Dopa-responsive dystonia: [18F]dopa positron emission tomography.

The syndrome of dopa-responsive dystonia comprises a minority of patients with dystonia, yet it is of considerable diagnostic importance because patients respond dramatically to L-dopa therapy. Benefits from this treatment are lasting, and the problems associated with long-term L-dopa therapy in patients with Parkinson's disease are generally absent. It has been suggested that this condition is due to a defect in the dopamine synthetic pathway, which is bypassed when patients are treated with L-dopa. We have studied [18F]dopa uptake in 6 patients with classic dopa-responsive dystonia (5 familial patients and 1 sporadic patient), aged 18 to 66 years. Data have been analyzed according to a graphic approach, calculating an influx constant for each region studied. We have also studied a seventh, clinically atypical, patient with juvenile dystonia-parkinsonism. Similar data have been calculated for a group of 10 healthy control subjects and 10 patients with Parkinson's disease. The 6 patients with typical dopa-responsive dystonia had a modest but significant reduction in the uptake of tracer into both caudate and putamen, which indicates a defect in the decarboxylation, vesicular uptake, and storage of [18F]dopa. This argues against the proposition that dopa-responsive dystonia is due to an inherited defect of tyrosine hydroxylase alone. In the atypical patient, however, we found a greater reduction of [18F]dopa uptake into both caudate and putamen, comparable with that in patients with Parkinson's disease.     

The metabolic anatomy of Parkinson's disease: complementary [18F]fluorodeoxyglucose and [18F]fluorodopa positron emission tomographic studies

We studied the metabolic anatomy of typical Parkinson's disease (PD) using [18F]fluorodeoxyglucose (FDG) and [18F]fluorodopa (FDOPA) and positron emission tomography (PET). Fourteen PD patients (mean age 49 years) had FDG/PET scans, of which 11 were scanned with both FDOPA and FDG. After the injection of FDOPA, brain uptake and arterial plasma radioactivity were monitored for 2 h. Striatal FDOPA uptake was analyzed with regard to a two-compartment model, and target-to-background ratios (TBRs) and TBR-versus-time slopes were also calculated. Regional patterns of metabolic covariation were extracted from FDG/PET data using the Scaled Subprofile Model (SSM). SSM pattern weights, FDOPA uptake constants (Ki), TBRs, and TBR slopes were correlated with clinical measures for bradykinesia, rigidity, tremor, gait disturbance, left-right asymmetry, dementia, and overall disease severity. In PD patients, rate constants for FDOPA uptake correlated with individual measures of bradykinesia (p = 0.001) and gait disability (p less than 0.05). SSM analysis revealed a distinct pattern of regional metabolic asymmetries, which correlated with motor asymmetries (p less than 0.001) and left-right differences in Ki (p less than 0.01). Our data suggest that in PD patients, FDG/PET and FDOPA/PET may provide unique and complementary information about underlying disease processes.     

Cerebral glucose utilization during sleep-wake cycle in man determined by positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose method

Using the [18F]fluorodeoxyglucose method and positron emission tomography, we studied cerebral glucose utilization during sleep and wakefulness in 11 young normal subjects. Each of them was studied at least thrice: during wakefulness, slow wave sleep (SWS) and rapid eye movement sleep (REMS), at 1 week intervals. Four stage 3-4 SWS and 4 REMS fulfilled the steady state conditions of the model. The control population consisted of 9 normal age-matched subjects studied twice during wakefulness at, at least, 1 week intervals. Under these conditions, the average difference between the first and the second cerebral glucose metabolic rates (CMRGlu was: -7.91 +/- 15.46%, which does not differ significantly from zero (P = 0.13). During SWS, a significant decrease in CMRGlu was observed as compared to wakefulness (mean difference: -43.80 +/- 14.10%, P less than 0.01). All brain regions were equally affected but thalamic nuclei had significantly lower glucose utilization than the average cortex. During REMS, the CMRGlu were as high as during wakefulness (mean difference: 4.30 +/- 7.40%, P = 0.35). The metabolic pattern during REMS appeared more heterogeneous than at wake. An activation of left temporal and occipital areas is suggested. It is hypothetized that energy requirements for maintaining membrane polarity are reduced during SWS because of a decreased rate of synaptic events. During REMS, cerebral glucose utilization is similar to that of wakefulness, presumably because of reactivated neurotransmission and increased need for ion gradients maintenance.     

