The diagnosis of Creutzfeldt- Jakob disease (CJD) is still made by exclusion of other dementias. We now evaluated lactate dehydrogenase (LDH) in the cerebrospinal fluid (CSF) as a possible additional diagnostic tool. CSF LDH levels of patients with CJD ( n = 26) were compared with those in other dementias ( n = 28). LDH isoenzymes were determined in a subset ( n = 9). Total LDH and isoenzyme LDH-1 were significantly higher, whereas the fractions of LDH-2 and LDH-3 were significantly lower in CJD patients. We conclude that in addition to established CSF parameters, LDH and its isoenzymes might serve as a further help to discriminate between CJD and other dementias. Copyright (C) 2004 S. Karger AG, Basel

Cepek, L.

Kretzschmar, H. A.

Niedmann, P.

Otto, M.

Poser, S.

Schmidt, H.

Schroter, A.

English

Open Access LMU ( Ludwig-Maximilians-Univ. München)

Original Research ArticleDement Geriatr Cogn Disord 2004;17:204–206DOI: 10.1159/000076357CSF Lactate Dehydrogenase Activity inPatients with Creutzfeldt-Jakob DiseaseExceeds That in Other DementiasH. Schmidta M. Ottoa P. Niedmannb L. Cepeka A. SchrötercH.A. Kretzschmard S. PoseraDepartments of aNeurology and bClinical Chemistry, University of Göttingen, Göttingen,cDepartment of Neurology, University of Würzburg, Würzburg, and dInstitute of Neuropathology,University of Munich, Munich, GermanyAccepted: August 13, 2003Published online: January 20, 2004Dr. med. H. SchmidtDepartment of Neurology, University of GöttingenRobert-Koch Strasse 40DE–37075 Göttingen (Germany)Tel. +49 551 398484, Fax +49 551 398405, E-Mail hschmid2@gwdg.deABCFax + 41 61 306 12 34E-Mail karger@karger.chwww.karger.com© 2004 S. Karger AG, Basel1420–8008/04/0173–0204$21.00/0Accessible online at:www.karger.com/demKey WordsLactate dehydrogenase W Creutzfeldt-Jakob disease WDementia W 14-3-3 protein W Tau protein W AlzheimerdiseaseAbstractThe diagnosis of Creutzfeldt-Jakob disease (CJD) is stillmade by exclusion of other dementias. We now evaluat-ed lactate dehydrogenase (LDH) in the cerebrospinalfluid (CSF) as a possible additional diagnostic tool. CSFLDH levels of patients with CJD (n = 26) were comparedwith those in other dementias (n = 28). LDH isoenzymeswere determined in a subset (n = 9). Total LDH and isoen-zyme LDH-1 were significantly higher, whereas the frac-tions of LDH-2 and LDH-3 were significantly lower in CJDpatients. We conclude that in addition to established CSFparameters, LDH and its isoenzymes might serve as afurther help to discriminate between CJD and otherdementias.Copyright © 2004 S. Karger AG, BaselIntroductionCreutzfeldt-Jakob disease (CJD) is a rare transmissibledisease with rapidly progressive dementia as the leadingsymptom. Patients usually die within less than a year afterthe onset of symptoms [1, 2]. A definite diagnosis of CJDcan only be made by neuropathological or immunochemi-cal demonstration of the pathological isoform of the prionprotein (PrPSc) in human brain tissue. Up to now, thereare no reliable diagnostic tests for PrPSc in serum or cere-brospinal fluid (CSF). The ante-mortem diagnosis ismade according to typical clinical symptoms [3, 4], sup-ported by typical EEG findings [5], increased concentra-tions of neuron-specific enolase (NSE) [6, 7], tau protein[8] protein 14-3-3 [6, 9, 10] and S-100 protein [11] in theCSF. The latter is also elevated in serum of patients withCJD [12]. However, these markers only reflect neuronaldestruction. LDH is another accepted marker for cellulardamage. LDH is released by all types of cells after loss ofmembrane integrity. CSF-LDH activity is increased incentral nervous system (CNS) infections [13, 14], headtrauma [15, 16], vascular accidents [17], intracerebrallymphoma [18], organophosphate poisoning [19], andmetastatic CNS disease [20]. However, LDH has not beeninvestigated, yet in CJD.MethodsPatientsWe investigated CSF samples of 54 patients. All patients withsuspected CJD were initially evaluated clinically [12]. Twenty-sixpatients were classified as having CJD by standard clinical criteria [4,21, 22], the remaining 28 patients suffered from other dementias.CSF-LDH in Creutzfeldt-Jakob Disease Dement Geriatr Cogn Disord 2004;17:204–206 205Fig. 1. a Total CSF activity of LDH inpatients with CJD dementia (n = 26) andnon-CJD dementia (n = 28); CSF LDH ofpatients negative for 14-3-3 protein (n = 3)are marked as dots. b LDH isoenzymesin patients with CJD dementia and non-CJD dementia. Median, 25th/75th percen-tile (box), 5th/95th percentile (whisker cap);n = 9 in each group.The male-to-female ratio of patients with CJD was 4/22, their agewas 65.0 B 10.7 years (mean B standard deviation).Twenty-three of 26 CJD patients were positive for the 14-3-3 pro-tein in the CSF, in 23 of 26 CJD patients the diagnosis was confirmedneuropathologically [23]. All three 14-3-3-negative patients wereamong the neuropathologically confirmed cases of CJD. All CJDpatients had an intact blood to CSF barrier, reflected by a normalCSF to serum albumin ratio according to Reiber [24].Other DementiasThis group comprised 28 patients (11 men, 17 women; age 62.2B 8.2 years, mean B SD). The final diagnosis in these patients wasmade on the basis of the most recent clinical assessment according toICD-10 or DSM-IV. The group with other dementias comprised thefollowing diagnoses: Alzheimer’s disease (n = 12), vascular dementia(n = 4), dementia due to encephalitis (n = 3), multisystem atrophy(n = 2), Huntington’s disease (n = 1), paraneoplastic syndrome (n =1), multiple sclerosis (n = 1), dementia of unknown origin (n = 4).The study was approved by the local ethics committee in Göt-tingen.LDH MeasurementThe total LDH activity was measured enzymatically according toMcKenzie and Henderson [25] in all patients. In 9 patients with CJDand 9 with other dementias CSF LDH isoenzymes were also mea-sured: CSF had to be concentrated five- to tenfold by ultracentrifuga-tion (Centrifree-System®, Millipore, Inc., USA). Afterwards, the con-centrated CSF was mounted onto agarose gel and separated electro-phoretically. A substrate-specific staining of the different fractions ofLDH was performed by addition of lactate and NAD yieldingNADH which in turn was allowed to react with p -nitroblue tetrazol-ium chloride (NBT) and phenazine methosulfate. This step results inoxidation of NADH to NAD and the formation of an NB-formazandye which reveals isoenzyme bands. The isoenzyme bands werequantitated by scanning densitometry at a wavelength of 600 nm.The test procedure was performed with a commercial electrophoresissystem (LD-Paragon®, Beckman Inc., USA).Statistical AnalysisAs the results of the CJD and non-CJD groups did not follow aGaussian distribution, calculations of median (25/75th percentile)and significances calculated with