Independent of prior therapy for both low- and high-grade astrocytomas, FDG accumulation can yield important information about prognosis. Patronas et al. pioneered the use of FDG PET results as a prognostic factor in gliomas, showing that patients with hypermetabolic tumors had an average survival of 5 months, while patients with eumetabolic or hypometabolic tumors had an average survival of 19 months [6]. In studies of patients with low-grade tumors, the development of focal areas of hypermetabolism has been associated with poorer prognosis [5–7].

The physiological high background FDG accumulation in gray matter structures such as the cerebral cortex and basal ganglia, makes the lesions less conspicuous and limits the ability of FDG PET to detect and characterize small lesions. The uptake of FDG is nonspecific and inflammatory/infectious lesions demonstrate variable FDG uptake [4–7]. Image interpretation can be greatly facilitated by coregistration with MRI and/or databases of FDG uptake in normal brains. A negative FDG PET can also be helpful to exclude a high-grade glioma [4–7].

MET is the most studied PET AA imaging modality for brain tumors, with an overall sensitivity of 76–97 % and specificity of 75–100 % in brain tumor detection and differentiation of benign from malignant lesions [9–15]. Ogawa et al. found 97 % sensitivity for MET-PET in 32 patients with high-grade astrocytomas but only 61 % sensitivity in low-grade astrocytomas [9]. Although the sensitivity is lower compared to the high-grade gliomas, a MET PET scan is particularly useful in detecting low-grade gliomas which are difficult to identify with enhancement characteristics on anatomical images [10, 11]. Ribom et al. reported that 94 % of low-grade gliomas demonstrated increased MET uptake, while only 38 % showed contrast enhancement on CT or MRI [11]. Similar results have been reported for high-grade gliomas. Kracht found that 29 of 53 surgical specimens of grade 3 and 4 astrocytomas presented with no signs of contrast enhancement on MRI but showed increased MET uptake [10]. Furthermore, Chung et al. reported that 89 % of 35 brain tumors with decreased or iso- FDG activity on PET could be detected and differentiated with high sensitivity and good contrast using MET PET [12]. The reported causes of false positives on a MET PET brain scan include demyelination, necrosis, subacute or chronic ischemia, leukoencephalitis, brain abscess, acute infarct, and hematoma. The mechanism of MET accumulation in benign inflammatory lesions is not clear, but thought to be due to the increased methionine uptake in the perivascular mononuclear infiltrate, gliotic reaction, increased blood flow, and blood–brain barrier breakdown [4, 9, 12, 13].

MET uptake correlates with cell proliferation, in vitro Ki-67 expression, proliferating cell nuclear antigen, and microvessel density, making it a potential biomarker for active tumor proliferation [4, 13]. However, unlike FDG PET, MET PET has not revealed a clear predictive value for grading with visual analysis [7, 14, 15]. Although the prognosis depends on the histological tumor grade, MET PET is a significant prognostic factor, even superior to FDG PET, independent of tumor grade and prior treatment. High MET uptake has been shown to be statistically associated with a poor survival time [7, 9–11, 14, 15].

FET is one of the most promising ¹⁸F AA radiotracer, which can be produced in large amounts for clinical purposes, and exhibits a similar diagnostic potential to MET [8, 16–18]. Unlike MET and FDG, FET exhibits low uptake in nonneoplastic inflammatory cells [8, 16–18]. The tumor specificity has been the major reason for the specific interest in FET, which was thought to be related to selective uptake of FET via a specific subtype of the LAT system [17, 18]. The sensitivity and specificity of FET were reported to be between 93 and 100 %, and 100 %, respectively, for both low- and high-grade gliomas with higher results for high-grade glioma [8, 16–20]. In a comparative study, MRI had a sensitivity of 96 % for the detection of tumor tissue, but a specificity of only 53 %. In contrast, the combined use of MRI and FET PET increased the specificity to 94 % with a sensitivity of 93 %. The combined use of MRI and FET PET was clearly superior to that of MRI alone for the noninvasive distinction of tumor tissue and peritumoral brain tissue in patients with cerebral gliomas [20]. In a similar study, Floeth et al. demonstrated that sensitivity and specificity for tumor detection were 100 and 81 % for MR spectroscopy (MRS) and 88 and 88 % for FET PET. The accuracy in distinguishing neoplastic from nonneoplastic tissue could be increased from 68 % with the use of MRI imaging alone to 97 % with MRI imaging in conjunction with FET PET and MRS [17].

