speciÞc for a tumor: NAA is synthesized in neuronal mitochondria and any brain disease severely affecting neuronal tissue can decrease NAA concentration levels. This is especially true for encephalitis or cerebritis, tumefactive demyelinating lesions, and infarction. Similarly, regular tCho signal intensity in all voxels of a non-necrotic space-occupying lesion will exclude high-grade gliomas with high accuracy. But a normal tCho does not exclude any glioma, since glioneuronal tumors, WHO grade II astrocytomas, and gliomatoses often show normal or only slightly increased choline concentrations (Fig. 4a). On the other hand, high tCho signals may be found in pilocytic astrocytomas (Porto et al. 2010), acute brain diseases with high cell membrane turnover like encephalitis, acute demyelinating diseases (Blasel et al. 2011a), active dysmyelination, tuberculosis, and acute radiation injury. Further, lipid signals and lactate are frequently described as tumor metabolites. Lipid signals may occur in tumors without obvious necrosis on conventional MRI, indicating microscopic or even intracellular lipids in high-grade gliomas. However, each of the above mentioned aggressive brain diseases may also yield lipid and lactate signals from necroses and hypoxia. High concentrations of myoinositol and creatine are reported in gliomatosis cerebri and lowergrade astrocytomas, but also in other brain diseases with augmented astrocytic proliferation and demyelinization (detailed discussion and references in Hattingen et al. 2008).

Several studies investigated the accuracy of proton spectroscopy to differentiate between tumors and non-neoplastic lesions and to differentiate low-grade from high-grade gliomas. The differentiation between high-grade and low-grade tumors and differentiation between astrocytoma and oligodendroglial tumors are both decisive for therapeutic decisions. High-grade brain tumors are usually treated more aggressively than low-grade tumors, and higher-grade oligodendroglial tumors are more sensitive to chemotherapy than other tumor entities. A detailed overview and description of these studies is provided by Horsk‡ and Barker (2010). The main drawback of the presented studies is the limited comparability due to the differing methodological approaches: SVS versus MRSI, different echo times, different post processing, and various metabolite ratios. Using ratios between different metabolites has the advantage of higher sensitivity if it is obvious that both metabolite concentrations change in the opposite direction. This is the case for the Cho/NAA resp NAA/Cho ratio in neoplastic lesions (Fig. 3a) (Stadlbauer et al. 2007; Vuori et al. 2004; Nelson 2001). However, for some metabolites like creatine and myoinositol, increase and decrease in concentrations were observed. The evaluation of creatine and myoinositol in brain tumors has important diagnostic and also prognostic value. Normally, both metabolite concentrations are decreased in brain tumors. However, elevated creatine and myoinositol levels have been found especially in low-grade gliomas. Higher creatine concentrations compared to normal

brain tissue were correlated with shorter progression-free survival (Hattingen et al. 2010). Higher myoinositol levels in brain tumors may support the diagnosis of a low-grade astrocytoma (Castillo et al. 2000), whereas higher glycine concentrations were found in high-grade gliomas as demonstrated in Fig. 6 (Hattingen et al. 2009; Davies et al. 2010).

Alternatively, heterogeneity of a tumor can be evaluated with MRSI analyzing a maximum metabolite level of the tumor related to the same metabolite from the contralateral healthy tissue (Di Costanzo et al. 2008). This approach yields a normalized value which takes interindividual and regional metabolite variations into account. The maximum normalized tCho (hot spot) is also a qualiÞed value for grading non-necrotic gliomas, and the respective voxel might be the target of stereotactic biopsy (Hermann et al. 2008; Senft et al. 2009). The selection of voxel with potentially most malignant tumor tissue is important for tumors in eloquent brain regions which have to be left partially in place.