Mann-Whitney U test are given.We obtained a cut-off value using the Youden Index [26], though thelimited number of patients does not allow its clinical use.ResultsCSF LDH activity was significantly higher in CJDpatients (mean 9, range 5–13 U/l) than in the non-CJDgroup (mean 5, range 4–7 U/l; p = 0.007). The levels ofLDH in 14-3-3-protein-negative CJD patients (n = 3)ranked among the lowest in the CJD group (fig. 1).The best cut-off value was 8 U/l, yielding a sensitivityof 69%, a specificy of 84% (Youden Index 0.53). Isoen-zymes LDH-1, LDH-2 and LDH-3 could be detected,fractions of LDH-4 and LDH-5 were usually below thedetection limit.The percentage of isoenzyme fractions differed signifi-cantly: LDH-1 was higher in CJD patients (median 92%;25th/75th percentile 75/96% vs. 57%; 50/61%; p = 0.001),while both LDH-2 (8%; 4/16% vs. 25%; 21/28%; p =0.003) and LDH-3 (1%; 0/9% vs. 18%; 15/21%; p =0.001) were lower as compared with the control group.DiscussionLDH release in the CSF occurs in various conditions ofacute brain cell damage. Even though CJD has a subacuteclinical course, the results show that the death rate of206 Dement Geriatr Cogn Disord 2004;17:204–206 Schmidt/Otto/Niedmann/Cepek/Schröter/Kretzschmar/Poserbrain cells is still important enough to cause a higherrelease of LDH into the CSF than in dementia of otherorigins.Since LDH-1 is the predominant brain LDH isoen-zyme [20], the increased proportion of this isoenzyme andthe increased total CSF LDH activity reflect the CJD-induced brain damage well.Three of the CJD patients were negative for 14-3-3protein. Their LDH activities were distinctly lower thanthe median value of all CJD patients. Hence, the absenceof the scaffolding protein 14-3-3 in CSF might be a sign ofcomparatively conserved cellular integrity in 14-3-3-nega-tive CJD patients.Our calculated cut-off value doubtless needs to beinterpreted with caution because of the small number ofinvestigated patients. However, it is already evident thatits differential diagnostic test is as good as that of othermarkers, such as 14-3-3, tau protein or S-100B.We conclude that CSF analysis of total LDH activityand its subfractions can help in the differential diagnosisof CJD in a cost-effective manner. Patients lacking 14-3-3in the CSF might have attenuated brain cell damage ascompared with those CJD patients who are positive forthis protein.AcknowledgementThe authors thank the physicians who provided data on suspectcases to the German CJD consultatory laboratory. This study was inpart supported by a grant from the Federal Ministry of Health(BMG) and Federal Ministry of Science and Technology (BMBF).References1 Brown P, Gibbs CJJ, Rodgers-Johnson P, Ash-er DM, Sulima MP, Bacote A: Human spongi-form encephalopathy: The National Instituteof Health series of 300 cases of experimentallytransmitted disease. Ann Neurol 1994;35:513–529.2 Geldmacher DS, Whitehouse PJ: Differentialdiagnosis of Alzheimer’s disease. Neurology1997;48:2–9.3 Will RG, Zeidler M, Brown P, Harrington M,Lee KH, Kenney KL: Cerebrospinal-fluid testfor new variant Creutzfeldt-Jakob disease.Lancet 1996;348:955.4 Masters CL, Harris JO, Gajdusek DC, GibbsCJJ, Bernoulli C, Asher DM: Creutzfeldt-Ja-kob disease: Patterns of worldwide occurrenceand the significance of familial and sporadicclustering. Ann Neurol 1979;5:177–188.5 Steinhoff BJ: EEG features of Creutzfeldt-Jakob disease