First attempts to detect CP markers in blood of patients with glioma resulted predominantly in the identification of markers differentially expressed between patients and healthy controls. Plasma- and serum-derived protein markers—such as immunosuppressive acidic protein, alpha-1 acidic glycoprotein and alpha-1 antitrypsin, the glycoprotein fibronectin, and the endothelial cell-derived thrombomodulin-1—were the first proteins to be found elevated in the blood of patients with glioma [
84,
110,
141,
145], followed by protein markers related to angiogenesis in gliomas. The serum and plasma protein levels of the marker VEGF have often been reported as significantly increased in patients with glioma compared to healthy controls [
2,
28,
37,
128,
131], and even higher in patients with metastatic brain lesions [
71,
128]. Soluble VEGFR-1 (sVEGFR-1), but not sVEGFR-2, -3, and basic fibroblast growth factor (bFGF, alternatively known as FGF-2), have been reported to be increased in pre-operatively collected serum samples from newly diagnosed glioblastoma patients [
39,
131]. Also, markers involved in tumor cell invasion and remodeling of extracellular matrix, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), were identified as potential diagnostic CP biomarkers. Increased levels of MMP-2 and 9 were observed in CSF of high-grade glioma patients [
51], and a larger study confirmed increased plasma levels of MMP-9 and TIMP-1 in patients with both grade II and IV glioma compared to healthy controls [
95]. Surprisingly, however, in this study no difference was observed in the plasma protein levels of MMP-9 and TIMP-1 of grade III glioma patients as compared to healthy controls. Serum and plasma levels of TIMP-1 allowed the discrimination of grade IV from lower grade gliomas, and were confirmed in two additional studies [
39,
95,
155,
157]. Furthermore, glial fibrillary acidic protein (GFAP) was suggested to have diagnostic value [
24,
68,
73,
80,
102]. An increase of circulating GFAP levels was observed in pre-operatively collected samples from grade III and IV glioma patients in both serum and plasma [
68,
73]. Also in a subset of patients with oligodendroglial tumors, high levels of GFAP were found in plasma, implying that circulating GFAP is not specific for high-grade malignant astrocytic neoplasms [
68]. Of interest, in patients with multiple sclerosis or a metastatic brain lesion, plasma GFAP levels were found to be within the reference range [
73,
102]. Plasma GFAP may, together with plasma placental growth factor (PlGF), differentiate between radiologically suspected high-grade glioma and brain metastases [
73]. Obviously, the fact that not only GFAP, but also other markers such as brain-derived neurotrophic factor (BDNF) and S100 calcium binding protein B (S100B), can be detected in the circulation of healthy controls negatively influences the specificity of such protein markers for detection of disease processes [
91]. Finally, urine protein levels of 2-hydroxyglutarate (2-HG) may aid in distinguishing
IDH1 mutant glioma patients from those with
IDH1 wild-type glioma [
98]. Assessment of the 2-HG metabolite in pre-operatively collected serum samples did not allow for such discrimination [
27]. Potential diagnostic value has also been reported for serum and/or plasma levels of EGFR protein [
127,
151], transforming growth factor beta (TGFb) [
147], tumor necrosis factor alpha (TNFa) [
2,
28,
59,
131], interleukin 2 (IL-2) and its receptor [
59,
192], Chitinase-3-like protein 1 (CHI3L1, also known as YKL-40) [
15,
167], S100B [
73,
102,
175], neural cell adhesion molecule (NCAM) [
171], neuropeptide Y (NPY) [
73] and BDNF [
73].