Bettina Beuthien-Baumann

Discrimination between Alzheimer Dementia and Controls by Automated Analysis of Multicenter FDG PET

A new diagnostic indicator of FDG PET scan abnormality, based on age-adjusted t statistics and an automated voxel-based procedure, is presented and validated in a large data set comprising 110 normal controls and 395 patients with probable Alzheimers disease (AD) that were studied in eight participating centers. The effect of differences in spatial resolution of PET scanners was minimized effectively by filtering and masking. In controls FDG uptake declined significantly with age in anterior cingulate and frontolateral perisylvian cortex. In patients with probable AD decline of FDG uptake in posterior cingulate, temporoparietal, and prefrontal association cortex was related to dementia severity. These effects were clearly distinct from age effects in controls, suggesting that the disease process of AD is not related to normal aging. Women with probable AD had significantly more frontal metabolic impairment than men. The new indicator of metabolic abnormality in AD-related regions provided 93% sensitivity and specificity for distinction of mild to moderate probable AD from normals, and 84% sensitivity at 93% specificity for detection of very mild probable AD (defined by Mini Mental Score 24 or better). All regions related to AD severity were already affected in very mild AD, suggesting that all vulnerable areas are affected to a similar degree already at disease onset. Ventromedial frontal cortex was also abnormal. In conclusion, automated analysis of multicenter FDG PET is feasible, provides insights into AD pathophysiology, and can be used potentially as a sensitive biomarker for early AD diagnosis.

Multicenter Standardized 18F-FDG PET Diagnosis of Mild Cognitive Impairment, Alzheimer's Disease, and Other Dementias

This multicenter study examined 18F-FDG PET measures in the differential diagnosis of Alzheimers disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) from normal aging and from each other and the relation of disease-specific patterns to mild cognitive impairment (MCI). Methods: We examined the 18F-FDG PET scans of 548 subjects, including 110 healthy elderly individuals (“normals” or NLs), 114 MCI, 199 AD, 98 FTD, and 27 DLB patients, collected at 7 participating centers. Individual PET scans were Z scored using automated voxel-based comparison with generation of disease-specific patterns of cortical and hippocampal 18F-FDG uptake that were then applied to characterize MCI. Results: Standardized disease-specific PET patterns were developed that correctly classified 95% AD, 92% DLB, 94% FTD, and 94% NL. MCI patients showed primarily posterior cingulate cortex and hippocampal hypometabolism (81%), whereas neocortical abnormalities varied according to neuropsychological profiles. An AD PET pattern was observed in 79% MCI with deficits in multiple cognitive domains and 31% amnesic MCI. 18F-FDG PET heterogeneity in MCI with nonmemory deficits ranged from absent hypometabolism to FTD and DLB PET patterns. Conclusion: Standardized automated analysis of 18F-FDG PET scans may provide an objective and sensitive support to the clinical diagnosis in early dementia.

Prognostic value of positron emission tomography in the evaluation of post‐treatment residual mass in patients with Hodgkin's disease and non‐Hodgkin's lymphoma

The prognostic value of 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) in the assessment of post‐treatment residual masses in patients with Hodgkins disease (HD) or non‐Hodgkins lymphomas (NHL) was evaluated. We prospectively studied 58 patients with HD (n = 43) or NHL (n = 15) who had post‐therapeutic complete remission with residual masses (CRu) indicated by computerized tomography. Analysis of 62 residual locations by FDG‐PET was performed separately for HD and NHL. Patients with a PET‐positive residual mass [standardized uptake value (SUV) > 3] had a recurrence rate of 62·5% (5/8 patients), whereas patients with PET‐negative residual mass (SUV ≤ 3·0) showed a recurrence rate of 4% (2/50 patients, P = 0·004). A positive FDG‐PET study correlated with a significantly poorer progression‐free survival (P < 0·00001). No recurrence occurred in any of the 39 HD patients with a negative PET scan (negative predictive value, 100%). Four out of four NHL patients with a positive PET study relapsed (positive predictive value, 100%). In conclusion, FDG‐PET is a suitable non‐invasive method with a high degree of accuracy in the prediction of early recurrence in lymphoma patients with CRu.

