Cerebrospinal fluid biomarkers of neurodegeneration in chronic ...

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Cerebrospinal fluid biomarkers of neurodegeneration in chronic neurological diseases Expert Rev. Mol. Diagn. 8(4), 479–494 (2008)

Hayrettin Tumani†, Charlotte Teunissen, Sigurd Süssmuth, Markus Otto, Albert C Ludolph and Johannes Brettschneider †

Author for correspondence Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany Tel.: +49 731 177 5207 Fax: +49 731 177 1202 [email protected]

Chronic neurological diseases (CND) like amyotrophic lateral sclerosis (ALS), dementia or multiple sclerosis (MS) share a chronic progressive course of disease that frequently leads to the common pathological pathway of neurodegeneration, including neuroaxonal damage, apoptosis and gliosis. There is an ongoing search for biomarkers that could support early diagnosis of CND and help to identify responders to interventions in therapeutic treatment trials. Cerebrospinal fluid (CSF) is a promising source of biomarkers in CND, since the CSF compartment is in close anatomical contact with the brain interstitial fluid, where biochemical changes related to CND are reflected. We review recent advances in CSF biomarkers research in CND and thereby focus on markers associated with neurodegeneration. KEYWORDS: amyotrophic lateral sclerosis • biomarker • cerebrospinal fluid • chronic neurological disease • dementia • multiple sclerosis • neurodegeneration

Chronic neurological diseases

Chronic neurological diseases (CND) like amyotrophic lateral sclerosis (ALS), and different subtypes of dementia or multiple sclerosis (MS) form an important challenge to diagnostic and therapeutical progress in neurology. Although clinically heterogeneous, these diseases share a chronic progressive course of disease that is frequently accompanied by clinically severe, debilitating symptoms. Furthermore, while those diseases demonstrate different pathophysiological origins, they may all lead to a common pathological pathway of neurodegeneration (FIGURE 1). These neurodegenerative pathways are characterized by a slow continuous process of degeneration, leading to the apoptosis of a selective population of neurons, frequently accompanied by a gliotic reaction [1–3]. Dementia occurs with a prevalence of approximately 20% in 75–85-year olds [4]. Set against the background of progressive aging of Western societies, dementia forms a huge socioeconomic burden to public health systems [5]. Alzheimer’s disease (AD) is the most common subtype of dementia. Pathological hallmarks are extensive amounts of senile plaques (amyloid-β is a major component) and neurofibrillary tangles (phosphorylated tau) as

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10.1586/14737159.8.4.479

well as a loss of cortical neurons and subcortical projections [6,7]. In vascular dementia (VD), damage to subcortical white matter is generally more pronounced [6]. In frontotemporal dementia (FTD), frontal cortical neurons, frontal white matter and in some cases the pyramidal tracts degenerate as well [2]. ALS is the most frequent motor neuron disease, occurring with an incidence of 1–2 cases per 100,000 [8]. It is characterized by selective degeneration of spinal and bulbar innervating motor neurons as well as pyramidal motor neurons, leading to death after a disease duration of approximately 3 years [9]. While several mutations such as in the gene encoding the cytosolic copper-zinc superoxide dismutase have been associated with rare cases of familial ALS, the pathophysiological origins of the majority of sporadic ALS remains unclear [9]. MS is a CND that most often initially presents as an inflammatory demyelinating disease [10]. However, the pathophysiological character may change with neurodegenerative aspects that dominate in later stages of disease [11,12]. Furthermore, histopathological studies show neuroaxonal damage to be present in early stages of disease [3,11] and to be the major morphological substrate of permanent clinical disability [13].

© 2008 Expert Reviews Ltd

ISSN 1473-7159

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Tumani, Teunissen, Süssmuth, Otto, Ludolph & Brettschneider

Biomarkers for CND

A biomarker is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention [14]. The term ‘biomarker’ is often used interchangeably with the term ‘surrogate marker’. However, there is a clear hierarchical distinction between those two terms: The term ‘surrogate’ indicates the ability of a biomarker to provide information about the clinical prognosis or efficacy of a therapy. It implies a strong correlation with a clinical end point, about which a surrogate must provide information in a shorter time than would be needed by following the clinical course of disease [14]. Prentice defined two conditions that ensure the surrogacy of a biomarker [15]: • The first requirement is a strong correlation between the biomarker and the clinical end point; • The second requirement is that a biomarker measures the net effect of the treatment on the clinical end point; While numerous biomarkers are able to reflect single clinical or pathophysiological aspects of CND, none to date have fulfilled the criteria of a surrogate marker. According to the review by Blennow and Hampel, biomarkers of CND may function as either state markers or stage markers [16]. While stage markers would give a measure of how far the degenerative process has proceeded, state markers would reflect the occurrence and intensity of the disease process. In CND, biomarkers reflecting neurodegeneration are in demand to support an early diagnosis, because upcoming treatment will be most effective if started early [17,18]. As an example, clinical diagnosis of early stages of AD may be difficult even for experienced neurologists, while only an early treatment with antidementive agents, such as cholinesterase inhibitors, was Alzheimer’s disease Neurofibrillary tangles Amyloid plaque formation

Amyotrophic lateral sclerosis

found to show noteworthy results [17]. Accordingly, there is a demand for biological markers to delineate potential early stages of disease, characterized by mild cognitive impairment (MCI), but without overt dementia [19]. Biomarkers with prognostic value could identify patients that will benefit from a specific treatment. Biomarkers could reflect specific pathophysiological aspects of CND and thereby help to identify responders to interventions in therapeutic treatment trials [14]. CSF fluid biomarkers

