Radionuclide Imaging in Parkinson’s Disease: Diagnosis, Treatment, and Disease Progression
Identifieur interne : 000C01 ( Istex/Corpus ); précédent : 000C00; suivant : 000C02Radionuclide Imaging in Parkinson’s Disease: Diagnosis, Treatment, and Disease Progression
Auteurs : Doris J. DoudetSource :
- Journal of Pharmacy Practice [ 0897-1900 ] ; 2001-08.
Abstract
This paper reviews the abilities of positron emission tomography (PET) and single photon emission tomography (SPECT) to detect Parkinson’s disease, monitor its progression and the effect of therapy. It also provides insights on the role these two modalities provide in terms of discriminating atypical syndromes from Parkinson’s disease. Both PET and SPECT are sensitive means of detecting alterations in metabolism and blood flow in the brain and impairments in neurotransmitter function, especially dopaminergic, in the striatum and, more recently, in extrastriatal structures. To date, PET presents the added advantage of quantification, better sensitivity and resolution and a greater variety of tracers for both the dopaminergic and nondopaminergic systems.
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DOI: 10.1106/76VR-VNP7-T1EW-6HGY
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Doudet</name><affiliation><mods:affiliation>Department of Medicine, Neurodegenerative Disorders Center, University of British Columbia, Room M36, Purdy Pavilion, 2221 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada,</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ddoudet@interchange.ubc.ca</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:AC45DABDF59E87F02CF8A847BC9B4BE7A0211051</idno><date when="2001" year="2001">2001</date><idno type="doi">10.1106/76VR-VNP7-T1EW-6HGY</idno><idno type="url">https://api-v5.istex.fr/document/AC45DABDF59E87F02CF8A847BC9B4BE7A0211051/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000C01</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000C01</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Radionuclide Imaging in Parkinson’s Disease: Diagnosis, Treatment, and Disease Progression</title><author wicri:is="90%"><name sortKey="Doudet, Doris J" sort="Doudet, Doris J" uniqKey="Doudet D" first="Doris J." last="Doudet">Doris J. Doudet</name><affiliation><mods:affiliation>Department of Medicine, Neurodegenerative Disorders Center, University of British Columbia, Room M36, Purdy Pavilion, 2221 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada,</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ddoudet@interchange.ubc.ca</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Pharmacy Practice</title><idno type="ISSN">0897-1900</idno><idno type="eISSN">1531-1937</idno><imprint><publisher>Sage Publications</publisher><pubPlace>Sage CA: Thousand Oaks, CA</pubPlace><date type="published" when="2001-08">2001-08</date><biblScope unit="volume">14</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="341">341</biblScope><biblScope unit="page" to="350">350</biblScope></imprint><idno type="ISSN">0897-1900</idno></series><idno type="istex">AC45DABDF59E87F02CF8A847BC9B4BE7A0211051</idno><idno type="DOI">10.1106/76VR-VNP7-T1EW-6HGY</idno><idno type="ArticleID">10.1106_76VR-VNP7-T1EW-6HGY</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0897-1900</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">This paper reviews the abilities of positron emission tomography (PET) and single photon emission tomography (SPECT) to detect Parkinson’s disease, monitor its progression and the effect of therapy. It also provides insights on the role these two modalities provide in terms of discriminating atypical syndromes from Parkinson’s disease. Both PET and SPECT are sensitive means of detecting alterations in metabolism and blood flow in the brain and impairments in neurotransmitter function, especially dopaminergic, in the striatum and, more recently, in extrastriatal structures. To date, PET presents the added advantage of quantification, better sensitivity and resolution and a greater variety of tracers for both the dopaminergic and nondopaminergic systems.</div></front></TEI><istex><corpusName>sage</corpusName><author><json:item><name>Doris J. Doudet</name><affiliations><json:string>Department of Medicine, Neurodegenerative Disorders Center, University of British Columbia, Room M36, Purdy Pavilion, 2221 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada,</json:string><json:string>E-mail: ddoudet@interchange.ubc.ca</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Parkinson’s disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PET</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>SPECT</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>dopamine system</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>disease progression</value></json:item></subject><articleId><json:string>10.1106_76VR-VNP7-T1EW-6HGY</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>This paper reviews the abilities of positron emission tomography (PET) and single photon emission tomography (SPECT) to detect Parkinson’s disease, monitor its progression and the effect of therapy. 