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Neuroimaging and Therapeutics in Movement Disorders

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Neuroimaging and Therapeutics in Movement Disorders View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref NeuroRx௡: The Journal of the American Society for Experimental NeuroTherapeutics Neuroimaging and Therapeutics in Movement Disorders Thomas Eckert*† and David Eidelberg†‡ *Department of Neurology II and Psychiatry, University of Magdeburg, Germany; †Center for Neurosciences, Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030; and ‡Department of Neurology, New York University School of Medicine, New York, New York 10016 Summary: In this review, we discuss the role of neuroimaging imaging strategies have provided novel insights into the mech- in assessing treatment options for movement disorders, partic- anisms underlying a variety of pharmacological and stereotaxic ularly Parkinson’s disease (PD). Imaging methods to assess surgical treatment strategies for PD and other movement dis- dopaminergic function have recently been applied in trials of orders. Key Words: Movement disorders, Parkinson’s disease, potential neuroprotective agents. Other imaging methods using Huntington’s disease, Tourette’s syndrome, dystonia, positron regional metabolism and/or cerebral perfusion have been re- emission tomography (PET), magnetic resonance imaging cently introduced to quantify the modulation of network activ- (MRI). ity as an objective marker of the treatment response. Both INTRODUCTION brain function can be assessed with generalized tracers for regional cerebral metabolism and blood flow.3,4 Movement disorders are a group of syndromes char- Brain imaging in movement disorders was originally acterized by an impairment of the regulation of voluntary introduced to visualize the pathological changes associ- motor activity without deficits of force, cerebellar func- ated with different clinical syndromes.5 Subsequently, tion, or sensation. This class of neurological diseases these techniques have been used in longitudinal studies includes hypokinetic disorders associated with a slowing designed to assess disease progression6,7 and the effects of movements such as Parkinson’s disease (PD), as well of potential neuroprotective strategies.8–10 Lately, func- as hyperkinetic disorders characterized by involuntary tional imaging has also been applied in the objective abnormal movements such as Huntington’s disease assessment of symptomatic treatment responses.11–14 In (HD), torsion dystonia, and tic disorders. Generally, the addition to providing an objective descriptor of the treat- clinical manifestations of movement disorders result ment response, brain imaging can also link clinical out- from dysfunction of the basal ganglia. Although his- come to alterations in regional brain function.15 topathologic studies reveal specific neurodegenerative In this review, we describe functional neuroimaging changes in some of these diseases (e.g., PD and HD), the strategies to evaluate and monitor therapeutic interven- pathologic basis for many movement disorders remains tions for movement disorders. Because PD is the most unknown. Various neuroimaging techniques have been common and broadly studied of these disorders, this used to visualize pathological changes in these disorders. review will focus on the use of imaging to assess treat- Radiotracer imaging techniques using positron emission ment options for this condition. tomography (PET) and single-photon emission com- puted tomography (SPECT) imaging can be used to eval- uate and quantify changes in specific neurochemical sys- DOPAMINERGIC IMAGING IN PARKINSON؅S tems.1,2 Alternatively, disease-related changes in local DISEASE: NEUROPROTECTION TRIALS PET and SPECT assessments of nigrostriatal dopaminer- gic function have been a traditional focus of imaging studies Address correspondence and reprint requests to Dr. David Eidelberg, in parkinsonism and other movement disorders. Presynaptic Center for Neurosciences, Institute for Medical Research, North Shore- Long Island Jewish Health System, 350 Community Drive, Manhasset, dopaminergic imaging can be conducted using the follow- NY 11030. E-mail: [email protected]. ing approaches: 1. [18F]-fluorodopa (FDOPA) PET to eval- Vol. 2, 361–371, April 2005 © The American Society for Experimental NeuroTherapeutics, Inc. 361 362 ECKERT AND EIDELBERG uate the uptake and conversion from fluorodopa to fluoro- decline in putamen DAT binding as measured by ␤-CIT dopamine by the aromatic acid decarboxylase (AADC); 2. SPECT.9 [11C]-dihydrotetrabenazine (DTBZ) PET to assess the den- These trials reveal discrepancies between the clinical sity of monoamine-containing synaptic vesicles; and 3. a assessment and radiotracer-based imaging of the presyn- variety of radiolabeled cocaine