Cerebrospinal fluid markers for differential
dementia diagnosis in a large memory
F.E. Reesink, MD
N.A. Verwey, MD, PhD
M.I. Kester, MD, PhD
C.E. Teunissen, PhD
P.M. van de Ven, PhD
Y.A.L. Pijnenburg, MD,
M.A. Blankenstein, PhD
A.J. Rozemuller, MD,
P. Scheltens, MD, PhD
W.M. van der Flier,
Objective: To determine how amyloid ? 42 (A?42), total tau (t-tau), and phosphorylated tau (p-tau)
levels in CSF behave in a large cohort of patients with different types of dementia.
Methods: Baseline CSF was collected from 512 patients with Alzheimer disease (AD) and 272
patients with other types of dementia (OD), 135 patients with a psychiatric disorder (PSY), and
275 patients with subjective memory complaints (SMC). A?42, t-tau, and p-tau (at amino acid
181) were measured in CSF by ELISA. Autopsy was obtained in a subgroup of 17 patients.
Results: A correct classification of patients with AD (92%) and patients with OD (66%) was ac-
complished when CSF A?42 and p-tau were combined. Patients with progressive supranuclear
palsy had normal CSF biomarker values in 90%. Patients with Creutzfeldt-Jakob disease demon-
strated an extremely high CSF t-tau at a relatively normal CSF p-tau. CSF AD biomarker profile
was seen in 47% of patients with dementia with Lewy bodies (DLB), 38% in corticobasal degen-
eration (CBD), and almost 30% in frontotemporal lobar degeneration (FTLD) and vascular demen-
tia (VaD). PSY and SMC patients had normal CSF biomarkers in 91% and 88%. Older patients
are more likely to have a CSF AD profile. Concordance between clinical and neuropathologic
diagnosis was 85%. CSF markers reflected neuropathology in 94%.
Conclusion: CSF A?42, t-tau, and p-tau are useful in differential dementia diagnosis. However, in
more autopsy confirmation in the future. Neurology®2012;78:47–54
A?42 ? amyloid ? 42; AD ? Alzheimer disease; BNE ? BrainNet Europe; CBD ? corticobasal degeneration; CI ? confidence
interval; CJD ? Creutzfeldt-Jakob disease; DLB ? dementia with Lewy bodies; FTLD ? frontotemporal lobar degeneration;
IQR ? interquartile range; MMSE ? Mini-Mental State Examination; NINDS ? National Institute of Neurological Disorders
and Stroke; OD ? other types of dementia; OR ? odds ratio; p-tau ? phosphorylated tau; PSP ? progressive supranuclear
palsy; PSY ? psychiatric disorder; SMC ? subjective memory complaints; t-tau ? total tau; VaD ? vascular dementia.
Differential dementia diagnosis is based on clinical criteria and ancillary investigations may
provide positive evidence for a specific, nosologic diagnosis. Measurements of biochemical
markers in CSF are increasingly used in the diagnostic process of dementia. The sensitivity
when using the combination of CSF A?42 and total tau (t-tau) for recognition of Alzheimer
disease (AD) is high.1However, specificity is suboptimal concerning patients with subjective
memory complaints (SMC)2and other types of dementia.3,4
There are several potential explanations for the finding of abnormal markers in patients with
other types of dementia. Clinical misdiagnosis or mixed pathology—which is a common find-
ing at autopsy4—may explain positive markers. Alternatively, amyloid ? and (phosphorylated)
tau play also a role in the pathogenesis of other types of dementias. Tau pathology is as well
seen in frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), cor-
ticobasal degeneration (CBD),5and prion diseases.6Amyloid deposition or disturbance in
amyloid metabolism is found in a few patients with FTLD.7
From the Departments of Neurology (N.S.M.S., N.A.V., M.I.K., Y.A.L.P., P.S., W.M.v.d.F.), Clinical Chemistry (N.A.V., C.E.T., M.A.B.),
Pathology (A.J.R.), and Epidemiology and Biostatistics (P.M.v.d.V., W.M.v.d.F.), VU University Medical Center, Alzheimer Center, Amsterdam; and
Department of Neurology (F.E.R.), Haga Ziekenhuis, Den Haag, The Netherlands.
