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Medical therapy in de novo Parkinson’s disease typically starts with a dopamine agonist or levodopa in combination with a decarboxylase inhibitor or if symptoms are still very mild with a MAO-B inhibitor. When patients do not (or no longer) respond satisfactorily to these initial therapies, different drugs can be initiated or combined (i.e., “add-on” treatments). These add-on therapies not only comprise oral agents but also intra-jejunal and intra-cutaneous treatments and functional neurosurgical procedures. This chapter starts with the treatment of de novo Parkinson’s disease whereafter indications and expected effects of the different “add-on” therapies will be described. The “add-on” therapies will be described in a hierarchical way and treatment algorithms will be provided based on prevailing symptoms including non-motor symptoms. The symptoms that will be discussed are: (1) bradykinesia and “wearing-OFF, " (2) tremor at rest, (3) dyskinesia, (4) gait and postural symptoms including freezing of gait, and (5) important non-motor symptoms. Finally, a comprehensive add-on treatment algorithm will be provided that takes into account non-motor symptoms that may limit the efficacy and tolerability of the different add-on therapies.

In the last decade, expanding animal studies on the cerebral organization of reward processing toward human in vivo situations has become possible. In this review, we define some of the concepts associated with reward, summarize the crucial importance of the dopaminergic system, and discuss the currently available neuroimaging studies in man. We will show that abstract concepts of human behavior like emotions, drive, arousal, and reinforcement are now open for further exploration in man at the level of neuronal circuit organization. The cerebral dopaminergic neurotransmitter circuitry does play an important role in the organization of both the motor and motivational system.

Objective: Parameters of a pharmacokinetic-pharmacodynamic (PK-PD) model of levodopa have been claimed to reflect the magnitude of the dopaminergic deficit in patients with Parkinson's disease. The aim of this study was to correlate such parameters with positron emission tomography (PET) with levodopa tagged with 6-fluorine 18, an established imaging method for striatal dopaminergic neurons. Methods. Twenty-three patients in different disease stages (Hoehm. and Yahr stage 2.5-5 [Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;4:427-42]; median duration, 12 years) were studied. PK-PD modeling followed a single oral dose of levodopa/benserazide. The sum score of the Columbia Rating Scale (CURS Sigma) was used for clinical assessments. A nonparametric effect compartment approach assuming a sigmoidal E-max model was applied to the PK-PD analysis of plasma levodopa concentrations and corresponding CURS Sigma. Thereafter 6-[F-18]levodopa PET was performed, and the influx rate constants (k(c)) for the putamen and the caudatus region were correlated with the median effective concentration (EC50) and the equilibrium half-life (T-eq) of the PK-PD model. Results: (1) A significant correlation was observed between PK-PD parameters or with k(c) putamen as the dependent variable and the duration of the disease as the independent variable, which explains 33% of the variability of the EC50, 42% of the variability of T-eq, and 36% of the variability of k(c). (2) Significant correlations were observed between k(c) and either EC50 or T-eq, yielding the closest correlation for the putamen region (r = -0.47, P

This article reviews possible clinical applications of positron emission tomography (PET) in brain tumor patients. PET allows quantitative assessment of brain tumor pathophysiology and biochemistry. It therefore provides different information about tumors when compared to histological or neuroradiological methods. Common clinical indications for PET comprise tumor delineation and identification of the metabolically most active tumor regions (target for biopsy, differentiation of viable tumor from necrosis). Further, the spatial relation between brain activated e.g., by speech, and the tumor bulk can be explored by activation studies. PET could also aid in the prediction of treatment response by measurement of tumor perfusion or hypoxia. Moreover, PET tracers could identify treatment targets e.g., gene products. The latter topic has not been systematically evaluated in human patients.

The computerized brain atlas (CBA) and statistical parametric mapping (SPM) are two procedures for voxel‐based statistical evaluation of PET activation studies. Each includes spatial standardization of image volumes, computation of a statistic, and evaluation of its significance. In addition, smoothing and correcting for differences of global means are commonly performed in SPM before statistical analysis. We report a comparison of methods in an analysis of regional cerebral blood flow (rCBF) in 10 human volunteers and 10 simulated activations. For the human studies, CBA or linear SPM standarization methods were followed by smoothing and computation of a statistic with the paired t‐test of CBA or general linear model of SPM. No standardization, linear, and nonlinear SPM standardization were applied to the simulations. Significance of the statistic was evaluated using the cluster‐size method common to SPM and CBA. SPM employs the theory of Gaussian random fields to estimate the cluster size distributions; simulations described in the Appendix provided empirical distributions derived from t‐maps. The quantities evaluated were number and size of functional regions (FRs), maximum statistic, average resting rCBF, and percentage change. For the simulations, the efficiency of signal detection and rate of false positives could be evaluated as well as the distributions of statistics and cluster size in the absense of signal. The similarity of the results yielded by similar methods of analysis for the human studies and the simulated activations substantiates the robustness of the methods for selecting functional regions. However, the analysis of simulated activations demonstrated that quantitative evaluation of significance of a functional region encounters important obstacles at every stage of the analysis. Hum. Brain Mapping 8:245–258, 1999. © 1999 Wiley‐Liss, Inc.