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It also provides insights on the role these two modalities provide in terms of discriminating atypical syndromes from Parkinson’s disease. Both PET and SPECT are sensitive means of detecting alterations in metabolism and blood flow in the brain and impairments in neurotransmitter function, especially dopaminergic, in the striatum and, more recently, in extrastriatal structures. To date, PET presents the added advantage of quantification, better sensitivity and resolution and a greater variety of tracers for both the dopaminergic and nondopaminergic systems.</p></abstract><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>Parkinson’s disease</term></item><item><term>PET</term></item><item><term>SPECT</term></item><item><term>dopamine system</term></item><item><term>disease progression</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2001-08">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api-v5.istex.fr/document/AC45DABDF59E87F02CF8A847BC9B4BE7A0211051/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus sage not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article" dtd-version="2.3" xml:lang="EN"><front><journal-meta><journal-id journal-id-type="hwp">spjpp</journal-id><journal-id journal-id-type="publisher-id">JPP</journal-id><journal-title>Journal of Pharmacy Practice</journal-title><issn pub-type="ppub">0897-1900</issn><publisher><publisher-name>Sage Publications</publisher-name><publisher-loc>Sage CA: Thousand Oaks, CA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1106/76VR-VNP7-T1EW-6HGY</article-id><article-id pub-id-type="publisher-id">10.1106_76VR-VNP7-T1EW-6HGY</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>Radionuclide Imaging in Parkinson’s Disease: Diagnosis, Treatment, and Disease Progression</article-title></title-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Doudet</surname><given-names>Doris J.</given-names></name><aff>Department of Medicine, Neurodegenerative Disorders Center, University of British Columbia, Room M36, Purdy Pavilion, 2221 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada, <email xlink:type="simple">ddoudet@interchange.ubc.ca</email></aff></contrib></contrib-group><pub-date pub-type="ppub"><month>08</month><year>2001</year></pub-date><volume>14</volume><issue>4</issue><fpage>341</fpage><lpage>350</lpage><abstract><p>This paper reviews the abilities of positron emission tomography (PET) and single photon emission tomography (SPECT) to detect Parkinson’s disease, monitor its progression and the effect of therapy. It also provides insights on the role these two modalities provide in terms of discriminating atypical syndromes from Parkinson’s disease. Both PET and SPECT are sensitive means of detecting alterations in metabolism and blood flow in the brain and impairments in neurotransmitter function, especially dopaminergic, in the striatum and, more recently, in extrastriatal structures. To date, PET presents the added advantage of quantification, better sensitivity and resolution and a greater variety of tracers for both the dopaminergic and nondopaminergic systems.</p></abstract><kwd-group><kwd>Parkinson’s disease</kwd><kwd>PET</kwd><kwd>SPECT</kwd><kwd>dopamine system</kwd><kwd>disease progression</kwd></kwd-group><custom-meta-wrap><custom-meta xlink:type="simple"><meta-name>sagemeta-type</meta-name><meta-value>Journal Article</meta-value></custom-meta><custom-meta xlink:type="simple"><meta-name>search-text</meta-name><meta-value> Radionuclide Imaging in Parkinson's Disease: Diagnosis, Treatment, and Disease Progression Doris J. Doudet This paper reviews the abilities of positron emission tomography (PET) and single photon emission to- mography (SPECT) to detect Parkinson's disease, monitor its progression and the effect of therapy. It also provides insights on the role these two modalities provide in terms of discriminating atypical syn- dromes from Parkinson's disease. Both PET and SPECT are sensitive means of detecting alterations in metabolism and blood flow in the brain and impairments in neurotransmitter function, especially