Biomarkers of CND include biochemical markers, which can be drawn from the cerebrospinal fluid (CSF). While blood, urine, tears or saliva can easily be obtained, these liquids are vulnerable to exogenous factors, such as inflammatory or metabolic influences, and results are consequently poorly reproducible in CNS diseases. By contrast, lumbar puncture of CSF is more invasive, although studies show complications to be rare if lumbar puncture is performed by an experienced neurologist and if nontraumatic needles with small gauge are used [20]. In general, CSF is a promising source of biomarkers in CND, since the CSF compartment is in close anatomical contact with the brain interstitial fluid, wherein biochemical changes related to the disease may be reflected. Accordingly, alterations in protein expression, post-translational modification or turnover within the tissue of the CNS associated with CND may be mirrored in corresponding changes in CSF protein content [16,21,22]. CSF physiology & its impact on CSF biomarker research

The majority of the protein content of the lumbar CSF is bloodderived (∼80%), while the remainder consists of brain-derived or intrathecally produced proteins (FIGURE 2). However, this recently Multiple sclerosis

Excitotoxicity Oxidative stress Glutamate toxicity

Inflammation (T-cell infiltration, macrophages, B-cell reaction)

Disturbance of axonal transport

Demyelination

Heterogeneous pathological onset of disease

Remyelination Common final pathway of neurodegeneration

Oligodendrocyte toxicity Neuroaxonal damage

Neuronal apoptosis

Glial reaction

Expert Rev. Mol. Diagn. © Future Science Group Ltd (2008)

Figure 1. Common final pathway of neurodegeneration in chronic neurological diseases with different pathophysiological origins.

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Cerebrospinal fluid biomarkers in neurodegenerative diseases

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became a matter of debate because the Blood compartment (5l) CSF proteome appears to be different from Arachnoid the plasma proteome [23]. Under physioBlood–brain barrier villi Ventricle Extracellular logical conditions, blood-derived proteins space enter the CSF compartment via passive Choroid Brain diffusion across the blood–CSF barrier. plexus Glial Depending on their molecular size and activation Glial their blood concentration, CSF proteins of Ca2+ proteins blood origin show a specific CSF-to-blood CSF–brain CSF ratio [24]. When molecular size and serum (150 ml) barrier Apoptosis/ levels are known, the CSF concentration of degeneration a given protein can be calculated [25,26]. If the concentration in the CSF exceeds the Blood–CSF barrier calculated value, it indicates local producDisturbed axonal tion of the protein within the CNS (i.e., transport intrathecal synthesis). Another important Neuroaxonal factor influencing the protein content is Spinal proteins nerve the permeability of the blood–CSF barrier. Lumbar sac Spinal cord roots The integrity of the blood–CSF barrier is Expert Rev. Mol. Diagn. © Future Science Group Ltd (2008) Blood best characterized by the albumin CSF-toserum ratio, since albumin is exclusively Figure 2. Compartments of the CNS and circulation of the CSF. produced in the liver and not by the nerDue to the close contact of the CSF with the brain and the spinal cord, the different steps in vous system. If the serum concentration the pathogenesis of chronic neurological diseases might be detectable by changes of and the albumin CSF-to-serum ratio are several markers. Between different compartments, there are distinct barriers to consider, taken into account, the extent to which such as the blood–CSF barrier, the blood–brain barrier and an albeit permeable CSF–brain each protein in the CSF is produced barrier that basically comprises the cell membranes. CSF: Cerebrospinal fluid. within the CNS can be detirmined. Various formulae, such as the IgG-index, IgG synthesis rate and IgG-loc, have been developed to discriminate should always be obtained at the time of the spinal tap and anabetween blood- and brain-derived fractions of immunoglobulins, lyzed in parallel. To ensure optimal performance and results, which are used to confirm or rule out an inflammatory process standardized protocols should be in place for the spinal tap and within the CNS [27–29]. sample processing. Furthermore, it is important to analyze the By contrast, CSF proteins that are predominantly synthesized in CSF in a specialized laboratory that is routinely evaluated for its the CNS (>95%), such as prostaglandin-D synthase, transthyretin performance. If measuring proteins that potentially originate or tau-protein, are not influenced by blood concentrations or from both blood and brain compartments, CSF and serum changes of barrier permeability and therefore do not have to be samples should be run in parallel in the same assay to minimize related to their respective blood levels or albumin CSF/serum ratio the coefficient of variability. when evaluated in CSF [30]. The sensitivity to detect intrathecally produced proteins in CSF also depends on the topographical relationship between Methods the site of the pathologic process and the CSF compartment. In the following review, we give an update on CSF biomarkers Certain areas of the brain, such as frontal, parietal or occipital in CND and thereby focus on markers associated with neuroregions of the cortex, are considered CSF-distant. Pathological degeneration, apoptosis and gliosis, which are common processes in these areas may not impact on the composition of pathophysiological features in CND (FIGURE 1). Furthermore, we lumbar CSF. Pathological processes localized in brain areas review literature on recent developments in CSF biomarker close to ventricular and lumbar CSF space are more prone to be research using different methods for CSF proteome analysis reflected by CSF changes [31]. Diseases of the meninges, peri- and show future perspectives in biomarker research in CND. ventricular area, temporobasal region, spinal cord and roots strongly impact on the CSF parameters detected in lumbar CSF. Several additional factors, such as circadian variation, vol- Markers of neuroaxonal damage ume of sampled CSF and rostrocaudal concentration gradient, Biomarkers of neuroaxonal damage (TABLES 1 & 2) are structural may influence the concentration of CSF proteins and must be proteins that are important for cytoskeletal stability and axonal considered when studying CSF biomarkers [30,32,33]. With transport. Following neuroaxonal damage, these proteins can respect to the impact of the blood compartment on CSF, serum be released into the intercellular space and from there into the


