Miolo rpm 124-3 (miolo 2).indd

Parkinson’s disease and
dopamine transporter
neuroimaging – a critical review
Laboratório Interdisciplinar de Neuroimagem e Cognição (LiNC), Universidade Federal de São Paulo and Instituto Israelita de Ensino e Pesquisa (IIEP), Hospital Israelita Albert Einstein (HIAE), São Paulo, Brazil disease patients manifest symptoms only when 50 to 80% of the nigrostriatal neurons are lost. Parkinson’s disease (PD) is a common neuro- neurodegenerative disorder characterized by Clinical diagnosis fails to identify individuals degenerative disorder that is mainly caused by dopaminergic neuron loss in the substantia the presence of Lewy bodies and progressive before they reach such a signifi cant loss of nigra. Several nuclear medicine radiotracers degeneration of dopaminergic neurons in the dopamine neurons. Such individuals would have been developed to evaluate PD diagnoses substantia nigra, with loss of their nerve termi- benefi t from early diagnosis, before dopamine and disease evolution in vivo in PD patients. nals in the basal ganglia structures, especially loss is too severe, with the aim of attempting to Positron emission tomography (PET) and single photon computerized emission tomog- in the striatum.1 Other etiopathogenic pro- implement the neuroprotective interventions raphy (SPECT) radiotracers for the dopamine cesses are suspected to incite and perpetuate that have been developed recently. Thus, im- transporter (DAT) provide good markers for PD, such as oxidative stress, mitochondrial provement in the accuracy of clinical diagnoses the integrity of the presynaptic dopaminergic system affected in PD. Over the last decade, of PD is needed for epidemiological studies radiotracers suitable for imaging the DAT have protein aggregation, which can lead to nigros- been the subject of most efforts. In this review, In this review, we discuss the relationship we provide a critical discussion on the utility of DAT imaging for Parkinson’s disease diagnosis The overall prevalence of PD is estimated between the dopamine system, especially the at 0.2% but rises with increasing age, affecting dopamine transporter (DAT), and Parkinson’s KEY WORDS: Parkinson disease. Dopamine.
as many as 0.5-1% of individuals aged 65-69 disease (PD). We also discuss the usefulness of Emission-computed tomography. Single-photon years and as many as 1-3% of individuals older DAT neuroimaging using positron emission emission-computerized tomography. Diagnosis.
than 80 years.3 PD diagnosis is substantially based on clinical symptoms and is character- sion computerized tomography (SPECT) for ized by resting tremor, rigidity, bradykinesia, and postural instability, and also favorable response to levodopa therapy,1,4 but few re- searchers have attempted to develop rigorous diagnostic criteria that can be applied consis- ing techniques such as magnetic resonance (CT) are not so useful for PD diagnosis. Parkinson’s disease in its initial phases of These techniques do, however, have a role clinical expression, three levels of diagnostic in the differential diagnosis with some other confi dence have been differentiated: defi nite, types of Parkinsonism. Researchers have been interested in developing sensitive diagnostic of possible and probable PD are based on techniques for early PD by assessing DAT clinical criteria alone, whereas the presence of concentrations in the striatum. The key to Lewy bodies in histopathological fi ndings is molecular imaging in nuclear medicine is required for defi nite PD diagnosis. However, radiotracers: substances that have high affi nity Lewy bodies are also present in many other and specifi city to a receptor site that is labeled diseases6,7 and are probably absent in autoso- with a radioisotope. These radioligands allow mal recessive juvenile Parkinsonism,8 which in vivo evaluation of receptor density and af- makes these diagnostic criteria not totally fi nity, measured as binding potential.12 The tracers are labeled with [123I] and [99mTc] for SPECT, or isotopes [11C], [18F], [15O] and 25% of cases with an antemortem clinical [13N] for PET. Although PET provides higher diagnosis of PD were found not to have PD resolution and better physical quantitative at postmortem examination.1,10 Parkinson’s capacity than SPECT, PET is less practical as a Sao Paulo Med J. 2006;124(3):168-75.
routine procedure because of its high cost and agents have been developed for diagnosing PD are chosen as ROI. Given that postmortem the shorter half-life of its radiotracers. On the and monitoring the treatment of PD patients, studies have shown a very low density of DAT other hand, SPECT uses isotopes with longer based on DAT antagonists such as methylphe- and SERT in occipital cortices and the cerebel- half-lives that can be stored on site.