Disclosure: Author disclosures are provided at the end of the article.
Correspondence and reprint
requests to Dr. Schoonenboom:
Copyright © 2011 by AAN Enterprises, Inc.
The aim of the present study is to investi-
gate how CSF A?42, t-tau, and phosphory-
lated tau (p-tau) levels behave in a large
sample of patients, recruited consecutively at
our memory clinic. First, CSF biomarker
levels are compared between patients with
different types of dementia, patients with
subjective memory complaints, and patients
with psychiatric disorders. Second, we aim
to identify the optimal combination of CSF
biomarkers for the discrimination of AD
from other types of dementias. For the ver-
ification of the clinical diagnosis, we use
postmortem diagnosis obtained by autopsy
in a subgroup of patients.
METHODS Patients. Between October 1999 and Novem-
ber 2009, baseline CSF was collected from 1,672 patients from
our outpatient memory clinic. CSF was obtained at a median of
2 months (interquartile range [IQR] 1–5 months) after diagno-
sis. From these 1,672 patients, 1,194 patients were selected: 512
patients with probable AD, 144 patients with FTLD (including
patients with behavioral type frontotemporal dementia, semantic
dementia, and progressive nonfluent aphasia), 52 patients
with dementia with Lewy bodies (DLB), 34 patients with
vascular dementia (VaD), 16 patients with CBD, 20 patients
with progressive supranuclear palsy (PSP), 6 patients with
Creutzfeldt-Jakob disease (CJD), 135 patients with a psychiatric
disorder (PSY), and 275 patients with SMC. Patients with mild
cognitive impairment (n ? 230), patients with possible AD (n ?
16), patients with a wide range of other neurologic diseases but
no dementia (n ? 73), and patients with other unclassified types
of dementia (n ? 21) were not included, nor were patients
whose diagnosis was postponed or unclear (n ? 138). All pa-
tients underwent a standardized dementia assessment including
medical history, informant-based history, physical and neuro-
logic examination, laboratory tests, neuropsychological testing,
EEG, and MRI of the brain. Diagnosis was made by consensus
in a multidisciplinary meeting, without knowledge of CSF
results, and according to clinical diagnostic criteria: National In-
stitute of Neurological and Communicative Disorders and
Stroke–Alzheimer’s Disease and Related Disorders Association
criteria for AD,8consensus criteria frontotemporal lobar degen-
eration for FTLD,9McKeith criteria for DLB,10National
Institute of Neurological Disorders and Stroke (NINDS)–Asso-
ciation Internationale pour la Recherche en l’Enseignement en
Neurosciences for VaD,11CBD according to criteria of Boeve,12
PSP according to the NINDS–Society for Progressive Supranu-
clear Palsy criteria,13and CJD according to recent criteria.14Pa-
tients were defined as having a psychiatric disorder (PSY) when
based on thorough investigation a neurodegenerative disease
seemed unlikely, and clinically there was a suspicion of a psychi-
atric disorder. Those patients were subsequently referred to a
psychiatrist. When clinical investigations yielded normal results
(i.e., criteria for MCI not fulfilled), patients were considered to
have SMC. Patients with SMC were considered as controls based
on normal clinical investigations. Dementia severity was assessed
using the Mini-Mental State Examination (MMSE).15
Standard protocol approvals, registrations, and patient
consents. The study was approved by the ethical review board
of the VU University Medical Center. Written informed consent
was obtained from all subjects participating in the study.
CSF analysis. CSF was obtained by lumbar puncture between
the L3/L4 or L4/L5 intervertebral space, using a 25-gauge nee-
dle, and collected in 10-mL polypropylene tubes. Within 2
hours, CSF samples were centrifuged at 2,100 g for 10 minutes
at 4°C. A small amount of CSF was used for routine analysis.
Aliquots of each sample were immediately frozen at ?80°C until
further analysis. CSF A?42, t-tau, and p-tau phosphorylated at
threonine 181 concentrations were determined using commercially
available sandwich ELISAs (Innogenetics, Ghent, Belgium).1The
performance of the assays was monitored with pools of surplus CSF
specimens available from an earlier study. Multiple specimens with
various concentrations included in 7–18 runs were used for this
purpose. The interassay coefficient of variation (mean ? SD) was
11.3 ? 4.9% for A?42, 9.3 ? 1.5% for t-tau, and 9.4 ? 2.5% for
p-tau-181.16The 3 biomarkers were simultaneously analyzed in ev-
13 cases, and p-tau-181 data in 6 cases.