and their differential diagnosis.Adv Clin Neurosci 1998;8:199–211.6 Beaudry P, Cohen P, Brandel JP, DelasnerieLaupetre N, Richard S, Launay JM, LaplancheJL: 14-3-3 protein, neuron-specific enolase,and S-100 protein in cerebrospinal fluid ofpatients with Creutzfeldt-Jakob disease. De-ment Geriatr Cogn Disord 1999;10:40–46.7 Jimi T, Wakayama Y, Shibuya S, Nakata H,Tomaru T, Takahashi Y: High levels of ner-vous system-specific proteins in cerebrospinalfluid in patients with early stage Creutzfeldt-Jakob disease. Clin Chim Acta 1992;211:37–46.8 Otto M, Wiltfang J, Cepek L, Neumann M,Mollenhauer B, Steinacker P, Ciesielczyk B,Schulz-Schaeffer W, Kretzschmar HA, Poser S:Tau protein and 14-3-3 protein in the differ-ential diagnosis of Creutzfeldt-Jakob disease.Neurology 2002;58:192–197.9 Zerr I, Bodemer M, Gefeller O: Detection of14-3-3 protein in the cerebrospinal fluid sup-ports the diagnosis of Creutzfeldt-Jakob dis-ease. Ann Neurol 1998;43:32–40.10 Hsich G, Kenney K, Gibbs CJ, Lee KH, Har-rington MG: The 14-3-3 brain protein in cere-brospinal fluid as a marker for transmissiblespongiform encephalopathies. N Engl J Med1996;335:924–930.11 Otto M, Stein H, Szudra A: S-100 protein con-centration in the cerebrospinal fluid of patientswith Creutzfeldt-Jakob disease. J Neurol 1997;244:566–570.12 Otto M, Wiltfang J, Schutz E: Diagnosis ofCreutzfeldt-Jakob disease by measurement ofS100 protein in serum: Prospective case-con-trol study. Br Med J 1998;316:577–582.13 Murphy EJ, Horrocks LA: Enzymatic changesin the cerebrospinal fluid in patients with infec-tions of the central nervous system. Acta Pae-diatr 1994;83:1146–1150.14 Sher PK, Hu S: GABA accumulating neuronsare relatively resistant to chronic hypoxia invitro: An auroradiographic study. Brain ResBull 1990;25:697–701.15 Levy G, Rivals A, Bertando J, François G: Doenzyme determinations have any prognosticvalue in neurotraumatology? Ann Anesth Fr1976;17:1279–1284.16 Rao CJ, Shukla PK, Mohanty S, Reddy YJ:Predictive value of serum lactate dehydroge-nase in head injury. J Neurol Neurosurg Psy-chiatry 1978;41:948–953.17 Donnan GA, Zapf P, Doyle AE, Bladin PF:CSF enzymes in lacunar and cortical stroke.Stroke 1983;14:266–269.18 Stewart DJ, Keating MJ, McCredie KB: Natu-ral history of central nervous system acute leu-kemia in adults. Cancer 1981;47:184–196.19 Kolesnichenko IP, Dolgo-Saburova IS, So-mova TV: Changes in the biochemical compo-sition of the cerebrospinal fluid in acute carbo-phos poisoning. Zh Nevropatol Psikhiatr 1992;92:95–99.20 Subash MN, Rao BS, Shankar SK: Changes inlactate dehydrogenase isoenzyme pattern in pa-tients with tumors of the central nervous sys-tem. Neurochem Int 1993;22:121–124.21 WHO: Consensus on criteria for sporadic CJD.Geneva: http://www.who.int/emc-documents/tse/docs/whoemczdi989.pdf, 1998.22 Will RG: Epidemiology of Creutzfeldt-Jakobdisease. Br Med Bull 1993;49:960–970.23 Kretzschmar HA, Ironside JW, DeArmondeSJ, Tateishi J: Diagnostic criteria for sporadicCreutzfeldt-Jakob disease. Arch Neurol 1996;53:913–920.24 Reiber HO: External quality assessment inclinical neurochemistry: Survey of analysis forcerebrospinal fluid (CSF) proteins based onCSF/serum quotients. Clin Chem 1995;41:256–263.25 McKenzie D, Henderson AR: Electrophoresisof lactate dehydrogenase isoenzymes. ClinChem 1983;29:189–195.26 Youden WJ: Index rating for diagnostic tests.Cancer 1950;3:32–35.