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Table 1. Cerebrospinal fluid markers of neuroaxonal damage. Marker

t-tau

Dementia

Amyotrophic lateral sclerosis

Multiple sclerosis

n

Main findings

n

Main findings

n

Main findings

75

↑↑ in AD and VD vs controls [153]

69

↑↑ in ALS vs controls [53]

36

↑↑ in MS vs controls [55]

241

↑↑ in AD vs controls [19]

20


60


64

↑↑ in AD vs FTD [43]

17

↔ in ALS vs controls [55]

52

↑↑ in MS vs controls; ↔ in RR-MS vs progressive MS [61]

77

↑↑ in AD vs FTD, VD and controls

18


52

↑↑ in CIS vs controls [94]

11


45

↓ in MS vs controls [62]

[44]

p-tau

NfL

NfH

78


407


50

↔ in MS vs controls [63]

72

↑↑ in AD vs controls, VD and FTD [37]

32

↑ in MS correlates with fast progression on the EDSS [65]

71


114 ↑↑ in MS vs controls [59]

55


20

↔ in MS vs controls [64]

40

↑↑ in AD and FTD vs controls [48]

17

↑↑ in active MS vs controls [58]

33

↑↑ in AD vs controls and DLB [49]

70


64



60


41

↑↑ in AD vs FTD, VD and controls [44]

41

↑↑ in AD vs controls; in FTD vs controls [68]

72

↑↑ in AD vs controls, VD, FTD [37]

154

↑↑ in AD vs controls and DLB [154]

77

↑ in MCI correlated with conversion to AD [155]

62

↑↑ in AD, VD and FTD vs controls [82]


99

↑↑ in MS vs controls and relapse [88]

10

↑↑ in AD, VD vs controls [81]

↑↑ in ALS vs controls; ↑↑ in sporadic vs SOD-1 familial ALS [77]

5

↑↑ in RR-MS vs controls [81]

78



60

↑↑ in RR-MS vs controls [89]

98

↔ in AD vs VD, ↑↑ in AD vs controls [86]

66


11


35


37


190

↑↑ in AD and VD vs controls [83]

34

↑↑ in progressive MS vs RR-MS [92]

37

↑ in subgroup of FTD [84]

41

↑↑ in ON vs controls [136]

98

↑↑ in AD vs VD and controls [86]

52

↑↑ in CIS vs controls [94]

34

↑↑ in MS vs controls; ↑ in RR-MS indicates with worse prognosis [93]

↑↑ in ALS vs controls; ↑↑ in ALS with dominant UMN affection [53]

↑: Increased; ↑↑: Significantly increased; ↓: Decreased; ↓↓: Significantly decreased; ↔: No alteration. AD: Alzheimer’s disease; ALS: Amyotrophic lateral sclerosis; DLB: Dementia with Lewy bodies; EDSS: Expanded Disability Status Scale; FTD: Frontotemporal dementia; MCI: Mild cognitive impairment; MS: Multiple sclerosis; Nfh: Heavy-chain neurofilament; Nfl: Light-chain neurofilament; ON: Optic neuritis; p-tau: Cerebrospinal fluid phosphorylated tau-protein; RR-MS: Relapsing-remitting multiple sclerosis; t-tau: Total cerebrospinal fluid tau; UMN: Upper motor neuron; VD: Vascular dementia.

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CSF where they can be quantified. Candidate markers of neuroaxonal damage include tau protein, different subtypes of neurofilaments (Nf ) as well as neuron-specific enolase (NSE) and 14-3-3 protein. Tau

Tau is a phosphoprotein that binds to tubulin and thereby promotes microtubule assembly and stability [34]. Because of alternative splicing of tau mRNA, there are six isoforms with molecular weights between 50 and 65 kDa [35]. The neurofibrillary tangles in AD are made up of an abnormally hyperphosphorylated form of tau. Because of this hyperphosphorylation, tau loses its ability to bind to the microtubules and to stimulate their assembly [36]. To date, four different ELISA methods for quantification of t-tau in CSF have been published [37–40]. CSF t-tau

Total CSF tau (t-tau) seems to reflect the extent of neuroaxonal damage, with highest CSF concentrations found in conditions with a rapid-progressive neuroaxonal degeneration [41,42]. Several studies consistently found a moderate-to-marked increase of CSF t-tau in patients with AD [20,43,44]. The mean sensitivity