The peri-enhancing tumor regions should also be sampled and analyzed with MRSI. In contrast to metastases, gliomas inÞltrate brain areas beyond the enhancing area, showing elevated tCho concentrations (Fig. 1) and increased Cho/ NAA ratios (Fig. 3a) in surrounding tissue (Stadlbauer et al. 2007; Di Costanzo et al. 2008). An investigation of the perienhancing border zone has also therapeutic relevance. Considering that all areas of viable tumor have to be targeted with high radiation dose, the ÒinvisibleÓ marginal zone might be undertreated. Recurrent tumors mostly occur in these marginal zones (Blasel et al. 2011b). Thus, integration of MRSI and/or MR perfusion in the treatment planning of high-grade gliomas would target more tumor tissue and might prolong progression-free survival of the patients. This has already been shown for Gamma Knife surgery (Chan et al. 2004).

Although phosphorus spectroscopy seems to be closer to the tumor biology, investigation of tumor heterogeneity or perienhancing tumor area is not possible due to its limited spatial resolution. An impression of the rather coarse grid size for 31P MRS can be obtained by comparing the grids in Figs. 4 and 5.

3.1Some Aspects of Differential Diagnosis

Bearing in mind the above described limitations, MR spectroscopy should only be used in conjunction with MR imaging and age and clinical symptoms of the patient to avoid misdiagnosis. The best diagnostic accuracy can be achieved by combining advanced imaging techniques (Tzika et al. 2003; Chang et al. 2009). Diffusion-weighted imaging is the best method to diagnose an abscess; MR perfusion of the tumor and the peri-enhancing region is highly accurate in grading gliomas and in differentiating inÞltrated from focal, non-inÞltrating brain tumors (Di Costanzo et al. 2008). Hereby, it is worth to mention that primary CNS lymphomas

Fig. 7 Monitoring lipids. Typical spectra from the two cases shown as parameter maps in Fig. 3. Lower traces show the normal-appear- ing tissue (yellow mark in the MRI at left panel) while upper traces show tumor tissue (red mark in the MRI). Note that lipid signals vis-

ible at short TE (spectra in middle panel, upper trace) for the glioblastoma (a) are not visible in the long TE spectra (right panel), while for the metastasis (b) spectra for both TE show lipids

are also inÞltrating brain tumors showing increased blood volume outside the enhancing area (Blasel et al. 2013). Inside the enhancing area of CNS lymphoma, the spectroscopic pattern is Òan intermediateÓ between high-grade gliomas and metastases, showing intermediate tCho increase and prominent lipid peaks at short TE (Harting et al. 2003). The lipid increase might be invisible in long TE MR spectra.

Metastases from different primary tumors show diverse spectroscopic pattern according to their biological heterogeneity. The Cho signal intensity is elevated in solid and proliferating metastases, but most metastases show only moderate Cho increase (Fig. 4b). Huge lipid signals are found in necrotic glioblastomas, but lipids are also the dominant peaks in most of the metastases (Fig. 7) (Poptani et al. 1995). Further, the Cho/NAA ratios of metastases from peritumoral areas differ from the ratios in inÞltrating gliomas, indicating the lack of tumor inÞltration in the former (Server et al. 2010).

There are some metabolites which are indicative, but not absolutely speciÞc for special tumor entities (Table 1). Taurine is an organic acid with many fundamental biological roles such as osmoregulation, antioxidation, membrane stabilization, and modulation of calcium signaling. High taurine signal intensities have been found in primitive neuroectodermal tumors (PNET) including medulloblastomas (Panigrahy et al. 2006; Kovanlikaya et al. 2005). Alanine, an amino acid, is found in meningiomas (Poptani et al. 1995; Kugel et al. 1992), but also in abscesses. The spectra of the later typically also show an increase of other amino acids. Multiplets of amino acids (0.9 ppm), lactate (at 1.3 ppm), and alanine (at 1.5 ppm) can be differentiated from lipids by their inversion with a long TE (135Ð144 ms) (see also Fig. 2 for detection of lactate). Amino acid increase in bacterial abscesses results from enhanced glycolysis yielding high levels of pyruvate, which is the substrate for the amino acid synthesis of alanine and others.