Differential neural structures, intrinsic functional connectivity, and episodic memory in subjective cognitive decline and healthy controls.

The neural correlates of subjective cognitive decline (SCD; i.e., without objectifiable deficit) remain to be elucidated. Possible causes of SCD include early neurodegeneration related to Alzheimer's disease or functional and structural changes related to sub-clinical depression. We investigated the relationship between episodic memory performance or memory complaints and structural or functional magnetic resonance imaging (MRI) measures in participants with SCD (n=18) but without psychiatric disorders and healthy controls (n=31). In SCD, memory complaints were not associated with memory performance but with sub-clinical depression and executive functions. SCD-associated memory complaints correlated with higher amygdala and parahippocampal gyrus (specifically subiculum) gray matter density. In controls, but not in SCD, mesiotemporal gray matter density and superior frontal gyrus functional connectivity predicted memory performance. In contrast, in SCD, only a trend toward a correlation between memory performance and gray matter density in the parietooccipital lobes was observed. In our memory-clinic sample of SCD, we did not observe incipient neurodegeneration (limited to structural and functional MRI) but rather sub-clinical depression underlying subjective cognitive complaints.

Prognostic impact of postoperative, pre-irradiation (18)F-fluoroethyl-l-tyrosine uptake in glioblastoma patients treated with radiochemotherapy.

BACKGROUND AND PURPOSE: Resection is considered as essential for the efficacy of modern adjuvant treatment of glioblastoma multiforme (GBM). Previous studies have indicated that amino acid PET is more specific than contrast enhancement on MRI for detecting residual tumor tissue after surgery. In a prospective study we investigated the prognostic impact of postoperative tumor volume and tumor/brain ratios (TBR) in PET using O-(2-[(18)F]fluoroethyl)-l-tyrosine (FET) in comparison with MRI. MATERIALS AND METHODS: Forty-four patients with GBM were investigated by FET PET and MRI after surgery. Tumor volume in FET PET with a tumor/brain ratio (TBR)>1.6 and a TBR>2, mean and maximum TBR and gadolinium contrast-enhancement on MRI (Gd-volume) were determined. Thereafter patients received a fractionated radiotherapy with concomitant temozolomide (RCX). The median follow-up was 15.4 (3-35) months. The prognostic value of postoperative residual tumor volume in FET PET, TBR(mean,) TBR(max) and Gd-volume was evaluated using Kaplan-Maier estimates for disease-free survival (DFS) and overall survival (OS). RESULTS: Postoperative tumor volume in FET PET had a significant independent influence on OS and DFS (OS 20.0 vs. 6.9 months; DFS 9.6 vs. 5.1 months, p<0.001; cut-off 25 ml). Similar results were observed when a TBR ≥ 2 (cut-off 10 ml) was used to define the tumor volume in (18)F-FET PET. The TBR(mean) and TBR(max) of FET uptake had a significant influence on DFS (p<0.05). Gd-volume in MRI had significant effect on OS and DFS in the univariate analysis. No independent significant influence in OS or DFS could be observed for Gd-volume in MRI. CONCLUSIONS: Our data indicate that the tumor volume in FET PET after surgery of GBM has a strong prognostic impact for these patients. FET PET appears to be helpful to determine the residual tumor volume after surgery of GBM and may serve as a valuable tool for optimal planning of radiation treatment.

Prognostic value of early [18F]fluoroethyltyrosine positron emission tomography after radiochemotherapy in glioblastoma multiforme.

PURPOSE: Early detection of treatment response in glioma patients after radiochemotherapy (RCX) is uncertain because treatment-related contrast enhancement in magnetic resonance imaging can mimic tumor progression. Positron emission tomography (PET) using the amino acid tracer [(18)F]fluoroethyltyrosine (FET) seems to be a promising tool for treatment monitoring. The aim of this prospective study was to evaluate the prognostic value of early changes of FET uptake after postoperative RCX in glioblastomas. METHODS AND MATERIALS: Twenty-two patients with glioblastoma were treated by surgery and subsequent RCX (whole dose 60-72 Gy). The FET-PET studies were performed before RCX, 7-10 days and 6-8 weeks after completion of RCX. Early treatment response in PET was defined as a decrease of the maximal tumor-to-brain ratio (TBR(max)) of FET uptake after RCX of more than 10%. The prognostic value of early changes of FET uptake after RCX was evaluated using Kaplan-Maier estimates for median disease-free survival and overall survival. RESULTS: The median overall and disease-free survival of the patients was 14.8 and 7.8 months. There were 16 early responders in FET-PET (72.7%) and 6 nonresponders (27.3%). Early PET responders had a significantly longer median disease-free survival (10.3 vs. 5.8 months; p < 0.01) and overall survival ("not reached" vs. 9.3 months; p < 0.001). No statistically significant differences between the patient subgroups were found concerning the defined prognostic parameters. CONCLUSIONS: FET-PET is a sensitive tool to predict treatment response in patients with glioblastomas at an early stage after RCX.

