Brain PET imaging

This presentation for all especially nuclear medicine residents
By Dr.Mustafa ahmed alazam
Middle euphrates cancer center
Iraq-Najaf

1. Tehran University of Medical Sciences Shariati Hospital Nuclear Medicine Department Dr. Mustafa Al-Thabhawee Brain PET imaging

2. Imaging for Tumors of the Brain Introduction. Normal pattern of uptake. Radiotracers . 2-Deoxy-2-[18F] Fluoro-D-Glucose ([18F]FDG ). Amino acid tracers. DNA Synthesis. Hypoxia Agents. Factors affecting uptake of radiopharmaceuticals in gliomas. Clinical indications to PET/CT and PET/MR imaging in gliomas. PET/MR . Key learning points. Primary Brain Tumors Site of better biopsy. Metabolic grading of the tumor . Pearls Pitfalls. The factors that affecting the FDG uptake SUV. Interpretation criteria

3. It is important that physicians who interpret PET brain scans review a large number of normal images before interpreting studies in patients with neuropsychiatric disorders. There are many histotypes of brain tumors, the most frequent being gliomas, i.e., tumors deriving from glia cells. Tumors deriving from neurons, typically the medulloblastoma, are much less frequent . In addition to gliomas, malignancies of the central nervous system (CNS) include meningiomas, primary brain lymphomas , and metastases from tumors outside the brain. The latter two types of tumors (lymphomas and brain metastases from primary non-CNS tumors ). Gliomas are classified as high-grade and low-grade gliomas . • Therapy of gliomas consists in surgery combined to radiotherapy . Introduction

4. a) The normal brain has high FDG uptake in the gray matter, with a gray-to-white matter activity ratio ranging from 2:5 to 4:1. b) The basal ganglia usually have slightly more uptake than the cortex. c) The medial temporal cortices typically have less uptake than the other cortical areas . d ) Mild focal areas of increased activity can be seen normally in the Frontal eye fields. Posterior cingulate cortex. Wernicke's region ( posterosuperior temporal lobe ). Visual cortex. Normal pattern of uptake

5. Age-related changes Cortical metabolism decreases with age, particularly in the frontal lobes . Other areas that can show decreased activity with aging are the insula. Temporal lobes (lateral), parietal lobes, and anterior and middle cingulate cortices. The least altered regions during aging are the primary motor cortices , occipital cortices, precuneus , mesial temporal lobes, basal ganglia, and cerebellum.

6. Patients with renal failure have decreased FDG uptake in the cortex and white matter compared to those with normal renal function . Renal function

7. There are often minimal asymmetries in uptake between areas in the left and right hemispheres. Asymmetric uptake should be interpreted with caution unless: There is a significant difference between the two sides that correlates with clinical findings . For example, any level of asymmetry in the temporal lobes in a patient with epilepsy should be considered a potential focus for seizure activity. Quantitatively , a difference of 10 to 15% is often considered significant but clinical correlation is paramount. b ) The asymmetry is fairly extensive and seen on multiple slices. Symmetry of uptake

8. Comparison with single-photon emission computed tomography ( SPECT) a ) FDG uptake usually correlates with uptake of SPECT perfusion tracers, except in cases where metabolism and perfusion are uncoupled (e.g., luxury perfusion post-infarct ). b ) The magnitude of hypometabolism seen on PET is usually greater than that of hypo-perfusion seen on SPECT. c ) Cerebellar uptake of FDG is variable but in general is less than seen on SPECT. This differs from brain SPECT images, where consistently the cerebellum appears more active than other brain structures .

9. Crossed cerebellar diaschisis The glucose metabolism in the cerebellar hemisphere contralateral to a supra-tentorial abnormality (tumor, infarct, or trauma) is frequently decreased in the acute phase of the disease and may change over time . This does not indicate cerebellar pathology . a) Diaschisis is thought to be related to interruption of the corticopontocerebellar pathway . b) Ipsilateral pontine hypometabolism and preservation of metabolism in the contralateral dentate nucleus have been reported .

