• cerebrospinal fluid;
  • diagnosis;
  • biomarker;
  • testing


  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. CSF markers recommended for use in clinical routine
  6. CSF markers with a future potential to be used in clinical routine
  7. References
  8. Reference Appendix

We reviewed the literature for disease-specific markers in cerebrospinal fluid (CSF) and evaluated their diagnostic and prognostic relevance in neurological diseases. High tau protein in combination with low amyloid β levels has a high sensitivity (80%) and specificity (90%) for Alzheimer’s disease (AD) against normal aging and can predict conversion of mild cognitive impairment to AD. The detection of 14-3-3 has a high sensitivity (80–90%) and specificity (90%) for the diagnosis of CJD. Low or undetectable CSF hypocretin-1 (orexin-1) levels constitute a diagnostic biomarker for narcolepsy with cataplexy. Detection of beta-2-transferrin indicates CSF contamination in oto- and rhinorrhoe with a sensitivity of >79% at a specificity of 95% similar to the beta-trace protein (sensitivity >90%, specificity 100%). However, beta-trace protein is faster and cheaper to perform. Possible future biomarkers are: elevated levels of vascular endothelial growth factor are relatively sensitive (51–100%) and specific (73–100%) for leptomeningeal metastases from solid tumors and are associated with a poor prognosis in this condition. Elevated CSF neurofilament (Nf) levels probably reflect acute neuronal degeneration. The prognostic value of CSF Nf levels is highest in acute conditions such as subarachnoid hemorrhage, acute optic neuritis and neuromyelitis optica.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. CSF markers recommended for use in clinical routine
  6. CSF markers with a future potential to be used in clinical routine
  7. References
  8. Reference Appendix

Investigation of the cerebrospinal fluid (CSF) in neurological diseases has a long history and a small number of molecules have become the standard repertoire in routine CSF work-up such as total protein, glucose, cell count and differentiation, as well as quantitative and qualitative detection of immunoglobulins [1]. In recent years, the search for biomarkers – a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention, as defined by the Biomarkers Definition Working Group [2] – in body fluids including the CSF has increased substantially. In addition to the guidelines on routine CSF investigations [1] we wanted to evaluate newer CSF markers with respect to their disease specificity or prognostic relevance.

Search strategy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. CSF markers recommended for use in clinical routine
  6. CSF markers with a future potential to be used in clinical routine
  7. References
  8. Reference Appendix

Tau protein, amyloid beta, 14-3-3 and myelin basic protein

PubMed was searched up to January 2008 for key words including ‘CSF’, ‘tau’, ‘amyloid’, ‘14-3-3’, ‘myelin basic protein’, and ‘mbp’, which yielded 1785 hits. Only papers in English and relating to adult clinical neurology were considered for further analysis.


A Medline search using the search terms cerebrospinal fluid (CSF), narcolepsy, sleep disorder, hypocretin and orexin was conducted. The search was limited to the time between 1 January 1980 and 1 May 2008. The key words were cross-referenced as follows: (‘cerebrospinal fluid’ or ‘CSF’) AND (‘hypocretin or orexin’) AND (‘narcolepsy OR sleep disorder OR cataplexy’). The search returned 73 documents. Abstracts which primarily did not deal with human sleep disorders, case reports, reviews, comments and original articles, which were not published in English, were excluded. The remaining 13 articles were further analyzed.

Beta 2 transferrin

(Cerebrospinal fluid OR CSF) and (beta 2 transferrin) and (otorrhea OR otorrhoea OR rhinorrhoea OR rhinorrhea) NOT beta trace resulted in 60 abstracts. Reviews and reports not dealing with diagnostic issues or with other fluids than CSF were excluded resulting in 42 articles.

Beta trace protein (prostaglandin D synthase)

(Beta-trace protein OR Prostaglandin D Synthase) and (otorrhea OR otorrhoea OR rhinorrhoea OR rhinorrhea) NOT beta 2 transferrin resulted in 16 abstracts.

Vascular endothelial growth factor

PubMed Search for (‘VEGF’ OR ‘vascular endothelial growth factor’) AND ‘CSF’; limits: 1980 until May 2008, Language German or English, reports on humans resulted in 51 Abstracts. Of those four reviews, 21 papers not related to diagnostic VEGF testing in CSF, and four pediatric reports were excluded. The remaining 22 papers were included for evaluation.


PubMed was searched up to January 2008 for key words including CSF, neurofilament (Nf), patients, which yielded 91 hits. Articles dealing with adult patients were included (children excluded). Articles excluded were: articles focussing on anti-Nf antibodies, serum analysis only, animal studies, reviews, case reports or method description rather than biomarker investigation in patients, animal studies and articles that were not in English.

Evidence was classified as class I–IV and recommendations as level A–C according to the scheme agreed for EFNS guidelines [3] with class I and level A being the strongest classes of evidence/recommendation.

In a conference held in March 2006, various potential CSF biomarkers and methods of detection were discussed by the members of the taskforce including CSF proteomics, markers of axonal damage focusing on different subsets of Nfs, neurotransmitters, autoantibodies, anti-neural antibodies, ferritin, Amyloid-β (Aβ), tau and hyperphosphorylated-tau, 14-3-3 protein, myelin basic protein, sulfatid, beta-2-transferrin, VEGF, and S-100. Of those, only the markers discussed below were felt to be relevant enough to receive further attention for the present report.

The Cochrane database and guideline papers of the American Academy of Neurology (AAN) were searched for all above topics. No relevant publication was found.

CSF markers recommended for use in clinical routine

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. CSF markers recommended for use in clinical routine
  6. CSF markers with a future potential to be used in clinical routine
  7. References
  8. Reference Appendix

Tau protein and amyloid-β peptide

Tau proteins are microtubule-associated proteins important for the maintenance of axonal microtubules. Hyperphosporylated tau (P-tau) is present in neuritic tangles in Alzheimer’s disease (AD). Amyloid-β (Aβ) peptides are derived from cleavage of the amyloid precursor protein by β- and γ-secretases, resulting in the Aβ1-40 and Aβ1-42 peptide fragments. Aβ1-42 has a strong tendency to aggregate, and is a major component of amyloid plaques in AD. Increased CSF concentrations of tau and P-tau and low CSF concentrations of Aβ1-42 are typical findings in AD, have been reviewed by a task force of the World Federation of Societies of Biological Psychiatry, and have been incorporated in the latest research criteria for the diagnosis of AD [4–7]. Tau proteins and Aβ peptides can be easily measured by commercially available sandwich ELISA, but Aβ measurements should be interpreted with some caution (see below).

At a specificity of 90%, the sensitivity for AD according to clinical criteria of the most commonly used tau immunoassay is approximately 80%, and the sensitivity of Aβ1-42 is 80–90% (class I) [4]. The sensitivity for the diagnosis of AD of P-tau assays, based on immunoassays recognizing tau phosphorylated on different serine and threonine residues, is more variable (class II) [4,8,9]. The combination of tau and Aβ1-42 has been assessed in several studies, and has been found to give a high sensitivity and specificity against normal aging and psychiatric disorders, whereas the specificity against other diseases is lower (class II) [10,11]. Increases in tau and low Aβ1-42 concentrations are also found in stroke, trauma and other diseases with a neurodegenerative component (Table 1). However, at least for stroke, P-tau levels have been reported as being normal [12,13]. P-tau may provide better specificity against dementia with Lewy bodies and frontotemporal dementia, but the phosphorylation sites providing the best discrimination may differ from one disease to another [14–18]. Low concentrations of Aβ1-42 and dramatic increases in tau without a similarly strong increase in P-tau, is observed in CJD (class I) [19–27]. In contrast, tau and P-tau increase in parallel in variant CJD (class III) [28]. The discrimination between different tau and Aβ isoforms in CSF may be useful for the discrimination between different disease processes, but larger studies are needed to address this in detail [29–33].

Table 1.   Summary of studies of total tau and amyloid β1-42 (Aβ1-42) peptide in cerebrospinal fluid in diseases other than Alzheimer dementia
Disease and resultsEvidence classificationReference
Multiple sclerosis (MS)
 Increase in tau and P-tau in MSClass II[62,169–172]
 Normal tau in most MS patientsClass II[173]
Dementia with Lewy bodies (LBD)
 Lower Aβ1-42 in LBDClass II[10,174]
 Increase in tau in LBDClass III[175,176]
 Normal tau and Aβ1-42 in LBDClass II[177]
 Lower Aβ1-42 and increased tau in LBDClass II[178,179]
Semantic dementia (SD)
 Increase in tau in SDClass III[180]
Frontotemporal dementia (FD)
 Increase in tau in FDClass III[175,176]
 Increase in tau in FDClass II[181]
 Increase in tau, decrease in Aβ1-42Class II[182]
 Low Aβ1-42 in FDClass III[183]
Parkinson disease (PD)
 Lower Aβ1-42 to Aβ1-37 ratio in PD with dementiaClass III[29]
 Normal Aβ1-42 in PDClass II[184]
 Lower Aβ1-42 and higher tau in PD with dementia, intermediate values in PDClass II[185]
 Low Aβ1-42 in PDClass III[183]
Multiple system atrophy (MSA)
 Higher tau in MSA than in PDClass II[186]
 Higher tau in MSA than in idiopathic cerebellar ataxiaClass II[187]
 Low Aβ1-42 in MSAClass II[184]
Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP)
 Higher tau in CBD than in PSPClass II[176,188]
 Normal Aβ1-42 in PSPClass II[184]
 Low Aβ1-42 in CBD and PSPClass III[189]
Vascular dementia (VD) and stroke
 Increase in tau in VDClass II[10]
 Increase in tau in strokeClass II[12]
 Increase in tau, low Aβ1-42 and normal P181-tau in VDClass II[13,190]
 Increase in tau, normal Aβ1-42 and normal P181-tau in VDClass II[190]
Neuromuscular diseases
 Increased tau in amyotrophic lateral sclerosisClass II[137]
 Low Aβ1-42 in ALSClass III[183]
 Increased tau in Guillain-Barré syndrome, correlation with prognosisClass II[191]
AIDS–dementia complex (ADC)
 Low Aβ1-42 and high tau in ADCClass II[192]
Head injury
 Increased tau in head injuryClass III[193,194]
 Decresed Aβ1-42 in head injuryClass III[193,195]
Normal pressure hydrocephalus (NPH)
 Low tau, P-tau and Aβ1-42 in NPHClass II[196]
 Increased tau in NPHClass III[176,197]

A special indication for CSF studies is the identification of patients with mild cognitive impairment with CSF findings typical of AD [4], as there is class I evidence that such patients may be at increased risk of progression to AD [34–43]. When interpreting the results of Aβ1-42 measurements, it should be taken into account that concentrations may decrease following glucocorticoid treatment (class III) [44] and show pronounced diurnal fluctuations [45], and erroneously low values of Aβ1-42 are found if the CSF is not sampled and handled optimally [46–48]. Indeed, freezing and prolonged storage impairs the discriminatory value of ELISA measurements of Aβ [49]. Furthermore, age-dependent reference values should be used for tau measurements, whereas Aβ1-42 values are independent of age. In one study, the reference value for Aβ1-42 was above 500 ng/l; for tau the reference value was <300 ng/l in patients from 21 to 50 years of age, <450 ng/l from 51 to 70 years of age, and <500 ng/l from 71 to 93 years of age [50].