Regional cerebral metabolism in early Alzheimer’s disease with clinically significant apathy or depression

BACKGROUND Alzheimers disease (AD) is clinically characterized by cognitive impairment and behavioral disturbances. The aim of the study was to identify regional alterations in brain function associated with neuropsychiatric symptoms in early AD. METHODS Patients underwent measures of cerebral glucose metabolism applying positron emission tomography (PET) and (18)F-fluorodeoxyglucose. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory (NPI). Positron emission tomography images of patients suffering a neuropsychiatric symptom of clinical significance (NPI subscore for a specific item >/=4 points) were compared with the images of patients without the specific symptom under study (NPI subscore for a specific item = 0 points). RESULTS A total of 53 patients with AD (Mini-Mental State Examination [MMSE] 22.5 +/- 2.94 points) entered the study. Of all symptoms, apathy and depression were most frequently encountered. The patient group with apathy (n = 17) revealed significant decreases in left orbitofrontal regions when compared with patients free of apathy. Depression of clinical significance (n = 10) was associated with hypometabolism in dorsolateral prefrontal regions. CONCLUSIONS These findings support the notion that different functional circuits underlie apathy and depression in early AD.

Orbitofrontal dysfunction related to both apathy and disinhibition in frontotemporal dementia

Orbitofrontal metabolic impairment is characteristic of the frontal variant of frontotemporal dementia (fv-FTD), as are early changes in emotional and social conduct. Two main types of behavioral disturbances have been distinguished in fv-FTD patients: apathetic and disinhibited manifestations. In this study, we searched for relationships between brain metabolism and presence of apathetic or disinhibited behavior. Metabolic activity and behavioral data were collected in 41 fv-FTD patients from European PET centers. A conjunction analysis of the PET data showed an expected impairment of metabolic activity in the anterior cingulate, ventromedial and orbital prefrontal cortex, the dorsolateral prefrontal cortex and the left anterior insula in fv-FTD subjects compared to matched controls. A correlation was observed between disinhibition scores on the Neuropsychiatric Inventory scale and a cluster of voxels located in the posterior orbitofrontal cortex (6, 28, –24). Comparison of brain activity between apathetic and nonapathetic fv-FTD patients from two centers also revealed a specific involvement of the posterior orbitofrontal cortex in apathetic subjects (4, 22, –22). The results confirm that the main cerebral metabolic impairment in fv-FTD patients affects areas specializing in emotional evaluation and demonstrate that decreased orbitofrontal activity is related to both disinhibited and apathetic syndromes in fv-FTD.

Changes in brain metabolism associated with remission in unipolar major depression

Objective:  Functional brain correlates of remission in patients with major depressive disorder (MDD) are measured with positron emission tomography (PET) and 18F‐fluorodeoxyglucose.

Diagnostic impact of PET with 18F-FDG, 18F-DOPA and 3-O-methyl-6-[18F]fluoro-DOPA in recurrent or metastatic medullary thyroid carcinoma.

PurposeIn patients with medullary thyroid carcinoma (MTC), rising levels of the tumour markers calcitonin and CEA after primary surgery indicate tumour recurrence or metastases. The only chance of cure is the resection of localised tumour tissue. For positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) and 18F-dihydroxyphenylalanine (18F-DOPA), sensitivities of 78% and 63% have been reported, but in a considerable percentage of MTC patients the source of tumour marker elevation is not detected. The aim of this retrospective data evaluation was to compare the value of PET with 18F-FDG, 18F-DOPA and the amino acid tracer 3-O-methyl-6-[18F]fluoro-DOPA (18F-OMFD) in the detection of MTC recurrence.MethodsFifteen patients with elevated calcitonin were investigated with PET as part of their individual clinical work-up. All patients underwent 18F-FDG PET and 18F-DOPA PET, and ten patients underwent 18F-OMFD PET.ResultsWith 18F-FDG, seven patients showed foci in the neck, mediastinum, upper abdomen or bone. In seven patients, 18F-DOPA revealed suspicious foci; five of these seven patients showed partially corresponding uptake of 18F-FDG in the neck and mediastinum. Two of these patients underwent surgery and metastases were verified. With 18F-OMFD, a small focus in the liver was suspected in one patient without a correlate on 18F-FDG PET, 18F-DOPA PET or conventional imaging.Conclusion18F-FDG and 18F-DOPA showed foci that were highly suspicious for local recurrence or metastasis of MTC, although histological verification in these patients with numerous previous surgical interventions was performed in only two patients. The amino acid tracer 18F-OMFD had no diagnostic impact in these patients.