Parametric mapping of [18F]fluoromisonidazole positron emission tomography using basis functions

In this study, we show a basis function method (BAFPIC) for voxelwise calculation of kinetic parameters (K₁, k₂, k₃, K_i) and blood volume using an irreversible two-tissue compartment model. BAFPIC was applied to rat ischaemic stroke micro-positron emission tomography data acquired with the hypoxia tracer [¹⁸F]fluoromisonidazole because irreversible two-tissue compartmental modelling provided good fits to data from both hypoxic and normoxic tissues. Simulated data show that BAFPIC produces kinetic parameters with significantly lower variability and bias than nonlinear least squares (NLLS) modelling in hypoxic tissue. The advantage of BAFPIC over NLLS is less pronounced in normoxic tissue. K_i determined from BAFPIC has lower variability than that from the Patlak–Gjedde graphical analysis (PGA) by up to 40% and lower bias, except for normoxic tissue at mid-high noise levels. Consistent with the simulation results, BAFPIC parametric maps of real data suffer less noise-induced variability than do NLLS and PGA. Delineation of hypoxia on BAFPIC k₃ maps is aided by low variability in normoxic tissue, which matches that in K_i maps. BAFPIC produces K_i values that correlate well with those from PGA (r²=0.93 to 0.97; slope 0.99 to 1.05, absolute intercept <0.00002 mL/g per min). BAFPIC is a computationally efficient method of determining parametric maps with low bias and variance.     

Mapping metabolic brain activation during human volitional swallowing: a positron emission tomography study using [18F]fluorodeoxyglucose.

We have previously shown that labelled water positron emission tomography (H2(15)O PET) can be used to identify regional cerebral blood flow (rCBF) changes in the human brain during volitional swallowing. (18F) fluorodeoxyglucose (FDG PET), by comparison, uses a glucose analogue to quantitatively measure regional cerebral glucose metabolism (rCMRglc) rather than rCBF. The main advantage of FDG PET is improved spatial resolution, and because of its pharmacodynamic properties, activation can be performed external to the scanner, allowing subjects to assume more physiologic positions. We therefore conducted a study of the brain's metabolic response while swallowing in the erect seated position, using FDG PET. Eight healthy male volunteers were studied with a randomised 2 scan paradigm of rest or water swallowing at 20-second intervals for 30 minutes. Data were analysed with SPM99 using multisubject conditions and covariates design. During swallowing, analysis identified increased rCMRglc (P<0.01) in the following areas: left sensorimotor cortex, cerebellum, thalamus, precuneus, anterior insula, left and right lateral postcentral gyrus, and left and right occipital cortex. Decreased rCMRglc were also seen in the right premotor cortex, right and left sensory and motor association cortices, left posterior insula and left cerebellum. Thus, FDG PET can be applied to measure the brain metabolic activity associated with volitional swallowing and has the advantage of normal task engagement. This has implications for future activation studies in patients, especially those suffering swallowing problems after brain injury.     

Quantification of dopamine transporter binding using [18F]FP-beta-CIT and positron emission tomography.

The purpose of this study was to compare different kinetic and semi-quantitative methods for analysing human [18F]FP-beta-CIT studies: plasma input models, simplified (SRTM) and full (FRTM) reference tissue models, standard uptake values (SUV) and SUV ratios (SUVr). Both simulations and clinical evaluations were performed to determine the effects of noise, scan duration and blood volume on Akaike model selection, and on precision and accuracy of estimated parameters. For typical noise levels (COV approximately 2.5%) and scan durations (<90 mins), simulations provided poor fits (Akaike criterion) in case of reversible plasma input models showing a relatively high number of outliers compared with the two-tissue irreversible model. Reference tissue models provided more reliable fits, which were nearly independent of noise and scan duration. For clinical data, two tissue irreversible and reversible plasma input models fitted striatum curves equally well (Akaike criterion). BP with plasma input models were less precise and contained more outliers than BP obtained with SRTM or FRTM. Among all methods tested, SRTM showed the highest contrast between patients and controls. When differentiating between patients and controls, SUVr performed almost equally well as SRTM, although contrast between striatum and background was lower. In conclusion, SRTM provided BP estimates with the highest precision and accuracy. Moreover, SRTM provided good contrast between patients and controls, and between striatum and background. SRTM is therefore the method of choice for quantitative [18F]FP-beta-CIT studies. SUVr might be an alternative for larger clinical trials.     