In studies assessing the sensitivity and specificity of CSF markers for AD, the diagnosis has not been confirmed neuropathologically. Aβ1-42 values should be interpreted with some caution. There is, however, evidence that tau, p-tau and Aβ1-42 measurements have high sensitivity and specificity for discriminating AD against normal aging, and may identify patients with mild cognitive impairment at an increased risk of progression to AD (level A rating). The latter finding is of clear importance if therapies affecting the disease course of AD become available in the future.

14-3-3 protein

14-3-3 is a ubiquitous protein with the highest concentrations found in brain [51]. Mostly, it is determined qualitatively by western blot techniques, although a quantitative ELISA method is available. An initial study showed the presence of 14-3-3 in CSF from 96% of 71 patients with Creutzfeldt-Jakob disease (CJD) (class II) [52]. In a prospective study including 805 patients with neuropathologically confirmed CJD the sensitivity of a positive 14-3-3 test was 94%, the specificity was 84%, and the 14-3-3 test was superior to EEG studies (class I) [53]. High sensitivity and specificity of 14-3-3 has also been found in other studies (class I) [54–58]. Increases in 14-3-3 protein are less frequent in new variant CJD (class III) [59], in familial forms of spongiform encephalopathies and in infrequent subtypes of CJD (class III) [56,60,61]. Furthermore, increases in 14-3-3 protein are less frequent early and late in the course of sporadic CJD and early in the course of iatrogenic (growth hormone-induced) CJD (class III) [14,43,62]. Positive results of the 14-3-3 test have also been reported in other dementias, cerebrovascular disease, metabolic and hypoxic encephalopathies, brain metastases and CNS infections (class III) [27,27,52,55,58,63,64]. The detection of 14-3-3 in CSF has been reported to indicate a poor prognosis in patients with transverse myelitis, clinically isolated syndromes suggestive of MS and MS (class II) [65–67]; another study did not confirm these findings (class III) [68].


The detection of 14-3-3 has been reported to have a high sensitivity (94%) and specificity (84%) for the diagnosis of CJD in patients with clinical findings suggestive of this disease, but 14-3-3 can also be detected in CSF from patients with more common diseases (level A rating).

Hypocretin-1 (orexin-1) levels in narcolepsy

Human narcolepsy is a sleep disorder which affects up to 0.5% of the population. It is characterized by hypersomnia, cataplexia, sleep paralysis and hypnagogic hallucinations [69]. The full spectrum of symptoms occurs only in a minority of patients. The disease is strongly associated with the HLA allele DQB1*0602. Based on animal models it is believed that narcolepsy is caused by a dysfunction of the hypocretin-1 (orexin-1) neurotransmitter system in the posterior and lateral hypothalamus. In human narcolepsy CSF hypocretin-1 (orexin-1) levels were reported to be low or absent. Thirteen studies were used to evaluate the role of CSF hypocretin-1 (orexin-1) in sleep disorders. Three studies were excluded from the analysis because of low patient numbers or lack of control groups [70–72]. The study Mignot et al. included patients from two previous studies, which were therefore also excluded from the analysis [73,74]. In all studies hypocretin-1 (orexin-1) levels in CSF were measured by radio immunoassay (RIA). Cut-off points ranged from 202 to 110 pg/ml. In most patients with narcolepsy with cataplexy orexin/hypocretin concentrations were low (sensitivities between 66% and 100%), in the majority of patients even below the detection limit of 40 pg/ml of the RIA (Table 2). This was in particular true for patients with HLA DQB1*0602 status [72]. Low levels of hypocretin-1 (orexin-1) were also found in a minority of narcolepsy without cataplexy patients and other neurological disease (specificities between 92% and 100%) [75].

Table 2.   Summary of the results from hypcretin-1/orexin-1 levels in narcolepsy
SensitivityPrevalence in controlsaCut-off (pg/ml)Class of evidenceReference
With cataplexyWithout cataplexyND including SDbND without SDc
  1. All hypcretin-1/orexin-1 measurements were performed by RIA; numbers in parenthesis refer to total number of investigated subjects; a100% minus these figures result in specificities; bNeurological disease including other sleep disorders; cNeurological disease without sleep disorders; dincluding patients with atypical cataplexia; epatients who had no sleep disorder; fsamples were included before in other studies gneurological diseases and pregnant women; hpatients who underwent back surgery; iidiopathic hypersomnia.

69.3%d (137)14.3% (21)1.7% (228)0% (47)e110IIIf[198]
91.7% (48)40% (15)0% (10)0% (50)g110II[199]
81.8 (9)0% (5)8.3% (12)nd194III[200]
70.6% (17)0% (9)nd0% (15)h200IV[201]
100% (14)100% (10)0% (24)gnd100IV[202]
88.5% (26)11.1% (9)0% (103)nd110II[203]
66.0% (47)0% (7)0%i (10)nd209 pg/dlII[204]

Based on three class II and several class III and IV studies, hypocretin-1 (orexin-1) levels of <110 pg/ml in CSF can be classified as a diagnostic biomarker for narcolepsy with cataplexy (level A recommendation, in compliance with the International Classification of Sleep Disorders). The value of measuring hypocretin-1 (orexin-1) in CSF of other sleep disorders is controversial.


Transferrin is a polypeptide of the ß-globulin family, which is involved in ferrous ion transport. Beta-2-transferrin (synonyms: asialotransferrin, tau-fraction) is a transferrin form, without sialic acid side chains. In healthy human beings beta-2-transferrin has only been demonstrated in CSF, perilymph and aqueous humor of the eye, but not in serum [76,77]. In patients with chronic liver diseases [78,79], inborn error of glycoprotein metabolism [80] and persons with a genetic variant of transferrin [78,81,82] beta-2-transferrin can be also found in the blood.

Due to shortcomings of earlier methods (high resolution electrophoresis) [83,84] an isoelectric pH-focusing method was developed followed by immunofixation and silver staining, for which as little as 5 μg total protein is necessary (class III). Various sources of error in use of beta-2-transferrin analysis for diagnosing cerebral spinal fluid leaks were described [85], such as transferrin isoforms especially in saliva with electrophoretic mobility similar to that of beta-2-transferrin (class IV) [86].

In combination with other methods like high resolution computed tomography the detection of beta-2-transferrin in CSF contaminated nasal discharges and blood was able to confirm oto- and rhinorrhoe of different etiologies [83,84,87–94] (all class III, except one class IV) and used to monitor patients after surgical reconstruction of the frontal skull base (class III) [95]. The test sensitivity varied between 79% and 100% (class III) [94,96,97] at a specificity of about 95% (class III) [97]. Venous blood sampled at the same time as CSF may exclude false positive results due to inborn errors of glycoprotein metabolism, genetic variants of transferrin or chronic liver disease (class IV) [81,92].


Measurement of beta-2-transferrin in combination with computed tomography of the scull detects CSF contamination in oto- and rhinorrhoea with high sensitivity (79–100%) at a specificity of 95% (level B recommendation).

Beta-trace protein, ß-TP (prostaglandin D synthase, PGDS)

ß-TP (molecular mass, 25 kDa) is one of the most abundant locally synthesized proteins in the CSF [98,99]. Based on amino acid sequencing, it has been identified as prostaglandin D synthase (PGDS) which is a member of the lipocalin superfamily composed of various secretory lipophilic ligand-carrier proteins [100]. Within the central nervous system, ß-TP has been localized by immunohistochemistry and in situ hybridization mainly in choroid plexus and leptomeninges [101]. Concentrations of ß-TP in CSF ranged between 8 and 40 mg/l (age-dependent) and between 0.4 and 1.5 mg/l in serum. Because of its relatively high CSF concentration ß-TP has been explored for the diagnosis of oto- and rhinoliquorrhea [102–104].

For quantitative nephelometric analysis, a sample volume of at least 5 μl is needed which is diluted with a dilution buffer to a total volume of 500 μl. The detection range of the assay is between 0.25 and 15.8 mg/l, the detection limit is at 2.5 mg/l. The test requires <15 min having the advantage of intraoperative use and repeated frequent testing, e.g. evaluation of treatment success of CSF fistula repair [105].

Highest sensitivities and specificities as well as accuracy values were reported using a cut-off value of 1.31–6 mg/l [103,106,107] (Table 3, twice class II, one class III study). In addition, a secretion/serum ratio of ß-TP has been introduced with a normal range below 1.57 yielding 100% specificity [108]. A cut-point at 1.11 mg/l for beta-trace protein gave the best trade-off between high sensitivity and high specificity when including the secretion/serum ratio [102]. In direct comparison to beta-2-transferrin the sensitivity and specificity values to detect CSF contamination in oto- and rhinorrhoea were similar (class II) [102,103].

Table 3.   Different cut-off values have been evaluated for diagnostic accuracy of CSF fistula (beta-trace protein)
SensitivitySpecificityRhino-/otorrhoeacut-offaNormal nasal secretion, mean, (range)aSerum mean, (range)aCSF mean, (range)aClass of evidenceReference
  1. CSF, cerebrospinal fluid; aAll units of measurements are mg/l.

92%100%>6 n = 330.9 n = 1070.5 n = 3411.1 n = 20II[106]
Not reportedNot reported>0.35 n = 200.016 (0.0–0.12) n = 290.6 (0.38–0–86) n = 13218.4 (9.4–29.2) n = 132III[107]
93%100%>1.31 (n = 53)0.4 (0.22–1.69) n = 1600.6 (0.12–1.44) n = 11619.6 (11.5–32.6) n = 19II[103]

A limitation of the ß-TP assay is that in patients with renal insufficiency and bacterial meningitis levels may substantially increase in serum and decrease in CSF, respectively. Hence, its use in such instances should be associated with cautious interpretation of the results.


The ß-TP test allows a quantitative detection of CSF fistulas with a high sensitivity and specificity (level A recommendation) in combination with computed tomography and clinical investigations. Due to procedural advantages ß-TP should be used as first line method depending on the frequency of requests (good practice point).

CSF markers with a future potential to be used in clinical routine

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. CSF markers recommended for use in clinical routine
  6. CSF markers with a future potential to be used in clinical routine
  7. References
  8. Reference Appendix

Vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) is a glycosylated homodimeric protein of approximately 45 kDa. It is produced by a broad range of cell types in response to stimuli such as hypoxia or tumor necrosis factor (TNF)-alpha [109–113]. VEGF is selectively mitogenic for endothelial cells and plays a fundamental role in both normal and abnormal angiogenesis [114]. VEGF can be measured with several commercially available sandwich enzyme-linked immunosorbent assays. Because those tests use various capture reagents, the resulting ‘normal’ ranges of VEGF in CSF depend on the test used.

Vascular endothelial growth factor in CSF was suggested to determine prognosis in several malignancies. VEGF was negatively correlated with survival in patients with leptomeningeal metastases [115,116] (class II), and astrocytic brain tumors [117,118] (class III). Furthermore, it serves as a biologic marker for the diagnosis and evaluation of treatment response in leptomeningeal metastases [119] (class III) (Table 4). VEGF is not detectable in lower grade gliomas (grade 2) [120] (class III).

Table 4.   Vascular endothelial growth factor diagnostic sensitivity and specificity in leptomeningeal metastases
SensitivitySpecificityCut-pointMethod /isoformClass of evidenceReference
100% (n = 19)73%(log tPA index–0.7229 * log VEGF index) < –0.18182ELISA/121,165 [205]
85% (n = 53)100%>262 ng/mlELISAII[115]
73% (n = 37) 51%93% 98.3%>100 ng/ml >250 ng/mlELISA/121,165II[116]
100% (n = 11)100%>633.1 ng/mlELISA/121,165III[119]

Studies investigating CSF VEGF in a number of other neurological conditions are summarized in Table 5 demonstrating a possible role in the pathogenesis of some diseases as well as some inconsistent findings.