dopaminergic, in the striatum and, more recently, in extrastriatal structures. To date, PET presents the added advantage of quantification, better sensitivity and resolution and a greater variety of tracers for both the dopaminergic and nondopaminergic systems. KEY WORDS: Parkinson's disease, PET, SPECT, dopamine system, disease progression. INTRODUCTION PARKINSON'S DISEASE (PD) is a progressive neurodegenerative disease of characteristic motor manifestations, most of them attributed to a progressive loss of dopaminergic (DA) neurons in the nigro-striatal pathway. Positron Emission Tomography (PET) and Single Pho- ton Emission Tomography (SPECT) provide the means to assess neurochemical activity in vivo. This ability has opened the way for early detection of preclinical PD in kindreds with fa- milial PD or in twins. It can be used in the dif- ferential diagnosis of parkinsonism based upon the presence or absence of deficits in DA presynaptic function, the pattern of the deficits and the status of postsynaptic DA receptors. Thus, these modalities provide new means of distinguishing between the various atypical parkinsonian syndromes such as striato-nigral degeneration (SND), pallidopontonigral de- generation (PPND), multiple systems atrophy (MSA) or progressive supranuclear palsy (PSP). Although these syndromes have clinical features in common with idiopathic PD, espe- cially in their early clinical stages, they are pathologically different and may require differ- ent treatment regimes. Similarly, the effects of surgical interventions such as fetal transplant or pallidotomy can be visualized in vivo using specific tracers. Another increasingly attractive use of PET/SPECT is to provide a somewhat more re- liable and objective quantification of disease progression and the efficacy of drugs to either stop or slow down the neurodegenerative pro- cess rather than that afforded by clinical rating scales. Scales such as the Hoehn and Yahr's scale categorize the patient into one of five stages, while others, such as the UPDRS (Unified Parkinson's Disease Rating Scale) or the modified Columbia score, characterize spe- cific aspects of the disease. Unfortunately, these rating scales are subjective. They can be influenced by the residual effect of medication 341JOURNAL OF PHARMACY PRACTICE, Volume 14, Number 4, August 2001 DOI: 10.1106/76VR-VNP7-T1EW-6HGY 2001 Sage Publications Doris J. Doudet, PhD, Associate Professor, Department of Medicine, Neurodegenerative Disorders Center, University of British Columbia, Room M36, Purdy Pavilion, 2221 Wesbrook Mall, Vancouver, BC, V6T 2B5, Canada. Email:ddoudet@interchange. ubc.ca and often reflect multiple aspects of daily liv- ing in addition of motor impairments, making the global changes in clinical severity difficult to relate to the actual progression of the neurodegenerative process or the true neuroprotective versus symptomatic effects of drugs. PET and SPECT properties are also exten- sively used in basic research to acquire insight into the physiological mechanisms underlying degeneration and the compensatory changes occurring in aging or in response to pharmaco- logical manipulations or the performance of various tasks in human subjects or in animal models. This latest aspect will, however, not be discussed, as the primary aim of this article is to provide a general review of clinical findings in PD, focusing mainly on assessment of the DA system. PD AND THE DOPAMINERGIC NIGRO-STRIATAL PATHWAY PD is characterized by hypokinesia, bradykinesia and rigidity, postural instability, gait disturbances and resting tremor. It most of- ten develops in the 4th or 5th decade of life but is preceded by a variable preclinical period. Degeneration of the DA nigro-striatal neurons is the most prominent pathological feature and is associated with decreased striatal levels of DA. Although the etiology of PD is unclear, it appears that multiple factors may play a role, both genetic and/or environmental. Familial parkinsonism has been linked to various genes in some kindreds, while exposure to toxins or viruses is suspected in other forms. The cell bodies of the DA neurons that de- generate in PD are located in a small nucleus of the midbrain, the substantia nigra. They project preferentially to the dorso-lateral part of the striatum (caudate nucleus and putamen). The terminals of the nigral DA neurons are found throughout the striatum and are especially abundant in its more motor part, the putamen. DA is predominantly synthesized in the DA ter- minals first from tyrosine into L-dopa under the actions of tyrosine hydroxylase (TH) then into DA by dopa