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to discriminate AD from nondemented aged individuals was approximately 80%, with a specificity of about 90% [19]. In VD, elevated CSF t-tau has been found by some [38,45], but not all studies [39,46]. These inconsistent findings may be due to discrepancies between the studies with regard to patients included and diagnostic criteria applied. Another factor influencing t-tau concentrations may be concomitant AD pathology, which has been frequently observed in VD [47]. Most other subtypes of dementia, such as FTD or Lewy body dementia, show normalto-mildly increased t-tau concentrations [38,43,48,49]. In patients with MCI, high t-tau was found to discriminate patients that developed AD during clinical follow-up [50–52]. In ALS, some studies reported elevated CSF t-tau concentrations [53,54], while others observed them to be normal [55–57]. Generally, t-tau appears to be inferior to Nf in monitoring neuroaxonal damage in ALS [53]. In MS, CSF t-tau levels were found to be increased by most [55,58–62], though not by all studies [63,64]. CSF t-tau concentrations correlated positively with gadolinium-enhancing lesions and relapse activity. On the other hand, an inverse correlation was seen between t-tau concentrations and disease duration, with highest values found in clinically isolated syndrome (CIS) patients and lowest in secondary progressive MS (SPMS)

Table 2. Cerebrospinal fluid markers of neuroaxonal damage. Marker

Dementia n

Main findings

Tubulin

Multiple sclerosis n

Main findings

35


Actin

20

↑↑ in AD homozygous for ApoE ε4-allele [156]

35


NSE

30

↓ in AD and VD vs controls [99]

66

66 ↔ in MS vs controls [90]

64

↑↑ in AD and VD vs controls; ↔ in AD vs VD [95]

91


43

↑↑ in dementia vs controls [96]

34


159

↔ in dementia vs controls (↑↑ in CJD) [98]

44

↔ in AD vs controls, ↓↓ in VD vs controls and AD [97]

58

↑↑ in CJD vs controls [100]

16

↑ increased persistent in CJD [102]

129


31


129

Positive in CJD vs controls [103]

63

14-3-3 detectable in 38% of MS [109]

31

Positive in CJD vs controls [101]

38

14-3-3 detectable in 13.2% of MS [108]

10

10β, γ, ε, η positive in CJD vs other dementia [107]

47

14-3-3 detectable in 8.2% of MS; associated with higher relapse rate [65]

37

14-3-3 detectable in 8% of MS [110]

46

↑↑ in RR-MS vs SPMS [112]

14-3-3

NAA

↑: Increased; ↑↑: Significantly increased; ↓: Decreased; ↓↓: Significantly decreased; ↔: No alteration. AD: Alzheimer’s disease; CJD: Creutzfeldt–Jakob disease; MS: Multiple sclerosis; NAA: N-acetyl aspartic acid; NSE: Neuron-specific enolase; RR-MS: Relapsing-remitting multiple sclerosis; SPMS: Secondary progressive multiple sclerosis; VD: Vascular dementia.


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patients [60,61]. One study suggested a prognostic relevance of t-tau in reporting a correlation of higher levels with faster clinical deterioration on the expanded disability-severity scale (EDSS) [65]. The results of the CSF tau studies support the fact that the intensity of the neuronal damage is most prominent in the early phase of MS. This finding is in accordance with histopathological findings from brain biopsies and magnetic resonance (MR) spectroscopy studies of MS patients [3,66]. CSF phosphorylated tau-protein

Hyperphosphorylation of tau has been observed in several neurological diseases, including AD [34,36]. CSF phosphorylated tau-protein (p-tau) levels were found to be normal or only mildly increased in neurological diseases such as Creutzfeldt–Jakob disease (CJD) that show a marked increase in CSF t-tau [51,67]. Consequently, p-tau does not appear to be a general marker of neuroaxonal damage, but to reflect specifically the phosphorylation state of tau. Comparable to t-tau, the sensitivity to discriminate AD from nondemented controls was about 80%, with a specificity of approximately 90% [16]. However, the sensitivity of p-tau to differentiate AD from controls was higher than for t-tau or amyloid-β1-42, but not necessarily more sensitive to distinguish AD from other subtypes of dementia [43,44,68,69]. A marked increase in CSF p-tau was found in MCI cases that progressed to AD during follow-up [67,70,71]. Normal levels for p-tau were reported in non-AD dementias such as VD, Lewy body dementia or FTD, as well as in other CND, such as ALS [43,44,57,68]. Differences between the studies may be due to ELISA methods specific for different phosphorylated tau epitopes [19]. Recently the combination of p-tau, t-tau and amyloid-β1-42 was seen as indicative for the development of AD in MCI patients [52]. The comparison between different p-tau epitopes gave only a minimal additional diagnostic improvement [72]. Neurofilaments

Neurofilaments belong to the class IV intermediate filaments. Nfs form an important component of the axoskeleton and are particularly abundant in large myelinated axons. Nfs are heteropolymers that are composed of four subunits: a light (NfL), medium (NfM) and heavy (NfH) chain and α-internexin [73]. The length of the C-terminal tail domain differs considerably between these subunits and accounts for the differences in molecular mass [73,74]. In ALS, an increased staining for phosphorylated NfH was observed in axons and neuronal cell bodies in ALS [75]. In CSF of ALS patients, elevation of NfL as well as of NfH was observed using ELISA [53,76,77]. NfL tended to be unstable in CSF due to a marked susceptibility to proteases [78], which considerably reduced their reliability as a biochemical marker. By contrast, the more heavily phosphorylated NfH proved to be more stable [78]. Like the aforementioned tau protein, both NfH and NfL were observed to be higher in patients with damage to predominantly the upper motor neurons [53,76]. As a possible explanation, it was suggested that upper motor neuron