Table 5.   VEGF levels in studies not investigating leptomeningeal metastases
Study population (N) VEGF meana values (pg/ml)aControl groupVEGF controls mean values (pg/ml)a Method/ isoformsClass of evidenceReference
  1. VEGF, vascular endothelial growth factor; CNS, central nervous system; aUnless stated otherwise; bTotal number derived from more than one study; csignificant difference between study population and one or more control groups; dlod: limit of detection; euncertain because VEGF concentrations are 1000 times higher than in most other studies; funcertain because of unusually high levels in ‘healthy’ controls.

 Tuberculous (48)b106c–144cVarious other forms of meningitis5.7–80.1ELISA/121, 165II[206,207]
 Eosinophilic (9)568None ELISA/165IV[208]
 Pneumococcal (10)Below loddViral meningitis (10) non-inflammatory controls (10)Slightly elevated below lodProtein arrayIII[209]
 Cryptococcal (95)37.5c (geometric mean)Spinal anesthesia (17)Below lodELISA/121,1652[210]
 Any bacterial (37)30% above cut-point (25 pg/ml)cViral meningitis (16) Non-inflammatory controls (35)Below lod Below lodELISAIII[211]
HIV with CNS infection (8)49.7HIV negative CNS infection (18)43.7ELISAIII[212]
HIV without CNS infection (19)42.6
CNS glioma grade 2 (7)Below lodControls unspecified (3)Below lodELISAIII[120]
CNS glioma grade 1 and 2 (7) CNS glioma grade 3 and 4 (19)Median 7.2 ng/ml 17.6 ng/mlcHydrocephalus (10)Median 8.3 ng/mlELISAUncertaine[117]
CNS glioma grade 3 and 4 (27)4.9 ng/mg of total proteinVarious tumors (31)0.006 ng/mg of total proteinNot statedIV[118]
Amyotrophic lateral sclerosis (105)bVarious ways of expressing VEGF levels (pg/ml, pg/l, int. Units)Various groups including ‘neurological’ controls, neurodegenerative disorders, headache, radiculopathies, total n = 124Ranging from significantly lower to equal to higherELISA/165All class III[213–217]
Pre-eclampsia (15)6.6Pregnant normal pressure5.5ELISAIII[218]
Alzheimer disease (43)bBelow lod 500c (only versus vasc. dementia)‘Healthy’controls (27) Vascular dementia (26) ‘Healthy’ controls (27)Below lod 330 130ELISA ELISA/165 ELISA/165III Uncertainf[219,220]
SAH (14) SAH (15)90 0–2000Non-SAH and ‘healthy’ controls (14) None13–19ELISA ELISA/165III, IV[221,222]
POEMS syndrome (10)6.8Other neurological disease, GBS, CIDP (total 40)3.0–9.1ELISAIII[223]

Elevated VEGF levels (cut-points between 100 and 650 pg/ml) in CSF are highly sensitive (73–100%) and specific (73–100%) for leptomeningeal metastases from solid but not from hematological tumors (level A recommendation) and are associated with a poor prognosis in this condition (level B recommendation). CSF VEGF levels appear to correlate with the grade of malignancy of CNS gliomas (level C recommendation). Normal to elevated as well as decreased VEGF in CSF can be found in various neurological diseases (bacterial meningitis, ALS, POEMS, and SAH) suggesting a possible pathogenic role without relevant diagnostic or prognostic value (level B recommendation).

CSF neurofilaments

Neurofilaments (Nfs) constitute the axonal cytoskeleton [121]. There are four Nf subunits: a light (NfL, 68 kDa), intermediate (NfM, 115 kDa) and heavy chain (NfH, 190–210 kDa) and also alpha-internexin. NFs are released into the CSF following axonal damage. The normal upper reference rages for CSF NfH and NfL levels are presented in Table 6.

Table 6.   Conditions in which increased NF has been shown
ConditionNF-HRemarksSensitivitySpecificityNF-LRemarksSensitivitySpecificityLevel of evidence
  1. AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; CBD, cortico–basal degeneration; DLB, diffuse Lewy body disease; FTLD, fronto–temporal lobar degeneration; GBS, Guillain–Barré syndrome; ICH, intracerebral hemorrhage; MMC, meningo–myelocele; MS, multiple sclerosis; MSA, multiple system atrophy; NMO, neuromyelitis optica; ON, optic neuritis; PD, Parkinson’s disease; PSP, progressive supranuclear palsy; SAH, subarachnoid hemorrhage; n.a., not available; n.d., not done.

Cut-off value0.73 ng/ml [122]Based on a reference population from a neurologial hospital (n = 416)  Rosengren: 125 pg/l; <60 years: <0.25 ng/ml; 60–70: 0.38 ng/ml; 71–80: <0.75 ng/ml; Norgren: 100 ng/l. Van Geel: 40 ng/l Population based reference values (healthy volunteers)   
Condition in which neurofilament is increased
 ALS[122,135,137]Five times higher than in controls. In upper motor symptoms two times higher than in lower motor symptomsAt cut-off of 0.73: 80% for ALS versus control. ALS versus AD: 8075% (ALS versus control) ALS versus AD: 97%[127,136,224]About 10 times increase in patients with upper motor symptoms. About two times increase in patients with lower motor symptomsn.a.n.a.Class II
 PD & MSA[143,145]About 3 times elevated in MSA, not elevated in IPDNfH: cut-off of 114.5: 83% for MSA-P versus IPD 77% for PSP from IPD (cut-off of 1.4 ng/ml)87% for MSA versus IPD; 94% for PSP versus IPD[144,145]About seven times elevated in MSA, not elevated in IPDNF-L: cut-off of 17.15: 83% for MSA-P versus IPD90%Class III
 PSP[143]The ROC optimised cut-off level of 1.48 ng/ml is used for distinguishing patients with PSP from those with PD or CBD76.5%93.8%[144]n.a.n.a.n.a.Class III
 MSIn most MS patients CSF NfH levels are within the normal reference range [122].At a cut-off: 160 pg/ml: sensitivity 34% and specificity 88% for conversion from CIS to RRMS [170]. Contradictory results found by Lim [134]. Relation with progression. Phophorylation rate eight times higher in severy disabled patients compared to mildly disabled patients [132] and also prognostic for deterioration at follow-up [131]. NfH increases during follow-up [121]n.a.n.a.[127,129,130] Not increased: [133]2–10 times higher during relapses versus remission or SP [129,130]. R progr-index: 0.29 (P < 0.023) [130]78% for MS; 91% for relapse, 44% for remission, 48% for SP92–100%Relation with progression: class II
 AD[225,226]Using ROC optimised cut-off levels. NfH higher in AD compared to controls. Effect size 0.71 [227][225] 57.5%77.0%[127,228–230]Increased in AD and VD compared to controls. In the meta-analysis the effect size distinguishing AD from controls was 1.27 with AD patients having the higher CSF NfL levels [227]58–78%28–77%Class II
 FTLD[226,230]NfH higher in FTLD compared to controls. Effect size 0.74 [227]   [226,228,230–232]NfL Higher in FTLD compared to controls. Effect size was 1.38 [227]82% to discriminate FTD from EAD in [226] contradictory with Pijnenburg et al.70%Class II
 VD[225]NfH is higher in VD then in ADn.a.n.a.[127,228,229,233]NfL Higher than in AD then in controls. Effect size 1.24 [227]85%68%Class II
 DLBD[226]Using ROC optimised cut-off levels. NfH higher in DLBD compared to late AD89%28% Using ROC optimised cut-off levels. NfH higher in DLBD compared to late AD33%82%Class III
 Spinal cord  injury n.d.   [234]5 to 450x increased in acute cervical spine injury, and levels increase during 21 days after the injuryCut-off of 125 ng/l, 100% sens for acute spinal cord injury, 18% for whiplash100%Class III
 AIDS–dementia  complexn.d.   [138–142]n = 8, three subjects increased NF-L after interruption. Noclinical signs, but f.u. time only 101 days. Subclinical marker?n.a.86% [139]Class II
 SAH[123–125]Prognostic for outcomeCut-off: highest value in survivors: 57–100% for unfavorable outcome71–75%[126–128]Lumbar CSFCut-off for unfavorable outcome: 6,400 ng/l: 100% sens50%Class I
 NPHn.d.   [196,235–237]Ten times increased compared to reference valuesn.a.n.a.Class III
 Binswanger  diseasen.d.   [235]Four times increased compared to reference values.n.a.n.a.Class III
 GBS[238]A prognostic marker for poor outcome. Not a diagnostic testn.a.n.a.n.d.   Class III
 Cardiac arrestn.d.   [239]Prognostic for axonal damage after cardiac arrestPoor outcome (Glasgow Coma Scale): 75–92%80–100% for different cut-offsClass III
 HSV encephalitis  relapsen.d.   [240]Higher during encephalitis relapsen.a.n.a.Class III

A comprehensive list of studies on NfL and NfH including cut-points and diagnostic sensitivity and specificity values is summarized in Table 6. Reference values depend on many pre-analytical and analytical factors and vary between laboratories. It is therefore, strongly encouraged that each laboratory establish its own reference values.

Neurofilaments are of prognostic value in subarachnoid hemorrhage (SAH). Increased levels of NfH and NfL in ventricular and lumbar CSF are related to poor outcome using the Glasgow outcome score (class I) [122–125] [126–128]. In MS, high CSF NfL levels were of prognostic value on a number of clinical outcome scales (class III) [129,130]. The heavy chain of Nfs in CSF was also related to progression within the subsequent year in RRMS patients (class III) [131–133]. Moreover, CSF NfH levels in the CSF or plasma of patients with optic neuritis (ON) predicted the degree of permanent loss of visual function (class III) [132,134]. Finally, CSF NfH levels were significantly higher in patients with neuromyelitis optica (NMO) which is consistent with the clinical experience of more severe disease and more extensive axonal loss in NMO than in MS (class III) [135].

In amyotrophic lateral sclerosis (ALS) patients high CSF NfH levels were related to a more rapid clinical progression and with upper motor neuron symptoms (class II) [136,137]. In the AIDS–dementia complex elevated CSF NfL levels were shown to be a good secondary outcome measure in an antiretroviral treatment trial (class III) [138–142]. CSF Nf levels could discriminate different Parkinsonian disorders. NfL and NfH levels were higher in patients with multi-system atrophy compared to patients with Parkinson’s disease (class II) [143–145].

A recent meta-analysis reviewing the value of CSF NfL and NfH in neurodegenerative dementia concluded that CSF NfL and NfH levels were increased in AD, frontotemporal lobar dementia (FTLD) and vascular dementia (class III) (see Table 6 for references and [122]). In comparison to CSF tau and Aβ1-42 levels the diagnostic accuracy of CSF NfL and NfH levels is lower.


Cerebrospinalfluid neurofilament levels can be used as a biomarker for neuronal death and axonal degeneration (level B rating). The prognostic value of CSF Nf levels is highest in acute conditions such as SAH, ALS, MSA, MS, acute ON and NMO (level B rating). There is further evidence from longitudinal studies that there is potential for CSF Nf to be used to monitor disease progression in SAH, MS and spinal cord injury (level B rating). Because reference values depend on many pre-analytical and analytical factors, laboratories should establish their own reference values.