Im folgenden wird die Wertigkeit von PET anhand von Fragen, wie sie immer wieder im neuroonkologischen Alltag auftreten, diskutiert.

We studied a patient with juvenile pilocytic astrocytoma (JPA) using positron emission tomography (PET), 18F-fluorodeoxyglucose (FDG), 11C-methionine (MET), and 82Rubidium (RUB). Non-linear fitting and multiple time graphical plotting of the dynamic PET data revealed values for tumor plasma volume, blood-brain barrier transport rate constants and tracer distribution volume in the range of glioblastomas and meningiomas, or higher. Likewise, the steady-state accumulation of MET and FDG was increased. With regard to the known vascular composition of JPA, our data suggest that increased transport and distribution considerably contribute to the high net tracer uptake observed in this tumor.

Thalamic glucose metabolism has been studied in 24 patients suffering from temporal lobe epilepsy (TLE) using interictal F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET). A total of 17 patients had a unilateral TL seizure onset, 11 of these patients had a mesial temporal lobe epilepsy syndrome (MTLE), with mesial gliosis and a mesial TL seizure origin. Three patients had a lateral TL seizure origin, and 3 patients had mesial TL tumors. Bilateral TLE was assumed in 7 patients. Only in the patient group with MTLE (n = 11), the ipsilateral thalamic glucose uptake showed a statistically significant lower value when compared to the thalamus of the contralateral side (Wilcoxon paired sign test, P = 0.012). There was a more pronounced hypometabolism in right TLE compared to left TLE. A 'hypersynchronous seizure onset pattern' in ictal EEG was only seen in 6 (26%) patients (1 patient with bilateral, 5 with unilateral TLE). No correlation existed between the thalamic, temporal glucose metabolism and the 'hypersynchronous seizure onset pattern'. (C) 1997 Elsevier Science B.V.

The technique of positron emission tomography (PET) is well established in the field of medical imaging. Non-medical applications have also been shown to be valuable in the measurement of dynamic chemical processes, specifically in the determination of the characteristics of small rock samples. Since rock is more dense than tissue, the problems of attenuation and scatter are accentuated. However, we are able to show that measurement of porosity in a large rock sample (21.5 cm diameter) is indeed practicable using three-dimensional (3-D) acquisition techniques. Due to multiple scattering of the photons in the rock and the cylindrical symmetry of the experiment, we measured a scatter distribution which is approximately homogeneous, allowing a correction for scattered radiation with a simple method. The problems of determining attenuation coefficients and applying a scatter correction makes absolute quantisation difficult. However, relative changers in porosity within the sample can be measured with a spatial resolution not appreciably different from that in water.

Cerebral glucose utilisation using 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) was measured in 4 patients with temporal lobe epilepsy during a selective anterior temporal lobe (TL) amobarbital test (ATLAT) and compared with their baseline values. 18F-FDG was injected intravenously immediately after administration of amobarbital into the anterior choroidal artery (acha) in the case of the superselective ATLAT and into the territories of acha, posterior communicating artery, and ophthalmic artery in the case of the ATLAT using the temporary balloon occlusion technique. A decrease in glucose uptake as a result of amobarbital application was observed in ipsilateral temporolateral (4 patients), ipsilateral temporomesial (2 patients) and bilateral frontolateral (1 patient) cortices. All patients showed decreased glucose uptake in contralateral temporolateral regions. Cerebellar diaschisis was observed in 2 patients. In conclusion, although aimed at selective inactivation of the mesiobasal TL structures, the ATLAT does not result in exclusive selective glucose hypometabolism of these structures. Relatively widespread ipsilateral and contralateral effects were observed suggesting local and remote metabolic deafferentation. No association was observed between the glucose uptake, clinical or memory performance.

Nine patients who underwent presurgical evaluation because of medically refractory temporal lobe epilepsy (TLE) showed either unilateral, although alternating in side, or bilateral simultaneous seizure onsets in both temporal lobes (TL). EEG recordings with semi-invasive foramen ovale electrodes revealed in seven patients a predominance of seizure onset in one TL of between 50% and 88%. In two patients the majority of seizures originated simultaneously in both TL. In four patients a unilateral selective amygdalohippocampectomy resulted in a good to excellent seizure outcome without noteworthy memory deficits and confirmed the preoperative lateralization of the primary epileptogenic focus by interictal (18) F-fluorodeoxyglucose positron emission tomography (PET). Five patients were rejected from surgery due to strong bilaterality of their epilepsy and/or divergent presurgical findings. PET contributed to the decision of whether surgery should be performed: all patients who underwent surgery had a unilateral TL hypometabolism which was concordant with the findings of other tests. Patients in whom surgery was denied had either bilateral temporal hypometabolism or the PET findings were discordant with other results obtained during the presurgical evaluation.