Integrated-boost IMRT or 3-D-CRT using FET-PET based auto-contoured target volume delineation for glioblastoma multiforme--a dosimetric comparison.

BACKGROUND: Biological brain tumor imaging using O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-PET combined with inverse treatment planning for locally restricted dose escalation in patients with glioblastoma multiforme seems to be a promising approach.The aim of this study was to compare inverse with forward treatment planning for an integrated boost dose application in patients suffering from a glioblastoma multiforme, while biological target volumes are based on FET-PET and MRI data sets. METHODS: In 16 glioblastoma patients an intensity-modulated radiotherapy technique comprising an integrated boost (IB-IMRT) and a 3-dimensional conventional radiotherapy (3D-CRT) technique were generated for dosimetric comparison. FET-PET, MRI and treatment planning CT (P-CT) were co-registrated. The integrated boost volume (PTV1) was auto-contoured using a cut-off tumor-to-brain ratio (TBR) of > or = 1.6 from FET-PET. PTV2 delineation was MRI-based. The total dose was prescribed to 72 and 60 Gy for PTV1 and PTV2, using daily fractions of 2.4 and 2 Gy. RESULTS: After auto-contouring of PTV1 a marked target shape complexity had an impact on the dosimetric outcome. Patients with 3-4 PTV1 subvolumes vs. a single volume revealed a significant decrease in mean dose (67.7 vs. 70.6 Gy). From convex to complex shaped PTV1 mean doses decreased from 71.3 Gy to 67.7 Gy. The homogeneity and conformity for PTV1 and PTV2 was significantly improved with IB-IMRT. With the use of IB-IMRT the minimum dose within PTV1 (61.1 vs. 57.4 Gy) and PTV2 (51.4 vs. 40.9 Gy) increased significantly, and the mean EUD for PTV2 was improved (59.9 vs. 55.3 Gy, p < 0.01). The EUD for PTV1 was only slightly improved (68.3 vs. 67.3 Gy). The EUD for the brain was equal with both planning techniques. CONCLUSION: In the presented planning study the integrated boost concept based on inversely planned IB-IMRT is feasible. The FET-PET-based automatically contoured PTV1 can lead to very complex geometric configurations, limiting the achievable mean dose in the boost volume. With IB-IMRT a better homogeneity and conformity, compared to 3D-CRT, could be achieved.

Comparison of O-(2-18F-fluoroethyl)-L-tyrosine PET and 3-123I-iodo-alpha-methyl-L-tyrosine SPECT in brain tumors.

UNLABELLED: The aim of this study was to compare PET with O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) and SPECT with 3-(123)I-iodo-alpha-methyl- L-tyrosine ((123)I-IMT) in patients with brain tumors. METHODS: Twenty patients with a suspected brain tumor were investigated by (18)F-FET PET, (123)I-IMT SPECT, and MRI within 3 wk. Region-of-interest analyses were performed on coregistered PET/SPECT/MRI images and the tumor-to-brain ratio (TBR), muscle-to-brain ratio (MBR), cerebellum-to-brain ratio (CerBR), and sinus-to-brain ratio (SBR) were calculated. In addition, the presence of tumor and the discrimination of anatomic structures on (18)F-FET PET and (123)I-IMT SPECT images were visually determined by 3 observers who were unaware of clinical data. RESULTS: The TBR of (18)F-FET and (123)I-IMT uptake in cerebral tumors showed a highly significant correlation (r = 0.96; P < 0.001). In the visual analysis for the presence or absence of tumors, no differences for (123)I-IMT SPECT and (18)F-FET PET were found in 19 of 20 patients; in one patient a low-grade glioma was only identified on (18)F-FET PET images but not on (123)I-IMT SPECT images. The contrast between tumor and normal brain was significantly higher in (18)F-FET PET (TBR, 2.0 +/- 0.9) than in (123)I-IMT SPECT (TBR, 1.5 +/- 0.5). The discrimination of anatomic structures yielded a significantly better score on (18)F-FET PET images (rating score, 2.6 +/- 0.9) compared with (123)I-IMT SPECT images (rating score, 1.7 +/- 0.9). The uptake of (18)F-FET in the muscles was significantly higher compared with (123)I-IMT (MBR (18)F-FET, 1.4 +/- 0.3; MBR (123)I-IMT, 0.6 +/- 0.2; P < 0.001) and (18)F-FET demonstrated a significantly higher blood-pool radioactivity than (123)I-IMT (SBR (18)F-FET, 1.3 +/- 0.2; SBR (123)I-IMT, 0.8 +/- 0.2; P < 0.001). CONCLUSION: The significant correlation of the TBRs of (18)F-FET and (123)I-IMT indicates that clinical experiences of brain tumor diagnostics with (123)I-IMT SPECT might be valid for (18)F-FET PET although substantial differences of the physiologic behavior were identified in extracerebral tissue. As (18)F-FET PET allows improved discrimination of anatomic structures and the tumor-to-brain contrast was significantly superior compared with (123)I-IMT SPECT scans, the results are encouraging for further evaluation of (18)F-FET for imaging brain tumors.