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damage would result in the degeneration of large caliber axons along the entire length of their spinal pathway, leading to the release of large quantities of NfH into the CSF. By contrast, degeneration of the lower motor neuron would only release NfH into the CSF from proximal axons adjacent to the anterior horn cell, which would be proportionally less important. Very high concentrations of CSF NfH were observed in patients with a rapidly progressive course of disease and may accordingly be associated with a poorer prognosis [53]. In AD plaques, increased staining for phosphorylated NfH is evident in the proximal axon and in the perikaryon [79,80]. NfH hyperphosphorylation in axons elongating from AD plaques has been interpreted as evidence of early axonal injury caused by toxic properties of the plaque components [80]. Several studies showed CSF NfH and NfL levels to be higher in patients with AD, FTD and VD when compared with age-matched nondemented controls [81–86]. The strongest difference was observed for the comparison of FTD patients with nondemented controls, both for NfL and NfH [84,87]. According to one study, increased CSF NfL levels were also able to separate patients with FTD from those with AD [85], while NfH showed no marked capacity to differentiate between subtypes of dementia [83,84]. Generally, CSF NfH and NfL levels do not appear to be useful as a screening test in the diagnosis of dementia. However, both Nf proteins may be of value for investigation of disease progression in some patients with FTD, VD and AD [87]. In MS, increased levels of NfL have been consistently reported by several studies [88–91]. NfL correlated with the degree of disability and relapse rate, indicating continuous axonal damage during the entire course of the disease with the most profound damage associated with acute relapses [89,90]. In another study, a significant higher proportion of patients with progressive MS showed an increase in NfH levels when compared with those with a relapsing-remitting (RR) course of disease [92]. Furthermore, NfH correlated with disability scales, indicating that cumulative neuroaxonal loss is associated with sustained disability and that elevated NfH levels may suggest a poor prognosis [92,93]. Together with t-tau, the NfH phosphoform NfHSMI35 could improve predicting conversion from CIS to clinically definite MS [94]. Together with Nf, microtubules are the main axoskeletal proteins. Tubulin-α and -β subunits form the major structural component of the microtubule. Actin is an important constituent of the microfilaments, which are part of presynaptic terminals and dendritic spines. One study found elevated CSF actin and tubulin concentrations in progressive MS as compared with RR-MS as well as controls, and also observed a correlation with severity of disease as measured by EDSS [91]. To date, confirmatory studies and data on CSF levels in other CND are missing. Neuron-specific enolase

Enolase is one of many glycolytic enzymes and consists of three subunits (α, β and γ). In the CNS, the α-γ and γ-γ isoforms are mainly localized within the neurons and therefore called NSE.



CJD

High AD

Elevated

VD, FT

Normal

Clinical manifestation

Rate of disease progression

14-3-3 proteins

Very high

Tau level

NSE converts 2-phospho-glycerate to phosphoenolpyruvate. Studies on CSF NSE in dementia are controversial. While some studies reported CSF NSE to be elevated in AD and VD as compared with nondemented controls [95,96], others observed no such difference [97,98] and one study even reported CSF NSE to be decreased in AD [99]. In contrast to these conflicting data, very high concentrations of CSF NSE are well established as a marker for diagnosis of CJD [100–103]. In MS, CSF NSE were within normal range compared with normal controls as well as between subtypes of MS [104,105].

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ALS, MS

Low The 14-3-3 proteins (∼30 kDa) are homologous dimeric proteins, expressed in almost all eukaryotic cells. In humans, Disease duration seven isoforms (β, γ, ε, η, σ, τ, ξ) are Late stages Early stages known. Five major isoforms are found in the CNS. 14-3-3 are mainly detected by Figure 3. Correlation of a biomarker with the dynamics of the natural course of chronic neurological diseases adapted from data on t-tau. In MS and ALS, neuronal nonquantitative western blots. To date, damage appears to predominate in a very early phase of the disease and in progressive only one study described detection of subtypes of disease. In dementia, higher levels of tau occur in later stages of diseases, 14-3-3 by an ELISA (awaiting further presumably indicating the cumulative involvement of neuronal loss. AD: Alzheimer’s disease; ALS: Amyotrophic lateral sclerosis; CJD: Creutzfeldt–Jakob confirmation) [106]. Similar to t-tau, S100β (S100b), NSE disease; FTD: Frontotemporal dementia; MS: Multiple sclerosis; t-tau: Total cerebrospinal fluid tau; VD: Vascular dementia. and 14-3-3 are well-known as diagnostic markers for CJD, which can be delineated by determination of specific 14-3-3 isoforms (β, γ, ε, η) damage. Accordingly, t-tau may function as a state marker from other subtypes of dementia [42,101,103,107]. In patients according to Blennow and Hampel [16]. In addition, within a with CIS, it was detected in five of 38 cases and its presence single disease entity the CSF t-tau concentration may be of predicted short-term evolution of RR-MS. These results were prognostic value, in other words, it may indicate a faster proconfirmed in larger cohorts of patients [65,108,109]. Another gression or conversion to definite disease (e.g., from MCI to group failed to confirm these results [110]. The reason for this AD, from CIS to RR-MS, or fast vs slow progressing ALS). Biomarkers of neuroaxonal damage represent a category of might be that the 14-3-3 antibodies which were used in these studies cross-react with the light chain of immunoglobulin, parameters with high surrogate potential in CND. Since which is elevated in MS patients [111]. However, further evalu- most CNDs are heterogeneous with regard to the further ation of 14-3-3 in a larger cohort of MS patients with an intraindividual disease course, the baseline CSF concentration of CSF biomarkers may become a relevant predictive improved protocol might be useful. diagnostic tool. While biomarkers of neurodegeneration are N-acetyl aspartic acid well established in patients with AD (tau-protein in combinaN-acetyl aspartic acid (NAA) is a neuron-specific marker con- tion with amyloid-β) and in patients with CJD (14-3-3 prostantly identified in MR-spectroscopy studies of the normal tein), thorough evaluation of these biomarkers in larger studand MS brain. One first study investigating CSF NAA in MS ies using standardized assays warrant further efforts in using gas chromatography mass spectrometry observed higher patients with ALS and MS [113]. concentrations in RR-MS as compared with SPMS as well as a correlation with severity of disease and MRI parameters [112]. In summary, the CSF concentration of markers of neuro- Apoptosis-related markers degeneration (e.g., t-tau), may be elevated in various diseases Transglutaminase associated with neuroaxonal damage regardless of underlying Transglutaminase belongs to a family of enzymes that catalyze etiology [58]. As illustrated in FIGURE 3, CSF t-tau concentrations the formation of a covalent bond between a free amine group appear to be mainly influenced by the intensity of the neuronal (e.g., protein-bound lysine) and the γ-carboxamide group of