10. Radiotracers

11. Factors affecting uptake of radiopharmaceuticals in gliomas

12. 2-Deoxy-2-[18F]Fluoro-d-Glucose ([18F]FDG) [ 18 F]FDG allows measurement of glucose metabolism. [ 18 F] FDG is the most commonly used tracer for brain tumor imaging . The tracer was described in the 1970’s to study brain metabolism. In the 1980’s, the tracer was used for brain tumor imaging, since brain tumor growth implies an increase in glucose consumption . The 2-deoxyglucose model for quantifying the cerebral metabolic rate for glucose (CMRglc) was defined by Sokoloff following auto-radiographic experiments in rats and subsequently adapted for human studies with PET by different authors . [18F]FDG enters the cell through a carrier-mediated system , and it is phosphorylated within the cytoplasm by the enzyme hexokinase. Phosphorylated [18F]FDG accumulates into the cytoplasm as a function of neural activity, it has no other metabolic side pathways, and therefore [18F]FDG accumulation rate can be easily modeled and quantified. Initially, dynamic scanning and arterial line-derived input function were adopted for clinical research with the aim of obtaining absolute quantitative (mg/gram/min) values of CMRglc . Glucose metabolism is 2–3 times higher in gray matter than in white matter. In conditions of sensory deprivation and in normal subjects, glucose metabolism is uniform across gray matter.

13. Amino Acid Tracers The most frequently used amino acid tracers are: [11C]methionine. O- (2-18F-fluoroethyl)-l-tyrosine ( 18F-FET) 3. dihydroxy-6-18F-fluorophenylalanine ( 18F-fluorodopa (18F-DOPA )).

14. A 32-year-old woman with anaplastic oligodendroglioma : [ 11 C]methionine PET image shows slightly elevated [ 11 C]methionine uptake. ( b ) T1-weighted MR image with gadolinium contrast medium shows no enhancement;

15. (c) fused [ 11 C]methionine PET and MR image . ( d) MR FLAIR image shows a remarkable increase in the FLAIR signal. The tumor was partially resected. The patient was alive at the time of this report 47.4 months after the operation

16. Combined [ 18 F]FDG (upper row) and [ 11 C]methionine (lower row) PET studies. This patient displays tumor recurrence as the primary glioblastoma grade IV, which is easily detectable with [ 11 C]MET (b) but not on [ 18 F]FDG (a).

17. This patient is affected by a primary oligo astrocytoma grade II, which is hot on [ 11 C]methionine PET (d) and cold on [ 18 F] FDG PET (c)

18. 18 F-FET PET and early postoperative T1-weighted MR . Early (48–72 h) postoperative post-contrast T1-weighted MR alone and fused to 18 F-FET PET scanning performed 2 weeks later for radiation treatment planning showing the superiority of PET with 18 F-FET over MR for definition of residual tumor volume after surgery .

19. (a) Residual metabolically active non-enhancing tumor remnant anterior to the resection cavity identified in the left frontal lobe (red arrow), presumably infiltrating glioblastoma. On MR, the tumor was evaluated as gross total resected. ( b) This patient was evaluated as partially resected based on a smaller contrast-enhancing region (blue arrow) in the depth of the resection cavity in the left temporal region. Lack of metabolic activity on 18 F-FET PET, however, suggests reactive changes. Areas of increased 18 F-FET uptake are found in subcortical white matter anterior and posterior to the cavity (red arrow), presumably infiltrating glioblastoma.