Assessment of tumor grade with FET PET has been considered of little value because of the individual variability of SUV FET [16, 17, 20–23]. However, the ratio of FET SUV to background has been found to correlate with clinical outcomes in patients with gliomas [22]. Interestingly, nonspecific incidental brain lesions, seen as circumscribed growth patterns on MRI and having normal or low FET uptake, were reported to be strong predictors for a benign course. If there was eventual development of a glioma, a diffuse growth pattern on MRI and increased FET uptake indicated a high risk for the development of a high-grade glioma [23].

FDOPA, is another amino acid analogue that is taken up by normal brain at the blood–brain barrier by the neutral amino acid transporter, trapped in striatum and was thought to be transported into but not trapped in tumors [24–26]. FDOPA has demonstrated a high specificity of 90–100 % for diagnosis of initial and recurrent gliomas in all grades. FDOPA uptake preceded tumor detection on MRI and FDOPA uptake has been reported in gliomas with no enhancement on MRI [26]. FDOPA PET demonstrated higher sensitivity than FDG PET and FDOPA uptake correlated better with Ki-67 values, and was a more powerful predictor of tumor progression and survival compared to FDG PET [25–27]. There are controversial studies related to correlation with neoplastic grade; however, compared to other AA radiotracers, FDOPA uptake kinetics have been demonstrated to correlate better with tumor grade [25–27].

FLT, developed as a PET tracer to evaluate tumor cell proliferation, and the uptake of FLT has been demonstrated to correlate with thymidine kinase-1 (TK1) activity and the proliferation index Ki-67 in gliomas [28, 29]. FLT seems to be superior to MET and FDG in noninvasive tumor grading, assessment of proliferation activity, progression and survival of the patients with gliomas of different grades [24, 30]. However, Jacobs et al. reported 78.3 % sensitivity for FLT PET for the detection of tumors, which was lower than the 91.3 % sensitivity of MET PET, especially for low-grade astrocytomas [30].

Choline has been targeted as a PET imaging molecule, a likely marker of metabolic activity, preferentially taken up by tumor cells, but not by chronic inflammatory cells. In gliomas, FCH uptake has been demonstrated to correlate well with tumor grade [31–34]. Abnormal metabolite profiles of increased levels of choline and decreased levels of N-acetyl acetate (NAA) correlate with high-grade intracranial malignancies on MRS. High-grade gliomas are distinguishable from oligodendrogliomas and other low-grade gliomas by higher uptake of choline tracers seen with PET and higher levels of choline metabolites using MRSI. However, with MRS, increased levels of choline metabolites may also be found in demyelinating lesions, which reduces the specificity of MRSI for diagnosing high-grade malignancies [17, 32]. Kwee et al. reported a case in which PET imaging with FCH aided in distinguishing a demyelinating lesion from a suspected high-grade glioma [32].

Hypoxia is the driving force in angiogenesis and it has been shown to be associated with resistance to therapy, poorer survival, and more malignant tumor phenotypes. Cher et al observed FMISO uptake in high-grade gliomas but not in low-grade gliomas. They also found a significant correlation between FMISO uptake and Ki-67 and VEGFR-1 expression [35]. Increased FMISO uptake was also demonstrated to be associated with shorter survival in this patient population [35, 36]. FMISO PET provides a noninvasive assessment of hypoxia in gliomas and is prognostic for treatment outcomes in a majority of patients.