Myelin basic protein

Myelin basic protein (MBP) is a major protein in CNS myelin, but constitutes a lesser proportion of myelin in the PNS [146]. The CSF concentration of MBP increases with age (class I) [147], and many disease processes, even diseases affecting mainly peripheral nerve myelin, may show increases in the CSF concentration of MBP (class II) [148–151]. It is mostly measured by radioimmunoassay, but ELISA assays have also been developed. The CSF concentration of MBP is increased in multiple sclerosis (MS) (class I), where it is higher in relapses than in progression (class I), correlates with the severity of the relapse (class II), is higher in patients with multifocal relapses than in monofocal relapses (class III), and is higher in relapses with new symptoms than with the recurrence of previous symptoms (class III) [152,153–159]. Increased CSF concentrations of MBP in patients in clinical remission may be associated with an increased relapse risk and a lower risk of a benign disease course (class III) [160,161].

The CSF concentration of MBP decreases in parallel with spontaneous remission of clinical symptoms and with the resolution of active brain lesions on Gd-enhanced MRI after treatment with methylprednisolone (class III) [162,163]. Increased CSF concentrations of MBP may indicate a better short-term response to treatment with methylprednisolone, but Gd-enhanced MRI studies are superior to MBP measurements in this respect (class III) [164,165].


Myelin basic protein immunoassays are technically demanding because the analyte exists both in free and lipid-bound forms and bound in immune complexes. This is often not considered in CSF research. Increased CSF concentrations of MBP are unspecific and can be found in a variety of diseases, not only in MS (level A rating). It is possible that MBP measurements could be of prognostic value in MS (level C rating).

Recommendations for future research

In general, disease-specific biomarkers for diagnostic, prognostic, and monitoring purposes should be validated using established protocols [166,167]. Furthermore, validation across laboratories is urgently needed for many biomarkers, as shown for Aβ and Tau proteins [168]. With respect to Aβ1-42, tau and P-tau, there is a need for evaluation of the precise predictive value of these methods in the differentiation between different neurodegenerative diseases, rather than as for the discrimination between healthy aging and patients with AD (incipient or definite). There seems to be a potential for assays recognizing different phosphoforms of tau in differential diagnosis, and this issue should be pursued in future studies.

Studies of 14-3-3 protein, Aβ1-42, tau and P-tau may also be helpful as diagnostic aids in patients with suspected CJD, but since CJD is a rare disorder, a very high diagnostic specificity against a wide spectrum of other diseases presenting with rapidly progressing dementia is necessary, and this issue needs to be investigated more thoroughly. The value of measuring hypocretin-1 (orexin-1) levels in CSF of other sleep disorders needs to be addressed. A serum marker for narcolepsy with cataplexy would be helpful for early diagnosis and serial analysis during the course and treatment of the disease.

The diagnostic and prognostic value of VEGF in leptomeningeal metastases should be confirmed in a larger prospective study, specifically in cytology-negative patients. For patients with leptomeningeal metastases from hematological tumors more sensitive markers need to be explored. Regarding the Nf assays, standardization of the assays and variation amongst different laboratories should be explored, in order to define reliable reference values. The use of Nfs in predicting neurological decline must be explored further. Further research should also focus on combining Nfs with other markers, as they will probably not be able to predict neurological decline with sufficient specificity and sensitivity as a stand alone marker.

