The diagnosis of AD usually relies on excluding other disorders with similar clinical features. To facilitate an early diagnosis, additional diagnostic tools related to causes of neuronal degeneration would be of great interest [15
]. Such molecules that have been shown to be associated with AD are free radicals and oxidative stress promoting molecules, proinflammatory cytokines and neurotoxic agents [16
]. Most of these biomarker molecules are studied in the blood and may not reflect central pathologic processes occurring in the brain of patients with AD. Therefore, CSF is a more suitable biological fluid for study of biomarker molecules in AD [17
]. Of the many potential areas for study of CSF, the field of proteomics is especially well suited for discovery of biomarkers in CSF; this is because proteins are abundant in CSF [15
Proteomics has emerged in the last few years as a multidisciplinary and technology-driven science that focuses on proteomes: the complex of proteins expressed in biological systems, their structures, interactions and post-translational modifications. In particular, proteomics examines changes in protein levels and other protein alterations that result from or foster specific diseases, or are affected by various external factors, such as toxic agents.
The combination of immunoassays and proteomic methods reveals that CSF proteins express differential protein patterns in AD, frontotemporal dementia (FTD), and PD patients; these findings suggest divergent underlying pathophysiological mechanisms and neuropathological changes underlying these diseases.
Potential biomarkers with pathophysiologic significance have been studied in the field of AD research with some success, especially in the area of genetic markers (apolipoprotein E epsilon4 allele), neuroimaging, and cerebrospinal fluid markers (Aβ42 and tau). Of these, results using proteomics combined with immunochemical studies are the most abundant. To date, combined clinical examinations and measurement of the biochemical markers (β-amyloid and tau) in CSF have become valuable diagnostic tools for predicting more than 80% of AD cases [20
]. Other proteins known to be associated with AD pathology are apolipoprotein E (apo E) and synaptic proteins which have been studied by immunoassays [16
]. Other candidate CSF biomarkers include: ubiquitin [21
], NF protein [22
], GAP43 (neuromodulin) [4
], NTP, and AD7c protein [25
]. An increasing number of studies suggest that supplementary use of these CSF markers preferably in combination, adds to the accuracy of AD diagnosis [20
Fibrinogen gamma chain (FGG) is the gamma component of fibrinogen, a blood-borne glycoprotein comprised of three pairs of non-identical polypeptide chains. FGG A precursor is one of the transcript variant isoforms due to alternative splicing [28
The functional features of the FGG include participation in fibrin polymerization and cross-linking, the initiation of fibrinolysis, a role in binding and regulating factor XIII activity, high affinity binding sites for integrin of platelets, leukocyte, and a role in mediating thrombin binding to fibrin, an inhibitory function originally termed 'antithrombin I' [29
It is well known that hemostatic factors and inflammatory proteins are closely related to atherosclerosis and cardiovascular risk [30
]. An additional hypothesis is that these factors might be related to vascular dementia. There are many reports that have discussed this relationship [32
]. However, there is limited evidence, and a paucity of information, on hemostatic markers for AD. Moreover, although there are reports on the association of AD with fibrinogen in blood [33
], there is no information of such an association in CSF.
In our study, fibrinogen gamma-A chain precursor was found to be increased in expression in both MCI and AD patients compared to normal controls. This expression was more prominent in AD patients than in both the normal controls and the MCI group, and appeared to be related to the severity of dementia. Although we cannot explain the actual relationship between FGG and AD at this point in time, these findings suggest that activated fibrinogen gamma-A chain precursor may be an important marker for the linear progression of MCI to AD and an important factor in the severity of AD. As regards the potential use for predicting AD development, a longitudinal analysis on MCI subjects is needed to verify the conversion to AD.
However, it can not be excluded that increased levels of FGG may be due to increased blood levels and/or increased permeability across the blood-CSF barrier. Both factors may influence the CSF FGG levels and thereby may cause the differences seen between AD and controls. Further studies will have to consider these putative factors to ensure specificity of the present findings.