A: Human spongiform encephalopathy: The National Institute of Health series of 300 cases of experimentally transmitted disease.

AR: Electrophoresis of lactate dehydrogenase isoenzymes. Clin Chem

Bladin PF: CSF enzymes in lacunar and cortical stroke. Stroke

Diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Arch Neurol

DM: Creutzfeldt-Jakob disease: Patterns of worldwide occurrence and the significance of familial and sporadic clustering.

E: Diagnosis of Creutzfeldt-Jakob disease by measurement of S100 protein in serum: Prospective case-control study.

EEG features of CreutzfeldtJakob disease and their differential diagnosis.

Epidemiology of Creutzfeldt-Jakob disease.

External quality assessment in clinical neurochemistry: Survey of analysis for cerebrospinal fluid (CSF) proteins based on CSF/serum quotients. Clin Chem 1995;41:

François G: Do enzyme determinations have any prognostic value in neurotraumatology? Ann Anesth Fr

Gefeller O: Detection of

High levels of nervous system-specific proteins in cerebrospinal fluid in patients with early stage CreutzfeldtJakob disease. Clin Chim Acta

Horrocks LA: Enzymatic changes in the cerebrospinal fluid in patients with infections of the central nervous system. Acta Paediatr

Hu S: GABA accumulating neurons are relatively resistant to chronic hypoxia in vitro: An auroradiographic study.

Index rating for diagnostic tests.

KB: Natural history of central nervous system acute leukemia in adults. Cancer

KL: Cerebrospinal-fluid test for new variant Creutzfeldt-Jakob disease. Lancet

Laplanche JL: 14-3-3 protein, neuron-specific enolase, and S-100 protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Dement Geriatr Cogn Disord

MG: The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies.

protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease.

Reddy YJ: Predictive value of serum lactate dehydrogenase in head injury.

Shankar SK: Changes in lactate dehydrogenase isoenzyme pattern in patients with tumors of the central nervous system.

Somova TV: Changes in the biochemical composition of the cerebrospinal fluid in acute carbophos poisoning. Zh Nevropatol Psikhiatr

Szudra A: S-100 protein concentration in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease.

Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt-Jakob disease.

Whitehouse PJ: Differential diagnosis of Alzheimer’s disease.

WHO: Consensus on criteria for sporadic CJD. Geneva: http://www.who.int/emc-documents/ tse/docs/whoemczdi989.pdf,

CSF lactate dehydrogenase activity in patients with Creutzfeldt-Jakob disease exceeds that in other dementias