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protein-bound glutamine (TABLE 3). Tissue transglutaminase (tTG) is activated during the apoptotic cell death cascade and plays a key role in the formation of apoptotic bodies [114]. In AD and VD (but also in other neurological diseases such as Parkinson’s disease), elevated CSF tTG levels have been reported, indicating increased neural cell apoptosis [115,116]. No capacity to differentiate between subtypes of dementia or correlation with clinical parameters was observed [115]. In ALS, low enzyme levels of CSF tTG have been found, suggesting that enzymatic activity becomes depleted at the terminal stages of the disease when most of the spinal motor neuronal perikarya have been destroyed [114]. A candidate marker related to transglutaminase activity is N-ε-γ-glutamyl-lysine isodipeptide, which is released from the breakdown of proteins crosslinked

by transglutaminase enzymes [117]. Similar to tTG, N-lysine isopeptide levels were observed to be elevated in AD and VD compared with nondemented controls, while no potential to differentiate between subtypes of dementia was observed [117]. Again, the specificity appears to be low because elevated CSF levels of N-ε-γ-glutamyl-lysine isodipeptide were also reported in other neurological diseases (e.g., Huntington’s disease) [118]. Ceramide was demonstrated to accumulate in neurons during acute or chronic neurodegeneration and to induce neuronal apoptosis by upregulation of proapoptotic mitochondrial proteins [119–121]. Ceramide was shown to be elevated in a presenilin-1 mouse model of AD and to induce apoptosis in neurons and glial cells in AD [119,122]. One study reported elevated CSF ceramide levels in AD as compared with ALS and other

Table 3. Cerebropsinal fluid markers of apoptosis and glial response. Biomarker

Dementia n

Main findings

Amyotrophic lateral sclerosis n

Main findings

Multiple sclerosis n

Main findings

Apoptosis-related cerebrospinal fluid markers tTG

51

↑↑ in AD vs controls; ↔ in VD vs controls [115]

N-lysine isopeptide

25

↑↑ in AD and VD vs controls; ↔ in VD vs AD [117]

Ceramide

16

↑↑ in AD vs ALS and controls [123]

17 ↑↑ in early stage ALS vs controls, significantly decreased in late-stage ALS vs controls [114]

Gliosis-related cerebrospinal fluid markers GFAP

27



65


13 ↑↑ in MS vs controls; correlation with clinical deficits [137]

23

↑↑ in NPH vs dementia and controls [133]

66 ↑↑ in SPMS vs controls; correlation with EDSS [90] 51 ↑ in MS with poor ambulation [135]

S100b

43


20 ↓ with ongoing disease [54]


119 ↑↑ in dementia vs controls and MS [157]


159 ↔ in dementia vs controls (↑↑ in CJD) [98]


129 ↑↑ in CJD vs controls [103]

10 Highest in third week after onset of relapse [134]

67


41 ↔ in ON vs controls [136]

68

↔ in AD vs controls; ↑↑ in early AD vs controls [129]

51 ↑↑ in RR-MS vs controls [135]

40

↑↑ in FTD vs controls [130]

↑: Increased; ↑↑: Significantly increased; ↓: Decreased; ↓↓: Significantly decreased; ↔: No alteration.

AD: Alzheimer’s disease; ALS: Amyotrophic lateral sclerosis; CJD: Creutzfeldt–Jakob disease; EDSS: Expanded Disability Status Scale; FTD: Frontotemporal dementia; GFAP: Glial fibrillary acidic protein; MS: Multiple sclerosis; ON: Optic neuritis; RR-MS: Relapsing-remitting multiple sclerosis; NPH: Normal pressure hydrocephalus; SPMS: Secondary progressive multiple sclerosis; tTG: Tissue transglutaminse; VD: Vascular dementia.