nidate and cocaine (tropane derivatives).18,40,41 lum,82-84 these reference regions with absent (or low) DAT density are taken to indicate able for DAT imaging have been the subject rivatives gain potency through halogenation nondisplaceable DAT activity and are used of great investigative efforts. Several DAT of their phenyl rings. On the other hand, lack to assess nonspecifi c binding. Quantitative ligands have been successfully used as meth- of ester linkages between tropane and phenyl studies that are coregistered to the template or ods for evaluating neuronal loss, for PD moiety sites is the main mechanism for cocaine performed with anatomically adjusted ROIs diagnosis.11,13-19 For this reason, DAT ligands inactivation and degradation. Table 1 summa- (using templates or MRI overlay techniques) have become well-established markers that are rizes the DAT radiotracers that have reached or on a pixelwise basis, in which they self- useful for evaluating changes in presynaptic phase III or IV of clinical applications, includ- correspond exactly to the three-dimensional DAT sites in vivo and in vitro.
ing [11C] cocaine, [123I] β-CIT (2b-carboxy- ROI map, ensure that the results are highly methoxy-3b-[4-iodophenyl] tropane), [123I] observer-independent, precise, and reproduc- FE-CIT (iofl upane), [123I]/[18F]/[11C] FP-CIT ible, because of the automated processing.85 (N-[3-fl uoropropyl]-2ss-carbomethoxy-3ss- Striatal dopamine ROI areas for monoamine described 30 years ago. It is an 80-kDa pro- [4-iodophenyl]nortropane), [18F]/[11C] CFT transporters, mainly refl ecting SERT,82 are (2beta-carbomethoxy-3betafl uorophenyl-tro- visually positioned on the summed transversal ning regions with the carboxyl and amino pane), [123I]/[11C] altropane, [123I]/[11C] PE2I slices of the hypothalamus/midbrain (includ- termini residing intracellularly.20 The protein (N-{3-iodoprop-(2E)-enyl}-2beta-carboxyme- ing the raphe nuclei, substantia nigra and col- is externally glycosylated and is localized thoxy-3beta-{4’methylphenyl} nortropane), liculi), the thalamus and the medial prefrontal in the axonal membranes of nigrostriatal area at the striatal level. These areas have been identifi ed through magnetic resonance imag- gene is localized on chromosome 5p15.3.22-24 with [18F] dopa and PET labeling for dopa- ing scans using a reference atlas.86 If available, DAT is located on the plasma membrane of decarboxylase (the enzyme involved in dopa- ROI defi nition may be based on individual nerve terminals in a small number of neurons mine synthesis) was considered to be the gold morphology, as obtained by image fusion with in the brain, especially in the striatum and standard for evaluating nigral dopaminergic MRI, which is particularly important when nucleus accumbens, but also in the globus neurons in PD42,43 before the advent of DAT low specifi c binding is expected (e.g. in cases pallidus, cingulate cortex, olfactory tubercle, tracers. Tropane derivative studies ([11C] CFT of severe loss or blockade of the DAT).
and [123I] β-CIT) have shown a direct correla- the dopamine concentration in the synaptic tion between decreased DAT in the putamen ding to the product of the free receptor and PD symptoms.13,44 Descriptions of the density and affi nity, is calculated as the ratio presynaptic neurons; it plays a central role characteristics of several DAT tracers, includ- of striatal specifi c binding to steady-state in the spatial and temporal buffering of ing time to reach tracer equilibrium (scan free unmetabolized plasma tracer concentra- the released dopamine.26 Its activity can be time); tracer maximum accumulation (peak tion.87 Given that each tracer attains a state of regulated by presynaptic receptors, protein striatal activity); differential contrast imaging equilibrium in the striatal and occipital areas kinases, and membrane traffi cking.27-29 DAT in the striatal area and the rest of the brain, at a certain time after its injection, the ratio exerts vital infl uence on dopamine function, especially in the cerebellum (signal to noise point at this time is used as an estimate for by modulating locomotor activity, cognition ratio); and affi nity competition inhibition of the BP.88 The specifi c DAT BP in the basal and the reward system.30 Pharmacologically, serotonin and dopamine transporters (SERT: ganglia is calculated as the difference between DAT serves as the binding site for drugs of DAT) are given in Table 1.13,19,32,39,45-79 striatal activity and the reference region, i.e. abuse31 (e.g. cocaine and amphetamine) and the occipital activity (OA) at equilibrium. therapeutic agents32 (e.g. methylphenidate and The ratio of the total binding in the striatum bupropion). It has been observed that striatal minus the nondisplaceable binding in the DAT declines at a rate of approximately 6-7% tive evaluation techniques have to be used to OA divided by the OA refl ects the specifi c- per decade in the human striatum.33-35 The assess specifi c DAT binding in the striatum density of DAT can be used as a marker for and over its subregions (head of caudate and putamen). The investigator performing the tifi cation, it is necessary to be aware of pos- sible technical artifacts (pitfalls) such as head subject’s demographic characteristics.80 Trans- motion, attenuation artifacts and technical verse/oblique slices are usually chosen for ROI artifacts due to gamma camera problems.