decarboxylase (DDC) (Figure 1). DA is stored in vesicles through transport by the vesicular monoamine trans- porter type 2 (VMAT2). Released into the synapse, DA interacts with postsynaptic DA re- ceptors (D1-and D2-like types) and D2 autoreceptors. DA is removed from the synap- 342 DORIS J. DOUDET JOURNAL OF PHARMACY PRACTICE, Volume 14, Number 4, August 2001 Figure 1. Simplified diagram of a typical dopaminergic synapse. For convenience, the DA D1 and D2 receptors are represented on the same postsynaptic neuron. DA: dopamine; TH: tyrosine hydroxylase; DDC: dopa decarboxyl- ase; MAO: monoamine oxidase; COMT: catechol-O-methyltransferase; DAT: membrane dopamine transporter; VMAT2: vesicular monoamine transporter; D1R: postsynaptic D1 dopamine receptor; D2R: postsynaptic D2 dopa- mine receptor; D2A: presynaptic D2 dopamine autoreceptor. tic cleft by two mechanisms: oxidation by monoamine oxidase B (MAO-B) and catechol- O-methyltransferase (COMT) in surrounding glia or reuptake by the membrane DA trans- porter for recycling or intraneuronal oxidation by MAO-A. Synthesis and release are regu- lated through autoreceptors and interactions with other neurotransmitters. PD AND IMAGING Metabolic Imaging Neuronal activity is the major contributor to glucose utilization, and cerebral blood flow (CBF) and glucose metabolism are tightly coupled under physiological conditions. Re- gionalbrainglucosemetabolismusingthe[18 F]- labeled glucose analogue 2-deoxyglucose (FDG) or CBF measurements with positron- emitting or single-photon-emitting tracers have provided functional imaging of brain ac- tivity used to determine specific patterns in PD (mainly a metabolic increase in pallidum) and atypical parkinsonian disorders (mainly wide- spread metabolic decreases in striatum),1,2 the physiological effect of restorative surgeries such as pallidotomy,3 or to assess regional functional changes induced by drugs that affect DA transmission. However, changes in metab- olism may result from direct changes in DA levels but may also reflect secondary adapta- tion (downstream from the DA nigro-striatal pathway) to varying levels of DA. The DA Presynaptic System The oldest (early 1980s) tracer of the DA system is [18 F] labeled L-dopa (6-[18 F]-fluoro- L-dopa; or FDOPA), an analog of the natural amino acid with similar kinetics and metabo- lism.4 Most clinical studies last 90120 min- utes and are analyzed by a multiple time graphical analysis (often called Patlak plot;5 for review see the paper by Logan6 ) using either a metabolite-corrected plasma or a nonspecific tissue (occipital or cerebellar) input function. This analysis yields an index of combined up- take, decarboxylation and storage, the uptake rate constant Ki. During scans of longer dura- tion (up to 4 hours), striatal activity declines, reflecting synaptic release of DA from the vesi- cles and conversion to non-trapped metabolites and their egress from the brain. This property can be used to estimate the effective rate of DA turnover from the brain.7 Alternatively, some groups use [11 C]-labeled L-Dopa with good re- sults. FDOPA has been validated against post- mortem nigral cell count: in vivo measures of striatal FDOPA uptake correlate with the num- ber of DA nigral neurons although the correla- tion is not perfect.8 One study has indeed shown that measurements of striatal FDOPA uptake vary with the PET method used but that, within the method used, FDOPA is both repro- ducible and sensitive to small changes in DA function.9 The main disadvantage of FDOPA is its ubiquitous conversion by COMT into 3-O- methyl-FDOPA both in the periphery and the brain, which complicates data analysis. In ad- dition, DDC activity (which FDOPA mainly re- flects) is subject to intrinsic regulation.10 Upregulation is one of the mechanisms sus- pected to be responsible for the delayed appear- ance of symptoms in PD. Our group has re- cently demonstrated in vivo DDC upregulation using FDOPA in PD.11 Therefore, FDOPA may not reflect exactly the number of DA terminals and the number of DA nigral neurons, despite the fact that there is a strong correlation be- tween them. There is a reduction of the striatal FDOPA uptake rate in patients with PD (Figure 2).5,12,13 Preliminary studies in our group suggest that this decreased uptake is accompanied by an in- crease in the effective DA turnover (unpub- lished results). Using 3D scanning to increase spatial resolution, focal changes in extrastriatal RADIONUCLIDE IMAGING IN PARKINSON'S DISEASE 343 FDOPA is reproducible and sensitive to small changes in DA function. JOURNAL OF PHARMACY PRACTICE, Volume 14, Number 4, August 2001 