Increases and decreases of synaptic activity in the brain are accompanied by proportional changes in capillary perfusion and local glucose consumption. These changes in glucose consumption are the effect of changed activity or density of the afferent nerve terminals in that region. Loss of neurons may result in decreased glucose consumption in distant brain regions by deafferentiation, while also increased regional glucose consumption by increased activation of afferent neurons can occur. The PET tracer [18F]fluorodeoxyglucose (FDG) allows the measurement of glucose consumption. FDG is a glucose analog with physiological aspects almost identical to glucose. It is transported from the blood to the brain by a carrier-mediated diffusion mechanism. FDG and glucose are phosphorylated by hexokinase as the first step of the glycolytic process. FDG differs from glucose in that a hydrogen atom replaced the hydroxyl group at the second carbon atom of the molecule. Glucose is then phosphorylated to glucose-6PO4, and continues along the glycolytic pathway for energy production. However, FDG is phosphorylated to FDG-6-PO4, which is not a substrate for further metabolism and trapped in tissues. As glucose is the only source of energy for the brain it reflects the neuronal integrity of underlying brain pathology. Since FDG is a competitive substrate with glucose for both transport and phosphorylation, it is important for tracer uptake to avoid high blood glucose levels during an FDG-PET scan in subjects with diabetes.

The adenosine A(2A) receptor (A(2A)R) is highly concentrated in the striatum, and a therapeutic target for Parkinson's disorder (PD) and Huntington's disease. High affinity and selective radiolabeled A(2A)R antagonists can be important research and diagnostic tools for PD. Positron Emission Tomography (PET) can play an important role by measuring radiolabeled A(2A) antagonists non-invasively in the brain. However, till date no complete review on A(2A)R PET ligands is available. The present article has been therefore focused on available PET tracers for A(2A)R and their detailed biological evaluation in rodents, nonhuman primates and humans. Drug design and development by molecular modeling including new lead structures that are potential candidates for radiolabeling and mapping of cerebral A(2A)Rs is discussed in the present article. A brief overview of functions of adenosine in health and disease, including the relevance of A(2A)R for PD has also been presented.

Iron and transferrin are required for DNA synthesis and cell division. Cellular iron uptake is mediated by transferrin receptors. In order to investigate whether iron uptake in brain tumors is associated with their histological grade, we studied 24 patients (5 astrocytoma, 11 glioblastoma, 8 meningioma) using positron emission tomography and 52Fe-citrate. Tracer uptake from blood into brain and tumor tissue was assessed 1. using multiple time graphical analysis yielding a measure for unidirectional net tracer uptake (Ki) and 2.) testing a one- and two-tissue kinetic compartment model, where K1 denotes tracer uptake from blood into tissue, k2 efflux from tissue into plasma, and k3 specific tracer binding. In the plasma, 52Fe was bound to a 80 kD protein (transferrin). Ki (in units of 10(-5)/min) was higher in glioblastomas (Ki mean +/- SD 13.6 +/- 6.1) compared with astrocytomas (4.8 +/- 3.5, Mann Whitney p = 0.015) and contralateral brain (2.2 +/- 0.9, Mann Whitney p = 0.009). Highest values were found in meningiomas (no blood-brain barrier (BBB); Ki 33.4 +/- 16.5, Mann Whitney p = 0.008 compared with glioblastomas). Among the compartment models, fitting with K1 and regional plasma volume explained the data best (one-tissue model), data fits were not significantly improved by addition of a k2 or k3 parameter. K1 and Ki values were significantly correlated (Spearman Rank, p = 0.0006). We conclude that 52Fe accumulation in tumors is governed by tracer uptake at the BBB, and does not reflect number of transferrin receptors at the level of tumor cells.

This study demonstrates that positron emission tomography (PET) and neutron radiography (NR) techniques are complementary methods for determining the fluid pathway and porosity in crystalline rock. After preliminary injection of an organic solvent (e.g. isopropanol) front followed by the injection of the polymer solution (e.g. epoxy used for both techniques) and resin hardening, rock cutting may be performed. Flow pathway may be imaged by using a β+ emitter (e.g. 68Ga) in the resin. With a high-resolution PET camera, determination of the original water carrier features is possible in granodiorite pieces 20 cm in size and in simulated features with porosities of the order of 0.2. The use of a β+ tracer and the camera field, however, limit the lateral resolution of the technique (10 mm). Neutron radiography makes it possible to visualize the simulated porous phases by neutron transmission. The transmission process depends on the neutron scattering properties of the hydrogen-rich material (e.g. epoxy resin). Combination of 2D pictures may rebuild the 3D pattern. Lateral resolution may be in the range of 1 mm; however, the thickness of the rock sample must not exceed 10 cm. Complementarity of these techniques is discussed and they are compared with other methods used to determine porosity.

The influence of the blood-brain barrier (BBB) on tracer uptake was investigated in 21 patients with gliomas and meningiomas using PET, [18F]fluorodeoxyglucose (FDG), [18C]methionine (MET) and the K+ analog rubidium-82 (RUB) whose uptake into brain is largely prevented if the BBB is intact. Tracer uptake was quantitated by (1) multiple time graphical plotting providing tracer distribution volume (VD), unidirectional tracer uptake (Ki), and (2) normalized uptake (NU) which is a measure of net tissue radioactivity related to administered activity and body weight. VD, Ki and NU of MET were higher in meningiomas compared to gliomas and were significantly correlated with NU RUB (Spearman rank: p0.005 (VD), p0.05 (Ki), p0.001 (NU)). NU MET correlated with VD (p0.001) and Ki (p0.005) of MET. For FDG, tumor VD was in the range of contralateral cortex. Ki and NU values of FDG were highest in glioblastomas. NU of FDG correlated significantly with Ki of FDG (p0.005) but not with VD. The results suggest, that alteration of MET uptake in tumors is governed by changes of tracer influx across the BBB, whereas FDG uptake is related to tracer metabolism. This makes FDG the appropriate tracer particularly for the differential diagnosis of contrast enhancing lesions in operated and irradiated patients.