sociation between PD and striatal DAT con- defi nition, such as transaxial slices oriented centration.37,38 Evaluation of DAT in human along the orbitomeatal line, and the two slices interaction with concomitant medications corresponding to the highest right and left must be taken into account and it is essential correlation of in vitro tracers such as [125I] striatal uptake are positioned on summed im- to objectively assess the semi-quantifi cation altropane and DAT reduction in PD.39 DAT ages.81 Data evaluation must always consider of striatal DAT binding. Inter-individual provides a good site for monitoring the integ- relevant morphological information (by CT quantitative results are based on compari- rity of the presynaptic dopaminergic systems or MRI), especially in structural lesions in the sons between specifi c DAT BP obtained in that are most affected in PD. Several DAT basal ganglia and the reference structures that the patients and normal controls that are Sao Paulo Med J. 2006;124(3):168-75.
preferably age-matched (thereby avoiding type of camera and the same image evaluation database, thus allowing comparative calcula- over-interpretation: age-dependency is a technique. If age-matched data comparisons tions for the different imaging protocols.
known pitfall/source of error). Age-specifi c are available, it is recommendable to use sensitivity and specifi city of DAT SPECT analytical approaches based on stereotactic imaging for differentiating patients with PD In routine clinical practice, even experi- from healthy subjects is greater than when normalities of DAT BP in an observer-inde- enced neurologists have diffi culty in differen- pendent manner. Moreover, it is important tiating early-stage PD from atypical Parkin- It is also important to utilize the same to establish a control group for the central sonian syndromes (APS).90,91 The accuracy of Table 1. Dopamine transporter radiotracers according to the literature
Peak striatal
Signal to
Scan time (min.)
SERT: DAT
References
activity (min.)
noise ratio
Logan et al., 199046Telang et al., 199947 CFT = 2beta-carbomethoxy-3betafl uorophenyl-tropane;WIN = [11C]2beta-carbomethoxy-3beta-(4-fl uorophenyl)-tropane; β-CIT = 2b-carboxymethoxy3b-[4-iodophenyl] tropane; RTI = [1R-(exo,exo)]- 3-[4-(iodo123)phenyl]-8-methyl-8-azabicyclo[3.2.1]o ctane-2-carb oxylic acid methyl ester; FE-CIT = iofl upane; FP-CIT = N-[3-fl uoropropyl]-2ss-carbomethoxy-3ss-[4-iodophenyl]nortropane; PE2I = N-{3-iodoprop-(2E)-enyl}-2beta-carboxymethoxy-3beta-{4’methylphenyl}nortropane; RTI-32 = methyl (1R-2-exo-3-exo)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate; TRODAT-1 = [2-[[2-[[[3-(4-chloro- phenyl)-8-methyl-8-azabicyclo[3, 2, 1]oct-2-yl]methyl] (2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3)]-oxo-[1R-(exo -exo)]; NA = not available; DAT = dopamine transporter; SERT = serotonin transporter; PET = photon emission tomography; SPECT = single photon emission computerized tomography. Sao Paulo Med J. 2006;124(3):168-75.