structures, mainly midbrain (nigral), pontine and cingulate regions have also been demon- strated in PD.14 Between 30% and 50% loss of FDOPA uptake in the putamen (80% loss of striatal DA) is estimated to be the threshold for onset of symptoms.15 In keeping with neurochemical postmortem findings,16 there is a rostro-caudal gradient of activity with the putamen affected more than the caudate.13 However, while this characteristic pattern may help differentiate idiopathic PD from parkin- son-plus or atypical parkinsonian syndromes, where the caudate and putamen are affected equally,13,17 one should exert caution in basing diagnosis on these findings as there is overlap in the actual range of caudate activity. FDOPA has been a useful tool in investigat- ing the genetics of PD. Piccini et al.,18 studying monozygotic (MZ) and dizygotic (DZ) twin pairs, in which one twin had a clinical diagnosis of PD and the other was asymptomatic, found that 55% of MZ but only 18% of DZ nonaffected twin had reduced FDOPA uptake in the putamen. Similarly, in seven kindreds with documented familial PD, 25% of asymp- tomatic adult relatives had decreased FDOPA uptake in the putamen (15% in general popu-lation).19 Thus, although these findings sup-port a role of inheritance/predisposition in PD, they do not exclude the role of exposure to environmental agent(s) in genetically suscep- tible subjects in the overall etiology of nigral degeneration. Longitudinal studies of disease progression on the striatal FDOPA uptake in PD conclude that the rate of nigral loss in PD is faster than in the normal population (0.4% to 3.5% of base- line in caudate and 2.9% to 8.9% of baseline in putamen depending on the method of analysis used),9,20 the rate of progression is more rapid in subjects with recent onset PD than in patients with longer disease duration9 and the mean rate 344 DORIS J. DOUDET Figure 2. Top: PET scan in a normal subject following administration of 6-[18F]fluoro-L-dopa (FDOPA) showing the characteristic pattern of striatal accumulation in the caudate nucleus and the putamen. Bottom: PET scans in an early, asymmetric Parkinson's disease patient following administration of three DA presynaptic tracers: FDOPA, [11C]d-threo-methylphenidate (MP) for the membrane DA transporter and [11C]dihydrotetrabenazine (DTBZ) for the vesicular monoamine transporter. Note the asymmetric uptake and the rostro-caudal gradient of activity. The arrow points to the lack of activity in the putamen, and especially the posterior putamen. JOURNAL OF PHARMACY PRACTICE, Volume 14, Number 4, August 2001 of progression in the putamen is faster than that in the caudate nucleus.9,21 The ability of FDOPA to reliably assess small changes in striatal DA, used to monitor the activity of human fetal nigral grafts, has demonstrated an increase in DA activity in the transplanted putamen (Figure 3).22 Similarly, there is an increasing interest in using PET and FDOPA to monitor more objectively the effects of putative neuroprotective therapies. Disap- pointingly, FDOPA has not provided clear an- swers on the etiology of motor complications in PD as considerable overlap exists between groups of patients with motor complications compared to those without (for review, see the paper by Brooks23 ). Other tracers have been developed to study presynaptic DDC activity, notably 6-[18 F]- fluoro-m-tyrosine (FMT). FMT data can be an- alyzed using the same methods, as FDOPA data and FMT uptake rate constant correlate well with those for FDOPA.24 The lack of nonspe- cific background in FMT studies makes it eas- ier to image extrastriatal structures such as the midbrain.25 Thus, for short clinical stud- ies, FMT may be an attractive alternative to FDOPA. Another site that has received a lot of atten- tion in recent years as a potential target to im- age presynaptic DA function is the membrane DA transporter (DAT). The DAT is the primary means of regulating the levels of synaptic DA. It is also the site of action of cocaine and plays a role in the action of multiple neurotoxins. The DAT has been labeled with a variety of positron and -emitters for PET and SPECT includ- ing many tropane derivatives, among them the well-known WIN 35,428 (CFT) and RTI-55 ( - CIT). The main disadvantage of these compounds is their generally slow kinetics. An attractive alternative is [11 C]-d-threo- methylphenidate (MP) developed by the Brookhaven group, a tracer with much more rapid kinetics than most of the tropane analogs and with excellent selectivity for the DAT. The analysis of most DAT data is often limited RADIONUCLIDE IMAGING IN PARKINSON'S DISEASE 345 Figure 