Estimation of local cerebral glucose utilization by positron emission tomography: comparison of [18F]2-fluoro-2-deoxy-D-glucose and [18F]2-fluoro-2-deoxy-D-mannose in patients with focal brain lesions

A comparative PET study of [18F]2-fluoro-2-deoxy-D-glucose (FDG) and [18F]2-fluoro-2-deoxy-D-mannose (FDM) uptake was performed in 13 patients with focal brain lesions. Differences between FDG and FDM with respect to model rate constants, lumped constant, and estimated metabolic rate for glucose were determined on a regional basis. Across whole brain, the transport rate constant K1* was almost unchanged, whereas k2*, describing the transport back from tissue to plasma, was 6% higher, and the phosphorylation rate constant k3* was 9% lower for FDM compared to FDG. This implies a 20% lower lumped constant for FDM. No significant regional variability of this differential tracer behavior was observed in normal or in lesioned brain tissue. Thus, results from previous FDG studies, where the radiotracer was not 100% pure FDG but contained varying amounts of FDM, can easily be corrected by adjustment of the lumped constant employed in metabolic quantitation.     

The role of positron emission tomography with [18F]fluorodeoxyglucose in the evaluation of the epilepsies

Cerebral glucose metabolic mapping using positron emission tomography (PET) and 2-[18F]fluoro-2-deoxyglucose (FDG) has been extensively studied in the epilepsies. Regions of interictal glucose hypometabolism are highly associated with cerebral sites of seizure generation-propagation in focal epilepsies. The volume of reduced glucose metabolism is often widespread and even bilateral in focal epilepsies, although ictal onset zones typically are located at the sites of most severe hypometabolism within a larger volume of hypometabolism.     

Dynamic [18F]fluorodeoxyglucose positron emission tomography and hypometabolic zones in seizures: Reduced capillary influx

We performed dynamic [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) positron emission tomographic (PET) analyses in 8 patients. Rate constants of influx (K₁^*), efflux (k₂^*), phosphorylation (k₃^*), and dephosphorylation (k₄^*) were derived for the regions of interest (ROIs), which included (1) the hypometabolic epilptogenic regions and (2) the homologous regions in the contralateral hemispheres. In addition, the four constants were determined from at least one clearly defined (control) ROI from the same plane and its homologous contralateral ROI. (K₁^*) in the eplieptogenic region was reduced in comparison with the contralateral ROI. Reductions in influx (K₁^*), which averaged 18 ± 13% (mean ± SD), [¹⁸F]FDG phosphorylation (k₃^*) (25 ± 20%), and brain glucose utization rates (26 ± 10%) were observed in the epileptogenic region. Reductions in efflux were not statistically significant (k₂^* = 13 ± 28%) but were comparable in magnitude to the average reduction in K₁^*. No ipsilateral versus contralateral differnces were seen for any rate constants measured outside the epileptogenic region. Influx correlated highly with phosphorylation in the epileptogenic region. Our data suggest that the hypometabolic epileptogenic focus seen in [¹⁸F]FDG-PET studies is also a region of reduced blood-brain barrier glucose transporter activity and that reductions in phosphorylation are proportional to reductions in [¹⁸]FDG influx.     

Use of [18F]fluorodeoxyglucose positron emission tomography in patients with primary malignant brain tumors

In patients with malignant gliomas, [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG-PET) may discriminate tumor progression from radionecrosis. We evaluated data from 50 patients undergoing FDG-PET for suspicion of tumor progression. Forty-nine were treated with surgery, 48 with radiotherapy, and 37 with chemotherapy. Twenty-one had intensive radiotherapy with either three daily treatments in two 5-day periods and intravenous carboplatin (17) or interstitial brachytherapy or stereotactic radiotherapy. Twenty underwent surgery after magnetic resonance imaging/FDG-PET; 9 demonstrated increased uptake of FDG and evidence of tumor, whereas 6 had decreased uptake and no evidence of tumor. In 5 patients, there was no correlation (all had intensive radiotherapy). In 17 patients who received bromodeoxyuridine intravenously just before surgery, the bromodeoxyuridine labeling index corresponded to the histological appearance in all but 2 patients (both had received intensive radiotherapy). In 30 patients without surgery, decreased uptake of FDG suggested prolonged survival; increased uptake of FDG did not predict survival. Eight of 10 with intensive radiotherapy had decreased label uptake. We conclude FDG-PET for evaluation of patients with possible recurrent tumors requires more study. In patients with intensive radiotherapy, FDG-PET results cannot be correlated accurately with tumor progression.     