Imaging of gliomas with Cis-4-[18F]fluoro-L-proline.

Tumor imaging with cis-4-[18F]fluoro-L-proline (cis-FPro) was compared to that of L-[3H]proline and L-[3H]methionine in F98 rat gliomas by dual-tracer autoradiography. All tracers exhibited high accumulation in the tumors but in the normal brain significant uptake was observed for L-[3H]methionine only. Tumor extent on autoradiograms with L-[3H]proline and L-[3H]methionine was identical to that of histological staining while autoradiograms of cis-FPro showed diffuse uptake in the penumbra of some tumors. First PET studies in 7 patients with cerebral gliomas demonstrated accumulation of cis-FPro in tumor areas with enhancement of Gd-DTPA on MR scans. Uptake of cis-FPro in normal brain tissue was negligible. In one patient with a glioblastoma accumulation of cis-FPro was also found in two brain areas without enhancement of Gd-DTPA on MR scans. Control of MRI suggested tumor growth in these areas at further follow up. Our results indicate that in most gliomas increased cis-FPro uptake is restricted to areas with disruption of the BBB which limits its clinical utility.

Whole-body distribution and dosimetry of O-(2-[18F]fluoroethyl)-L-tyrosine.

The whole-body distribution of O-(2-[(18)F]fluoroethyl)- l-tyrosine (FET) was studied in seven patients with brain tumours by positron emission tomography (PET). Based on the IMEDOSE and MIRDOSE procedures, radiation absorbed doses were estimated from whole-body PET scans acquired approximately 70 and 200 min after i.v. injection of 400 MBq FET. After injection of FET, the peak of radioactivity in the blood was observed after 1.5 min, and a plateau of nearly constant radioactivity was reached at 20 min. The whole-body distribution of FET showed the highest activities in the urinary tract. All other organs exhibited only moderate FET uptake (SUV

Transport of cis- and trans-4-[(18)F]fluoro-L-proline in F98 glioma cells.

The transport mechanisms of cis-4-[(18)F]fluoro-L-proline (cis-FPro) and trans-4-[(18)F]fluoro-L-proline (trans-FPro) were studied in F98 rat glioma cells in comparison to the natural parent [(3)H]-L-proline. Uptake rates of cis-FPro and trans-FPro in F98 glioma cells were 50-70% lower than those of [(3)H]-L-proline. The amino transport system A inhibitor MeAIB reduced the uptake of [(3)H]-L-proline by 30% and uptake of cis-FPro by 46% while uptake of trans-FPro was not significantly changed. BCH inhibited the uptake of all tracers by 35-44%, serine by 70-90% and L-proline by 60 -80%. Absence of Na(+) reduced uptake of all tracers significantly but no further inhibitory effect could be observed which suggests a component of unspecific uptake. Radioactivity of cis- and trans-FPro in the acid precipitable fraction was < 1% after 120 min incubation time while [(3)H]-L-proline exhibited a 20% incorporation into protein. Whole body PET scans in humans demonstrated a retention of cis-FPro in the renal cortex, liver and the pancreas while trans-FPro was retained particularly in muscles. We conclude that system A amino acid transport appears to be selectively relevant for cis-FPro which may contribute to the observed differences in whole body distribution of cis-FPro and trans-FPro in humans.