Autopsy. In the 10-year period of CSF sampling, 17 patients
underwent autopsy. The neuropathologic diagnosis from these
patients was compared to the clinical diagnosis and to the ante-
mortem CSF biomarker profile. For AD, the criteria of Braak
were used modified for thin sections17and vascular amyloid ?
deposits were assessed according to BrainNet Europe (BNE) in-
structions.18For FTLD, the Cairns classification was used.19For
DLB, the Braak criteria were used20modified according to the
BNE instructions.21VaD was classified according to Kalaria et
al.,22CJD according to Cali et al.,23and PSP according to Litvan
et al.24The neuropathologist was unaware of the CSF biomarker
Statistical analysis. For statistical analysis, SPSS, version
16.0, was used. As all variables, except for age, were not normally
distributed, nonparametric analyses (Kruskal-Wallis followed by
the Mann-Whitney U test) were used to compare groups. Post
hoc, the different groups were compared with AD and SMC
only. For categorical data, we used the ?2test. Correlations are
estimated with the Spearman method. Patients with CJD were
omitted from the statistical analyses when comparing groups,
because of their small number. Logistic regression analysis with
backward stepwise selection was used to estimate the simultane-
ous impact of the continuous variables CSF A?42, t-tau, and
p-tau on the diagnosis AD compared to controls and compared
to the pooled groups of other types of dementia. SMC and PSY
are pooled as controls, based on the comparability of their bio-
marker results. Patients with other types of dementia are collec-
tively defined other dementias (OD). An optimal cutoff line was
calculated comparing AD vs OD. Based on the cutoff line the
percentage of patients with a CSF AD profile was calculated.
Age, MMSE, and disease severity were compared between pa-
tients with and without a CSF AD profile. Statistical significance
was set at p ? 0.05.
RESULTS Patients. Baseline characteristics are
shown in table 1. Age differed among groups, with
patients with VaD, DLB, and AD being oldest, and
PSY, SMC, and CBD being youngest. There are also
sex differences among groups, with an overrepresen-
tation of men in DLB and VaD.
Neurology 78January 3, 2012
CSF analysis. CSF levels of A?42, t-tau, and p-tau. Me-
dian CSF levels of the 3 biomarkers by diagnostic
group are shown in table 1. Table 2 summarizes the
behavior of the CSF biomarkers in each diagnostic
group as compared to SMC. In FTLD, (moderately)
decreased levels of CSF A?42 and (moderately) in-
creased levels of CSF t-tau are found compared to
SMC subjects, while CSF p-tau levels were normal.
In DLB, CSF levels of A?42 are slightly decreased
and CSF t-tau and p-tau levels are increased. In VaD,
CSF A?42 is decreased but CSF t-tau and p-tau are
normal. In CBD there is a trend toward a decreased
CSF A?42 (p ? 0.06) at a normal CSF t-tau and
p-tau (although the latter with remarkable overlap).
Patients with CJD exhibit an extremely high CSF
t-tau, while CSF p-tau is relatively less elevated and
CSF A?42 levels are normal. In PSP and PSY, CSF
levels of A?42, t-tau, and p-tau are comparable to
CSF biomarkers, age, and dementia severity. In pa-
tients with FTLD, DLB, VaD, PSY, and SMC, CSF
tau and p-tau levels are higher in older patients (CSF
t-tau; FTLD: r ? 0.34, DLB: r ? 0.43, VaD: r ?
0.42, PSY: r ? 0.36, SMC: r ? 0.40, all p ? 0.05;
CSF p-tau; FTLD: r ? 0.40, DLB: r ? 0.36, VaD:
r ? 0.50, PSY: r ? 0.32, SMC: r ? 0.36, all p ?
0.05). In DLB and SMC CSF A?42 is lower in older
patients (DLB: r ? ?0.37; SMC: r ? ?0.19, p ?