3. PET scans with 6-[18F]fluoro-L-dopa (FDOPA) before and 6 months, 1 and 3 years following bilateral fetal nigral transplant in the putamen. Note that the activity remains constant in the ungrafted caudate nucleus while there is sustained increase in putaminal uptake (arrows). JOURNAL OF PHARMACY PRACTICE, Volume 14, Number 4, August 2001 to a specific (striatum-cerebellum)/nonspecific (cerebellum) ratio, but a tracer with fast kinet- ics such as MP allows the use of multiple time graphical analysis for reversible tracers.6 In addition, the reproducibility of most tropane DAT tracers is not as good (1216%) as that of FDOPA. However, the sensitivity of DAT ligands to small reductions in striatal DA compensates for this reduced reproducibility. Decreases have been reported in aging.26 Both PET- and SPECT- labeled DAT tracers easily discrimi- nate early parkinsonian patients from normals (Figure 2).27,28 In longitudinal studies of dis- ease progression, an annual decline in DAT function was found in normal controls using [18 F]-CFT (2% to 3% for both caudate and putamen),29 while annual declines of 12% to 13% from baseline were reported in parkinsonian patients using both [18 F]-CFT and [123 I]- -CIT.29,30 As was found with FDOPA, patients with early PD progressed faster than patients with later stage disease. As with FDOPA, binding to the DAT also re- flects a regulated process. DAT activity can be influenced by a variety of factors, either intrin- sic (compensatory adaptation to the degenera- tive process) or external, including exposure to dopaminomimetics,31 drugs increasingly used to treat parkinsonism. A recent study by Lee et al.11 has shown in vivo downregulation in early parkinsonism. Thus, DAT tracers may re- flect compensatory mechanisms as much as disease progression itself. In contrast, the vesicular monoamine trans- porter system type 2 (VMAT2) is not known to be subject to regulation32 and thus, may be the most reliable marker of striatal DA nerve termi- nal density. Although the VMAT2 is not spe- cific for DA neurotransmission, as it is expressed by other monoaminergic neurons, the majority of VMAT2 binding in the striatum comes from DA neurons. [11 C] Dihydrotetrabenazine (DTBZ) appears to be the best VMAT2 marker with higher signal-to- noise ratio and low metabolism. Unfortunately, because no brain tissue is truly devoid of monoaminergic innervation, there is no true nonspecific binding region, and many of the simpler methods of analysis not requir- ing an arterial input function may be subject to biases. Frey et al.33 demonstrated a 61% reduction in DTBZ binding in PD patients. In addition, our group has also shown an anterior-posterior loss in DTBZ binding in PD patients with the caudate less affected than the putamen (Fig- ure 2).11 As evident from above, each of these ap- proaches provides somewhat similar informa- tion. Although to date, only striatal FDOPA up- take has been shown to correlate with the number of surviving nigral DA neurons and the striatal concentrations of DA,8 the other DA presynaptic tracers should be expected to cor- relate roughly with the number of DA termi- nals. Differences, however, can be expected, as each tracer labels different process(es) some of which (DDC or DAT activities) are known to be regulated and may reflect not only the number of terminals but also the state of regulation. Our group recently initiated a five year longitudinal study with FDOPA, MP and DTBZ, to compare these tracers and their respective abilities to im- age DA terminals and to determine whether disease progression and therapeutic regimens affect them differently. Preliminary studies demonstrated subtle differences in sensitivity, although the general pattern of activity was similar throughout the striatum for all three tracers.11 Thus, the ligand should be carefully chosen for each specific study. For instance, a DAT tracer may be the best choice for studies in very early patients or "at-risk" patients (asymp- tomatic relatives in families with PD, for exam- ple), while a VMAT2 tracer may be preferable if one suspects a possible effect of treatment intervention. 