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neurological diseases, although no correlation with clinical parameters was observed [123]. In vitro, ceramide was found to induce apoptosis in oligodendrocytes [124], indicating a possible involvement in MS pathology, although no study on ceramide CSF levels in MS exists at present. Markers of glial activation

Glial activation generally occurs very early in the cascade of neurodegeneration (TABLE 3) [125]. S100b and glial fibrillary acidic protein (GFAP) are candidate markers for the measurement of glial activation. S100b is an acidic calcium-binding protein found mostly in specific glial cells, such as astrocytes and Schwann cells [126]. GFAP is the major structural protein of the intermediate filament of astrocytes [127]. In AD, mildly to moderately elevated levels of CSF S100b have been reported by various studies [98,128,129], with one study suggesting that levels may be highest in early stages of disease [129]. Generally, no correlation with severity of dementia was observed, although one study reported a correlation with brain atrophy [128]. Elevation of S100b was also observed in other subtypes of dementia, such as FTD, indicating that S100b has no potential as a marker for differential diagnosis in dementia [98,128,130]. Similar to S100b, CSF GFAP was observed to be elevated in AD [131,132], but also in other subtypes of dementia (e.g., FTD or normal pressure hydrocephalus) [132,133]. As for S100b, no consistent correlation of GFAP with clinical severity of dementia could be observed [131,132]. In ALS, S100b levels were found to be within the normal reference range with a weak correlation with duration of the disease [54]. However, studies of CSF S100b in a larger cohort of ALS patients are still missing. In MS, increased CSF S100b was reported particularly during an acute relapse [93,104,134], which is in line with observations on pathology that described S100b and GFAP in acute inflammatory plaques associated with activation or destruction of astrocytes [12,127]. One author reported significantly higher S100b levels in RR-MS as compared with chronic progressive subtypes [135], although this could not be confirmed by another study [136]. In RR-MS, CSF GFAP levels were observed to correlate with clinical deficits [90,135,137] and to increase over a 24-month followup period [135,137]. Therefore, GFAP may serve as a biomarker in MS for disease progression, probably reflecting the increasing rate of astrogliosis. In summary, gliosis-related markers appear to have only low potential for differential diagnosis of CND. However, further evaluation of their surrogacy potential is needed in larger cohorts and with standardized assays. Identification of new biomarkers using proteome analysis

Research with unbiased approaches, such as proteomics, belongs to the more recent omics technologies that have been applied to discover new candidate biomarkers in CSF [138]. To analyze the


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CSF proteome (e.g., the total protein content) in patients with CND, different technical approaches have been used. SELDITOF mass spectrometry has been successfully applied in dementia as well as ALS [139–141]. Alternative approaches are 2D gel electrophoresis followed by MALDI-TOF mass spectrometry as well as liquid chromatography (LC) mass spectrometry in conjunction with ICAT. TABLE 4 provides an overview of different CSF proteomics studies in CND. Each of the available methods has specific inherent advantages as well as limitations. SELDI-TOF mass spectrometry does not have a high sensitivity, which makes protein identification difficult, and mainly detects proteins with a lower molecular weight, and thus may miss potentially interesting markers [140,141]. 2D gel electrophoresis followed by MALDI-TOF mass spectrometry is labor-intensive because it requires isolating each protein spot before identification of the protein [142]. The most abundant proteins (e.g., albumin or immunoglobulins) limit the total amount of protein that can be loaded on the 2D gel [143]. To increase the detection of less abundant proteins, CSF must be preprocessed by extracting the bulk of extracerebral proteins and salts. To enable preprocessing steps, large quantities of CSF are necessary. This demand can be met by pooling of CSF samples; however, pooling may impede the detection of protein alterations found in individual patients [142]. A recent study performed an integrated analysis of the CSF peptidome and proteome by combination of SDS-PAGE with nano-LC mass spectrometry, and identified 798 proteins in the whole CSF proteome [23]. Using a bead-based method for MALDI tandem mass spectrometry, approximately 150 mass-intensity peaks of peptides and proteins of less than 30 kDa could be identified in a volume of 100 µl of CSF [144]. In LC mass spectrometry labeled with ICAT, only cysteine-containing peptides are labeled (∼90% of the CSF proteome contains cysteine residues). Another setback is that during each run, only a subset of peptides separated by LC gains access to the mass spectrometer, accounting for marked differences between successive runs of identical samples, which limit the reproducibility of this approach [145,146]. Generally, the different methodical approaches to proteome analysis are semiquantitative methods [147,148]. Accordingly, results must be validated using easier, quantitative assays, such as multiparameter immunoassays. Expert commentary

Although several studies have been conducted to date, only a few markers are used in clinical practice. While biomarkers of neurodegeneration are well established in patients with AD (tau-protein in combination with amyloid-β) and in patients with CJD (14-33 protein), in patients with ALS and MS, thorough evaluation of biomarkers in larger studies using standardized assays are warranted. The great majority of biochemical–biological studies, although of paramount importance (as discussed above), generally suffer from several drawbacks: • The studies are monocentric and samples sizes are too small, resulting in underpowered studies;

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Table 4. Candidate cerebrospinal fluid biomarkers from proteome analysis. Dementia

Amyotrophic lateral sclerosis Multiple sclerosis

SELDI-TOF mass spectometry Cystatin C ↑ β2-microglobulin ↑ VGF precursor protein ↓ [139]

↓ transthyretin, ↓ cystatin C, c-terminal fragment of neuroendocrine protein 7B2 [140] ↓ cystatin C, ↓ fragment of VGF, ↓ 7.6 kDa protein that could not be identified [141]

2D GE followed by MALDI-TOF mass spetrometry In AD, significantly altered (increased or decreased) vs controls: ↑ transthyretin, ↑ retinol-binding protein, ↑ β2-microglobulin, ↓ ApoA1, ↓ ApoE [158] ↓ granin-like neuroendocrine precursor, ↓ Apo E, ↓ pigment epithelium-derived factor, ↓ retinol-binding protein, ↓ haptoglobin [159]