The MPTP-lesioned monkey is considered as the best animal model for Parkinson's disease (PD). It has damage to dopaminergic cell groups and motor dysfunction similar to that seen in PD. Correlations between these two parameters have been described but there is a lack of formal statistical analyses on dopaminergic function as assessed by [(18)F]-F-DOPA PET and objectively rated motor behavior in longitudinal experiments. Eight rhesus monkeys received two MPTP infusions: first in one carotid artery, and after eight weeks in the other. Motor behavior and [(18)F]-F-DOPA uptake were measured at three stages: baseline, unilateral and bilateral. We correlated movement with radiotracer uptake across these three stages. MPTP caused the expected parkinsonian motor signs which were accompanied by lower radioactivity concentrations in the striatum. There were significant correlations between dopaminergic function and behavior. In conclusion, striatal [(18)F]-F-DOPA uptake correlates inversely with the severity of motor impairment in MPTP-lesioned non-human primates. Both behavioral scoring and [(18)F]-F-DOPA PET scans are useful and sensitive methods to monitor dopaminergic degeneration within subjects.

Tissue perfusion and cerebral energy metabolism in brain tumor patients are regionally abnormal, and certain patterns of pathological changes may be demonstrated in and around tumor tissue. Tumor CBF may vary widely between subjects, whereas oxygen extraction is almost always markedly reduced. This is in apparent contradiction with the tumor tissue oxygen tension data (see previous chapter): since these are low, an increase of OER would be expected. Still, as discussed above, oxygen consumption calculated from oxygen tension or PET data yield the same relative decreases (0.3) of tumor oxygen utilization compared to normal brain. This suggests that the characteristic pathological changes of tumor cell energy metabolism have diminished oxygen demand and changed the level of coupling between CBF and OER. Since all published data on OER in tumor patients have been obtained by the steady state method, possibly resulting in an underestimation of OER, it will be mandatory to apply dynamic oxygen uptake measurements to circumvent this methodological problem and e.g. to make use of distribution volume of water to correct for tissue composition as has been reported in one paper studying patients with breast tumors. Because of the conspicuous regional changes in tumor oxygen metabolism it is expected that effectivity of chemotherapeutic measures is directly reflected by characteristical adaptations of metabolism. Systematic studies in this context have not been reported to date. Whether oxygen metabolism changes would be more sensitive than just CBF measurements as indicator of treatment effectivity remains to be seen.

Positron emission tomography and 18F-fluorodeoxyglucose were used to measure the regional cerebral glucose consumption in a 15-year-old choreatic girl with classical Sydenham's chorea shortly after the onset of hyperkinetic movements and 5 months later after chorea had resolved and in a 74-year-old hemichoreatic woman with long-standing hyperkinesia as a residuum of Sydenham's chorea in adolescence. Whereas cerebellar, thalamic, and cortical glucose consumption was within normal limits in both patients, lentiform and caudate glucose consumption was significantly increased in both hemispheres of the 15-year-old patient and in the hemisphere contralateral to the chorea in the 74-year-old patient. In the younger patient, striatal glucose consumption returned to normal after her hyperkinesia had disappeared with antibiotic therapy. The observation of an increase in striatal glucose consumption in Sydenham's chorea, in contrast to the decrease of this variable encountered in the vast majority of other choreatic disorders, leads to questioning the pathophysiology of chorea in humans and suggests the use of emission tomographic measurement of variables related to cerebral energy metabolism for differential diagnosis in choreatic disorders.

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 doparesponsive 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 doparesponsive 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 published functional neuroimaging results indicate that the major finding in neuroacanthocytosis (NA) is severe striatal hypometabolism, either with or without atrophy. There is some evidence that the right side is more affected than the left. Cortical abnormalities are either not present or subtle, but if present appear to be particularly located in the frontal cortex. As with NA, an intriguing variety of devastating movement disorders may arise when specific striatal lesions occur. Due to the low prevalence of NA only a few patients have been investigated to date, and further studies are needed.

Many studies indicate a role of the cerebral dopaminergic reward system in addiction. Motivated by these findings, we examined in opiate addicts whether brain regions involved in the reward circuitry also react to human prototypical rewards. We measured regional cerebral blood flow (rCBF) with H(2)(15)O positron emission tomography (PET) during a visuo-spatial recognition task with delayed response in control subjects and in opiate addicts participating in a methadone program. Three conditions were defined by the types of feedback: nonsense feedback; nonmonetary reinforcement; or monetary reward, received by the subjects for a correct response. We found in the control subjects rCBF increases in regions associated with the meso-striatal and meso-corticolimbic circuits in response to both monetary reward and nonmonetary reinforcement. In opiate addicts, these regions were activated only in response to monetary reward. Furthermore, nonmonetary reinforcement elicited rCBF increases in limbic regions of the opiate addicts that were not activated in the control subjects. Because psychoactive drugs serve as rewards and directly affect regions of the dopaminergic system like the striatum, we conclude that the differences in rCBF increases between controls and addicts can be attributed to an adaptive consequence of the addiction process.