346 DORIS J. DOUDET Each tracer labels different process(es). JOURNAL OF PHARMACY PRACTICE, Volume 14, Number 4, August 2001 The DA Postsynaptic System Several tracers, most of them antagonists, of DA, D1 and D2 receptors have been developed for PET and SPECT. Increased D2 binding is consistently reported in early PD,34 gradually returning to normal after a few years. In gen- eral, studies of D1 and D2 receptor binding have been disappointing, failing to demon- strate a relationship between receptor binding and disease progression (Figure 4) and any ba- sis for the complications of therapy in PD.23 In contrast, such atypical parkinsonian syn- dromes as PSP and MSA are mostly associated with striatal loss of D2 receptors,35 while an- other atypical syndrome, PPND, shows normal to elevated D2 binding,36 and yet another rigid- akinetic syndrome, manganism, is associated with normal FDOPA uptake and D2 receptor binding.37 Nevertheless, alterations in the binding of [11 C]-raclopride for PET and [123 I]- iodobenzamide for SPECT following adminis- tration of drugs that alter DA function, can be used to indirectly measure synaptic DA con- centrations in vivo. These two tracers, while highly specific for D2 receptors, have a com- paratively low affinity and compete with en- dogenous DA for the receptor site.38 For in- stance, a decrease in raclopride binding potential is interpreted as being the result of competition with increased DA endogenous DA release. In PD, acute administration of a high dose of intravenous L-dopa reduces raclopride binding in the putamen of advanced patients but not of early patients.39 When investigating changes in raclopride binding fol- lowing therapeutic doses of oral L-dopa, our group demonstrated differences in DA turnover between patients with a stable response to medication and those with age-related fluc- tuations.40 Changes in raclopride binding have also been used to establish the ability of embryonic grafts to restore basal and drug- induced DA release in the transplanted putamen.41 RADIONUCLIDE IMAGING IN PARKINSON'S DISEASE 347 Figure 4. PET scans with [11C]raclopride and [11C]SCH23390 in patients with early Parkinson's disease. Note the increased activity in the putamen (arrow) in the raclopride scan. JOURNAL OF PHARMACY PRACTICE, Volume 14, Number 4, August 2001 Other Neurotransmitter Systems The opiate system has begun to receive more attention due to its hypothesized involvement in the motor complications of PD.42 Postmor- tem studies in PD patients and studies in animal models of PD have revealed deranged opioid transmission. A significant decrease in [18 F]- cyclofoxy (an antagonist of and receptors) binding in many subcortical structures includ- ing striatum, thalamus and amygdala without changes in cortical binding was reported in levodopa-naive MPTP-lesioned monkeys.43 Using [11 C]-diprenorphine, a tracer of , and sites, significant reductions were found in striatum and thalamus in dyskinetic patients compared with patients without dyskinesias.44 Thus, it is of interest to further investigate the exact role of the opiate system not only in PD and in the motor complications associated with it but also in the normal physiology of the out- put pathways of the basal ganglia. In keeping with postmortem findings, [11 C] PK11195, a compound that binds to activated microglia, revealed increased binding through- out the basal ganglia in PD,45 suggesting the presence of an ongoing inflammatory process. 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It also provides insights on the role these two modalities provide in terms of discriminating atypical syndromes from Parkinson’s disease. Both PET and SPECT are sensitive means of detecting alterations in metabolism and blood flow in the brain and impairments in neurotransmitter function, especially dopaminergic, in the striatum and, more recently, in extrastriatal structures. To date, PET presents the added advantage of quantification, better sensitivity and resolution and a greater variety of tracers for both the dopaminergic and nondopaminergic systems.</abstract><subject><genre>keywords</genre><topic>Parkinson’s disease</topic><topic>PET</topic><topic>SPECT</topic><topic>dopamine system</topic><topic>disease progression</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Pharmacy Practice</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0897-1900</identifier><identifier type="eISSN">1531-1937</identifier><identifier type="PublisherID">JPP</identifier><identifier type="PublisherID-hwp">spjpp</identifier><part><date>2001</date><detail type="volume"><caption>vol.</caption><number>14</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>341</start><end>350</end></extent></part></relatedItem><identifier type="istex">AC45DABDF59E87F02CF8A847BC9B4BE7A0211051</identifier><identifier type="DOI">10.1106/76VR-VNP7-T1EW-6HGY</identifier><identifier type="ArticleID">10.1106_76VR-VNP7-T1EW-6HGY</identifier><recordInfo><recordContentSource>SAGE</recordContentSource></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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