the clinical diagnoses of PD, multiple system ing assessed by [123I]IPT in patients with early atrophy (MSA), progressive supranuclear palsy Parkinson’s disease demonstrates the potential (PSP), cortical basal degeneration (CBD) and provides robust estimates of disease sever- of this method to detect preclinical disease.112 vascular Parkinsonism is imperfect and error ity, correlating with the duration of PD.101 Prunier et al. (2003), studying nonhuman rates can be as high as 25%.4 Although DAT However, variability in uptake values suggests primates chronically treated with 1-methyl-4- imaging is the best parameter for evaluating that factors other than nigrostriatal degenera- phenyl-1,2,3,6-tetrahydropyridine according dopamine neuron loss and differentiating be- tion may contribute towards disease severity. to a regimen that consistently produces a tween Parkinsonism and non-Parkinsonism, it There is a correlation with bradykinesia but progressive Parkinsonian state, have shown may not be useful for differentiating PD from not with tremor, thus suggesting that the that [123I]-PE2I SPECT was able to detect origin of tremors is beyond the DAT system. presymptomatic lesions of nigrostriatal neu- kinsonism.92,93 Postsynaptic dopamine recep- rons and suggested that this method could with or without the Parkinsonism gene has now be used clinically for early diagnosis of techniques such as diffusion weighted imaging now found that Parkinsonism-related disease or volumetry are more likely to contribute to may be associated with a higher degree of a differential diagnosis between PD/APS and nigrostriatal impairment, independent of the clinical severity of the disease, and more Although there is controversy in the literature, evaluating PD progression. DAT radiotrac- be helpful for differentiating between PSP and ers seem to be the best markers for identify- PD in routine clinical practice.96 Combining ing PD patients, with high sensitivity and this with D2 receptor imaging can differenti- good correlation between the H&Y and UP- specifi city. DAT reduction correlates with ate between MSA and PD,97 because each type DRS scales.103 This method is useful for early dopamine neurons loss in the substantia nigra of Parkinsonian syndrome has its own physio- PD detection,104 and it has been suggested that and striatum.26,114,115 This is why the striatal pathology and rates of dopamine neuron loss it may be useful for differential diagnosis of concentration of DAT, preferentially puta- and post-synaptic receptor compensation in some kinds of movement disorders.105 Results men DAT, is a highly sensitive parameter for the striatum (caudate and putamen). In con- from a crossover study have suggested that detecting early phases of PD.39 DAT ligands trast, the distinction between CBD and other are well-established markers that are useful in reliable alternative to [18F]-dopa PET in the evaluating changes in presynaptic DAT sites evaluation of clinical PD patients.106 A repro- ducibility study using TRODAT-1 scans from The PET isotopes and [123I] are produced 20 PD patients showed excellent test-retest in cyclotrons and have limited availability reliability in evaluating PD progression.107 and relatively high cost, thus limiting the The most-used radiotracer is [123I] β-CIT. In The diagnostic accuracy of [99mTc]-TRODAT-1 availability of such DAT tracers for routine an evaluation of 113 PD patients, there was SPECT showed sensitivity of 0.79 and specifi c- application in DAT imaging106 Studies have a good correlation between DAT density loss ity of 0.92 in distinguishing 29 patients with and PD symptoms (Unifi ed Parkinson’s Dis- early PD from 38 healthy volunteers.108 Fur- useful.105,116 The ready availability and ease of ease Rating Scale, UPDRS), and the decrease thermore, in a sample of patients with different use of [99mTc] agents using a modifi ed TRO- in signal ranged from 35% in a Hoehn-Yahr stages of PD and healthy controls, another DAT-1 preparation kit117 are advantages that (H&Y) stage I patient to 75% in an H&Y research group found good concordance when provide a powerful incentive for their routine stage V patient.92 Using [123I] β-CIT, a mul- visual interpretation of [99mTc]-TRODAT-1 ticenter study found sensitivity of 98% and SPET images was used to evaluate the pres- Although PD is characterized by selective specifi city of 83% for PD diagnosis, in dif- ence of PD (sensitivity 0.98 and specifi city loss of dopamine neurons in the basal ganglia ferentiation from PSP and essential tremor 0.86).109 Using age-matched PD patients and and substantia nigra, these are not the only (ET).39 A six-month follow-up study on 35 healthy controls, Weng et al. (2004) showed brain changes occurring in these patients’ suspected PD patients found that [123I] β-CIT brains. Several other changes leading to neuro- was more accurate (sensitivity 0.92; specifi city sensitivity and specifi city for measuring the psychological defi cits cannot be explained by 1.00) than the clinical diagnosis (sensitivity decrement of DAT in PD patients.110 A cross- dopamine loss.118 In a study on 32 PD patients 0.92; specifi city 0.30).98 A retrospective study sectional study on 96 early-stage patients com- using [123I] β-CIT, it was found that although on 72 early-stage untreated