Universität München: Elektronischen Publikationen

Original Research Article
Dement Geriatr Cogn Disord 2004;17:204–206
DOI: 10.1159/000076357
CSF Lactate Dehydrogenase Activity in
Patients with Creutzfeldt-Jakob Disease
Exceeds That in Other Dementias
H. Schmidta M. Ottoa P. Niedmannb L. Cepeka A. Schröterc
H.A. Kretzschmard S. Posera
Departments of aNeurology and bClinical Chemistry, University of Göttingen, Göttingen,
cDepartment of Neurology, University of Würzburg, Würzburg, and dInstitute of Neuropathology,
University of Munich, Munich, Germany
Accepted: August 13, 2003
Published online: January 20, 2004
Dr. med. H. Schmidt
Department of Neurology, University of Göttingen
Robert-Koch Strasse 40
DE–37075 Göttingen (Germany)
Tel. +49 551 398484, Fax +49 551 398405, E-Mail hschmid2@gwdg.de
ABC
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
© 2004 S. Karger AG, Basel
1420–8008/04/0173–0204$21.00/0
Accessible online at:
www.karger.com/dem
Key Words
Lactate dehydrogenase W Creutzfeldt-Jakob disease W
Dementia W 14-3-3 protein W Tau protein W Alzheimer
disease
Abstract
The diagnosis of Creutzfeldt-Jakob disease (CJD) is still
made by exclusion of other dementias. We now evaluat-
ed lactate dehydrogenase (LDH) in the cerebrospinal
fluid (CSF) as a possible additional diagnostic tool. CSF
LDH levels of patients with CJD (n = 26) were compared
with those in other dementias (n = 28). LDH isoenzymes
were determined in a subset (n = 9). Total LDH and isoen-
zyme LDH-1 were significantly higher, whereas the frac-
tions of LDH-2 and LDH-3 were significantly lower in CJD
patients. We conclude that in addition to established CSF
parameters, LDH and its isoenzymes might serve as a
further help to discriminate between CJD and other
dementias.
Copyright © 2004 S. Karger AG, Basel
Introduction
Creutzfeldt-Jakob disease (CJD) is a rare transmissible
disease with rapidly progressive dementia as the leading
symptom. Patients usually die within less than a year after
the onset of symptoms [1, 2]. A definite diagnosis of CJD
can only be made by neuropathological or immunochemi-
cal demonstration of the pathological isoform of the prion
protein (PrPSc) in human brain tissue. Up to now, there
are no reliable diagnostic tests for PrPSc in serum or cere-
brospinal fluid (CSF). The ante-mortem diagnosis is
made according to typical clinical symptoms [3, 4], sup-
ported by typical EEG findings [5], increased concentra-
tions of neuron-specific enolase (NSE) [6, 7], tau protein
[8] protein 14-3-3 [6, 9, 10] and S-100 protein [11] in the
CSF. The latter is also elevated in serum of patients with
CJD [12]. However, these markers only reflect neuronal
destruction. LDH is another accepted marker for cellular
damage. LDH is released by all types of cells after loss of
membrane integrity. CSF-LDH activity is increased in
central nervous system (CNS) infections [13, 14], head
trauma [15, 16], vascular accidents [17], intracerebral
lymphoma [18], organophosphate poisoning [19], and
metastatic CNS disease [20]. However, LDH has not been
investigated, yet in CJD.
Methods
Patients
We investigated CSF samples of 54 patients. All patients with
suspected CJD were initially evaluated clinically [12]. Twenty-six
patients were classified as having CJD by standard clinical criteria [4,
21, 22], the remaining 28 patients suffered from other dementias.
CSF-LDH in Creutzfeldt-Jakob Disease Dement Geriatr Cogn Disord 2004;17:204–206 205
Fig. 1. a Total CSF activity of LDH in
patients with CJD dementia (n = 26) and
non-CJD dementia (n = 28); CSF LDH of
patients negative for 14-3-3 protein (n = 3)
are marked as dots. b LDH isoenzymes
in patients with CJD dementia and non-
CJD dementia. Median, 25th/75th percen-
tile (box), 5th/95th percentile (whisker cap);
n = 9 in each group.
The male-to-female ratio of patients with CJD was 4/22, their age
was 65.0 B 10.7 years (mean B standard deviation).