Reference Appendix

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy
  5. CSF markers recommended for use in clinical routine
  6. CSF markers with a future potential to be used in clinical routine
  7. References
  8. Reference Appendix
  • 1
    Deisenhammer F, Bartos A, Egg R, et al. Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force. European Journal of Neurology 2006; 13: 913922.
  • 2
    Biomarkers Definition Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clinical Pharmacology and Therapeutics 2001; 69: 8995.
  • 3
    Brainin M, Barnes M, Baron JC, et al. Guidance for the preparation of neurological management guidelines by EFNS scientific task forces--revised recommendations 2004. European Journal of Neurology 2004; 11: 577581.
  • 4
    Blennow K, Hampel H. CSF markers for incipient Alzheimer’s disease. Lancet Neurology 2003; 2: 605613.
  • 5
    Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurology 2007; 6: 734746.
  • 6
    Sunderland T, Linker G, Mirza N, et al. Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA 2003; 289: 20942103.
  • 7
    Wiltfang J, Lewczuk P, Riederer P, et al. Consensus paper of the WFSBP Task Force on Biological Markers of Dementia: the role of CSF and blood analysis in the early and differential diagnosis of dementia. World Journal of Biological Psychiatry 2005; 6: 6984.
  • 8
    Ishiguro K, Ohno H, Arai H, et al. Phosphorylated tau in human cerebrospinal fluid is a diagnostic marker for Alzheimer’s disease. Neuroscience Letters 1999; 270: 9194.
  • 9
    Itoh N, Arai H, Urakami K, et al. Large-scale, multicenter study of cerebrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer’s disease. Annals of Neurology 2001; 50: 150156.
  • 10
    Andreasen N, Minthon L, Davidsson P, et al. Evaluation of CSF-tau and CSF-Abeta42 as diagnostic markers for Alzheimer disease in clinical practice. Archives of Neurology 2001; 58: 373379.
  • 11
    Hulstaert F, Blennow K, Ivanoiu A, et al. Improved discrimination of AD patients using beta-amyloid(1-42) and tau levels in CSF. Neurology 1999; 52: 15551562.
  • 12
    Hesse C, Rosengren L, Vanmechelen E, et al. Cerebrospinal fluid markers for Alzheimer’s disease evaluated after acute ischemic stroke. Journal of Alzheimers Disease 2000; 4: 199206.
  • 13
    Nagga K, Gottfries J, Blennow K, Marcusson J. Cerebrospinal fluid phospho-tau, total tau and beta-amyloid(1-42) in the differentiation between Alzheimer’s disease and vascular dementia. Dementia and Geriatric Cognitive Disorders 2002; 14: 183190.
  • 14
    Hampel H, Buerger K, Zinkowski R, et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Archives of General Psychiatry 2004; 61: 95102.
  • 15
    Parnetti L, Lanari A, Amici S, Gallai V, Vanmechelen E, Hulstaert F. CSF phosphorylated tau is a possible marker for discriminating Alzheimer’s disease from dementia with Lewy bodies. Phospho-Tau International Study Group. Neurology Science 2001; 22: 7778.
  • 16
    Schoonenboom NS, Pijnenburg YA, Mulder C, et al. Amyloid beta(1-42) and phosphorylated tau in CSF as markers for early-onset Alzheimer disease. Neurology 2004; 62: 15801584.
  • 17
    Vanderstichele H, De VK, Blennow K, et al. Analytical performance and clinical utility of the INNOTEST PHOSPHO-TAU181P assay for discrimination between Alzheimer’s disease and dementia with Lewy bodies. Clinical Chemistry and Laboratory Medicine 2006; 44: 14721480.
  • 18
    Vanmechelen E, Vanderstichele H, Davidsson P, et al. Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: a sandwich ELISA with a synthetic phosphopeptide for standardization. Neuroscience Letters 2000; 285: 4952.
  • 19
    Blennow K, Johansson A, Zetterberg H. Diagnostic value of 14-3-3beta immunoblot and T-tau/P-tau ratio in clinically suspected Creutzfeldt-Jakob disease. International Journal of Molecular Medicine 2005; 16: 11471149.
  • 20
    Buerger K, Otto M, Teipel SJ, et al. Dissociation between CSF total tau and tau protein phosphorylated at threonine 231 in Creutzfeldt-Jakob disease. Neurobiology of Aging 2006; 27: 1015.
  • 21
    Otto M, Esselmann H, Schulz-Shaeffer W, et al. Decreased beta-amyloid1-42 in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurology 2000; 54: 10991102.
  • 22
    Otto M, Wiltfang J, Cepek L, et al. Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology 2002; 58: 192197.
  • 23
    Riemenschneider M, Wagenpfeil S, Vanderstichele H, et al. Phospho-tau/total tau ratio in cerebrospinal fluid discriminates Creutzfeldt-Jakob disease from other dementias. Molecular Psychiatry 2003; 8: 343347.
  • 24
    Satoh K, Shirabe S, Eguchi H, et al. 14-3-3 protein, total tau and phosphorylated tau in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease and neurodegenerative disease in Japan. Cellular and Molecular Neurobiology 2006; 26: 4552.
  • 25
    Van Everbroeck B, Green AJ, Pals P, Martin JJ, Cras P. Decreased Levels of Amyloid-beta 1-42 in Cerebrospinal Fluid of Creutzfeldt-Jakob Disease Patients. Journal of Alzheimers Disease 1999; 1: 419424.
  • 26
    Van Everbroeck B, Green AJ, Vanmechelen E, et al. Phosphorylated tau in cerebrospinal fluid as a marker for Creutzfeldt-Jakob disease. Journal of Neurology, Neurosurgery and Psychiatry 2002; 73: 7981.
  • 27
    Van Everbroeck B, Quoilin S, Boons J, Martin JJ, Cras P. A prospective study of CSF markers in 250 patients with possible Creutzfeldt-Jakob disease. Journal of Neurology, Neurosurgery and Psychiatry 2003; 74: 12101214.
  • 28
    Goodall CA, Head MW, Everington D, Ironside JW, Knight RS, Green AJ. Raised CSF phospho-tau concentrations in variant Creutzfeldt-Jakob disease: diagnostic and pathological implications. Journal of Neurology, Neurosurgery and Psychiatry 2006; 77: 8991.
  • 29
    Bibl M, Mollenhauer B, Esselmann H, et al. CSF amyloid-beta-peptides in Alzheimer’s disease, dementia with Lewy bodies and Parkinson’s disease dementia. Brain 2006; 5: 11771187.
  • 30
    Bibl M, Mollenhauer B, Lewczuk P, et al. Validation of amyloid-beta peptides in CSF diagnosis of neurodegenerative dementias. Molecular Psychiatry 2007; 12: 671680.
  • 31
    Bibl M, Mollenhauer B, Wolf S, et al. Reduced CSF carboxyterminally truncated Abeta peptides in frontotemporal lobe degenerations. Journal of Neural Transmission 2007; 114: 621628.
  • 32
    Borroni B, Gardoni F, Parnetti L, et al. Pattern of Tau forms in CSF is altered in progressive supranuclear palsy. Neurobiology of Aging 2009; 30: 3440.
  • 33
    Mollenhauer B, Bibl M, Esselmann H, et al. Tauopathies and synucleinopathies: do cerebrospinal fluid beta-amyloid peptides reflect disease-specific pathogenesis? Journal of Neural Transmission 2007; 114: 919927.
  • 34
    Andersson C, Blennow K, Almkvist O, et al. Increasing CSF phospho-tau levels during cognitive decline and progression to dementia. Neurobiology of Aging 2008; 29: 14661473.
  • 35
    Buerger K, Teipel SJ, Zinkowski R, et al. CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects. Neurology 2002; 59: 627629.
  • 36
    Buerger K, Ewers M, Andreasen N, et al. Phosphorylated tau predicts rate of cognitive decline in MCI subjects: a comparative CSF study. Neurology 2005; 65: 15021503.
  • 37
    Ewers M, Buerger K, Teipel SJ, et al. Multicenter assessment of CSF-phosphorylated tau for the prediction of conversion of MCI. Neurology 2007; 69: 22052212.
  • 38
    Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Archives of Neurology 2007; 64: 343349.
  • 39
    Gustafson DR, Skoog I, Rosengren L, Zetterberg H, Blennow K. Cerebrospinal fluid beta-amyloid 1-42 concentration may predict cognitive decline in older women. Journal of Neurology, Neurosurgery and Psychiatry 2007; 78: 461464.
  • 40
    Riemenschneider M, Lautenschlager N, Wagenpfeil S, Diehl J, Drzezga A, Kurz A. Cerebrospinal fluid tau and beta-amyloid 42 proteins identify Alzheimer disease in subjects with mild cognitive impairment. Archives of Neurology 2002; 59: 17291734.
  • 41
    Schonknecht P, Pantel J, Kaiser E, Thomann P, Schroder J. Increased tau protein differentiates mild cognitive impairment from geriatric depression and predicts conversion to dementia. Neuroscience Letters 2007; 416: 3942.
  • 42
    Stomrud E, Hansson O, Blennow K, Minthon L, Londos E. Cerebrospinal fluid biomarkers predict decline in subjective cognitive function over 3 years in healthy elderly. Dementia and Geriatric Cognitive Disorders 2007; 24: 118124.
  • 43
    Zetterberg H, Wahlund LO, Blennow K. Cerebrospinal fluid markers for prediction of Alzheimer’s disease. Neuroscience Letters 2003; 352: 6769.
  • 44
    Tokuda T, Oide T, Tamaoka A, Ishii K, Matsuno S, Ikeda S. Prednisolone (30–60 mg/day) for diseases other than AD decreases amyloid beta-peptides in CSF. Neurology 2002; 58: 14151418.
  • 45
    Bateman RJ, Wen G, Morris JC, Holtzman DM. Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker. Neurology 2007; 68: 666669.
  • 46
    Kaiser E, Schonknecht P, Thomann PA, Hunt A, Schroder J. Influence of delayed CSF storage on concentrations of phospho-tau protein (181), total tau protein and beta-amyloid (1-42). Neuroscience Letters 2007; 417: 193195.
  • 47
    Lewczuk P, Beck G, Esselmann H, et al. Effect of sample collection tubes on cerebrospinal fluid concentrations of tau proteins and amyloid beta peptides. Clinical Chemistry 2006; 52: 332334.
  • 48
    Schoonenboom NS, Mulder C, Vanderstichele H, et al. Effects of processing and storage conditions on amyloid beta (1-42) and tau concentrations in cerebrospinal fluid: implications for use in clinical practice. Clinical Chemistry 2005; 51: 189195.
  • 49
    Bibl M, Esselmann H, Otto M, et al. Cerebrospinal fluid amyloid beta peptide patterns in Alzheimer’s disease patients and nondemented controls depend on sample pretreatment: indication of carrier-mediated epitope masking of amyloid beta peptides. Electrophoresis 2004; 25: 29122918.
  • 50
    Sjogren M, Vanderstichele H, Agren H, et al. Tau and Abeta42 in cerebrospinal fluid from healthy adults 21-93 years of age: establishment of reference values. Clinical Chemistry 2001; 47: 17761781.
  • 51
    Boston PF, Jackson P, Thompson RJ. Human 14-3-3 protein: radioimmunoassay, tissue distribution, and cerebrospinal fluid levels in patients with neurological disorders. Journal of Neurochemistry 1982; 38: 14751482.
  • 52
    Hsich G, Kenney K, Gibbs CJ, Lee KH, Harrington MG. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. New England Journal of Medicine 1996; 335: 924930.
  • 53
    Zerr I, Pocchiari M, Collins S, et al. Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease. Neurology 2000; 55: 811815.
  • 54
    Beaudry P, Cohen P, Brandel JP, et al. 14-3-3 protein, neuron-specific enolase, and S-100 protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Dementia and Geriatric Cognitive Disorders 1999; 10: 4046.
  • 55
    Collins S, Boyd A, Fletcher A, et al. Creutzfeldt-Jakob disease: diagnostic utility of 14-3-3 protein immunodetection in cerebrospinal fluid. Journal of Clinical Neuroscience 2000; 7: 203208.
  • 56
    Collins SJ, Sanchez-Juan P, Masters CL, et al. Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease. Brain 2006; 9: 22782287.
  • 57
    Kenney K, Brechtel C, Takahashi H, Kurohara K, Anderson P, Gibbs CJ Jr. An enzyme-linked immunosorbent assay to quantify 14-3-3 proteins in the cerebrospinal fluid of suspected Creutzfeldt-Jakob disease patients. Annals of Neurology 2000; 48: 395398.
  • 58
    Lemstra AW, Van Meegen MT, Vreyling JP, et al. 14-3-3 testing in diagnosing Creutzfeldt-Jakob disease: a prospective study in 112 patients. Neurology 2000; 55: 514516.
  • 59
    Green AJ, Ramljak S, Muller WE, Knight RS, Schroder HC. 14-3-3 in the cerebrospinal fluid of patients with variant and sporadic Creutzfeldt-Jakob disease measured using capture assay able to detect low levels of 14-3-3 protein. Neuroscience Letters 2002; 324: 5760.
  • 60
    Zerr I, Schulz-Schaeffer WJ, Giese A, et al. Current clinical diagnosis in Creutzfeldt-Jakob disease: identification of uncommon variants. Annals of Neurology 2000; 48: 323329.