Parkinsonian paring [123I] FP-CIT and [99mTc] TRODAT-1, striatal uptake was correlated with clinical syndrome (PS) patients revealed lower caudate found sensitivity/specifi city of 0.95/0.86 and severity, the annual percentage loss of striatal nucleus binding ratios and higher putamen uptake did not correlate with the annual loss binding ratios among cases that were later in measurements of clinical function.119 On diagnosed or rediagnosed as APS and IPD, erature involving other tropane derivatives, the other hand, there was a non-signifi cant thus showing that striatal involvement ap- and so far only preliminary experiences have difference in progression rate across three peared to have little predictive value in these been presented. [18F] β-CFT was found to be scans obtained over a fi ve-year period among a sensitive marker for dopaminergic dysfunc- 24 early PD patients.120 In a longitudinal study tion that could be used in diagnoses, disease assessing PD progression, the annual rate of severity assessments and patient follow-up.47 reduction of striatal DAT uptake was approxi- 93% specifi city for differentiating between Reduced striatal dopamine transporter bind- mately 6 to 13% in PD patients, compared Sao Paulo Med J. 2006;124(3):168-75.
with 0 to 2.5% in healthy controls, which was exposure to enriched environments (a com- routine clinical studies and favors its general in line with the results from [18F] dopa-PET bination of exercise, social interaction and introduction. As noted, the application of studies.121-123 However, most of these studies learning);125 the use of MAO-inhibitors;126 these methods in our country is very recent. were conducted among patients with advanced L-dopa coadministered with the adenosine Today, the fi rst neuroimaging pilot study on PD.124 Furthermore, DAT tracers present cer- A2A receptor agonist;127 and gene neuropro- tain problems in evaluating PD progression, tective therapy models (neurotrophic factors, derway in Brazil for evaluating PD patients.132 because of changes in the DAT system (up or i.e. genes to prevent apoptosis or detoxify Several other research protocols using [99mTc] downregulation) induced by drug treatment, free radical species that protect and restore and this method has not been fully validated investigate DAT in neuropsychiatric disorders as an outcome measurement for trials on PD involving the dopaminergic system, such as treatments. Future studies should focus on early onset Parkinson’s disease, attention defi cit the early stages of PD, i.e. the time when and hyperactivity disorder (ADHD), obsessive- the diagnosis is uncertain and DAT imaging duced in cyclotrons and have limited avail- compulsive disorder (OCD), post-traumatic ability, relatively short half-life and high cost, stress disorder (PTSD) and schizophrenia.
thereby limiting the accessibility of DAT tracers.106 In Brazil, the use of those cyclotron- tion process, which indeed is the main phys- generated radioligands is limited by the vol- iopathology of PD as far as the early stages ume of tracer production, which is restricted ferential diagnosis between Parkinsonian and of the disease are concerned. In fact, few to certain government institutions.129 This non-Parkinsonian syndromes and in cases of studies have evaluated the usefulness of DAT restriction limits the availability of radiotracers uncertainty involving essential tremor. The imaging for providing clear diagnosis in the and, more importantly, inhibits the develop- high sensitivity and specifi city of SPECT semi- early stages of PD. Further studies examining ment of the radiopharmacy laboratories and quantitative images makes this method a useful the specifi city of the diagnosis of PD using radiochemists that are fundamental for the tool in the early clinical PD evaluation and in DAT imaging are needed. Nevertheless, early advance of molecular imaging in Brazil.130 preclinical screening for asymptomatic patients. dopamine neuron loss can easily be detected The advantage of tracers such as [99mTc] At the present moment, DAT imaging is the TRODAT-1 is the ready availability and ease best biomarker for evaluating dopamine neuron cation. Early dopamine neuron loss detection manipulation of 99mTc using a modifi ed prepa- loss, which is responsible for most of the motor enables interventions for minimizing and ration of TRODAT-1 by means of a kit.117 stabilizing these progressions by means of In Brazil, some animal studies using [99mTc] neuroprotection treatments. Although neu- easy to manipulate. Recent data suggest that roprotective therapy is still controversial and group performed the fi rst studies on humans it can be safely used in Brazil.131-133 Although so far non-existent for PD, several strategies using this tracer and obtained encouraging the current availability is restricted to research have been studied and it is hoped that they results. The data so far suggests that this centers, it is expected that it will soon be avail- will soon be in use. These strategies include tracer is an uncomplicated and reliable tool for 1. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson 11. Brooks DJ. PET studies on the early and differential diagnosis of tomography in patients with parkinsonism. Eur J Nucl Med. disease. Arch Neurol. 1999;56(1):33-9.