Twenty-three of 26 CJD patients were positive for the 14-3-3 pro-
tein in the CSF, in 23 of 26 CJD patients the diagnosis was confirmed
neuropathologically [23]. All three 14-3-3-negative patients were
among the neuropathologically confirmed cases of CJD. All CJD
patients had an intact blood to CSF barrier, reflected by a normal
CSF to serum albumin ratio according to Reiber [24].
Other Dementias
This group comprised 28 patients (11 men, 17 women; age 62.2
B 8.2 years, mean B SD). The final diagnosis in these patients was
made on the basis of the most recent clinical assessment according to
ICD-10 or DSM-IV. The group with other dementias comprised the
following diagnoses: Alzheimer’s disease (n = 12), vascular dementia
(n = 4), dementia due to encephalitis (n = 3), multisystem atrophy
(n = 2), Huntington’s disease (n = 1), paraneoplastic syndrome (n =
1), multiple sclerosis (n = 1), dementia of unknown origin (n = 4).
The study was approved by the local ethics committee in Göt-
tingen.
LDH Measurement
The total LDH activity was measured enzymatically according to
McKenzie and Henderson [25] in all patients. In 9 patients with CJD
and 9 with other dementias CSF LDH isoenzymes were also mea-
sured: CSF had to be concentrated five- to tenfold by ultracentrifuga-
tion (Centrifree-System®, Millipore, Inc., USA). Afterwards, the con-
centrated CSF was mounted onto agarose gel and separated electro-
phoretically. A substrate-specific staining of the different fractions of
LDH was performed by addition of lactate and NAD yielding
NADH which in turn was allowed to react with p -nitroblue tetrazol-
ium chloride (NBT) and phenazine methosulfate. This step results in
oxidation of NADH to NAD and the formation of an NB-formazan
dye which reveals isoenzyme bands. The isoenzyme bands were
quantitated by scanning densitometry at a wavelength of 600 nm.
The test procedure was performed with a commercial electrophoresis
system (LD-Paragon®, Beckman Inc., USA).
Statistical Analysis
As the results of the CJD and non-CJD groups did not follow a
Gaussian distribution, calculations of median (25/75th percentile)
and significances calculated with Mann-Whitney U test are given.
We obtained a cut-off value using the Youden Index [26], though the
limited number of patients does not allow its clinical use.
Results
CSF LDH activity was significantly higher in CJD
patients (mean 9, range 5–13 U/l) than in the non-CJD
group (mean 5, range 4–7 U/l; p = 0.007). The levels of
LDH in 14-3-3-protein-negative CJD patients (n = 3)
ranked among the lowest in the CJD group (fig. 1).
The best cut-off value was 8 U/l, yielding a sensitivity
of 69%, a specificy of 84% (Youden Index 0.53). Isoen-
zymes LDH-1, LDH-2 and LDH-3 could be detected,
fractions of LDH-4 and LDH-5 were usually below the
detection limit.
The percentage of isoenzyme fractions differed signifi-
cantly: LDH-1 was higher in CJD patients (median 92%;
25th/75th percentile 75/96% vs. 57%; 50/61%; p = 0.001),
while both LDH-2 (8%; 4/16% vs. 25%; 21/28%; p =
0.003) and LDH-3 (1%; 0/9% vs. 18%; 15/21%; p =
0.001) were lower as compared with the control group.
Discussion
LDH release in the CSF occurs in various conditions of
acute brain cell damage. Even though CJD has a subacute
clinical course, the results show that the death rate of
206 Dement Geriatr Cogn Disord 2004;17:204–206 Schmidt/Otto/Niedmann/Cepek/Schröter/
Kretzschmar/Poser
brain cells is still important enough to cause a higher
release of LDH into the CSF than in dementia of other
origins.
Since LDH-1 is the predominant brain LDH isoen-
zyme [20], the increased proportion of this isoenzyme and
the increased total CSF LDH activity reflect the CJD-
induced brain damage well.
Three of the CJD patients were negative for 14-3-3
protein. Their LDH activities were distinctly lower than
the median value of all CJD patients. Hence, the absence
of the scaffolding protein 14-3-3 in CSF might be a sign of