20. Radiolabeled Choline Radiolabeled choline (either [ 11 C]choline or 18 F-fluorocholine) is a phospholipid precursor. The uptake of the tracer is thought to reflect membrane proliferation, particularly choline-derived membrane phospholipids. In vivo studies with proton magnetic resonance spectroscopy have shown increased concentration of choline-containing phospholipids (i.e ., phosphoryl choline and glycerol- phospho -choline ) in brain tumors. In physiological conditions the tracer has no significant uptake in the brain, and therefore it is suitable for imaging gliomas with high sensitivity. Either [ 11 C]choline or 18 F-fluorocholine is available to most PET centers since the tracer is successfully used for imaging prostate cancer. This availability facilitated the application of radiolabeled choline for detection of brain tumors, yielding promising results. False-positive findings may occur owing to tracer uptake by inflammatory lesions, in brain metastases, and in meningiomas . Images are acquired using a static scan 2 min after injection. Image interpretation is similar to what is described for amino acid tracers.

21. Positive 18 F-FDOPA PET/CT and 18 F-FDOPA PET/MR images . (a–c) Glioblastoma multiforme. The axial FLAIR image ( a) shows a lesion in the left insula and temporal lobe involving the ipsilateral ventral striatum (arrow). The 18 F-FDOPA PET image (b) and fused PET/MR image (c) clearly show asymmetrical uptake in the ventral striatum , greater on the left, matching the lesion on MRI.

22. The axial FLAIR image (d) shows an extensive infiltrative lesion involving the left frontal and temporal lobe extending to the genu of the corpus callosum and to the ipsilateral ventral and dorsal striatum. The 18 F-FDOPA PET image (e) and fused PET/ MR image (f) show increased uptake and a modified outline of the left striatum .

23. ( g – i ) Glioblastoma multiforme. The axial FLAIR image ( g )shows an extensive infiltrative lesion involving the left temporal-parietal lobe , the ipsilateral thalamus, and the dorsal striatum (putamen ). The 18F-FDOPA PET image (h) and fused PET/MR image ( i ) show increased uptake and a modified outline of the left putamen, matching the lesion on MRI.

24. Combined 18 F-DOPA (upper row) and [ 18 F]FDG (lower row) PET studies. A 27-year-old man with right frontal grade II oligoastrocytoma treated primarily with surgery and radiotherapy, presented with clinical suspicion of recurrence. Trans-axial 18 F-DOPA PET (a) and PET/CT (b) images show tracer accumulation in a right frontal lobe lesion (arrows) suggestive of recurrence.

25. Transaxial [ 18 F]FDG PET ( c) and PET/CT (d) images show no abnormal focus of tracer uptake and are negative for recurrence. The patient underwent reoperation and was found to have recurrent grade III glioma (anaplastic astrocytoma) on histopathology.

26. DNA synthesis is a fundamental step for cell proliferation . Thymidine is a pyrimidine used for DNA but not for RNA synthesis . Thymidine is incorporated into DNA through the salvage pathway for pyrimidines. The amount of DNA synthetized is lower than through the de novo pathway ; however, because of the limited number of compartments involved and modeling assumptions, DNA synthesis can be more easily quantified . Tracers designed to quantify DNA replication are also named proliferation tracers . Initial studies with PET and [ 11 C]thymidine showed rapid metabolism of the compound, which implied complex corrections of the input function for recirculating radiolabeled metabolites. Subsequently, 3-deoxy-3- 18 F-fluorothymidine ( 18 F-FLT , a thymidine analog) was synthetized. 18 F-FLT has the advantages of 18 F-labeling and of a more favorable metabolism. However, the BBB limits cellular uptake of 18 F-FLT, and kinetic analysis is needed to accurately quantify DNA synthesis . However, studies provided conflicting results on the correlation between 18 FFLT kinetic parameters and Ki-67, an index of cellular Replication. DNA Synthesis

27. Images were traditionally obtained through a two-tissue Compartment: 1) Four-rate constant kinetic model, which yields parametric images of the blood-to-tissue transport (K 1 ). 2) Net 18 F-FLT transport into the brain (K FLT ). However , very recently it was shown that a late acquisition 1-h post-injection can be reasonably used in the clinical setting eliminating the need of the cumbersome kinetic analysis. In physiological conditions , uptake of the tracer in the brain is negligible, so that images resemble amino acid images

28. T2-weighted MR, [ 18 F]FDG, and 18 F-FLT PET images of a 33-year-old woman with a grade II astrocytoma. There is only very subtle decrease in glucose metabolism in the right anterior cingulus in comparison to the left size and no tumor 18 F-FLT uptake (arrow ).