derivatives [e.g., [123I]-2␤- aptic dopaminergic system, and raise the question of carbomethyl-3␤-(4-iodophenyl) tropane (␤-CIT)] to quan- comparability of these measures as neuroprotection out- tify the expression of the dopamine transporter (DAT), come variables. Even though most imaging descriptors which facilitates the release and reabsorption of dopamine of nigrostriatal dopaminergic function correlate with in- in the nigrostriatal intersynaptic cleft. The relative merits of dependent disease severity measures (see Ravina et al.2 these agents have been summarized elsewhere.1,2 for review), these techniques do not directly assess the Radiotracer imaging of the presynaptic nigrostriatal number or density of nigral dopaminergic neurons. dopaminergic system has been used to assess the rate of Moreover, these radiotracer-based imaging methods re- disease progression deterioration in PD. FDOPA PET quire simplifying assumptions for the acquisition and and ␤-CIT SPECT show a 4% to 13% yearly reduction in analysis of data. Thus, the results of these imaging stud- baseline putamen uptake compared with 0–2.5% in ies may be affected by factors other than the primary healthy controls in longitudinal studies.6,7 This technique biological process under study. has also been used to estimate the duration of the pre- A critical issue in this regard is the occurrence of clinical period of PD using a linear regression analysis.16 possible temporal up- and downregulation of neuropep- Striatal FDOPA measurements correlate with dopamine tides and receptors that can affect the results of imaging cell counts measured in postmortem specimens17,18 and studies. A study comparing FDOPA, DTBZ, and a DAT striatal DAT binding decreases with age in healthy vol- ligand, in the same PD subjects revealed a relative up- unteers and PD patients.19–21 regulation of AADC and downregulation of DAT.23 This The precise determination of neuroprotective treat- suggests that surviving neurons may synthesize more ment effects represents a major challenge in current dopamine but perhaps also take up less from the synaptic movement disorders therapeutics. Although well estab- cleft. Dopaminergic treatment can change the amount of lished in clinical trials for PD, clinical rating scales like the available dopamine at the synaptic level, which may Unified Parkinson’s Disease Rating Scale (UPDRS) 22 may differentially influence the regulation of AADC and not be sufficiently sensitive to detect subtle changes in rates DAT. Although a number of studies have not revealed an of progression, as are likely to be encountered in neuropro- effect of dopaminergic treatment on presynaptic dopa- tective trials. Moreover, clinical ratings reflect long-term minergic imaging measures,8,24,25 other evidence sug- symptomatic effects, which are apt to persist following gests that dopaminergic treatment can affect these pa- protracted medication washout.9 rameters in PD patients.26,27 Specifically, Guttman et Imaging assessment of presynaptic nigrostriatal func- al.27 reported a decline in DAT binding after treatment tion has been used for evaluation of disease progression with levodopa, which was not significant after in PD patients (see above) and may therefore provide a pramipexole treatment. Similar treatment effects in the useful adjunct to clinical assessment in assessing disease CALM-PD study could have contributed to the differ- progression in pharmacologic therapeutic trials of poten- ences in imaging measures that were observed with the tial neuroprotective agents.2 Two large randomized, pramipexole and levodopa treatment groups. Further in- blinded studies have employed imaging to investigate vestigations with larger numbers of patients will be re- disease progression in patients receiving dopamine ago- quired to characterize time-dependent changes in the reg- nists relative to those treated with levodopa. In both ulation of neuropeptides or receptors that might occur studies, imaging based descriptors of neuroprotection di- with treatment. Indeed, the optimal duration of medica- verged from the clinical outcome measures. The tion washout before imaging will need to be determined CALM-PD study investigated early treatment with levo- before further studies of this sort can be pursued effec- dopa versus pramipexole.10 It was found that PD patients tively. receiving levodopa did better clinically, although they Lastly, the evaluation of disease progression in PD experienced more motor complications. The REAL-PET with radiotracer imaging has relied upon the notion that study disclosed similar results in a comparison of levo- pathology is limited to the nigrostriatal neurons. This dopa with ropinirole. By contrast, presynaptic dopami- assumption may be overly restrictive given that other nergic imaging with ␤-CIT SPECT
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