RR-MS vs controls: Igκ chain precursor, transferrin, serine proteinase inhibitor, α2-HS-glycoprotein, apoE, transthyretin CIS vs controls: IgGκ chain, pro-ApoA1, serum albumin precursor, complement factor-3, serine proteinase inhibitor, vitamin D-binding protein, translation-initiation factor elF-4-γ, apoE, transthyretin [142]

LC mass spectrometry 163 different proteins AD vs controls; of these, 39 had ACR-ASAP ≥1.2 and 46 had ACR-ASAP ≤0.8 [145]

Total of 430 spots in the MS CSF proteome representing 61 distinct proteins: 103 spots were not seen on control gels; all but four of these 103 were proteins known to be present in normal human CSF [147]: • CRTAC-1B (cartilage acidic protein) • Tetranectin (a plasminogen-binding protein) • SPARC-like protein (a calcium-binding cell signaling glycoprotein) • Autotaxin T (phosphodiesterase) 65 different proteins were identified from 300 spots; 18 of these proteins have not been reported previously on 2D gel in human CSF [148]: • Aldolase A • Annexin 1 • Calmodulin-related protein NB-1 • Cystatin A • EWI-2 (CD81 partner 3) • Glutathione peroxidase • N-acetyllactosaminide β-1,3,-N-acetyl glucosaminyltransferase • Niemann-Pick disease type C2 protein • Procollagen C-proteinase enhancer protein • Psoriasin (s100A7) • Semenogelin 1 and 2 • Superoxide dismutase • Tetranectin • Complement factor H-related protein 1 • Dermcidin • Galectin-7 • Hornerin

ACR-ASAP: Alzheimer/controls ratio-automated statistical analysis of proteine abundance; AD: Alzheimer’s disease; CSF: Cerebrospinal fluid; LC: Liquid chromatography; MS: Multiple sclerosis; RR-MS: Relapsing-remitting multiple sclerosis; SPARC: Secreted protein acidic and rich in cysteine.

• Sample collection and storage conditions are not standardized; • Clinical/biological data collection is not standardized and incomplete and clinical characteristics are often missing; • Biochemical–biological methods have not been validated internally and externally; 488

• The studies are mainly cross-sectional and no appropriate control groups are included (healthy instead of neurological controls, which are seen in clinical practice); • Study goals are poorly defined and sample size estimations are usually missing;



• Confirmation studies with an independent set of samples are missing; • Important covariates and confounders are not considered; • The statistical methods are not appropriate and rarely pre-defined; • Such small single center projects are just able to create primary exploratory data and technical validation of assays; • In addition, for most markers tested in the CSF, the blood–CSF barrier function has not been considered sufficiently, in order to discriminate whether the biomarker of interest originates from the systemic circulation or from intrathecal synthesis, which would indicate the CNS specificity. Five-year view

Standardization of sampling protocols as well as ethical protocols is necessary in future biomarker research studies in CND. This would allow combining sample sets from different research groups within multicenter studies. Such protocols

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would also allow investigators to replicate the studies with samples that match the initial pilot study. In addition to standardized sampling protocols, there is a growing need for standardized guidelines for other steps of biomarker research, including experimental design, criteria for data analysis and representation and proof-of-principle research. Several guidelines for reporting research in different areas (REMARK, STARD, MIAME and PROTEOMICS) already exist [149–152]. Similar approaches are on the way for CSF biomarker research in MS and in other neurological diseases [201]. Financial & competing interests disclosure

This work has been supported in part by fundings of the Deutsche Forschungsgemeinschaft to ACL (DFG LU 336/12-1-KFO142-TP P4). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Chronic neurological diseases (CND) such as amyotrophic lateral sclerosis (ALS), different subtypes of dementia or multiple sclerosis (MS), form an important challenge to diagnostic and therapeutical progress in neurology. • CND may all lead to the common pathological pathway of neurodegeneration, including neuroaxonal damage, neuronal apoptosis and glial reaction. • Biomarkers could support early diagnosis of CND and help to identify responders to interventions in therapeutic treatment trials. • Cerebrospinal fluid (CSF) is a promising source of biomarkers in CND, since the CSF compartment is in close anatomical contact with the brain interstitial fluid, where biochemical changes related to CND are reflected. • Different approaches of CSF proteome analysis have recently been applied to identify new candidate biomarkers in CND. • To increase validity and power of future biomarker studies in CND, a multicenter approach based on standardization of sampling protocols, experimental design and data analysis is necessary. 5

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Sigurd Suessmuth, MD Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany Tel.: +49 731 177 1206 Fax: +49 731 177 1202 [email protected]

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Markus Otto Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany Tel.: +49 731 500 63019 Fax: +49 731 500 63012 [email protected]

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Albert C Ludolph, MD Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany Tel.: +49 731 177 1201 Fax: +49 731 177 1202 [email protected]

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Johannes Brettschneider, MD Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany Tel.: +49 731 177 1206 Fax: +49 731 177 1202 [email protected]

Website 201

European BioMS Society www.BioMS.eu

Affiliations •

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Hayrettin Tumani, MD Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany Tel.: +49 731 177 5207 Fax: +49 731 177 1202 [email protected] Charlotte Teunissen, PhD Department of Molecular Cell Biology & Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands Tel.: +31 20 444 8061 Fax: +31 20 444 8081 [email protected]