29. The interest in imaging tumor hypoxia is due to the fact that hypoxia is associated with resistance to radiotherapy and to some chemotherapy regimens and therefore with tumor progression. Several radiopharmaceuticals have been evaluated as hypoxia tracers . These tracers include nitroimidazole compounds, e.g ., 18 F-fluoromisonidazole ( 18 F-MISO), 18 F-azomycin arabinoside ( 18 F-FAZA ), and 64 Cu-labeled methylthiosemicarbazone ( 64 Cu-ATSM ). The common property of these tracers is that they all are bio-reductive agents and their tissue binding is dependent on tissue oxygen concentration. Specifically , as tissue hypoxia increases , trapping also increases. PET studies of brain tumor hypoxia are mostly limited to the use of 18 F-MISO. 18 F-MISO freely crosses the blood brain barrier and rapidly equilibrates within tissues inde pendent of perfusion. Tracer uptake in glioblastoma multiforme is heterogeneous. Increased 18F-MISO tumor uptake is generally found in the periphery but not in the necrotic center of glioblastomas multiforme. The necrotic center is photopenic. Hypoxia Agents

30. Sensitivity and specificity for diagnosis of brain gliomas/ glioma recurrence for most common PET tracers Sensitivity and specificity are both higher than 80% with most tracers for both indications in most studies, with higher specificity for amino acid tracers for the differential diagnosis.

31. Indications to PET/CT or PET/MR

32. Key Learning Points • There are several indications to PET/CT or PET/ MR for brain tumor imaging, the most common being the differential diagnosis between tumor recurrence and radiation necrosis and through the metabolic characterization of the brain mass, to support the MR-based suspect of glioma . • Sensitivity and specificity are both higher than 80% with most tracers for both indications in most studies, with higher specificity for amino acid tracers for the differential diagnosis. PET has an increasingly important role in defining the brain tumor edges before surgery and radiotherapy, to increase the accuracy of both procedures . • Many studies have been performed in glioma patients with virtually any tracer and consistently showed that PET can be successfully used for any clinical indication and that, therefore, PET should be used in the work-up of all glioma patients . • There are some differences among tracers: amino acid tracers are best for differentiation between tumor recurrence and radiation necrosis; moreover, they are often used for defining the radiation therapy plan .

33. • All tracers carry prognostic information . • [ 18 F]FDG is more advantageous for tumor grading, but it is increasingly less used nowadays as amino acid tracers find broader acceptance . • Hypoxia tracers, proliferation tracers, and radiolabeled choline are at this moment of second choice PET tracers. PET/CT is the current state-of-the-art imaging technique for brain tumors; it is well established and widely available for all nuclear medicine centers throughout the world . • PET/MR represents an innovative technique, as it combines two techniques that are mandatory in the diagnostic process and avoids exposure to CT-radiation. • However, PET/MR is less accessible and so far its clinical use is restricted to academic research centers.

34. Possible clinical applications include Determining the best biopsy site for optimal grading of the tumor Despite the overall low degree of FOG uptake in law-grade gliomas, PET may be more useful for stereotactic biopsy target selection in law-grade gliomas (inhomogeneous gliomas without contrast enhancement ) than in high-grade gliomas3 as contrast enhancement can be used in the latter case. 2. Metabolic grading of the tumor: The degree of glucose metabolism correlates with prognosis and outcome in these patients . This is independent of other prognostic factors. For example. In one study, hypometabolic low-grade gliomas were associated with a longer average survival compared to hypermetabolic low-grade gliomas. Ln one report , the accuracy of FDG PET/CT for grading glioma was superior to that of MRI. In a meta-analysis, l8-F-FET PET was much more accurate than FOG PET for the brain tumor diagnosis (distinguishing tumoral from non tumoral lesions but both tracers performed similarly for glioma grading .