  • 61
    Castellani RJ, Colucci M, Xie Z, et al. Sensitivity of 14-3-3 protein test varies in subtypes of sporadic Creutzfeldt-Jakob disease. Neurology 2004; 63: 436442.
  • 62
    Bartosik-Psujek H, Stelmasiak Z. The CSF levels of total-tau and phosphotau in patients with relapsing-remitting multiple sclerosis. Journal of Neural Transmission 2006; 113: 339345.
  • 63
    Zerr I, Bodemer M, Gefeller O, et al. Detection of 14-3-3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease. Annals of Neurology 1998; 43: 3240.
  • 64
    Burkhard PR, Sanchez JC, Landis T, Hochstrasser DF. CSF detection of the 14-3-3 protein in unselected patients with dementia. Neurology 2001; 56: 15281533.
  • 65
    Irani DN, Kerr DA. 14-3-3 protein in the cerebrospinal fluid of patients with acute transverse myelitis. Lancet 2000; 355: 901.
  • 66
    Colucci M, Roccatagliata L, Capello E, et al. The 14-3-3 protein in multiple sclerosis: a marker of disease severity. Multiple Sclerosis 2004; 10: 477481.
  • 67
    Martinez-Yelamos A, Rovira A, Sanchez-Valle R, et al. CSF 14-3-3 protein assay and MRI as prognostic markers in patients with a clinically isolated syndrome suggestive of MS. Journal of Neurology 2004; 251: 12781279.
  • 68
    De Seze J, Peoc’h K, Ferriby D, Stojkovic T, Laplanche JL, Vermersch P. 14-3-3 Protein in the cerebrospinal fluid of patients with acute transverse myelitis and multiple sclerosis. Journal of Neurology 2002; 249: 626627.
  • 69
    Yasui K, Inoue Y, Kanbayashi T, Nomura T, Kusumi M, Nakashima K. CSF orexin levels of Parkinson’s disease, dementia with Lewy bodies, progressive supranuclear palsy and corticobasal degeneration. Journal of the Neurological Sciences 2006; 250: 120123.
  • 70
    Wurtman RJ. Narcolepsy and the hypocretins. Metabolism 2006; 55(10 Suppl 2): S36S39.
  • 71
    Dohi K, Nishino S, Nakamachi T, et al. CSF orexin A concentrations and expressions of the orexin-1 receptor in rat hippocampus after cardiac arrest. Neuropeptides 2006; 40: 245250.
  • 72
    Oyama K, Takahashi T, Shoji Y, et al. Niemann-Pick disease type C: cataplexy and hypocretin in cerebrospinal fluid. Tohoku Journal of Experimental Medicine 2006; 209: 263267.
  • 73
    Grady SP, Nishino S, Czeisler CA, Hepner D, Scammell TE. Diurnal variation in CSF orexin-A in healthy male subjects. Sleep 2006; 29: 295297.
  • 74
    Baumann CR, Khatami R, Werth E, Bassetti CL. Hypocretin (orexin) deficiency predicts severe objective excessive daytime sleepiness in narcolepsy with cataplexy. Journal of Neurology, Neurosurgery and Psychiatry 2006; 77: 402404.
  • 75
    Gaus SE, Lin L, Mignot E. CSF hypocretin levels are normal in Huntington’s disease patients. Sleep 2005; 28: 16071608.
  • 76
    Arrer E, Oberascher G, Gibitz HJ. Protein distribution in the human perilymph. A comparative study between perilymph (post mortem), CSF and blood serum. Acta Oto-Laryngologica 1988; 2: 117123.
  • 77
    Arrer E, Gibitz HJ. Detection of beta 2-transferrin with agarose gel electrophoresis, immunofixation and silver staining in cerebrospinal fluid, secretions and other body fluids. Journal of Clinical Chemistry and Clinical Biochemistry 1987; 25: 113116.
  • 78
    Stibler H. Carbohydrate-deficient transferrin in serum: a new marker of potentially harmful alcohol consumption reviewed. Clinical Chemistry 1991; 37: 20292037.
  • 79
    Bell H, Tallaksen C, Sjaheim T, et al. Serum carbohydrate-deficient transferrin as a marker of alcohol consumption in patients with chronic liver diseases. Alcoholism, Clinical and Experimental Research 1993; 17: 246252.
  • 80
    Kristiansson B, Andersson M, Tonnby B, Hagberg B. Disialotransferrin developmental deficiency syndrome. Archives of Disease in Childhood 1989; 64: 7176.
  • 81
    Sloman AJ, Kelly RH. Transferrin allelic variants may cause false positives in the detection of cerebrospinal fluid fistulae. Clinical Chemistry 1993; 39: 14441445.
  • 82
    Jaeken J, Van Eijk HG, Van Der HC, Corbeel L, Eeckels R, Eggermont E. Sialic acid-deficient serum and cerebrospinal fluid transferrin in a newly recognized genetic syndrome. Clinica Chimica Acta 1984; 144: 245247.
  • 83
    Zaret DL, Morrison N, Gulbranson R, Keren DF. Immunofixation to quantify beta 2-transferrin in cerebrospinal fluid to detect leakage of cerebrospinal fluid from skull injury. Clinical Chemistry 1992; 38: 19081912.
  • 84
    Oberascher G. Cerebrospinal fluid otorrhea--new trends in diagnosis. American Journal of Otology 1988; 9: 102108.
  • 85
    Skedros DG, Cass SP, Hirsch BE, Kelly RH. Sources of error in use of beta-2 transferrin analysis for diagnosing perilymphatic and cerebral spinal fluid leaks. Otolaryngology - Head and Neck Surgery 1993; 109: 861864.
  • 86
    Kelly RH, Kelly CM, Busis SN. Factitious hearing loss and otorrhea in an adolescent boy. Clinica Chimica Acta 2000; 299: 205209.
  • 87
    Nandapalan V, Watson ID, Swift AC. Beta-2-transferrin and cerebrospinal fluid rhinorrhoea. Clinical Otolaryngology and Allied Sciences 1996; 21: 259264.
  • 88
    Roelandse FW, Van Der ZN, Didden JH, Van LJ, Souverijn JH. Detection of CSF leakage by isoelectric focusing on polyacrylamide gel, direct immunofixation of transferrins, and silver staining. Clinical Chemistry 1998; 44: 351353.
  • 89
    Normansell DE, Stacy EK, Booker CF, Butler TZ. Detection of beta-2 transferrin in otorrhea and rhinorrhea in a routine clinical laboratory setting. Clinical and Diagnostic Laboratory Immunology 1994; 1: 6870.
  • 90
    Keir G, Zeman A, Brookes G, Porter M, Thompson EJ. Immunoblotting of transferrin in the identification of cerebrospinal fluid otorrhoea and rhinorrhoea. Annals of Clinical Biochemistry 1992; 29(Pt 2): 210213.
  • 91
    Ryall RG, Peacock MK, Simpson DA. Usefulness of beta 2-transferrin assay in the detection of cerebrospinal fluid leaks following head injury. Journal of Neurosurgery 1992; 77: 737739.
  • 92
    Bateman N, Jones NS. Rhinorrhoea feigning cerebrospinal fluid leak: nine illustrative cases. Journal of Laryngology and Otology 2000; 114: 462464.
  • 93
    Warnecke A, Averbeck T, Wurster U, Harmening M, Lenarz T, Stover T. Diagnostic relevance of beta2-transferrin for the detection of cerebrospinal fluid fistulas. Archives of Otolaryngology - Head and Neck Surgery 2004; 130: 11781184.
  • 94
    Oberascher G. A modern concept of cerebrospinal fluid diagnosis in oto- and rhinorrhea. Rhinology 1988; 26: 89103.
  • 95
    Seidl RO, Todt I, Ernst A. Reconstruction of traumatic skull base defects with alloplastic, resorbable fleece. HNO 2000; 48: 753757.
  • 96
    Simmen D, Bischoff T, Schuknecht B. Experiences with assessment of frontobasal defects, a diagnostic concept. Laryngo-Rhino-Otologie 1997; 76: 583587.
  • 97
    Skedros DG, Cass SP, Hirsch BE, Kelly RH. Beta-2 transferrin assay in clinical management of cerebral spinal fluid and perilymphatic fluid leaks. Journal of Otolaryngology 1993; 22: 341344.
  • 98
    Tumani H, Reiber H, Nau R, et al. Beta-trace protein concentration in cerebrospinal fluid is decreased in patients with bacterial meningitis. Neuroscience Letters 1998; 242: 58.
  • 99
    Hochwald GM, Pepe AJ, Thorbecke GJ. Trace proteins in biological fluids. IV. Physicochemical properties and sites of formation of gamma-trace and beta-trace proteins. Proceedings of the Society for Experimental Biology and Medicine 1967; 124: 961966.
  • 100
    Urade Y, Tanaka T, Eguchi N, et al. Structural and functional significance of cysteine residues of glutathione-independent prostaglandin D synthase. Identification of Cys65 as an essential thiol. Journal of Biological Chemistry 1995; 270: 14221428.
  • 101
    Blodorn B, Mader M, Urade Y, Hayaishi O, Felgenhauer K, Bruck W. Choroid plexus: the major site of mRNA expression for the beta-trace protein (prostaglandin D synthase) in human brain. Neuroscience Letters 1996; 209: 117120.
  • 102
    Bachmann-Harildstad G. Diagnostic values of beta-2 transferrin and beta-trace protein as markers for cerebrospinal fluid fistula. Rhinology 2008; 46: 8285.
  • 103
    Meco C, Oberascher G, Arrer E, Moser G, Albegger K. Beta-trace protein test: new guidelines for the reliable diagnosis of cerebrospinal fluid fistula. Otolaryngology - Head and Neck Surgery 2003; 129: 508517.
  • 104
    Felgenhauer K, Schadlich HJ, Nekic M. Beta trace-protein as marker for cerebrospinal fluid fistula. Klinische Wochenschrift 1987; 65: 764768.
  • 105
    Meco C, Arrer E, Oberascher G. Efficacy of cerebrospinal fluid fistula repair: sensitive quality control using the beta-trace protein test. American Journal of Rhinology 2007; 21: 729736.
  • 106
    Petereit HF, Bachmann G, Nekic M, Althaus H, Pukrop R. A new nephelometric assay for beta-trace protein (prostaglandin D synthase) as an indicator of liquorrhoea. Journal of Neurology, Neurosurgery and Psychiatry 2001; 71: 347351.
  • 107
    Reiber H, Walther K, Althaus H. Beta-trace protein as sensitive marker for CSF rhinorhea and CSF otorhea. Acta Neurologica Scandinavica 2003; 108: 359362.
  • 108
    Bachmann-Harildstad G. Incidence of CSF fistula after paranasal sinus surgery: the Northern Norwegian experience. Rhinology 2007; 45: 305307.
  • 109
    Inoue T, Kibata K, Suzuki M, Nakamura S, Motoda R, Orita K. Identification of a vascular endothelial growth factor (VEGF) antagonist, sFlt-1, from a human hematopoietic cell line NALM-16. FEBS Letters 2000; 469: 1418.
  • 110
    Gaudry M, Bregerie O, Andrieu V, El Benna J, Pocidalo MA, Hakim J. Intracellular pool of vascular endothelial growth factor in human neutrophils. Blood 1997; 90: 41534161.
  • 111
    Perez-Ruiz M, Ros J, Morales-Ruiz M, et al. Vascular endothelial growth factor production in peritoneal macrophages of cirrhotic patients: regulation by cytokines and bacterial lipopolysaccharide. Hepatology 1999; 29: 10571063.
  • 112
    Xiong M, Elson G, Legarda D, Leibovich SJ. Production of vascular endothelial growth factor by murine macrophages: regulation by hypoxia, lactate, and the inducible nitric oxide synthase pathway. American Journal of Pathology 1998; 153: 587598.
  • 113
    Williams B, Quinn-Baker A, Gallacher B. Serum and platelet-derived growth factor-induced expression of vascular permeability factor mRNA by human vascular smooth muscle cells in vitro. Clinical Science (London) 1995; 88: 141147.
  • 114
    Ferrara N. Role of vascular endothelial growth factor in regulation of physiological angiogenesis. American Journal of Physiology. Cell Physiology 2001; 280: C1358C1366.
  • 115
    Reijneveld JC, Brandsma D, Boogerd W, et al. CSF levels of angiogenesis-related proteins in patients with leptomeningeal metastases. Neurology 2005; 65: 11201122.
  • 116
    Herrlinger U, Wiendl H, Renninger M, Forschler H, Dichgans J, Weller M. Vascular endothelial growth factor (VEGF) in leptomeningeal metastasis: diagnostic and prognostic value. British Journal of Cancer 2004; 91: 219224.
  • 117
    Peles E, Lidar Z, Simon AJ, Grossman R, Nass D, Ram Z. Angiogenic factors in the cerebrospinal fluid of patients with astrocytic brain tumors. Neurosurgery 2004; 55: 562567.
  • 118
    Sampath P, Weaver CE, Sungarian A, Cortez S, Alderson L, Stopa EG. Cerebrospinal fluid (vascular endothelial growth factor) and serologic (recoverin) tumor markers for malignant glioma. Cancer Control 2004; 11: 174180.
  • 119
    Stockhammer G, Poewe W, Burgstaller S, et al. Vascular endothelial growth factor in CSF: A biological marker for carcinomatous meningitis. Neurology 2000; 54: 16701676.
  • 120
    Ribom D, Larsson A, Pietras K, Smits A. Growth factor analysis of low-grade glioma CSF: PDGF and VEGF are not detectable. Neurology Science 2003; 24: 7073.
  • 121
    Petzold A. Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss. Journal of the Neurological Sciences 2005; 233: 183198.
  • 122
    Petzold A, Baker D, Pryce G, Keir G, Thompson EJ, Giovannoni G. Quantification of neurodegeneration by measurement of brain-specific proteins. Journal of Neuroimmunology 2003; 138: 4548.
