18F-labelled CCR1-receptor antagonist is not suitable for imaging of Alzheimer's disease.

Diagnosis of Alzheimer's disease (AD) with positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) relies on typical alterations of brain glucose metabolism which are, however, not disease specific. Amyloid-ß imaging has not entered clinical routine yet. Post mortem histological specimen of brain tissue from AD patients revealed enhanced expression of the chemotactic cytocine receptor 1 (CCR1). PARTICIPANTS, METHODS: CCR1-antagonist ZK811460 was labeled with fluorine-18 to explore its possible use as specific diagnostic tool in AD. Tracer characterization comprising PET imaging of brain and metabolite analysis was performed in AD patients and controls. RESULTS: Neither qualitative evaluation nor quantitative compartment analysis of PET data did show any enhanced binding of the 18F-labeled CCR1-antagonist in the brain of AD patients or controls. CONCLUSION: 18F-ZK811460 did not fulfill the expectation as diagnostic tracer in PET imaging of AD.

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. METHOD: Glucose metabolism was measured in patients (n = 41) with moderate to severe MDD during acute depression and in the remitted state defined as a period of asymptomatic condition over 12 weeks. Data analyses used a region-of-interest (ROI) approach and statistical parametric mapping (SPM). RESULTS: There were significant decreases in metabolism upon remission with respect to the baseline scan in left prefrontal, anterior temporal and anterior cingulate cortex and bilateral thalamus (SPM analysis) and bilateral putamen and cerebellum (SPM and ROI analyses). There was a significant asymmetry in prefrontal and anterior cingulate cortex metabolism with lower metabolism in the left hemisphere that persisted despite clinical remission. CONCLUSION: These findings support the hypothesis that selective monoamine reuptake inhibition leads to an attenuation of a brain circuit that mediates depressive symptomatology.

[Changes in regional cerebral perfusion in depression.SPECT monitoring of response to treatment]. / Regionale Funktionsstörung bei der Depression. Hirn-SPECT zur Verlaufskontrolle.

The objective of this study was to investigate the relationship between the effect of sleep deprivation, recovery and regional brain perfusion in patients with major depression. Regional cerebral blood flow was assessed by 99mTc-HMPAO-SPECT before and after sleep deprivation in fourteen medicated patients. Three of the patients underwent a follow-up measurement after clinical recovery and with an unchanged antidepressant medication. Before sleep deprivation the responding patients had a significantly higher anterior cingulate perfusion than the nonresponding patients, that normalized after sleep deprivation. Cingulate perfusion uniquely differentiated eventual treatment response from non-responders, as perfusion in no other region under study discriminated the two groups. At baseline all patients revealed hypoperfusion in the left prefrontal cortex when compared to the right side, which was not affected by sleep deprivation, whereas prefrontal hypoperfusion was reversible upon remission. These findings are in agreement with previous PET investigations and provide evidence for cingulate and prefrontal dysfunction associated with depression, that are reversible by successful treatment and may represent state markers.

Discordant twins with Parkinson's disease: positron emission tomography and early signs of impaired cognitive circuits.

We evaluated 7 pairs of twins (2 monozygotic and 5 dizygotic) discordant for Parkinson's disease (PD), of whom the cotwins showed no signs of motor impairment on neurological examination. All subjects underwent positron emission tomographic measurements of cerebral glucose metabolism and dopaminergic, nigrostriatal function following injection of 2-[18F]fluoro-2-deoxy-D-glucose and L-6-[18F]fluorodopa ([18F]dopa), respectively, as well as testing for anterograde, verbal episodic, and semantic memory performance. Statistical analysis demonstrated significant reduction of striatal [18F]dopa uptake not only in the twin patients with PD but also in all of the cotwins, who showed significantly (p < 0.05) impaired [18F]dopa metabolism in at least one of the striatal measures including caudate, putaminal, and the rostrocaudal putaminal gradient of [18F]dopa uptake. Compared with age-matched controls, regional glucose metabolism was unchanged in all the twins. Neuropsychological testing showed significant (p < 0.05) impairment in verbal memory processing in the twin patients with PD and in 6 of the cotwins. Semantic memory skills were affected in 2 twin patients only. A significant correlation was found between scores obtained in Buschke's Selective Reminding Test and striatal [18F]dopa uptake, further substantiating the role of dopaminergic pathways in memory processing. The present study is the first to reveal not only significant disturbance of nigrostriatal dopaminergic function in verbal episodic memory that is known to be affected in PD. Larger studies with a longitudinal design will be necessary to answer the question of whether cognitive changes found in the cotwin group are signs of incipient PD.

In vivo metabolism of childhood posterior fossa tumors and primitive neuroectodermal tumors before and after treatment.