The identification of discrete patterns of altered functional brain circuitry in preclinical Huntington's disease (HD) gene carriers is important to understanding the pathophysiology of this disorder and could be useful as a biologic disease marker. The purpose of this study was to use PET imaging of regional cerebral glucose metabolism to identify abnormal networks of brain regions that are specifically related to the preclinical phase of HD.Eighteen presymptomatic HD gene carriers, 13 early-stage HD patients, and 8 age-matched gene-negative relatives were scanned using PET with [(18)F]FDG to quantify regional glucose utilization. A network modeling strategy was applied to the FDG PET data to identify disease-related regional metabolic covariance patterns in the preclinical HD cohort. The outcome measures were the region weights defining the metabolic topography of the HD gene carriers and the subject scores quantifying the expression of the pattern in individual subjects.Network analysis of the presymptomatic carriers and the gene-negative control subjects revealed a significant metabolic covariance pattern characterized by caudate and putamenal hypometabolism but also included mediotemporal metabolic reductions as well as relative metabolic increases in the occipital cortex. Subject scores for this pattern were abnormally elevated in the preclinical group compared with those of the control group (P0.005) and in the early symptomatic group compared with those of the presymptomatic group (P0.005).These findings show that FDG PET with network analysis can be used to identify specific patterns of abnormal brain function in preclinical HD. The presence of discrete patterns of metabolic abnormality in preclinical HD carriers may provide a useful means of quantifying the rate of disease progression during the earliest phases of this illness.

Tobacco smoking is the most frequent form of substance abuse. Several studies have shown that the addictive action of nicotine is mediated by the mesolimbic dopamine system. This system is implicated in reward processing. In order to better understand the relationship between nicotine addiction and reward in humans, we investigated differences between smokers and nonsmokers in the activation of brain regions involved in processing reward information. Using [H2(15O)] positron emission tomography (PET), we measured regional cerebral blood flow (rCBF) in healthy smokers and nonsmokers while they performed a prelearned, pattern-recognition task. We compared two conditions involving nonmonetary reinforcement or monetary reward with a baseline condition in which nonsense feedback was presented. With monetary reward, we found activation in the frontal and orbitofrontal cortex, occipital cortex, cingulate gyrus, cerebellum, and midbrain in both groups. Additionally, monetary reward activated typical dopaminergic regions such as the striatum in nonsmokers but not in smokers. We found a similar pattern of activation associated with nonmonetary reinforcement in nonsmokers, whereas activation was found in smokers only in the cerebellum. The different patterns of activation suggest that the brains of smokers react in a different way to reward than those of nonsmokers. This difference involves in particular the regions of the dopaminergic system including the striatum. In principle these observations could be interpreted either as a consequence of tobacco use or as a primitive condition of the brain that led people to smoke. Supported by related nonimaging studies, we interpret these differences as a consequence of tobacco smoking, even if a short-term effect of smoking prior to the experiment cannot be excluded.

Parkinson's disease is one of the most frequent neurodegenerative brain diseases. Its time course is slow and is characterized by progressive loss of dopaminergic and other brainstem neurons resulting in malfunctioning of the cerebral neuronal systems responsible for motor functions. The clinical signs are slowness of movement, muscle rigidity and rest-tremor amongst other features. The cause of the disease is unknown, but recently involvement of genetic factors is being researched. Positron emission tomography (PET) allows in vivo determination of striatai dopaminergic activity. This has increased our insight in the pathophysiology of the disease and permits direct study of disease progression at a biochemical level and equally to monitor whether potential neuroprotective interventions are indeed effective. Thus far no drug has emerged but promising substances are currently being studied.

Abnormality of iron either its increase or decrease in the tissue is associated with some of the most devastating diseases in human. Until very recently very little attention was paid to iron metabolism in the brain. Reduction in brain iron is thought to cause cognitive and learning impairment in infants and young children (Youdim et al.,1989) (Yehuda and Youdim, 1989; Youdim and Yehuda, 2000) Indeed, in animal studies in which nutritionally iron deficiency was induced in young rats (28–80 day old) brain iron was reduced by 30–40%. These animals exhibit learning deficits in Y-water maze and Morris water tank. Iron supplementation restored iron levels cognitive and behavioral deficits to normal. In contrast, if iron deficiency is induced in newborn rats (10 day old) iron supplementation could not reverse brain iron and the learning deficits even after long-term treatment.