  • 123
    Petzold A, Rejdak K, Belli A, et al. Axonal pathology in subarachnoid and intracerebral hemorrhage. Journal of Neurotrauma 2005; 22: 407414.
  • 124
    Lewis SB, Wolper RA, Miralia L, Yang C, Shaw G. Detection of phosphorylated NF-H in the cerebrospinal fluid and blood of aneurysmal subarachnoid hemorrhage patients. Journal of Cerebral Blood Flow and Metabolism 2008; 28: 12611271.
  • 125
    Petzold A, Keir G, Kay A, Kerr M, Thompson EJ. Axonal damage and outcome in subarachnoid haemorrhage. Journal of Neurology, Neurosurgery and Psychiatry 2006; 77: 753759.
  • 126
    Nylen K, Csajbok LZ, Ost M, et al. CSF -Neurofilament correlates with outcome after aneurysmal subarachnoid hemorrhage. Neuroscience Letters 2006; 404: 132136.
  • 127
    Norgren N, Rosengren L, Stigbrand T. Elevated neurofilament levels in neurological diseases. Brain Research 2003; 987: 2531.
  • 128
    Van Geel WJ, Rosengren LE, Verbeek MM. An enzyme immunoassay to quantify neurofilament light chain in cerebrospinal fluid. Journal of Immunological Methods 2005; 296: 179185.
  • 129
    Malmestrom C, Haghighi S, Rosengren L, Andersen O, Lycke J. Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS. Neurology 2003; 61: 17201725.
  • 130
    Norgren N, Sundstrom P, Svenningsson A, Rosengren L, Stigbrand T, Gunnarsson M. Neurofilament and glial fibrillary acidic protein in multiple sclerosis. Neurology 2004; 63: 15861590.
  • 131
    Lim ET, Sellebjerg F, Jensen CV, et al. Acute axonal damage predicts clinical outcome in patients with multiple sclerosis. Multiple Sclerosis 2005; 11: 532536.
  • 132
    Petzold A, Eikelenboom MI, Keir G, et al. The new global multiple sclerosis severity score (MSSS) correlates with axonal but not glial biomarkers. Multiple Sclerosis 2006; 12: 325328.
  • 133
    Eikelenboom MJ, Petzold A, Lazeron RH, et al. Multiple sclerosis: neurofilament light chain antibodies are correlated to cerebral atrophy. Neurology 2003; 60: 219223.
  • 134
    Lim ET, Grant D, Pashenkov M, et al. Cerebrospinal fluid levels of brain specific proteins in optic neuritis 2. Multiple Sclerosis 2004; 10: 261265.
  • 135
    Miyazawa I, Nakashima I, Petzold A, Fujihara K, Sato S, Itoyama Y. High CSF neurofilament heavy chain levels in neuromyelitis optica. Neurology 2007; 68: 865867.
  • 136
    Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelso C. Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. Journal of Neurochemistry 1996; 67: 20132018.
  • 137
    Brettschneider J, Petzold A, Sussmuth SD, Ludolph AC, Tumani H. Axonal damage markers in cerebrospinal fluid are increased in ALS. Neurology 2006; 66: 852856.
  • 138
    Gisslen M, Rosengren L, Hagberg L, Deeks SG, Price RW. Cerebrospinal fluid signs of neuronal damage after antiretroviral treatment interruption in HIV-1 infection. AIDS Research and Therapy 2005; 2: 6.
  • 139
    Hagberg L, Fuchs D, Rosengren L, Gisslen M. Intrathecal immune activation is associated with cerebrospinal fluid markers of neuronal destruction in AIDS patients. Journal of Neuroimmunology 2000; 102: 5155.
  • 140
    Gisslen M, Hagberg L, Brew BJ, Cinque P, Price RW, Rosengren L. Elevated cerebrospinal fluid neurofilament light protein concentrations predict the development of AIDS dementia complex. Journal of Infectious Diseases 2007; 195: 17741778.
  • 141
    Abdulle S, Mellgren A, Brew BJ, et al. CSF neurofilament protein (NFL) – a marker of active HIV-related neurodegeneration. Journal of Neurology 2007; 254: 10261032.
  • 142
    Mellgren A, Price RW, Hagberg L, Rosengren L, Brew BJ, Gisslen M. Antiretroviral treatment reduces increased CSF neurofilament protein (NFL) in HIV-1 infection. Neurology 2007; 69: 15361541.
  • 143
    Brettschneider J, Petzold A, Sussmuth SD, et al. Neurofilament heavy-chain NfH(SMI35) in cerebrospinal fluid supports the differential diagnosis of Parkinsonian syndromes. Movement Disorders 2006; 21: 22242227.
  • 144
    Holmberg B, Rosengren L, Karlsson JE, Johnels B. Increased cerebrospinal fluid levels of neurofilament protein in progressive supranuclear palsy and multiple-system atrophy compared with Parkinson’s disease. Movement Disorders 1998; 13: 7077.
  • 145
    Abdo WF, Bloem BR, Van Geel WJ, Esselink RA, Verbeek MM. CSF neurofilament light chain and tau differentiate multiple system atrophy from Parkinson’s disease. Neurobiology of Aging 2007; 28: 742747.
  • 146
    Baumann N, Pham-Dinh D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiological Reviews 2001; 81: 871927.
  • 147
    Van Engelen BG, Lamers KJ, Gabreels FJ, Wevers RA, Van Geel WJ, Borm GF. Age-related changes of neuron-specific enolase, S-100 protein, and myelin basic protein concentrations in cerebrospinal fluid. Clinical Chemistry 1992; 38: 813816.
  • 148
    Cornblath DR, Griffin JW, Tennekoon GI. Immunoreactive myelin basic protein in cerebrospinal fluid of patients with peripheral neuropathies. Annals of Neurology 1986; 20: 370372.
  • 149
    Edstrom S, Hanner P, Andersen O, Rosenhall U, Vahlne A, Karlsson B. Elevated levels of myelin basic protein in CSF in relation to auditory brainstem responses in Bell’s palsy. Acta Oto-Laryngologica 1987; 103: 198203.
  • 150
    Davies L, McLeod JG, Muir A, Hensley WJ. Diagnostic value of cerebrospinal fluid myelin basic protein in patients with neurological illness. Clinical and Experimental Neurology 1987; 24: 510.
  • 151
    Lamers KJ, Van Engelen BG, Gabreels FJ, Hommes OR, Borm GF, Wevers RA. Cerebrospinal neuron-specific enolase, S-100 and myelin basic protein in neurological disorders. Acta Neurologica Scandinavica 1995; 92: 247251.
  • 152
    Cohen SR, Herndon RM, McKhann GM. Radioimmunoassay of myelin basic protein in spinal fluid. An index of active demyelination. New England Journal of Medicine 1976; 295: 14551457.
  • 153
    Noppe M, Crols R, Andries D, Lowenthal A. Determination in human cerebrospinal fluid of glial fibrillary acidic protein, S-100 and myelin basic protein as indices of non-specific or specific central nervous tissue pathology. Clinica Chimica Acta 1986; 155: 143150.
  • 154
    Whitaker JN. Myelin encephalitogenic protein fragments in cerebrospinal fluid of persons with multiple sclerosis. Neurology 1977; 27: 911920.
  • 155
    Thomson AJ, Brazil J, Feighery C, et al. CSF myelin basic protein in multiple sclerosis. Acta Neurologica Scandinavica 1985; 72: 577583.
  • 156
    Cohen SR, Brune MJ, Herndon RM, McKhann GM. Cerebrospinal fluid myelin basic protein and multiple sclerosis. Advances in Experimental Medicine and Biology 1978; 100: 513519.
  • 157
    Martin-Mondiere C, Jacque C, Delassalle A, Cesaro P, Carydakis C, Degos JD. Cerebrospinal myelin basic protein in multiple sclerosis. Identification of two groups of patients with acute exacerbation. Archives of Neurology 1987; 44: 276278.
  • 158
    Sellebjerg F, Jensen CV, Christiansen M. Intrathecal IgG synthesis and autoantibody-secreting cells in multiple sclerosis. Journal of Neuroimmunology 2000; 2: 207215.
  • 159
    Warren KG, Catz I, McPherson TA. CSF myelin basic protein levels in acute optic neuritis and multiple sclerosis. Canadian Journal of Neurological Sciences 1983; 10: 235238.
  • 160
    Thompson AJ, Hutchinson M, Brazil J, Feighery C, Martin EA. A clinical and laboratory study of benign multiple sclerosis. Quarterly Journal of Medicine 1986; 58: 6980.
  • 161
    Thompson AJ, Brazil J, Hutchinson M, Feighery C. Three possible laboratory indexes of disease activity in multiple sclerosis. Neurology 1987; 37: 515519.
  • 162
    Barkhof F, Frequin ST, Hommes OR, et al. A correlative triad of gadolinium-DTPA MRI, EDSS, and CSF-MBP in relapsing multiple sclerosis patients treated with high-dose intravenous methylprednisolone. Neurology 1992; 42: 6367.
  • 163
    Sellebjerg F, Christiansen M, Jensen J, Frederiksen JL. Immunological effects of oral high-dose methylprednisolone in acute optic neuritis and multiple sclerosis. European Journal of Neurology 2000; 7: 281289.
  • 164
    Whitaker JN, Layton BA, Herman PK, Kachelhofer RD, Burgard S, Bartolucci AA. Correlation of myelin basic protein-like material in cerebrospinal fluid of multiple sclerosis patients with their response to glucocorticoid treatment. Annals of Neurology 1993; 33: 1017.
  • 165
    Sellebjerg F, Jensen CV, Larsson HB, Frederiksen JL. Gadolinium-enhanced magnetic resonance imaging predicts response to methylprednisolone in multiple sclerosis. Multiple Sclerosis 2003; 9: 102107.
  • 166
    Bossuyt PM, Reitsma JB, Bruns DE, et al. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Standards for Reporting of Diagnostic Accuracy. Clinical Chemistry 2003; 49: 16.
  • 167
    McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. REporting recommendations for tumour MARKer prognostic studies (REMARK). British Journal of Cancer 2005; 93: 387391.
  • 168
    Lewczuk P, Beck G, Ganslandt O, et al. International quality control survey of neurochemical dementia diagnostics. Neuroscience Letters 2006; 409: 14.
  • 169
    Bartosik-Psujek H, Archelos JJ. Tau protein and 14-3-3 are elevated in the cerebrospinal fluid of patients with multiple sclerosis and correlate with intrathecal synthesis of IgG. Journal of Neurology 2004; 251: 414420.
  • 170
    Brettschneider J, Petzold A, Junker A, Tumani H. Axonal damage markers in the cerebrospinal fluid of patients with clinically isolated syndrome improve predicting conversion to definite multiple sclerosis. Multiple Sclerosis 2006; 12: 143148.
  • 171
    Martinez-Yelamos A, Saiz A, Bas J, Hernandez JJ, Graus F, Arbizu T. Tau protein in cerebrospinal fluid: a possible marker of poor outcome in patients with early relapsing-remitting multiple sclerosis. Neuroscience Letters 2004; 363: 1417.
  • 172
    Terzi M, Birinci A, Cetinkaya E, Onar MK. Cerebrospinal fluid total tau protein levels in patients with multiple sclerosis. Acta Neurologica Scandinavica 2007; 115: 325330.
  • 173
    Guimaraes I, Cardoso MI, Sa MJ. Tau protein seems not to be a useful routine clinical marker of axonal damage in multiple sclerosis. Multiple Sclerosis 2006; 12: 354356.
  • 174
    Kanemaru K, Kameda N, Yamanouchi H. Decreased CSF amyloid beta42 and normal tau levels in dementia with Lewy bodies. Neurology 2000; 54: 18751876.
  • 175
    Arai H, Morikawa Y, Higuchi M, et al. Cerebrospinal fluid tau levels in neurodegenerative diseases with distinct tau-related pathology. Biochemical and Biophysical Research Communications 1997; 236: 262264.
  • 176
    Shoji M, Matsubara E, Murakami T, et al. Cerebrospinal fluid tau in dementia disorders: a large scale multicenter study by a Japanese study group. Neurobiology of Aging 2002; 23: 363370.
  • 177
    Gomez-Tortosa E, Gonzalo I, Fanjul S, et al. Cerebrospinal fluid markers in dementia with lewy bodies compared with Alzheimer disease. Archives of Neurology 2003; 60: 12181222.
  • 178
    Mollenhauer B, Cepek L, Bibl M, et al. Tau protein, Abeta42 and S-100B protein in cerebrospinal fluid of patients with dementia with Lewy bodies. Dementia and Geriatric Cognitive Disorders 2005; 19: 164170.
  • 179
    Mollenhauer B, Bibl M, Wiltfang J, et al. Total tau protein, phosphorylated tau (181p) protein, beta-amyloid(1-42), and beta-amyloid(1-40) in cerebrospinal fluid of patients with dementia with Lewy bodies. Clinical Chemistry and Laboratory Medicine 2006; 44: 192195.
  • 180
    Andersen C, Froelich FS, Ostberg P, Lannfelt L, Wahlund L. Tau protein in cerebrospinal fluid from semantic dementia patients. Neuroscience Letters 2000; 294: 155158.
  • 181
    Pijnenburg YA, Schoonenboom SN, Barkhof F, et al. CSF biomarkers in frontotemporal lobar degeneration: relations with clinical characteristics, apolipoprotein E genotype, and neuroimaging. Journal of Neurology, Neurosurgery and Psychiatry 2006; 77: 246248.
  • 182
    Riemenschneider M, Wagenpfeil S, Diehl J, et al. Tau and Abeta42 protein in CSF of patients with frontotemporal degeneration. Neurology 2002; 58: 16221628.
  • 183