Identification of early recurrence of primary central nervous system tumors by [18F]fluorodeoxyglucose positron emission tomography

As aggressive neurosurgery and adjuvant therapy have become standard care for most patients with primary central nervous system (CNS) tumors, limitations of posttreatment neuroimaging techniques have become more apparent. Interpretation of computed cranial tomography (CT) and magnetic resonance imaging (MRI) in patients with brain tumors is complicated by changes related to surgery, corticosteroids, radiation, and chemotherapy. We investigated the role of 18F-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (FDG-PET) in these difficult diagnostic situations by obtaining FDG-PET scans in 5 patients following temporal lobectomy for epilepsy, in 5 patients with recurrent anaplastic gliomas before and after corticosteroid therapy, and in 5 patients after the development of histologically confirmed radionecrosis. We also obtained postoperative FDG-PET scans in 32 consecutive patients undergoing initial resection of a primary brain tumor. Our results indicate that glucose uptake as detected by FDG-PET scanning with [18F]fluorodeoxyglucose is not increased in the postoperative period; is not affected by steroid therapy; and accurately predicts early recurrence of tumor, supplementing other predictors of tumor behavior, including extent of resection, histological diagnosis, and postoperative CT. Thus PET using [18F]fluorodeoxyglucose can contribute to the optimum management of patients with primary brain tumors.     

Inhibition of L-[18F]fluorodopa uptake into human brain by amino acids demonstrated by positron emission tomography

The brain uptake of L-[18F]fluorodopa was measured by positron emission tomography in a healthy male volunteer both under fasting conditions and during intravenous amino acid loading. A significant reduction of tracer uptake into the brain was demonstrated with amino acid loading. This finding represents the first direct evidence for competition between L-dopa and other amino acids for uptake across the blood-brain barrier obtained in vivo in a human subject. It underlines the possible importance of interference by dietary amino acids with the therapeutic actions of L-dopa in Parkinson's disease.     

The added value of [18F]-fluoro-D-deoxyglucose positron emission tomography in screening for temporal lobe epilepsy surgery

PURPOSE: [18F]-Fluoro-d-deoxyglucose positron emission tomography (FDG-PET) is an expensive, invasive, and not widely available technique used in the presurgical evaluation of temporal lobe epilepsy. We assessed its added value to the decision-making process in relation to other commonly used tests. METHODS: In a retrospective study of a large series of consecutive patients referred to the national Dutch epilepsy surgery program between 1996 and 2002, the contribution of FDG-PET, magnetic resonance imaging (MRI), and video-electroencephalogram (video-EEG) monitoring findings, alone or in combination, to the decision whether to perform surgery was investigated. The impact of FDG-PET was quantified by comparing documented decisions concerning surgery before and after FDG-PET results. RESULTS: Of 469 included patients, 110 (23%) underwent FDG-PET. In 78 of these patients (71%), FDG-PET findings led clinicians to change the decision they had made based on MRI and video-EEG monitoring findings. In 17% of all referred patients, the decision regarding surgical candidacy was based on FDG-PET findings. FDG-PET was most useful when previous MRI results were normal (p < 0.0001) or did not show unilateral temporal abnormalities (p < 0.0001), or when ictal EEG results were not consistent with MRI findings (p < 0.0001) or videotaped seizure semiology (p = 0.027). The positive and negative predictive values for MRI and video-EEG monitoring, which ranged from 0.48 to 0.67, were improved to 0.62 to 0.86 in combination with FDG-PET. CONCLUSIONS: In patients referred for TLE surgery, FDG-PET findings can form the basis for deciding whether a patient is eligible for surgery, and especially when MRI or video-EEG monitoring are nonlocalizing.     