35. 3. Evaluation possible transformation of a low grade glioma to high grade tumor . Increased FDG uptake in a previously diagnosed low-grade lesion is suggestive of malignant transformation and associated with decreased survival.

36. The factors that affecting the FDG uptake Corticosteroids. Cushing disease. Sedatives and anticonvulsant drugs. Gray matter uptake of FDG. Glucose level. Hyperglycemia. Delayed imaging.

37. SUV may not be as useful in the brain, as it may not correlate well with regional glucose metabolism . Tumor to white matter or cortex ratios may be preferable. SUV max cutoff of 5.7 had a 75 % accuracy for detection of progression, and a normalized SUVmax (ratio of SUV in the lesion to the SUV in the contralateral normal white matter) cutoff of 1.9 had an accuracy of 83%. Glucose-corrected SUVmax>4.3D has also been used to differentiated recurrent high-grade glioma from post-treatment change. Combining MRS (normalized choline/ creatinine ratio) and PET results (normalized SUVmax.) improves accuracy . SUV

38. False negatives. Small low-grade neoplasms are often undetectable on PET. A minority of high grade tumors are also not appear on PET . 2. False positives: a) Low grade neoplasms such as pilocytic astrocytoma , pleomorphic xantboastrocytoma. gangtioglioma , and oligodendroglioma can be hypermetabolic. b ) Benign lesions such as meningioma , pituitary adenoma and histiocytosis can be hyper metabolic . • There is a substantial range of uptake in meningiomas . with some lesions as high as normal gray matter, while others are hypometabolic . Glucose consumption in meningiomas may be related to tumor aggressiveness and probability of recurrence. c ) Seizures at the time of FDG administration can cause false-positive results due to activated cortex adjacent to the tumor site . d ) Hypermetabolic flare phenomenon may be seen in glioblastoma treated with chemotherapy if PET is performed 24 hours after the first dose. This may predict longer survival . Pitfalls

39. Pituitary adenoma. ( a} Sagittal T1 "Weighted MRI scan demonstrates a pituitary macro adenoma. ( b) Sagittal PET scan demonstrates intense uptake in this adenoma

40. Tumor recurrence. (a) Axial MRI scan demonstrates enhancement at the margin of a light parietal glioma resection site post-radiation , equivocal for radiation necrosis vs. tumor. (b) Axial PET scan demonstrates increased uptake (arrow) in the area of enhancement seen on MRI. consistent with tumor recurrence. Note that it is important to differentiate this activity from normal gray matter activity decreased ln Intensity post-radiation . There was no gray matter In this region by MRI correlation. (c) Follow-up axial MRI done several months after the P£T scan demonstrates further increased enhancement in this region which show has the exact configuration as the uptake seen on PET.

41. CNS lymphoma. Axial PET ( a) and contrast enhanced MRI (b) in a patient with diffuse large B-cell lymphoma demonstrated Intense uptake. In the enhancing frontal lobe mass and decreased uptake in the surrounding edema. Both the intense uptake in the lesion and the decreased white matter uptake are helpful In differentiating CNS lymphoma from glioma .

42. Interpretation criteria Visual criteria : The main criterion for diagnosing recurrence of tumor on PET is relatively increased uptake compared to the adjacent or contralateral white matter. The ipsilateral white matter may be less suitable as a reference because. • Tumor cells may infiltrate around a focal lesion causing diffuse increased white matter uptake ipsilaterally . • Areas of encephalomalacia from prior surgery can cause apparent decreased white matter uptake . However. this will be apparent when PET and MRl images are compared. Uptake greater than contralateral gray matter can also be used as a criterion for a positive. b ) SUV.

43. If you have any question or notes about the topic, please don’t hesitate to contact me: - [email protected] https:// www.facebook.com/mustafa.a.ala zam https:// t.me/JcjvTA_yWN 45 OGU 8