    Sjogren M, Davidsson P, Wallin A, et al. Decreased CSF-beta-amyloid 42 in Alzheimer’s disease and amyotrophic lateral sclerosis may reflect mismetabolism of beta-amyloid induced by disparate mechanisms. Dementia and Geriatric Cognitive Disorders 2002; 13: 112118.
  • 184
    Holmberg B, Johnels B, Blennow K, Rosengren L. Cerebrospinal fluid Abeta42 is reduced in multiple system atrophy but normal in Parkinson’s disease and progressive supranuclear palsy. Movement Disorders 2003; 18: 186190.
  • 185
    Mollenhauer B, Trenkwalder C, Von AN, et al. Beta-amlyoid 1-42 and Tau-protein in cerebrospinal fluid of patients with Parkinson’s disease dementia. Dementia and Geriatric Cognitive Disorders 2006; 22: 200208.
  • 186
    Abdo WF, De JD, Hendriks JC, et al. Cerebrospinal fluid analysis differentiates multiple system atrophy from Parkinson’s disease. Movement Disorders 2004; 19: 571579.
  • 187
    Abdo WF, Van De Warrenburg BP, Munneke M, et al. CSF analysis differentiates multiple-system atrophy from idiopathic late-onset cerebellar ataxia. Neurology 2006; 67: 474479.
  • 188
    Urakami K, Mori M, Wada K, et al. A comparison of tau protein in cerebrospinal fluid between corticobasal degeneration and progressive supranuclear palsy. Neuroscience Letters 1999; 259: 127129.
  • 189
    Noguchi M, Yoshita M, Matsumoto Y, Ono K, Iwasa K, Yamada M. Decreased beta-amyloid peptide42 in cerebrospinal fluid of patients with progressive supranuclear palsy and corticobasal degeneration. Journal of the Neurological Sciences 2005; 237: 6165.
  • 190
    Stefani A, Bernardini S, Panella M, et al. AD with subcortical white matter lesions and vascular dementia: CSF markers for differential diagnosis. Journal of the Neurological Sciences 2005; 237: 8388.
  • 191
    Jin K, Takeda A, Shiga Y, et al. CSF tau protein: a new prognostic marker for Guillain-Barre syndrome. Neurology 2006; 67: 14701472.
  • 192
    Brew BJ, Pemberton L, Blennow K, Wallin A, Hagberg L. CSF amyloid beta42 and tau levels correlate with AIDS dementia complex. Neurology 2005; 65: 14901492.
  • 193
    Franz G, Beer R, Kampfl A, et al. Amyloid beta 1-42 and tau in cerebrospinal fluid after severe traumatic brain injury. Neurology 2003; 60: 14571461.
  • 194
    Ost M, Nylen K, Csajbok L, et al. Initial CSF total tau correlates with 1-year outcome in patients with traumatic brain injury. Neurology 2006; 67: 16001604.
  • 195
    Kay AD, Petzold A, Kerr M, Keir G, Thompson E, Nicoll JA. Alterations in cerebrospinal fluid apolipoprotein E and amyloid beta-protein after traumatic brain injury. Journal of Neurotrauma 2003; 20: 943952.
  • 196
    Ågren-Wilsson A, Lekman A, Sjoberg W, et al. CSF biomarkers in the evaluation of idiopathic normal pressure hydrocephalus. Acta Neurologica Scandinavica 2007; 116: 333339.
  • 197
    Kapaki EN, Paraskevas GP, Tzerakis NG, et al. Cerebrospinal fluid tau, phospho-tau181 and beta-amyloid1-42 in idiopathic normal pressure hydrocephalus: a discrimination from Alzheimer’s disease. European Journal of Neurology 2007; 14: 168173.
  • 198
    Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Archives of Neurology 2002; 59: 15531562.
  • 199
    Hong SC, Lin L, Jeong JH, et al. A study of the diagnostic utility of HLA typing, CSF hypocretin-1 measurements, and MSLT testing for the diagnosis of narcolepsy in 163 Korean patients with unexplained excessive daytime sleepiness. Sleep 2006; 29: 14291438.
  • 200
    Kanbayashi T, Inoue Y, Chiba S, et al. CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia. Journal of Sleep Research 2002; 11: 9193.
  • 201
    Krahn LE, Pankratz VS, Oliver L, Boeve BF, Silber MH. Hypocretin (orexin) levels in cerebrospinal fluid of patients with narcolepsy: relationship to cataplexy and HLA DQB1*0602 status. Sleep 2002; 25: 733736.
  • 202
    Ebrahim IO, Sharief MK, De LS, et al. Hypocretin (orexin) deficiency in narcolepsy and primary hypersomnia. Journal of Neurology, Neurosurgery and Psychiatry 2003; 74: 127130.
  • 203
    Dauvilliers Y, Baumann CR, Carlander B, et al. CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions. Journal of Neurology, Neurosurgery and Psychiatry 2003; 74: 16671673.
  • 204
    Heier MS, Evsiukova T, Vilming S, Gjerstad MD, Schrader H, Gautvik K. CSF hypocretin-1 levels and clinical profiles in narcolepsy and idiopathic CNS hypersomnia in Norway. Sleep 2007; 30: 969973.
  • 205
    Van De Langerijt B, Gijtenbeek JM, De Reus HP, et al. CSF levels of growth factors and plasminogen activators in leptomeningeal metastases. Neurology 2006; 67: 114119.
  • 206
    Husain N, Awasthi S, Haris M, Gupta RK, Husain M. Vascular endothelial growth factor as a marker of disease activity in neurotuberculosis. Journal of Infection 2008; 56: 114119.
  • 207
    Matsuyama W, Hashiguchi T, Umehara F, et al. Expression of vascular endothelial growth factor in tuberculous meningitis. Journal of the Neurological Sciences 2001; 186: 7579.
  • 208
    Tsai HC, Liu YC, Lee SS, Chen ER, Yen CM. Vascular endothelial growth factor is associated with blood brain barrier dysfunction in eosinophilic meningitis caused by Angiostrongylus cantonensis infection. American Journal of Tropical Medicine and Hygiene 2007; 76: 592595.
  • 209
    Kastenbauer S, Angele B, Sporer B, Pfister HW, Koedel U. Patterns of protein expression in infectious meningitis: a cerebrospinal fluid protein array analysis. Journal of Neuroimmunology 2005; 164: 134139.
  • 210
    Coenjaerts FE, Van Der FM, Mwinzi PN, et al. Intrathecal production and secretion of vascular endothelial growth factor during Cryptococcal Meningitis. Journal of Infectious Diseases 2004; 190: 13101317.
  • 211
    Van Der FM, Hoppenreijs S, Van Rensburg AJ, et al. Vascular endothelial growth factor and blood-brain barrier disruption in tuberculous meningitis. Pediatric Infectious Disease Journal 2004; 23: 608613.
  • 212
    Sporer B, Koedel U, Paul R, Eberle J, Arendt G, Pfister HW. Vascular endothelial growth factor (VEGF) is increased in serum, but not in cerebrospinal fluid in HIV associated CNS diseases. Journal of Neurology, Neurosurgery and Psychiatry 2004; 75: 298300.
  • 213
    Moreau C, Devos D, Brunaud-Danel V, et al. Paradoxical response of VEGF expression to hypoxia in CSF of patients with ALS. Journal of Neurology, Neurosurgery and Psychiatry 2006; 77: 255257.
  • 214
    Just N, Moreau C, Lassalle P, et al. High erythropoietin and low vascular endothelial growth factor levels in cerebrospinal fluid from hypoxemic ALS patients suggest an abnormal response to hypoxia. Neuromuscular Disorders 2007; 17: 169173.
  • 215
    Nagata T, Nagano I, Shiote M, et al. Elevation of MCP-1 and MCP-1/VEGF ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients. Neurological Research 2007; 29: 772776.
  • 216
    Devos D, Moreau C, Lassalle P, et al. Low levels of the vascular endothelial growth factor in CSF from early ALS patients. Neurology 2004; 62: 21272129.
  • 217
    Ilzecka J. Cerebrospinal fluid vascular endothelial growth factor in patients with amyotrophic lateral sclerosis. Clinical Neurology and Neurosurgery 2004; 106: 289293.
  • 218
    Foyouzi N, Norwitz ER, Tsen LC, Buhimschi CS, Buhimschi IA. Placental growth factor in the cerebrospinal fluid of women with preeclampsia. International Journal of Gynaecology and Obstetrics 2006; 92: 3237.
  • 219
    Blasko I, Lederer W, Oberbauer H, et al. Measurement of thirteen biological markers in CSF of patients with Alzheimer’s disease and other dementias. Dementia and Geriatric Cognitive Disorders 2006; 21: 915.
  • 220
    Tarkowski E, Issa R, Sjogren M, et al. Increased intrathecal levels of the angiogenic factors VEGF and TGF-beta in Alzheimer’s disease and vascular dementia. Neurobiology of Aging 2002; 23: 237243.
  • 221
    Scheufler KM, Drevs J, Van V, et al. Implications of vascular endothelial growth factor, sFlt-1, and sTie-2 in plasma, serum and cerebrospinal fluid during cerebral ischemia in man. Journal of Cerebral Blood Flow and Metabolism 2003; 23: 99110.
  • 222
    Borel CO, McKee A, Parra A, et al. Possible role for vascular cell proliferation in cerebral vasospasm after subarachnoid hemorrhage. Stroke 2003; 34: 427433.
  • 223
    Watanabe O, Maruyama I, Arimura K, et al. Overproduction of vascular endothelial growth factor/vascular permeability factor is causative in Crow-Fukase (POEMS) syndrome. Muscle and Nerve 1998; 21: 13901397.
  • 224
    Zetterberg H, Jacobsson J, Rosengren L, Blennow K, Andersen PM. Cerebrospinal fluid neurofilament light levels in amyotrophic lateral sclerosis: impact of SOD1 genotype. European Journal of Neurology 2007; 14: 13291333.
  • 225
    Brettschneider J, Petzold A, Schottle D, Claus A, Riepe M, Tumani H. The neurofilament heavy chain (NfH) in the cerebrospinal fluid diagnosis of Alzheimer’s disease. Dementia and Geriatric Cognitive Disorders 2006; 6: 291295.
  • 226
    De Jong D, Jansen RW, Pijnenburg YA, et al. CSF neurofilament proteins in the differential diagnosis of dementia. Journal of Neurology, Neurosurgery and Psychiatry 2007; 78: 936938.
  • 227
    Petzold A, Keir G, Warren J, Fox N, Rossor MN. A systematic review and meta-analysis of CSF neurofilament protein levels as biomarkers in dementia. Neurodegenerative Disease 2007; 4: 185194.
  • 228
    Rosengren LE, Karlsson JE, Sjogren M, Blennow K, Wallin A. Neurofilament protein levels in CSF are increased in dementia. Neurology 1999; 52: 10901093.
  • 229
    Sjögren M, Blomberg M, Jonsson M, et al. Neurofilament protein in cerebrospinal fluid: a marker of white matter changes. Journal of Neuroscience Research 2001; 66: 510516.
  • 230
    Pijnenburg YA, Janssen JC, Schoonenboom NS, et al. CSF neurofilaments in frontotemporal dementia compared with early onset Alzheimer’s disease and controls. Dementia and Geriatric Cognitive Disorders 2007; 23: 225230.
  • 231
    Sjogren M, Rosengren L, Minthon L, Davidsson P, Blennow K, Wallin A. Cytoskeleton proteins in CSF distinguish frontotemporal dementia from AD. Neurology 2000; 54: 19601964.
  • 232
    Sjogren M, Wallin A. Pathophysiological aspects of frontotemporal dementia--emphasis on cytoskeleton proteins and autoimmunity. Mechanisms of Ageing and Development 2001; 122: 19231935.
  • 233
    Wallin A, Sjogren M. Cerebrospinal fluid cytoskeleton proteins in patients with subcortical white-matter dementia. Mechanisms of Ageing and Development 2001; 122: 19371949.
  • 234
    Guez M, Hildingsson C, Rosengren L, Karlsson K, Toolanen G. Nervous tissue damage markers in cerebrospinal fluid after cervical spine injuries and whiplash trauma. Journal of Neurotrauma 2003; 20: 853858.
  • 235
    Tullberg M, Hultin L, Ekholm S, Mansson JE, Fredman P, Wikkelso C. White matter changes in normal pressure hydrocephalus and Binswanger disease: specificity, predictive value and correlations to axonal degeneration and demyelination. Acta Neurologica Scandinavica 2002; 105: 417426.
  • 236
    Tisell M, Tullberg M, Mansson JE, Fredman P, Blennow K, Wikkelso C. Differences in cerebrospinal fluid dynamics do not affect the levels of biochemical markers in ventricular CSF from patients with aqueductal stenosis and idiopathic normal pressure hydrocephalus. European Journal of Neurology 2004; 11: 1723.
  • 237
    Tullberg M, Blennow K, Mansson JE, Fredman P, Tisell M, Wikkelso C. Ventricular cerebrospinal fluid neurofilament protein levels decrease in parallel with white matter pathology after shunt surgery in normal pressure hydrocephalus. European Journal of Neurology 2007; 14: 248254.
  • 238
    Petzold A, Hinds N, Murray NM, et al. CSF neurofilament levels: a potential prognostic marker in Guillain-Barre syndrome. Neurology 2006; 67: 10711073.
  • 239
    Rosen H, Karlsson JE, Rosengren L. CSF levels of neurofilament is a valuable predictor of long-term outcome after cardiac arrest. Journal of the Neurological Sciences 2004; 221: 1924.
  • 240
    Skoldenberg B, Aurelius E, Hjalmarsson A, et al. Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis in adults. Journal of Neurology 2006; 253: 163170.