Regional cerebral blood flow (rCBF) in healthy controls and non-demented, non-depressed Parkinsonian patients was measured using H(2)(15)0 PET while subjects performed a prelearned pattern recognition task with delayed response. To investigate differences between the two groups in response to reward, the experimental design consisted of three reinforcement conditions: no reinforcement consisting of nonsense feedback, positive symbolic reinforcement and monetary reward. In the controls, monetary reward activated bilaterally the striatum and anterior cingulate gyrus, as well as unilaterally the left cerebellum, midbrain and medial frontal gyrus. Symbolic reinforcement revealed a similar pattern of activation, except that the striatum and left midbrain showed no activation. The Parkinsonian patients responded to monetary reward with increased activation bilaterally in the cerebellum, medial frontal gyrus, and anterior cingulate gyrus as well as unilaterally in the right fusiform gyrus and midbrain and left caudate nucleus and precentral gyrus. Symbolic reinforcement induced significantly increased rCBF in the right cerebellum only. Compared with symbolic reinforcement, monetary reward produced extended activation of temporoparietal association cortex. The pattern observed in the controls demonstrates the role in reward processing of dopaminergic mesolimbic pathways in the healthy human brain, whereas the pattern in the Parkinsonian patients suggests the involvement of compensatory cortical loops in the diseased brain. NeuroReport 11:3681-3687 (C) 2000 Lippincott Williams & Wilkins.

Toxicity of abundant copper is the main cause of brain and liver tissue damage in patients with Wilson's disease (WD). However, there is also evidence of a disturbed iron metabolism in this genetically determined disorder. This PET study was undertaken to assess cerebral iron metabolism in WD patients.We used 52Fe-citrate, which converts to 52Fe-transferrin in blood plasma, to study basic pharmacokinetic features of the cerebral iron transport in 6 WD patients and in 16 healthy volunteers (control subjects). A 2-tissue-compartment model and multiple time graphic plotting were used to calculate 52Fe-transferrin distribution volumes and transport rates.Net iron uptake (Ki) from plasma into brain tissue was significantly (P0.001) higher in WD patients (Ki [mean +/- SEM] = 15.1E-05 +/- 7.13E-05 [1/min]) than in healthy volunteers (Ki = 2.66E-05 +/- 0.351E-05 [1/min]). There was no difference of tracer iron distribution in the cerebral plasma volume between patients and healthy volunteers. Iron uptake values resulting from 2 methods to model PET data of patients and healthy volunteers were highly correlated (P0.001).An abnormally increased cerebral 52Fe-transferrin uptake was found in WD patients.

We used positron emission tomography and [11C]flumazenil to analyze the benzodiazepine receptor binding in symptomatic and asymptomatic carriers of the Huntington's disease gene. We found an inverse relationship between [11C]flumazenil and [11C]raclopride binding in the putamen of symptomatic patients, and interpret this result as GABA receptor upregulation.

Cervical dystonia is a disabling basal ganglia disorder characterized by an involuntary head deviation to one side. A typical but also mysterious feature is the impressive improvement of muscle spasms and involuntary head posture by application of a sensory facial stimulus (sensory trick). Here, we report the effect of a sensory trick on cortical activation patterns in 7 patients with cervical dystonia by using H2(15)O positron emission tomography. The application of the sensory trick stimulus, resulting in a near-neutral head position, led to an increased activation mainly of the superior and inferior parietal lobule (ipsilateral to the original head turn) and bilateral occipital cortex and to a decreased activity of the supplementary motor area and the primary sensorimotor cortex (contralateral to the head turn). We propose that a perceptual dysbalance induced by a sensory trick maneuver leads to a relative displacement of the egocentric midvertical reference to the opposite side and a decrease in motor cortex activity. This modulation of motor programming gives novel insights into the mechanisms involved in sensorimotor integration in movement disorders.

Background: Single cases of parkinsonism have been associated with hydrocarbon solvents. Objective: To determine whether exposure to hydrocarbon solvents is related to PD. Methods: Cohort study of 990 patients with PD according to Core Assessment Program for Intracerebral Transplantations (CAPIT) criteria, selected from 1455 consecutive subjects presenting at a referral center; case–control study assessing Unified PD Rating Scale scores (motor score as primary endpoint) in all subjects with positive history of hydrocarbon solvent exposure (n = 188), matched for duration of disease and gender to 188 subjects selected from the remaining 802 with a negative history. Two subgroups in the case–control study included the following: 1) response to apomorphine (n = 26); 2) brain MRI (n = 15). PET imaging (n = 9) was compared with that of historic controls. Results: Exposed patients were younger (61.0 ± 9.4 versus 64.7 ± 9.4 years, p = 0.002), predominantly male (76.4% versus 45.2%, p = 0.0001), less educated (8.4 ± 4.2 versus 10.1 ± 4.4 years, p = 0.0001), and younger at onset of disease (55.2 ± 9.8 versus 58.6 ± 10 years, p = 0.014). Exposure to hydrocarbon solvents directly correlated to disease severity ( r = 0.311) and inversely correlated to latency period ( r = −0.252). Nine blue-collar occupations accounted for 91.1% of exposures. Conclusions: Occupations involving the use of hydrocarbon solvents are a risk factor for earlier onset of symptoms of PD and more severe disease throughout its course. Hydrocarbon solvents may be involved in the etiopathogenesis of PD, which does not have a major genetic component.

