Albrecht, P.

Hartung, H.-P.

Hemmer, B.

Methner, Axel

Otto, M.

Schmitz, M.

Zerr, I.

English

PubMed

Otto, Markus

Hemmer, Bernhard

GRO.publications (Univ. Göttingen)

Free caspase activity in CSF of patients with dementia

P. Albrecht

M. Schmitz

M. Otto

B. Hemmer

I. Zerr

H.-P. Hartung

Axel Methner

Springer - Publisher Connector

LETTER TO THE EDITORS
Free caspase activity in CSF of patients with dementia
P. Albrecht Æ M. Schmitz Æ M. Otto Æ B. Hemmer Æ
I. Zerr Æ H.-P. Hartung Æ Axel Methner
Received: 11 December 2008 / Revised: 4 January 2009 / Accepted: 17 April 2009 / Published online: 8 May 2009
 Springer-Verlag 2009
Sirs,
Neurodegenerative dementias such as sporadic Creutz-
feldt–Jakob disease (sCJD), Alzheimer’s disease (AD), and
dementia with Lewy bodies (DLB) are difficult to diag-
nose. Quantification of brain-derived proteins, 14-3-3 in
sCJD, and tau and amyloid-b in AD, can support the
clinical diagnosis, but results vary considerably [3, 6].
Caspase-mediated apoptosis was reported to be involved in
the pathogenesis of sCJD [4] and appears to play a role in
later stages of AD and DLB (reviewed in [5]). We
hypothesized that the activity of effector caspases-3 and -7
might be a sensitive indicator of apoptotic activity and
potentially indicative of disease severity. Previous studies
on the role of apoptosis in post mortem tissue yielded
contradictory results, probably due to the fact that cell
death in these illnesses occurs over decades, whereas the
suicide program in the single cell is executed within a few
hours. Thus, synchronous detection of a substantial number
of apoptotic neurons seems almost impossible [5]. Cell-free
caspase activity in contrast is stable over a significant
period of time and can be measured in serum, where it
correlates with hepatic degeneration in patients with
chronic hepatitis [7], and in cerebrospinal fluid (CSF),
where it correlates with intracranial pressure in patients
with head trauma [8].
In this contribution, we evaluated the use of free caspase
activity in CSF as a marker for the activity of apoptosis in
neurodegenerative dementias by measuring caspase-3/7
activity in CSF from patients with sCJD (n = 13), AD
(n = 9), DLB (n = 7), and controls (n = 8). We correlated
caspase activity with clinical status, course of disease, and
established paraclinical tests.
AD and DLB was diagnosed according to DSM-IV and
sCJD to WHO 98. Three sCJD patients were tapped con-
secutively for diagnostic reasons. Controls were two
patients with isolated cervical dystonia, one with pseudo-
tumor cerebri, and five without neurological disease, who
gave informed consent. Clinical status was scored using the
modified Rankin scale [1] and mini-mental-state exami-
nation (MMSE) [2]. Caspase activity was measured using
Caspase-Glo 3/7 (Promega) and normalized with purified
caspase-3 (Biomol). Protein 14-3-3 immunoblots and tau
and amyloid-b 1-42 enzyme-linked immunosorbent assay
(ELISA) were performed as described [3, 4].
Mean caspase activity in CSF was 1,377 U/l (standard
error of the mean, SEM 434.6 U/l) for sCJD patients,
338 U/l (SEM 84.8 U/l) for AD patients, and 222 U/l
(SEM 15.7 U/l) for DLB patients; for controls it was
215.1 U/l (SEM 24.3 U/l) (Fig. 1a). Only sCJD patients
differed significantly from controls (P \ 0.05, two-tailed t
test; no repeated measurements were used for statistical
analysis). In two patients with damage to the blood–brain
barrier indicated by increased albumin quotient (QALB 10.5
and 11.5), caspase activity was higher in CSF, suggesting
P. Albrecht  H.-P. Hartung  A. Methner (&)
Department of Neurology,
Heinrich-Heine Universita¨t Du¨sseldorf,
Moorenstr. 5, 40225 Du¨sseldorf, Germany
e-mail: axel.methner@gmail.com
M. Schmitz  I. Zerr
Department of Neurology, University Medical School,
Georg-August University of Go¨ttingen, Go¨ttingen, Germany
M. Otto
Department of Neurology, University Clinic of Ulm,
Ulm, Germany
B. Hemmer
Department of Neurology, Klinikum rechts der Isar,
Technical University, Munich, Germany
123
J Neurol (2009) 256:1561–1562
DOI 10.1007/s00415-009-5145-z
an origin within the nervous system. Elevated caspase
activity correlated with clinical disability (r = 0.670,
P = 0.020, Spearman, Fig. 1b), remaining lifespan
(r = 0.648, P = 0.025, Spearman, Fig. 1c), and levels of
protein tau (r = 0.779, P = 0.003, Pearson, Fig. 1d) only
in patients with sCJD. In AD and DLB, caspase activity did
not correlate with disease duration or MMSE. We observed
no correlation of caspase activity with levels of amyloid-b
or of protein tau with Rankin scale. In consecutively tapped
patients, free caspase levels and clinical disability
increased over time (not shown).
We conclude that cell-free caspase activity can be
measured in CSF and is significantly increased in sCJD, but
not in AD or DLB. Caspase activity correlated with time to
death, protein tau levels, and clinical status only in sCJD.
Caspase activity cannot distinguish AD/DLB from sCJD
but favors a diagnosis of sCJD and suggests a highly
active disease, as rapidly deteriorating patients had higher
caspase levels. Studies on a larger collective are underway
to confirm the value of this novel marker of disease
activity.
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Ctrls CJD LBD
Ca
sp
as
e 
10
00
U/
l
A B
modified Rankin scale
1 2 3 4 5
C
time to death (days)
D
Tau (µg/ml)
5 10 15 20 25450 350 250 150 50
0
AD
1
2
3
4
5
6
0
1
2
3
4
5
6
0
1
2
3
4
5
6
0
1
2
4
6
Ca
sp
as
e 
10
00
U/
l
Fig. 1 a Dot plot of free caspase-3 and -7 activity in CSF from 13
sCJD patients, 9 AD patients, 7 DLB patients, and 8 controls,
b caspase activity over clinical status and c remaining lifespan after
spinal tap in sCJD-patients, d correlation of caspase-3 and -7 activity
with protein tau levels in CSF of sCJD patients
1562 J Neurol (2009) 256:1561–1562
123


Recovery of motor function after stroke.

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Free caspase activity in CSF of patients with dementia

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