comparatively conserved cellular integrity in 14-3-3-nega-
tive CJD patients.
Our calculated cut-off value doubtless needs to be
interpreted with caution because of the small number of
investigated patients. However, it is already evident that
its differential diagnostic test is as good as that of other
markers, such as 14-3-3, tau protein or S-100B.
We conclude that CSF analysis of total LDH activity
and its subfractions can help in the differential diagnosis
of CJD in a cost-effective manner. Patients lacking 14-3-3
in the CSF might have attenuated brain cell damage as
compared with those CJD patients who are positive for
this protein.
Acknowledgement
The authors thank the physicians who provided data on suspect
cases to the German CJD consultatory laboratory. This study was in
part supported by a grant from the Federal Ministry of Health
(BMG) and Federal Ministry of Science and Technology (BMBF).
References
1 Brown P, Gibbs CJJ, Rodgers-Johnson P, Ash-
er DM, Sulima MP, Bacote A: Human spongi-
form encephalopathy: The National Institute
of Health series of 300 cases of experimentally
transmitted disease. Ann Neurol 1994;35:513–
529.
2 Geldmacher DS, Whitehouse PJ: Differential
diagnosis of Alzheimer’s disease. Neurology
1997;48:2–9.
3 Will RG, Zeidler M, Brown P, Harrington M,
Lee KH, Kenney KL: Cerebrospinal-fluid test
for new variant Creutzfeldt-Jakob disease.
Lancet 1996;348:955.
4 Masters CL, Harris JO, Gajdusek DC, Gibbs
CJJ, Bernoulli C, Asher DM: Creutzfeldt-Ja-
kob disease: Patterns of worldwide occurrence
and the significance of familial and sporadic
clustering. Ann Neurol 1979;5:177–188.
5 Steinhoff BJ: EEG features of Creutzfeldt-
Jakob disease and their differential diagnosis.
Adv Clin Neurosci 1998;8:199–211.
6 Beaudry P, Cohen P, Brandel JP, Delasnerie
Laupetre N, Richard S, Launay JM, Laplanche
JL: 14-3-3 protein, neuron-specific enolase,
and S-100 protein in cerebrospinal fluid of
patients with Creutzfeldt-Jakob disease. De-
ment Geriatr Cogn Disord 1999;10:40–46.
7 Jimi T, Wakayama Y, Shibuya S, Nakata H,
Tomaru T, Takahashi Y: High levels of ner-
vous system-specific proteins in cerebrospinal
fluid in patients with early stage Creutzfeldt-
Jakob disease. Clin Chim Acta 1992;211:37–
46.
8 Otto M, Wiltfang J, Cepek L, Neumann M,
Mollenhauer B, Steinacker P, Ciesielczyk B,
Schulz-Schaeffer W, Kretzschmar HA, Poser S:
Tau protein and 14-3-3 protein in the differ-
ential diagnosis of Creutzfeldt-Jakob disease.
Neurology 2002;58:192–197.
9 Zerr I, Bodemer M, Gefeller O: Detection of
14-3-3 protein in the cerebrospinal fluid sup-
ports the diagnosis of Creutzfeldt-Jakob dis-
ease. Ann Neurol 1998;43:32–40.
10 Hsich G, Kenney K, Gibbs CJ, Lee KH, Har-
rington MG: The 14-3-3 brain protein in cere-
brospinal fluid as a marker for transmissible
spongiform encephalopathies. N Engl J Med
1996;335:924–930.
11 Otto M, Stein H, Szudra A: S-100 protein con-
centration in the cerebrospinal fluid of patients
with Creutzfeldt-Jakob disease. J Neurol 1997;
244:566–570.
12 Otto M, Wiltfang J, Schutz E: Diagnosis of
Creutzfeldt-Jakob disease by measurement of
S100 protein in serum: Prospective case-con-
trol study. Br Med J 1998;316:577–582.
13 Murphy EJ, Horrocks LA: Enzymatic changes
in the cerebrospinal fluid in patients with infec-
tions of the central nervous system. Acta Pae-
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Otto, Markus

Kretzschmar, Hans A.

Poser, Sigrid

GRO.publications (Univ. Göttingen)

H. Schmidt

M. Otto

P. Niedmann

L. Cepek

A. Schröter

H.A. Kretzschmar

S. Poser

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CSF Lactate Dehydrogenase Activity in Patients with Creutzfeldt-Jakob Disease Exceeds That in Other Dementias

https://epub.ub.uni-muenchen.de/16925/1/10_1159_000076357.pdf

CSF lactate dehydrogenase activity in patients with Creutzfeldt-Jakob disease exceeds that in other dementias

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