This article reviews possible clinical applications of positron emission tomography (PET) in patients with CNS lymphomas. PET allows quantitative assessment of brain tumor pathophysiology and biochemistry in vivo. Therefore, it provides different information about tumors when compared to histological or neuroradiological methods. In a diagnostic setting, PET cannot differentiate between primary lymphomas of the CNS, brain secondaries, or malignant gliomas, since various brain tumors share biochemical alterations. In HIV patients with contrast-enhancing brain tumors, however, data from the literature suggest that PET with the tracer F-18 fluoro-deoxyglucose may help to discriminate neoplastic (CNS lymphoma) from inflammatory (e.g. toxoplasmosis) lesions. Assuming that tumor biochemistry is highly abnormal in the most malignant parts of tumors, PET may also assist in defining targets for stereotactic biopsy. With regard to treatment evaluation, the prediction of individual treatment response is among the most challenging clinical applications of PET. On the one hand, this could be achieved on the basis of measures like tumor perfusion, oxygen consumption, or hypoxia. On the other hand, PET tracer methods may allow to quantify the expression of gene products following gene therapy. However, in CNS lymphoma patients these topics have yet not been addressed with PET.

It is well known that chronic administration of pergolide and other dopamine agonists may induce a downregulation of dopamine D2 receptors in the rat model of Parkinson's disease (PD). To our knowledge, this effect has not been demonstrated in vivo in patients with PD. At present, the status of striatal dopamine D2 receptors can be studied with use of positron emission tomographic (PET) technology. Five patients with PD chronically treated with levodopa were studied with use of PET and [11C]-raclopride before and after 6 months of pergolide treatment (dose range = 4.5-7.5 mg/d). We found a slight reduction in the specific striatal [11C]-raclopride uptake index (mean reduction 14% in putamen and 9% in caudate) after pergolide treatment. This reduction appears to be related to downregulation of the receptor, although competitive binding of pergolide at the D2 receptor cannot be excluded.

In a previous [18F]fluorodeoxyglucose (FDG) PET study we analyzed regional metabolic data from a combined group of Parkinson's disease (PD) patients and healthy volunteers (N), using network analysis. By this method, we identified a unique pattern of regional metabolic covariation with an expression which accurately discriminated patients from healthy volunteers. To assess the reproducibility of this pattern as a potential marker for PD, we compared the pattern's topography with that of the disease-related covariance patterns identified in three other independent populations of patients with PD and healthy individuals studied in different PET laboratories.The following patient populations were studied: group A (original cohort: 22 PD, 20 N; resolution: 7.5 mm full width at half maximum [FWHM]); group B (18 PD, 12 N; resolution: 4.2 mm FWHM); group C (25 PD, 15 N; resolution: 8.0 mm FWHM); and group D (14 PD, 10 N; resolution: 10 mm FWHM). Region weights for the PD-related covariance pattern (PDRP) identified in the group A analysis were correlated with those for the disease-related patterns identified in the analyses of groups B, C and D. In addition, subject scores for the group A PDRP were computed prospectively for every individual in each of the study populations. PDRP scores for PD and N within each cohort were compared.The PDRP topography identified in group A was highly correlated with each of the corresponding topographies identified in the other populations (r2 approximately 0.60, P0.0001). Prospectively computed subject scores for the group A PDRP significantly discriminated PD from N in each population (P0.004).The PDRP topography identified previously in Group A is highly reproducible across patient populations and tomographs. Prospectively computed PDRP scores can accurately discriminate patients from controls in multiple populations studied with different tomographs. Brain network imaging with FDG PET can provide robust metabolic markers for the diagnosis of PD.

Tactile discrimination of macrogeometric objects in a two‐alternative forced‐choice procedure represents a demanding task involving somatosensory pathways and higher cognitive processing. The objects for somatosensory discrimination, i.e., rectangular parallelepipeds differing only in oblongness, were presented in sequential pairs to normal volunteers and 12 parkinsonian patients. The performance of patients was significantly impaired compared to normal volunteers. From a biochemical point of view, the patients were characterized by a severely reduced 6‐[(18)F]‐fluoro‐L‐dopa (FDOPA) tracer metabolism in the basal ganglia, as measured using positron emission tomography (PET). Furthermore, reduced specific FDOPA metabolism in the putamen was consistent with the impaired motor capacities of the patients. The reduced specific FDOPA‐uptake within the caudate nucleus was associated with additionally diminished somatosensory discrimination. This association, of low perception during task performance and decreased FDOPA‐uptake, provides direct evidence for the role of the caudate nucleus in the cognitive part of the task. We suggest that directed attention and working memory were critically involved as a result of disturbed interactions between the head of the caudate nucleus and the dorsolateral prefrontal cortex. Furthermore, there were indications of an additional involvement of the mesolimbic system, which might be of importance during challenging situations such as forced choice. We conclude that differential effects on parts of the basal ganglia, during evolution of the degenerative process characteristic of Parkinson's disease, have profound consequences on the performance of skills, as shown here for a somatosensory discrimination task. Hum. Brain Mapping 8:1–12, 1999. © 1999 Wiley‐Liss, Inc.

The primary sensorimotor cortex of the adult brain is capable of significant reorganization of topographic maps after deafferentation and de-efferentation. Here we show that patients with spinal cord injury exhibit extensive changes in the activation of cortical and subcortical brain areas during hand movements, irrespective of normal (paraplegic) or impaired (tetraplegic patients) hand function. Positron emission tomography ([15O]-H2O-PET) revealed not only an expansion of the cortical 'hand area' towards the cortical 'leg area', but also an enhanced bilateral activation of the thalamus and cerebellum. The areas of the brain which were activated were qualitatively the same in both paraplegic and tetraplegic patients, but differed quantitatively as a function of the level of their spinal cord injury. We postulate that the changes in brain activation following spinal cord injury may reflect an adaptation of hand movement to a new body reference scheme secondary to a reduced and altered spino-thalamic and spino-cerebellar input.

