CSF Proteomic Applications in Central Nervous System Diseases

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Several CSF proteins, discovered by 2-DE, have been proposed as diagnostic markers for neurodegenerative disorders; for example, the 14-3-3y protein (originally p130 and p131) as a surrogate marker for Creutzfeldt-Jakob disease (CJD) [27, 60], and the middle isoform of a2-haptoglobulin for Alzheimer's disease (AD) and schizophrenia [30]. In AD, many studies have found various assays for CSF tau and CSF ^-amyloid to be very informative [61-63].

Since the 14-3-3y protein assay is perhaps the first proteomic-derived test, some discussion of its application is worthwhile. Most CJD surveillance units incorporate this in their assessment of suspected cases of CJD in a dementia population. The original discovery of 14-3-3y protein presented it as a surrogate marker to distinguish CJD in the context of clinical dementia, when we noted that a small number of false positive or negative testing would occur since it merely reflects neuronal damage from which 14-3-3y leaks, apparently at a continuous rate of production mainly in the prion dementias. Occasional 14-3-3y production will come from a number of other conditions, most of which can be clinically excluded. This seems to surprise some people [64], but if interpreted with appropriate caution, the overwhelming experience of several retrospective and prospective studies have validated the 14-3-3y immunoassay for CJD [60, 65-71]. In this context, the American Academy of Neurology endorsed the use of this test in their guidelines for the work-up of dementia if CJD is suspected [72].

Only a few comparative proteomic analyses of CSF proteins have been employed for studies of pathophysiological mechanisms in neurodegenerative diseases. Using 2-DE gel and the silver staining technique, large differences in protein patterns in CSF between patients with brain disorders such as AD, schizophrenia, Parkinson's disease, and multiple sclerosis were shown [24, 25, 28, 73], however many of these proteins have not yet been identified. Fonteh and Harrington reported at the 2002 meeting in Siena an increase of specific isoforms of apo-lipoproteins A1, J, K and prostaglandin D synthase (PGDS) in the CSF of AD study participants [74]. Moreover, Harrington and colleagues have described significant changes in the abundance of 10 CSF proteins during the headache phase of migraine and more subtle changes in isoforms of two other proteins in the wellstate of a migraineur population compared with controls who were not susceptible to headaches [75, 76]. In a proteomic study of CSF proteins in a group of AD

patients, the levels of six proteins and their isoforms, including pro-apolipopro-tein, apolipoprotein E, /^-microglobulin, retinol-binding protein, transthyretin, and ubiquitin were significantly altered. The most notable changes were seen among the apolipoproteins, especially pro-apolipoprotein [7], which is consistent with the previously reported results of reduced levels of apolipoproteins in AD [77].

Protein oxidation has long been discussed in the pathophysiology of AD and protein modifications to reactive oxygen species were demonstrated more frequently in AD, with a-enolase identified as one of the target proteins [20]. Aging is the highest risk factor for AD. Merril and Harrington demonstrated five proteins that were age-affected in CSF from normal controls [31], and a quantitative proteome analysis identified 35 proteins in relation to aging that may partly reflect some of the pathophysiological components involved in AD [78]. Normal aging itself is a complex event and the proteomic approach could be important in determining its molecular complexity.

One of the most common types of dementia is frontotemporal dementia (FTD), which is often misdiagnosed as AD. A recent study showed for the first time that several proteins involved in FTD pathology are not altered in the CSF of AD patients, and vice versa, thus establishing differences in pathophysiological mechanisms between FTD and AD, two of the most common neurodegenerative disorders [12].

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