0.05). Furthermore, lower MMSE is associated with
lower CSF A?42 levels in AD, FTLD, DLB, with a
trend in CBD (AD: r ? 0.12, FTLD: r ? 0.21, DLB:
r ? 0.37 [all p ? 0.05]; CBD: r ? 0.41, p ? 0.10).
Combination of biomarkers. Logistic regression anal-
ysis with diagnosis AD vs controls (SMC ? PSY) as
dependent variable and CSF A?42, t-tau, and p-tau
as independent variables result in correct classifica-
tion of 465 out of 508 patients with AD (92%) and
355 out of 405 controls (88%), with an overall cor-
rect percentage of 90%, using a combination of CSF
A?42 (odds ratio [OR] ? 0.994; 95% confidence
interval [CI] ? 0.993–0.995) and t-tau (OR ?
1.006; 95% CI ? 1.005–1.007). In this model CSF
p-tau does not contribute significantly to the dis-
Table 1 Clinical and biomarker data by diagnostic groupa
Age, y FemaleMMSE Duration, yA?42, pg/mL Tau, pg/mLp-tau, pg/mL
AD (n ? 512 )
264 (52)21 (18–24)b
3 (2–4) 447 (365–535)b
FTLD (n ? 144)
DLB (n ? 52)
3 (2–4)638 (467–790)b,c
VaD (n ? 34)
2 (2–3)627 (432–862)b,c
CBD (n ? 16)
59 (55–73)6 (38) 25 (21–27)b,c
2 (1–4)681 (435–998)c
PSP (n ? 20)
3 (2–4)767 (563–963)c
CJD (n ? 6)d
61 (52–66)5 (83)17 (14–20)1 (0.4–1)755 (705–886) 2,060 (1,884–4,920)54 (40–102)
PSY (n ? 135)
62 (46) 28 (27–29)b,c
SMC (n ? 275)
124 (45)29 (28–30)c
2 (1–4)863 (691–1,045)245 (179–318)45 (36–57)
Abbreviations: A?42 ? amyloid ? 42; AD ? Alzheimer disease; CBD ? corticobasal degeneration; CJD ? Creutzfeldt-Jakob disease; DLB ? dementia with
Lewy bodies; FTLD ? frontotemporal lobar degeneration; MMSE ? Mini-Mental State Examination; PSP ? progressive supranuclear palsy; PSY ? psychi-
atric disorder; p-tau ? phosphorylated tau; SMC ? subjective memory complaints; VaD ? vascular dementia.
aData are expressed as median (interquartile range) or n (%). Statistical analyses were performed using Kruskal-Wallis followed by Mann-Whitney U tests
and ?2tests. Post hoc, all groups were compared to AD and SMC.
bp ? 0.05 compared to SMC.
cp ? 0.05 compared to AD.
dStatistics were not performed on the small group of patients with CJD.
Table 2Summary of CSF biomarkers by
diagnostic group as compared to
patients with SMCa
CBD ? corticobasal degeneration; CJD ? Creutzfeldt-Jakob
disease; DLB ? dementia with Lewy bodies; FTLD ? fronto-
temporal lobar degeneration; p-tau ? phosphorylated tau;
order; SMC ? subjective memory complaints; VaD ? vascular
a22, Strongly decreased, compared to SMC and patients
with other types of dementia (OD); 11, strongly increased,
1, increased compared to SMC; ?, comparable with SMC;
111, extremely increased, compared to all other groups.
Neurology 78January 3, 2012
crimination of patients with AD from controls. Lo-
gistic regression analysis with AD vs OD results in
correct classification of 171 out of 259 patients with
OD (66%), with an overall correct classification of
83%, using CSF A?42 (OR ? 0.996; 95% CI ?
0.995–0.997) and CSF p-tau (OR ? 1.033; 95%
CI ? 1.026–1.041); i.e., 66% of the patients with
OD have normal CSF A?42 and normal p-tau levels.