BACKGROUND: Despite an increasing interest in the clinical application of positron emission tomography (PET) in tumors of the adult patient as a diagnostic and prognostic tool, only a few studies have been concerned with the usefulness of PET with [18F]2-deoxy-2-fluoro-D-glucose (FDG) in childhood tumors. METHODS: Fifteen children and young adults (0.5-26.0 years of age) with histologically confirmed brain tumors were studied with PET and FDG. Seven children with medulloblastoma (n = 5) or primitive neuroectodermal tumor (PNET) (n = 2) underwent repeated PET studies during their therapy. The other eight children with medulloblastoma (n = 5) or astrocytoma (n = 3) were studied only once before initiation of treatment. A close clinical follow-up was performed in every case. RESULTS: Comparison of local glucose metabolic rates obtained in the various tumor lesions revealed that the mean rates found in medulloblastomas (mean glucose metabolic rate, 42.8 +/- 14.03 mumol/100 g/min) were twice as high as the rates measured in either PNET (17.3 +/- 4.5 mumol/100g/min) or infratentorial gliomas (21.8 +/- 4.2 mumol/100g/min). The high metabolism of medulloblastomas enabled the observer to identify the tumor more easily and to clearly separate it from the surrounding unaffected brain tissue. In the seven patients with follow-up PET studies during therapy, decreasing or increasing ratios of tumor-to-white matter metabolic rate were not only commensurate with neuroradiologically defined tumor reduction or growth, but also corresponded to the duration of initial clinical improvement. CONCLUSIONS: These preliminary results suggest that PET with FDG may be a useful tool to evaluate metabolic activity of pediatric brain tumors over time and to assess response to treatment.

Positron emission tomography measures of benzodiazepine receptors in Huntington's disease.

We performed positron emission tomographic (PET) measurements of the regional distribution volume of benzodiazepine receptors and regional glucose metabolism in 6 drug-free patients with early Huntington's disease following injection of [11C]flumazenil, a nonsubtype selective central benzodiazepine receptor antagonist, and 18F-2-fluoro-2-deoxy-D-glucose, respectively. Flumazenil data were analyzed with a recently developed two-compartment, two-parameter tracer kinetic model. Benzodiazepine receptor density is related to distribution volume for flumazenil. In comparison with a group of healthy volunteers, benzodiazepine receptor density was significantly decreased in the caudate nucleus. Glucose metabolism was significantly reduced not only in the caudate nucleus but also in the putamen and thalamus. The changes in benzodiazepine receptor density observed in the caudate nucleus are commensurate with data obtained in postmortem autoradiographic studies of receptor density. Based on such postmortem studies we also anticipated changes in putamen and thalamic benzodiazepine receptor density. However, relatively little is known on receptor changes in early Huntington's disease, because the autoradiographic data available were obtained mostly in patients with advanced disease. The decreased glucose metabolism in the caudate and putamen agrees well with previously published results of PET studies, whereas metabolic impairment of the thalamus has not yet been described in Huntington's disease. The present study suggests that regional metabolism and gamma-aminobutyric acid (GABA)-benzodiazepine receptor changes in subcortical structures of patients with early Huntington's disease do not occur with the same time course: Caudate benzodiazepine receptor density is already severely impaired when other subcortical structures reveal only minor abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

Positron emission tomography demonstrates frontal cortex and basal ganglia hypometabolism in dystonia.

We studied 15 dystonic patients with positron emission tomography (PET) and (18F)-2-fluoro-2-deoxy-D-glucose (FDG). The group comprised patients with focal (n = 5), multifocal (n = 1), and generalized (n = 4) dystonia as well as patients with hemidystonia (n = 5). The age at onset was during childhood in four, during adolescence in two, and during adulthood in nine of the subjects. In dystonic patients, global cerebral glucose metabolism was unaltered when compared with normal controls, whereas the pattern of regional cerebral metabolic rate for glucose (rCMR[Glu]) was significantly different (p = 0.0001). rCMR(Glu) was significantly decreased in the caudate and lentiform nucleus and in the frontal projection field of the mediodorsal thalamic nucleus. The study confirms the concept that dystonia is caused by impaired connections between the basal ganglia, the thalamus, and frontal association areas.

Parametric in vivo imaging of benzodiazepine receptor distribution in human brain.

Emission computed tomographic methods for the in vivo quantification of radioligand-binding sites in human brain have previously been limited either by a lack of correction for possible effects of altered ligand transport or by highly complicated physiological models that preclude display of binding data in a detailed anatomical format. We investigated the application of a simplified compartmental model to the kinetic analysis of in vivo ligand binding to central benzodiazepine receptors. The human brain distribution of [11C]flumazenil, as determined by dynamic positron emission tomography, combined with metabolite-corrected arterial blood samples, permitted estimations of local cerebral ligand transport and of receptor binding. This approach allows calculation of transport and binding "maps" on a pixel-by-pixel basis, resulting in the display of binding data in a familiar tomographic format while maintaining much of the physiological accuracy inherent in more complex methods. The results obtained in a study of 6 normal volunteers revealed good interindividual precision, with coefficients of variation between 10 and 15% of mean regional values, suggesting the utility of this approach in future clinical studies of benzodiazepine receptor binding.