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PRO-DOC research grant from Coordenação de Aper- 101. Benamer HT, Patterson J, Wyper DJ, Hadley DM, Macphee Brucke T. Measuring the rate of progression of Parkinson’s dis- feiçoamento de Pessoal de Nível Superior (CAPES). M.C. GJ, Grosset DG. Correlation of Parkinson’s disease severity ease over a 5-year period with beta-CIT SPECT. Mov Disord. Shih is supported by a PhD scholarship from CAPES and and duration with 123I-FP-CIT SPECT striatal uptake. Mov Instituto Israelita de Ensino e Pesquisa Albert Einstein.
121. Pirker W, Djamshidian S, Asenbaum S, et al. Progression of Sources of funding: Not declared
102. Varrone A, Pellecchia MT, Amboni M, et al. Imaging of dopa- dopaminergic degeneration in Parkinson’s disease and atypical Confl ict of interest: Not declared
Date of fi rst submission: July 28, 2005
minergic dysfunction with [123I]FP-CIT SPECT in early-onset parkinsonism: a longitudinal beta-CIT SPECT study. Mov Last received: May 29, 2006
parkin disease. Neurology. 2004;63(11):2097-103.
Accepted: May 30, 2006
Sao Paulo Med J. 2006;124(3):168-75.
Ming Chi Shih, MD. Laboratório Interdisciplinar de
Doença de Parkinson e neuroimagem do transportador de dopamina – uma revisão crítica
Neuroimagem e Cognição (LiNC), Universidade Federal de São Paulo; and Instituto Israelita de Ensino e Pesquisa A doença de Parkinson (DP) é uma desordem neurodegenerativa causada por perda de neurônios do- (IIEP), Hospital Israelita Albert Einstein (HIAE), São Paulo, paminérgicos na substância negra. Vários traçadores da medicina nuclear têm sido desenvolvidos para avaliar o diagnóstico e acompanhamento da DP. Traçadores para o transportador de dopamina (TDA) utilizados na tomografi a por emissão de pósitrons (PET) e tomografi a por emissão de fóton único (SPECT) Marcelo Queiroz Hoexter, MD. Laboratório Interdisci-
plinar de Neuroimagem e Cognição (LiNC), Universidade demonstram boa marcação na integridade de sistema dopaminergico pré-sináptico, afetada na DP. Na Federal de São Paulo, São Paulo, Brazil.
última década, radiotraçadores apropriados para imagens de TDA têm sido mais estudados. Nesta revisão, provemos uma discussão crítica sobre a utilidade dessas imagens de TDA para o diagnóstico de Luiz Augusto Franco de Andrade MD, PhD. Instituto
DP (sensibilidade e especifi cidade).
Israelita de Ensino e Pesquisa (IIEP), Hospital Israelita Albert Einstein (HIAE), São Paulo, Brazil. PALAVRAS-CHAVE: Doença de Parkinson. Dopamina. Tomografi a computadorizada de emissão. Tomografi a
Rodrigo Affonseca Bressan, MD, PhD. Laboratório
computadorizada de emissão de fóton único. Diagnóstico.
Interdisciplinar de Neuroimagem e Cognição (LiNC), Uni-versidade Federal de São Paulo, São Paulo, Brazil.
Address for correspondence:
Ming Chi Shih
Rodrigo Affonseca Bressan
LiNC - Laboratório Interdisciplinar de Neuroimagem e Cognição, Departamento de PsiquiatriaUniversidade Federal de São PauloRua Dr. Bacelar, 334São Paulo (SP) — Brasil – CEP 04026-001Tel. (+55 11) 5084-7060Fax. (+55 11) 5084-7061E-mail: [email protected]: [email protected] Copyright 2006, Associação Paulista de Medicina Sao Paulo Med J. 2006;124(3):168-75.

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