In this model CSF t-tau does not contribute signifi-
cantly to the differentiation of AD from OD. In the
figure, CSF A?42 and p-tau are plotted for AD vs
OD with the cutoff line A?42 ? 152 ? 8.25 ?
p-tau for optimal separation (based on the results of
the logistic regression analysis). In table 3 the per-
centages of patients with a CSF AD profile—defined
as a score below 1, calculated with the formula
A?42/152 ? 8.25 ? p-tau—are shown for each di-
agnostic group. FTLD, DLB, VaD, SMC, and PSY
subjects with a CSF AD profile are older and have a
lower MMSE in FTLD, DLB, and AD than patients
with a non-AD (or normal) CSF AD profile. In AD,
this is reverse: younger patients are more likely to
have a CSF AD profile. There is no difference in
disease severity between the groups.
Autopsy. In table 4, patients who went to autopsy are
shown, including the clinical diagnosis, antemortem
CSF biomarker levels, and neuropathologic diagnosis
obtained at autopsy. In 15 out of 17 (85%) patients,
clinical diagnosis corresponded with the neuropatho-
logic diagnosis. The CSF–neuropathologic concor-
dance is comparable: the CSF biomarker profile
correctly classifies during life 15 out of 17 patients
(85%) as AD or non-AD. This is even higher (16 out
of 17, 94%) if additional AD pathology is taken into
account. Patient 17 has a clinical diagnosis of CBD,
while the neuropathologic diagnosis reveals PSP with
Braak stage 3b. The CSF profile exhibits a high CSF
p-tau (88 pg/mL) and t-tau (604 pg/mL), at a bor-
derline CSF A?42 (567 pg/mL). It should be noted
that this patient was 80 years old at autopsy.
In 6 out of 7 patients with clinically diagnosed
AD, a CSF AD profile was found, except for patient
6, who has a CSF profile congruent with non-AD
Figure Scatterplot of CSF amyloid ? 42 (A?42) and phosphorylated tau (p-tau) in other dementias
The equation of the line for optimal separation is A?42 ? 152 ? 8.25 ? p-tau (obtained from logistic regression analysis
comparing Alzheimer disease with the pooled group of other dementias). CBD ? corticobasal degeneration; CJD ?
Creutzfeldt-Jakob disease; DLB ? dementia with Lewy bodies; FTLD ? frontotemporal lobar degeneration; PSP ? progres-
sive supranuclear palsy; VAD ? vascular dementia.
Neurology 78 January 3, 2012
and a neuropathologic diagnosis of DLB. Revision of
the clinical data reveals a change in diagnosis to prob-
able PSP instead of AD. Patient 12 has an ambiguous
clinical diagnosis with both FTLD and alcohol
abuse, and neuropathologically hippocampal sclero-
sis, which fits both clinical diagnoses. CSF A?42 is
decreased in this patient (418 pg/mL), while CSF
p-tau is normal (42 pg/mL), resulting in a borderline
CSF AD profile. Because of the hippocampal sclero-
sis plaques or tangles could not be well characterized
in this patient.
DISCUSSION In the current study, we evaluate
CSF biomarker results in a very large cohort of care-
fully characterized memory clinic patients with a va-
riety of diagnoses. For the differential diagnosis of
patients with AD vs patients with other types of
dementia, the combination of CSF A?42 and
p-tau yields the best diagnostic accuracy. Sensitiv-
ity is high for AD, but specificity for other types of
dementias is moderate. In DLB almost half of the
patients fall into the category AD according to
their CSF biomarker profile. Also in FTLD, VaD,
and CBD, a substantial proportion of patients
have a CSF AD profile. Patients with CJD and
PSP can be separated from AD based on the com-
bination of CSF biomarkers. In PSY and SMC a
CSF AD profile, based on the cutoff line compar-
ing AD with OD, is uncommon.
What could cause the overlap in CSF AD profile
between the different types of dementias? First, mis-
diagnosis cannot be ruled out. In the present study
clinical diagnosis is used as gold standard. This diag-
nosis is based on a large battery of investigations and
on expert opinion after consensus in a multidisci-
plinary team. Most subjects are followed for years,
increasing our confidence in baseline diagnosis. The
small sample of patients with diagnosis at autopsy
reveals a reasonable clinico-pathologic concordance.