Morphine-induced metabolic changes in human brain. Studies with positron emission tomography and [fluorine 18]fluorodeoxyglucose

Morphine sulfate effects (30 mg, intramuscularly) on cerebral glucose utilization and subjective self-reports were examined in 12 polydrug abusers by positron emission tomography and [fluorine 18]fluorodeoxyglucose in a double-blind placebo-controlled crossover study. During testing, subjects sat with eyes covered, listening to white noise and "beep" prompts. Morphine significantly reduced glucose utilization by 10% in whole brain and by about 5% to 15% in telencephalic areas and the cerebellar cortex, assuming no contribution of hypercapnia. When the contribution of PaCO2 (45 minutes after morphine was administered) was partialled out, significant morphine-induced reductions persisted in whole brain and six cortical areas. Irrespective of morphine, left-greater-than-right asymmetry occurred in the temporal cortex, and an interaction between hemisphere and drug was noted in the postcentral gyrus. In most cases, effects on glucose utilization were not significantly related to measures of euphoria.     

Estimation of local cerebral glucose utilization by positron emission tomography of [18F]2-fluoro-2-deoxy-D-glucose: a critical appraisal of optimization procedures

Various approaches estimating local cerebral glucose utilization by positron emission tomography of labeled deoxyglucose are compared. Autoradiographic methods that predict the glucose utilization rate from a single scan are unreliable in pathologic tissue because of abnormal values of the model rate constants. A normalization procedure using the ratio of measured tissue activity to activity calculated with standard rate constants is proposed to readjust the values of the rate constants. Reliable estimates of metabolic rates can be obtained from dynamic recordings of tracer uptake. In the graphic approach, metabolic rate can be derived from the slope of a segment of a transformed uptake curve, which becomes linear at 15-20 min after intravenous tracer injection, with an accuracy comparable with that in complete dynamic studies. However, by recording and analyzing full-length uptake curves, in addition to metabolic rate, the model rate constants can be determined regionally. The physiological significance of those parameters is demonstrated in crossed cerebellar deactivation in 30 patients with supratentorial infarcts. Mild hypometabolism both within the ischemic lesion and in the morphologically intact cerebellum is accompanied by a reduction of the phosphorylation rate only. Severe metabolic depression, by contrast, affects both cerebellar transport and phosphorylation processes, whereas in the cerebrum, only the rate constant k1 is significantly correlated with the degree of metabolic disturbance.     

The value of [18F]-fluorodeoxyglucose–positron emission tomography/CT scanning in the diagnosis of neurosarcoidosis

Sarcoidosis is a granulomatous disease of unknown aetiology which primarily affects the lungs, but can affect other tissues including the central nervous system (CNS). In neurosarcoidodis, the CNS is often the only affected site, which makes a tissue diagnosis difficult. Although a clinical diagnosis of neurosarcoidosis can often be made, the wide range of potential differential diagnoses, including other steroid responsive conditions (such as idiopathic lymphocytic meningitis) means that a confirmed diagnosis is invaluable. This is particularly important because neurosarcoidosis has a poor prognosis and aggressive immunosuppressive treatment is generally recommended. We present a man with clinically suspected neurosarcoidosis where attempts to obtain histological confirmation of the disease through skin and meningeal biopsy was unhelpful, but a lymph node biopsy, directed with the use of [18F]-fluorodeoxyglucose–positron emission tomography/CT scanning was diagnostic.     

Progression in Parkinson's disease: a positron emission tomography study with a dopamine transporter ligand [18F]CFT

We studied the rate of progression of striatal dopamine transporter function in Parkinson's disease (PD). Eight patients with early PD without antiparkinsonian medication and 7 healthy volunteers were investigated with [18F]CFT positron emission tomography (PET). The PET scan was carried out twice at an approximate 2-year interval. The uptake of [18F]CFT was calculated as a region-cerebellum:cerebellum ratio at 180 to 210 minutes after injection. At the first PET scan, the [18F]CFT uptake in PD patients in the putamen was 1.45 +/- 0.45 (mean +/- SD) (42% of the control mean) and 2.43 +/- 0.59 in the caudate nucleus (76% of the control mean). The ratios declined by the time of the second PET scan, and the rate of annual decline of the baseline mean in PD patients was 13.1% in the putamen and 12.5% in the caudate nucleus. In controls, the corresponding figures were 2.1% for the putamen and 2.9% for the caudate nucleus. The decline in [18F]CFT uptake was significantly higher in PD patients than in controls. Thus, dopamine transporter ligands such as [18F]CFT seem to be sensitive markers for the rate of progression in PD.