tau231 level was 90.2% (74/82) sensitive and correctly allocated
162 (84.4%) of 192 subjects. In discriminating the AD from the nondemented
groups (HC and OND), p-tau231 levels correctly classified more
than 90% of subjects (101 of 103 and 102 of 108 subjects, respectively). Sensitivity
(21/21 [100.0%]) and specificity (19/21 [90.5%]) levels remained stable for
comparison of age- and sex-matched AD and HC subjects. When the AD group was
compared with the combined group of other dementia disorders (FTD, VD, and
LBD), 117 (80.7%) of 145 and 101 (71.1%) of 142 cases were correctly classified
using p-tau231 and t-tau, respectively. In particular, sensitivity
between AD and FTD was improved by p-tau231 level, compared with
that of the t-tau level, from 57.5% (46/80) to 90.2% (74/82) at a specificity
of 92.3% (24/26) for both markers. With CSF p-tau231 levels, 98
(90.7%) of 108 cases were correctly allocated, compared with 70 (66.0%) of
106 using t-tau levels. Comparison of AD with VD and with LBD yielded correct
classification rates of 87.3% (89/102) and 76.8% (76/99), respectively, using
p-tau231 levels.
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Table 2. Sensitivity, Specificity, and Correctly Allocated Cases Using
ROC Analysis for CSF p-Tau231 and t-Tau*
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To test for differences in diagnostic accuracy between p-tau231 and t-tau levels, we compared the AUC values. Discriminative power
between subjects with and without AD and between those with AD and all other
dementing disorders was significantly higher for p-tau231 compared
with t-tau levels (P<.001). Diagnostic accuracy
was also significantly improved using levels of p-tau231 compared
with t-tau in differentiating AD and FTD (P<.001).
We found no significant difference in the AUC between p-tau231
and t-tau levels when AD was compared with LBD and VD. The AUC for the AD
vs HC group was increased for levels of p-tau231 compared with
t-tau (P = .03). The AUC comparison was not separately
tested for AD vs OND, because t-tau levels were measured only in 9 of 26 subjects
in the OND group due to limited CSF volume.
COMMENT
In the present study, we investigated to what extent CSF p-tau231 levels discriminate between subjects with AD, those with other common
causes of dementia, and nondemented controls. The p-tau231 levels
discriminated with a specificity of 80.0% and a sensitivity of 90.2% between
the group with clinically diagnosed AD and the combined non-AD groups. The
phosphorylation of the threonine 231 epitope has been specifically implicated
in the tau pathology of AD.15 The results of
our study indicate that p-tau231 levels in CSF may be a clinically
applicable biomarker for AD, reflecting an important feature of AD pathophysiology.9
The CSF p-tau231 levels showed an excellent discriminative
power between the AD and control (HC and OND) groups, with sensitivity and
specificity levels ranging from 90% to 100%. This finding, which was obtained
in an independent sample, confirms previous results.10
In our first study, we had used an AD brain extract for construction
of a standard curve.10 We subsequently found
that serial dilutions of AD CSF produced a nonlinear response in the assay.
To better mimic the response of patient CSF in the current assay, we used
an AD CSF pool to generate a standard curve. We showed a parallelism between
the AD brain extract and the AD CSF pool by performing ROC curve analysis
for samples assayed with both of the standards and then comparing the AUC
as a measure of diagnostic accuracy.24 The
difference in the AUC between the 2 standards was statistically insignificant.
Thus, in terms of diagnostic accuracy, the standards are equivalent.
Moreover, CSF p-tau231 levels correctly allocated 80.7% of
subjects when AD was compared with other dementia disorders. Levels of p-tau231 in the CSF were found to clearly distinguish AD from FTD, with a
sensitivity of 90.2% and a specificity of 92.3%. The high level of discrimination
is likely due to the fact that the biochemical and molecular signatures of
tau pathology are distinctly different between the two diseases.25
Thus, CSF p-tau231 levels appear to be particularly accurate in
discrimination between AD and FTD and may also serve this differential diagnosis
in clinical practice.