Moreover, there is a good concordance between CSF
biomarker classification and neuropathologic diag-
nosis. Remarkably, the agreement between neuro-
pathologic diagnoses vs CSF biomarker profile is in
the same order of magnitude as the agreement be-
tween clinical diagnoses vs CSF biomarker profile,
which strengthens our opinion that CSF biomarkers
give a good reflection of the neuropathology, even in
cases with clinical doubt or mixed pathology.4,25
A second explanation for the overlap in CSF AD
profile is that mixed dementias is a common finding at
of dementias are a minority in the whole spectrum of
dementias.26–29Our findings of overlap in CSF A?42
and CSF (p)t-tau between the different dementias are
thus not that surprising. In most studies low sensitivity
and specificity figures of clinical diagnosis are found in
autopsy confirmed cases.30Furthermore, synergistic
mechanisms between major pathologic proteins (amy-
loid ?, tau, ?-synuclein, TDP-43) suggest common
and our findings of low CSF A?42 correspond with
earlier studies.3In DLB AD-related pathology is found
ment.33We find an association between MMSE and
age with CSF A?42 in DLB, which suggests the pres-
ence of plaques in the brain of the patients with the
most severe dementia and aged patients with DLB.34
in FTLD could be due to inclusion of patients with
progressive nonfluent aphasia in this group, exhibiting
plaques and tangles in the brain as in AD.27
The moderately decreased CSF levels of A?42
and increased p-tau levels in CBD are not surprising
as this type of dementia is linked with a number of
pathologies, including AD pathology.35Decreased
CSF A?42 levels in CBD have been shown before, as
well as increased CSF p-tau.36The increase of CSF
p-tau in some of the patients with CBD could be
teristic of CBD pathology (classified as tauopathy) or as
increased in CSF and not t-tau.
90 67 vs 69c
21 vs 23d
28 66 vs 62c
24 vs 26c
47 73 vs 67c
20 vs 24d
27 75 vs 65c
23 vs 23
38 61 vs 58 26 vs 25
10 69 vs 68 26 vs 26
963 vs 57c
28 vs 28
12 67 vs 58c
29 vs 29
Abbreviations: A?42 ? amyloid ? 42; AD ? Alzheimer dis-
ease; CBD ? corticobasal degeneration; DLB ? dementia
with Lewy bodies; FTLD ? frontotemporal lobar degenera-
tion; MMSE ? Mini-Mental State Examination; p-tau ?
phosphorylated tau; PSP ? progressive supranuclear palsy;
PSY ? psychiatric disorder; SMC ? subjective memory
complaints; VaD ? vascular dementia.
aCSF AD profile: score below 1 using the formula CSF
A?42/152 ? 8.25 ? p-tau, obtained from the cutoff line for
optimal separation of Alzheimer disease vs other types of
dementias (see also the figure).
bAge and MMSE (median values) are compared between
patients with a CSF AD profile vs patients with a CSF
non-AD profile using Mann-Whitney U test.
cp ? 0.05.
dTrend; p ? 0.1.
Neurology 78January 3, 2012
As far as we know, this is the largest single center
sample thus far reported. This large sample size
makes our data robust, especially in view of the inclu-
sion of patients with other types of dementia.4,30
However, there are a few limitations to this study.
First, we included patients with SMC instead of
healthy controls, and consider them as the “worried
well” of our memory clinic population, based on
their normal clinical investigations. Our SMC popu-
lation show normal CSF biomarker levels in 88%,
comparable with the prevalence in a previously pub-
lished population-based sample without cognitive
complaints (i.e., 12% CSF AD profile).37We are
currently performing follow-up studies to study the
predictive value of CSF biomarkers in SMC. Second,
our study group is relatively young. Pathology differs
between young and old patients with AD, patients
with dementia, and patients without dementia.38
Our study clearly shows that patients with different
types of dementia and older patients with SMC are
more prone to have a CSF AD profile. In line with
former studies, older individuals are more likely to
have AD-like biomarkers.16,39Conversely, this im-
plies that CSF biomarkers may be most informative
in younger patients, which should be taken into ac-
count for use in clinical practice. Third, we have neu-
ropathologic data only in a small subgroup of
patients, forming an unintended selection of the
more complex patients. In this selected group the
clinico-neuropathologic-CSF biomarker concor-
dance is high, but prospective studies would reveal
whether this is also the case in unselected patients. A
recent study showed low sensitivity for DLB compar-
ing clinical with autopsy diagnosis, especially in pa-
tients with more severe dementia.40Clinical
diagnosis is the gold standard in the present study.