Tactile discrimination of macrogeometric objects in a two-alternative forced-choice procedure represents a complex task including somatosensory and higher-order cognitive processing. The objects for somatosensory discrimination were rectangular parallelepipeds that differed in oblongness only. They were presented in sequential pairs to 12 normal volunteers and 13 parkinsonian patients. Owing to the dichotomy of the task, we calculated estimates of the probability of a correct answer by a binomial approach. The probability of a correct answer could be calculated on the basis of a logistic model ensuring that the probability values lie in the interval [0, 1]. The relationship between the probability of a correct answer and the difference in oblongness of the objects could be described solely by one coefficient determined by logistic regression. This coefficient summarized the effectiveness of the simultaneous and consecutive operations inherent in the task and allowed characterization of performances in groups and individuals.

We studied a patient with juvenile pilocytic astrocytoma (JPA) using positron emission tomography (PET), 18F-fluorodeoxyglucose (FDG), 11C-methionine (MET), and 82Rubidium (RUB). Non-linear fitting and multiple time graphical plotting of the dynamic PET data revealed values for tumor plasma volume, blood-brain barrier transport rate constants and tracer distribution volume in the range of glioblastomas and meningiomas, or higher. Likewise, the steady-state accumulation of MET and FDG was increased. With regard to the known vascular composition of JPA, our data suggest that increased transport and distribution considerably contribute to the high net tracer uptake observed in this tumor.

We used [11C]raclopride and positron emission tomography (PET) to assess the relationship between striatal dopamine D2 receptor binding, trinucleotide repeat number (CAG), and subject age in 10 asymptomatic and 8 symptomatic carriers of the Huntington's disease (HD) mutation. In both preclinical and symptomatic gene carriers, we found significant correlations between CAG repeat length and the ratio of percent loss in striatal D2 receptor binding divided by age. In accord with neuropathological studies, we obtained an intercept at 35.5 CAG repeats in the symptomatic HD patients. Nonetheless, we noted that the slopes of the correlation lines differed significantly for the presymptomatic and symptomatic cohorts. These PET results support the notion that the HD disease process is a function of trinucleotide length and age, and that the development of clinical signs and symptoms is associated with CAG repeat lengths greater than 35.5. However, our analysis also suggests that striatal degeneration may proceed in a nonlinear fashion. These findings have implications for the design of neuroprotective strategies for the treatment of HD.

In a previous study, we found that relearning of a task with one hand might negatively be influenced by previous, opposite hand training of the analogue task, Thut G., et al., Exp. Brain Res., 108 (1996) 321-327. Drawing of a figure with the right hand, following left hand training, was slower than right hand drawing of an unknown figure. These conditions were termed right hand transfer learning (rTL) and right hand original learning (rOL). The present study aimed to identify the cerebral areas associated with these influences by measuring regional cerebral blood flow (rCBF) in 16 right-handed, healthy subjects during rTL and rOL. Positron emission tomography and statistical parametric mapping were used. Compared with rOL, rTL was associated with increased rCBF in the left medial prefrontal cortex and the right prefrontal convexity. Individual rCBF changes in the area homotopic to the right prefrontal convexity furthermore correlated with individual changes in rTL performance. While the smallest rCBF increases were found in subjects with weakest slowing of rTL relative to rOL, highest rCBF increases were present when rTL slowing dominated. Comparisons between rTL and rOL, however, revealed on average no performance differences. Our data suggest that relearning after previous opposite hand training activates neural mechanisms within the prefrontal convexity which might have an inhibitory function but that inhibition does not have to be the net final behavioral result.

In a previous [F-18]fluorodeoxyglucose (FDG) PET study we analyzed regional metabolic data from a combined group of Parkinson's disease (PD) patients and healthy volunteers (N), using network analysis. By this method, we identified a unique pattern of regional metabolic covariation with an expression which accurately discriminated patients from healthy volunteers. To assess the reproducibility of this pattern as a potential marker for PD, we compared the pattern's topography with that of the disease-related covariance patterns identified in three other independent populations of patients with PD and healthy individuals studied in different PET laboratories. Methods: The following patient populations were studied: group A (original cohort: 22 PD, 20 N; resolution: 7.5 mm full width at half maximum [FWHM]); group B (18 PD, 12 N; resolution: 4.2 mm FWHM); group C (25 PD, 15 N; resolution: 8.0 mm FWHM); and group D (14 PD, 10 N; resolution: 10 mm FWHM). Region weights for the PD-related covariance pattern (PDRP) identified in the group A analysis were correlated with those for the disease-related patterns identified in the analyses of groups B, C and D, In addition, subject scores for the group A PDRP were computed prospectively for every individual in each of the study populations. PDRP scores for PD and N within each cohort were compared. Results: The PDRP topography identified in group A was highly correlated with each of the corresponding topographies identified in the other populations (r(2) similar to 0.60, P