We found an increase of p-tau231 levels in some patients
with VD and LBD. Concomitant AD pathology including neurofibrillary tangles
has been described for a considerable number of patients with VD26
and LBD27 who are clinically indistinguishable
from those with "pure" VD and LBD, respectively. Most likely, our VD and LBD
groups were heterogeneous with regard to underlying ADpathology, resulting
in an increase of p-tau231 levels in some of the patients with
VD and LBD. This decreases the discriminative power of p-tau231
between AD and VD and between AD and LBD.
Our findings on the high discriminative power of CSF p-tau231
level as a single biomarker between the AD and non-AD groups are consistent
with those of a report on CSF tau phosphorylated at serine 199.12
In addition, we show the potential of p-tau231 to discriminate
patients with AD from those with other relevant dementia disorders and from
subjects without dementia. We found no effect of age, sex, or clinical dementia
severity on levels of p-tau231. Moreover, investigating the applicability
of p-tau231 levels across several study sites, we found no effect
of center on p-tau231 levels.
These findings indicate that p-tau231 levels may be a valuable
marker for the clinical diagnosis of AD, irrespective of age, sex, dementia
severity, and diagnostic center. We avoided a potential bias of our results
because none of the diagnostic groups investigated herein was exclusively
recruited by a single center.
The present study also investigated whether p-tau231 levels
have a superior discriminative power compared with t-tau levels. Our CSF t-tau
levels in AD and other disorders are consistent with those of previous reports.28 Compared with t-tau levels, CSF p-tau231
levels allowed a significantly better discrimination between the AD and the
combined non-AD groups, between the AD and HC groups, and between the AD and
non-AD dementia groups. In particular, p-tau231 levels were superior
to t-tau levels for distinguishing AD from FTD.
CONCLUSIONS
Our data indicate that CSF p-tau231 levels may be a useful
biological marker to differentiate patients with clinically diagnosed AD from
those with OND and other dementia disorders, particularly FTD, and from HC
subjects. We show that p-tau231 levels fulfill the core criteria
of a useful biomarker of AD as outlined by the consensus report of the Working
Group on Molecular and Biochemical Markers of Alzheimer's Disease.9 The diagnostic accuracy of the various p-tau epitopes
should be evaluated through a comparative study applying the immunoassays
of the different p-tau epitopes on the same set of patients. Part of our sample
is enrolled in a neuropathological program designed to confirm diagnoses and
to provide subjects with autopsy-confirmed disease. Neuropathological studies
in clinically well-characterized patients are warranted to further establish
CSF p-tau231 levels as a clinically applicable diagnostic tool.
A biochemical marker to accurately discriminate patients with AD from healthy
controls would be useful in the early diagnosis of AD. A biomarker for differential
diagnosis of AD would be clinically relevant for therapeutic interventions,
caregiver counseling, and prognosis. Our findings suggest that CSF p-tau231 levels might be such a marker.
AUTHOR INFORMATION
Accepted for publication April 8, 2002.
Author contributions: Study concept and design (Drs Buerger, Arai, Blennow, Andreasen, Kerkman, Zinkowski, Davies,
and Hampel); acquisition of data (Drs Buerger, Zinkowski,
Tapiola, Arai, Andreasen, Hofmann-Kiefer, Kohnken, Pirttilä, Schapiro,
and Rapoport and Ms McCulloch); analysis and interpretation of data (Drs Buerger, Zinkowski, Teipel, Arai, Blennow, Andreasen, DeBernardis,
Kerkman, Padberg, Möller, and Hampel and Ms McCulloch); drafting
of the manuscript (Drs Buerger, Arai, Andreasen, Zinkowski,
and Hampel); critical revision of the manuscript for important intellectual
content (Drs Buerger, Zinkowski, Teipel, Tapiola, Blennow,
Andreasen, Hofmann-Kiefer, DeBernardis, Kerkman, Padberg, Pirttilä, Schapiro,
Rapoport, Möller, Davies, and Hampel and Ms McCulloch); statistical
expertise (Drs Buerger and Teipel); obtained funding (Drs Andreasen and Hampel); administrative, technical,
and material support (Drs Zinkowski, Tapiola, Arai, Blennow,
Hofmann-Kiefer, DeBernardis, Kerkman, Kohnken, Schapiro, Rapoport, Möller,
Davies, and Hampel and Ms McCulloch); and study supervision (Drs Zinkowski, Kerkman, Padberg, and Hampel).