Differentiation of radioligand delivery and binding in the brain: validation of a two-compartment model for [11C]flumazenil.

We recently developed a two-compartment, two-parameter tracer kinetic model to estimate the in vivo ligand transport rate (K1) and distribution volume (DV) for the benzodiazepine antagonist [11C]flumazenil (FMZ) as measured by positron emission tomography (PET). The aim of the present study was to validate that this simplified model provides a stable measure of regional benzodiazepine receptor availability even when ligand delivery is altered. Six young normal volunteers underwent two PET studies subsequent to intravenous injections of [11C]FMZ. Each FMZ study was immediately preceded by measurements of CBF following injection of [15O]water. One set of scans (water/FMZ) was acquired under resting conditions and the other set during audiovisual stimulation. Six additional volunteers underwent two FMZ studies under identical resting conditions. Parametric images were analyzed and a comparison of test-retest studies in the stimulation group revealed a significant increase of CBF and K1 of FMZ in the occipital cortex evoked by visual activation, whereas no regional changes were noted for the DV of FMZ. No significant changes were noted for either K1 or DV of FMZ when comparing studies in the rest-rest setting. The results indicate that the use of a simple two-compartment model for the tracer kinetic analysis of [11C]FMZ makes it possible to separate high-affinity binding from altered radio-ligand delivery to the human brain.

Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography.

The in vivo kinetic behavior of [11C]flumazenil ([11C]FMZ), a non-subtype-specific central benzodiazepine antagonist, is characterized using compartmental analysis with the aim of producing an optimized data acquisition protocol and tracer kinetic model configuration for the assessment of [11C]FMZ binding to benzodiazepine receptors (BZRs) in human brain. The approach presented is simple, requiring only a single radioligand injection. Dynamic positron emission tomography data were acquired on 18 normal volunteers using a 60- to 90-min sequence of scans and were analyzed with model configurations that included a three-compartment, four-parameter model, a three-compartment, three-parameter model, with a fixed value for free plus nonspecific binding; and a two-compartment, two-parameter model. Statistical analysis indicated that a four-parameter model did not yield significantly better fits than a three-parameter model. Goodness of fit was improved for three- versus two-parameter configurations in regions with low receptor density, but not in regions with moderate to high receptor density. Thus, a two-compartment, two-parameter configuration was found to adequately describe the kinetic behavior of [11C]FMZ in human brain, with stable estimates of the model parameters obtainable from as little as 20-30 min of data. Pixel-by-pixel analysis yields functional images of transport rate (K1) and ligand distribution volume (DV"), and thus provides independent estimates of ligand delivery and BZR binding.

Positron emission tomography in Creutzfeldt-Jakob disease.

Regional cerebral glucose metabolism was studied in a 73-year-old woman with autopsy-confirmed Creutzfeldt-Jakob disease, using positron emission tomography of 2-(18F)fluorodeoxyglucose. Regional absolute values were analyzed in 14 partially overlapping slices. Clinically, the patient was in an advanced stage of disease when positron emission tomographic scans revealed severe, diffuse hypometabolism, and neuropathological findings showed diffuse spongiform changes throughout the brain, with neuronal cell loss being obvious only in the cerebellum. Computed tomography was unremarkable for age, whereas the positron emission tomographic results were in accordance with histological findings and the patient's clinical condition. This article suggests that positron emission tomography depicts neuronal dysfunction rather than neuronal cell loss.

Positron emission tomography findings relevant to neurosurgery for epilepsy.

Using the 2-[F-18]fluorodeoxyglucose method, 213 positron emission tomographic (PET) studies of local brain glucose metabolism (CMRglu) were performed in 124 patients with various forms of epilepsy. Interictal PET scans of primary epileptics typically showed some global metabolic depression and decreased functional activity of insular, basal and anterior temporal cortex. Epilepsia partialis continua Kozevnikov was characterized by hypo- or hyper-metabolism of perirolandic cortex. Tuberous sclerosis was distinguished by neocortical foci of significantly decreased glucose consumption. Even in the interictal resting state, with regard to sensitivity (greater than 90%) and accuracy of focus localization. PET was superior to other diagnostic methods in typical temporal lobe epilepsy. Averaging 23% below normal CMRglu, the majority of hypometabolic foci were found in mesial temporal structures. Improved distinction between the epileptogenic area and the surrounding tissue showing comparatively normal functional responsiveness, was achieved by psychophysical activation using emotional speech or continuous visual recognition during PET scanning. In patients who had undergone total cerebral hemispherectomy because of uncontrolled epilepsy, remarkable recruitment of association areas was observed on both motor and speech activation.