Prediction of clonogenic cell survival curves based on the number of residual DNA double strand breaks measured by gammaH2AX staining.

Purpose: To assess the potential of using the residual phosphorylation of histone H2AX (γH2AX) after irradiation as a marker of radiosensitivity in vitro. Material and methods: Confluent cell cultures of FaDu and SKX human squamous cell carcinoma lines were irradiated with graded single doses. Twenty-four hours after irradiation cells were seeded for standard colony forming assay (CFA). In parallel, staining for γH2AX was performed to visualise the residual foci. Results: In the CFA, FaDu showed a higher radioresistance than SKX. After analysis of the residual foci data, we constructed ‘predicted’ survival curves using two different methods. First, the proportion of nuclei with <3 foci was found to correlate closely with the observed surviving fraction (SF) in FaDu, with a slight overestimation of the true SF in SKX. Second, there was a strong linear correlation of the mean number of residual foci and observed −lnSF. Based on regression analysis, we calculated the SF for both cell lines based on the mean number of residual γH2AX foci. This second approach again led to a good correlation of predicted and observed SF values in FaDu and a (slight) overestimation in SKX. Conclusion: In the two cell lines investigated the mean number of residual foci of γH2AX can be used to predict differences in the radiation dose response relationship in vitro.

Preparation of fluorine-18 labelled sugars and derivatives and their application as tracer for positron-emission-tomography

The usefulness of 18F-labelled carbohydrates, especially 2-deoxy-2-[18F]fluoro-D-glucose, to study pathophysiological processes in man non-invasively using positron-emission-tomography (PET) led to a widespread investigation of different 18F-labelled sugars and sugar derivatives. In consideration of the short half-life of fluorine-18 (T(1/2) = 110 min) synthetic strategies concerning precursor design, labelling conditions and deprotection of the intermediate compounds were developed to guarantee an efficient high radiochemical yield synthesis for diagnostic purposes. Besides some aspects of medical application of 2-deoxy-2-[18F]fluoro-D-glucose, a few synthetic strategies are described reflecting development work on promising 18F-labelled sugars for diagnostic purposes during the last two decades.

Diagnostic Value of 18F-FDG Positron Emission Tomography for Detection and Treatment Control of Malignant Germ Cell Tumors

Introduction: The role of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) is currently under evaluation in urologic oncology. The aim of the present study was to investigate the use of [18F]FDG positron emission tomography ([18F]FDG-PET) in the detection and treatment control of malignant germ cell tumors compared to computed tomography (CT). Materials and Methods: Thirty-two PET studies and CT scans were carried out in 23 patients with histologically proven germ cell tumors (10 seminomas, 12 non-seminomatous germ cell tumors (NSGCT), 1 unclassified serologic recurrent disease) Lugano stage I–III. The scans were done either after initial diagnosis (n = 21) and/or within 3–45 days after chemotherapy was completed (n = 11). PET and CT were validated either by histology (n = 7) or clinical follow-up of 6–11 months after the last PET study has been performed (n = 16). Sensitivity, specificity, accuracy, positive and negative predictive values were determined for PET and CT. Differences between PET and CT for parameters of diagnostic value were evaluated by χ2 test. Results: Although not statistically significant, the sensitivity, accuracy and negative predictive value were higher for PET than for CT with respect to the detection of metastatic infradiaphragmatic and supradiaphragmatic lesions after initial diagnosis. The specificity and positive predictive value of PET and CT were comparable. After chemotherapy, PET was found to be significantly superior in specificity and accuracy compared to CT with respect to infradiaphragmatic lesions (p < 0.05). False-positive PET findings in supradiaphragmatic lesions after chemotherapy occurred in the case of inflammatory processes and resulted in a loss of specificity and accuracy compared to CT (p < 0.05). Conclusions: These preliminary results demonstrate [18F]FDG-PET to be a useful diagnostic tool for the initial staging and treatment control in patients with germ cell tumors. Possible advantages compared to CT, however, are as yet not clearly defined. The possibility of false-positive PET findings due to reactive supradiaphragmatic inflammatory processes early after chemotherapy have to be considered.