This study was supported by grants from the Volkswagen-Foundation, Hannover,
Germany (Dr Hampel); the Hirnliga eV, Nürmbrecht, Germany (Drs Buerger
and Hampel); Bayer-Vital GmbH, Leverkusen, Germany (Drs Buerger and Hampel);
and the Foerderprogramm fuer Forschung und Lehre, Faculty of Medicine, Ludwig-Maximilian
University, Munich (Drs Buerger, Teipel, and Hampel).
This study was presented in part in abstract form at the 17th World
Congress of the International Association of Gerontology, Vancouver, British
Columbia, July 3, 2001, and at the 31st Annual Meeting of the Society for
Neuroscience, San Diego, Calif, November 12, 2001.
We thank Felician Jancu, Bea Riemenschneider, Jenny Wagner, and Oliver
Pogarell, MD, for clinical support; Tom Nolde, PhD, and Heike Gluba for technical
assistance; and Arun L. W. Bokde, PhD, for helpful discussion of the manuscript.
Corresponding authors: Katharina Buerger, MD, and Harald Hampel,
MD, Dementia Research Section and Memory Clinic, Alzheimer Memorial Center,
Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University,
Nussbaumstrasse 7, 80336 Munich, Germany (e-mail: katharina.buerger{at}psy.med.uni-muenchen.de; hampel{at}psy.med.uni-muenchen.de).
Reprints:
Raymond Zinkowski, PhD, Molecular Geriatrics Corporation, 50 Lakeview Pkwy,
Vernon Hills, IL 60061 (e-mail: zinkowski{at}moleculargeriatrics.com).
From the Dementia Research Section and Memory Clinic, Alzheimer Memorial
Center, Geriatric Psychiatry Branch, Department of Psychiatry (Drs Buerger,
Teipel, Padberg, Möller, and Hampel), and the Department of Anesthesiology
(Dr Hofmann-Kiefer), Ludwig-Maximilian University, Munich, Germany; the Molecular
Geriatrics Corporation, Vernon Hills, Ill (Drs Zinkowski, DeBernardis, Kerkman,
and Kohnken and Ms McCulloch); the Department of Neuroscience and Neurology,
University Hospital, University of Kuopio, Kuopio, Finland (Drs Tapiola and
Pirttilä); the Department of Geriatric Medicine, Tohoku University School
of Medicine, Sendai, Japan (Dr Arai); the Unit of Neurochemistry, Department
of Clinical Neuroscience, University of Göteborg, Sahlgren's University
Hospital, Mölndal, Sweden (Dr Blennow); the Department of Rehabilitation,
Pitea River Valley Hospital, Pitea, Sweden (Dr Andreasen); the Division of
Pediatric Neurology, Children's Hospital Medical Center, Cincinnati, Ohio
(Dr Schapiro); the Brain Physiology and Metabolism Section, National Institute
on Aging, National Institutes of Health, Bethesda, Md (Dr Rapoport); and the
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY (Dr
Davies). Dr Andreasen is now affiliated with the Division of Geriatric Medicine,
Karolinska Institutet, Neurotec, Huddinge University Hospital, Stockholm,
Sweden.
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