To date, pathology remains the true gold standard
for diagnosing the presence of biological disease, al-
though this can also be debated, as postmortem in-
formation is by definition post hoc, mostly years
after the diagnosis was first made.
Our data support the value of CSF biomarkers for
confirmation of the clinical diagnosis of AD, or to
exclude AD with high degree of certainty. Further
studies need to focus on the discovery of more spe-
cific biomarkers as well as on comparing CSF bio-
markers with autopsy to understand the overlap
between different types of dementias and the hetero-
geneity of AD.
Dr. Schoonenboom wrote the manuscript and analyzed the data. Dr.
Reesink assisted in writing and analyzing the data and contributed equally
to this work. Dr. Verwey critically read the manuscript and assisted in
writing. Dr. Kester critically read the manuscript and assisted in writing.
Dr. Teunissen supervised laboratory examinations and critically read the
manuscript. Dr. van de Ven advised and assisted in statistics. Dr. Pijnen-
burg critically read the manuscript and assisted in writing. Dr. Blanken-
stein supervised laboratory examinations and critically read the
manuscript. Dr. Rozemuller provided background information about the
neuropathological data and critically read the manuscript. Dr. Scheltens
critically read the manuscript and assisted in writing. Dr. Van der Flier
provided the data and assisted in statistics and writing.
Dr. Schoonenboom, Dr. Reesink, Dr. Verwey, and Dr. Kester report no
disclosures. Dr. Teunissen serves on a scientific advisory board for Inno-
genetics and has a patent pending re: Biomarkers for Alzheimer disease.
Dr. Van de Ven and Dr. Pijnenburg report no disclosures. Dr. Blanken-
stein has received speaker honoraria from Abbott and Ferring and serves as
an Associate Editor for Annals of Clinical Biochemistry. Prof. Rozemuller
has received research support from the EU FP6 and the International
Foundation for Alzheimer Research (ISAO). Dr. Scheltens serves on sci-
entific advisory boards for Danone, Wyeth/Elan Corporation, Bristol-
Myers Squibb, Genentech, Inc., Pfizer Inc, and GE Healthcare; has
received funding for travel or speaker honoraria from Lundbeck Inc.;
served as an Associate Editor of the Journal of Neurology, Neurosurgery &
Psychiatry; serves a Book Review Editor for Alzheimer’s Disease and Associ-
ated Disorders and on the editorial board of Dementia Geriatric Cognitive
Disorders; serves as a consultant for Pfizer Inc, GE Healthcare, Avid Ra-
diopharmaceuticals, Inc./Eli Lilly and Company, Genentech, Inc., and
Janssen AI; and receives research support from Alzheimer Nederland, the
Alzheimer Center, and Stichting VUmc fonds. Dr. Van der Flier reports
Received June 19, 2011. Accepted in final form August 31, 2011.
Table 4 Clinical-CSF-neuropathologic concordancea
at diagnosis, y
ADAD AD, Braak 6c
AD ADAD, Braak 6b
AD ADAD, Braak 6c
ADAD AD, Braak 6c
AD AD AD, Braak 5c
ADAD Braak 6c
FTLD Non-ADFTLD, TDP-43
FTLD Non-AD FTLD, TDP-43, Braak 2c
FTLDNon-AD FTLD, TDP-43
FTLD Non-ADFTLD, TDP-43, Braak 1a
FTLD Non-AD FTLD, TDP-43
DLB Non-AD DLB, Braak 2a
CBDAD PSP, Braak 3b
Abbreviations: A?42 ? amyloid ? 42; AD ? Alzheimer disease; CBD ? corticobasal degen-
eration; CJD ? Creutzfeldt-Jakob disease; DLB ? dementia with Lewy bodies; FTLD ? fron-
totemporal lobar degeneration; p-tau ? phosphorylated tau; PSP ? progressive
aCSF biomarker profile: AD: score ?1 using formula CSF A?42/152 ? 8.25 ? p-tau, ob-
tained from logistic regression analysis; non-AD: score ?1 using formula CSF A?42/152 ?
8.25 ? p-tau.
Neurology 78January 3, 2012
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