Morphological and functional imaging studies on the diagnosis and progression of Parkinson s disease

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1 J Neurol (2000) 247 [Suppl 2] : II/11 II/ Steinkopff Verlag 2000 David J. Brooks Morphological and functional imaging studies on the diagnosis and progression of Parkinson s disease D. J. Brooks ( ) MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, UK david.brooks@csc.mrc.ac.uk Tel.: Fax: Abstract This paper reviews the relative abilities of magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission tomography (SPECT), and proton magnetic resonance spectroscopy (MRS) to detect Parkinson s disease and monitor its progression. Currently, the main role of MRI lies in its ability to discriminate atypical syndromes from Parkinson s disease; however, new volumetric approaches may soon allow progression of nigral degeneration to be followed. Proton MRS can also detect reduced levels of putamen N-acetyl aspartate (NAA) in many patients with atypical parkinsonian syndromes. PET and SPECT are both sensitive means of detecting the presence of impaired dopamine terminal function in the striatum and following its progression. PET currently has the greater spatial resolution and provides the added advantages that it also allows extra-striatal dopaminergic function to be monitored. Key Words Diagnosis MRI MRS Parkinson s disease SPECT PET Magnetic resonance imaging Conventional MRI of patients with idiopathic Parkinson s disease (PD) are generally normal, although occasionally patients show increased signal from the substantia nigra, which probably represents gliosis, on T 2 -weighted sequences [13, 50]. It is now possible, however, to detect the presence of nigral atrophy and gliosis more sensitively using novel inversion recovery white and grey matter signal-suppressing sequences along with volumetry [46]. This new approach can detect the characteristic lateral nigral targeting of dopamine cells in PD and will conceivably allow progression of the disorder to be monitored in the future. Patients with typical PD have normal putamen signal on proton density or T 2 -weighted magnetic resonance imaging (MPI), whereas patients with striatonigral degeneration (SND) or multiple system atrophy (MSA) have been reported to show reduced posterolateral putamen signal, thought to represent excess iron deposition [12, 43, 50, 52]. This low signal may be accompanied by a slit-like hyperintensity tracking around the lateral edge of the putamen which matches the pattern of gliosis observed at autopsy (Fig. 1a) [25, 52, 67]. If patients have the full spectrum of MSA with rigidity and ataxia, they may also show increased pontine tegmentum signal due to degeneration of pontine nuclei and transverse fibres leading to a hot cross bun appearance (Fig. 1b) [19, 67]. Evidence of brainstem and/or cerebellar atrophy may also be present, along with increased signal from the middle cerebellar peduncles on T 2 -weighted images [50, 52, 67]. While these MRI features are of diagnostic value, they are often absent in patients with early disease. An initial report suggested that, like MSA, progressive supranuclear palsy (PSP) is associated with low putamen signal on T 2 -weighted MR sequences [12]. Such a finding, however, would contradict the known distribution of pathology, which tends to spare the putamen, and other MRI series have not reproduced this observation [50, 52, 67]. In contrast to MSA, the majority of cases of clinically probable PSP show midbrain atrophy and third ventricular dilatation while the cerebellum is spared [19, 52, 67]. Additional MRI features of established PSP revealed on T 2 -

2 II/12 Fig. 1 T 2 -weighted MRIs of patients with multiple system atrophy (a) increased lateral and decreased posterior putamen signal (b) hot cross bun appearance of the pons a b weighted sequences include diffuse high signal from the midbrain and pontine tegmentum and midbrain tectum [67], increased inferior olivary signal [67], and low superior colliculus signal [52]. Functional imaging Functional imaging (positron emission tomography [PET], single photon emission tomography [SPECT], proton magnetic resonance spectroscopy [proton MRS]) provides a means of assessing the function of dopamine terminals and striatal neurons in vivo and of demonstrating characteristic patterns of dysfunction. Measures of dopamine terminal integrity with PET have also allowed preclinical disease to be detected in relatives at risk of developing parkinsonian disorders. Dopamine terminal function F-6-fluorodopa PET was the first functional imaging approach to be developed for assessing in vivo dopamine terminal function in PD. Following its intravenous administration, F-dopa is taken up by the terminals of the nigro-striatal dopaminergic projections and decarboxylated to F-dopamine and its metabolites F-DOPAC and F-HVA [16]. In early hemiparkinsonian cases, with the older generation cameras used in two-dimensional mode, PET showed normal caudate F-dopa uptake, but putamen uptake was bilaterally reduced, most severely contralateral to the affected limbs [5, 27, 28, 34, 39]. This characteristic pattern of loss of striatal dopaminergic function allows F-dopa PET to discriminate 100% of patients diagnosed as having PD from healthy subjects using clinical criteria [54]. PD patients show, on average, a 50% loss of specific putamen F-dopa uptake [5] compared with the 60 80% loss of ventrolateral nigra compacta cells reported at post-mortem [15, 49]. As putamen dopamine levels are reduced by over 90% in end-stage PD [2, 24], striatal uptake of F-dopa is more a reflection of the terminal density of nigro-striatal projections than of endogenous tyrosine hydroxylase activity. In support of this view, striatal F-dopa uptake obtained pre-mortem has been found to correlate with subsequent nigral cell counts obtained at autopsy [63]. Patients with early hemi-pd show at least a 30% loss of F-dopa uptake in the putamen contralateral to their affected limbs [37], suggesting that a loss of 30% of nigral dopaminergic cells may be the threshold for the onset of symptoms. This hypothesis is supported by the findings of a cross-sectional postmortem study where nigral cell counts were correlated with clinical disease duration and a 30% threshold was also estimated [15]. Conventionally, PET has been designed to detect brain tracer activity within given transaxial slices (two-dimensional mode). A far more sensitive approach is to register all activity in the brain volume simultaneously (three-dimensional mode), and recent software advances now enable this approach to be adopted. The result is a six-fold increase in the signal-to-noise ratio allowing regions with low tracer uptake to be sampled more sensitively at an increased spatial resolution. Additionally, the crude images of F-dopa uptake can now be converted to parametric maps of tracer influx constants (K i ) on a voxel by voxel basis, which reflect regional dopa decarboxylase activity. This in turn allows statistical parametric mapping (SPM) to be applied to these parametric images so that areas of significantly reduced F-dopa uptake can be localised at a voxel level without the need to define regions of interest (ROI) beforehand. With this three-dimensional SPM approach, F-dopa PET can now demonstrate that F-dopa uptake in the asymptomatic putamen is reduced in all pa-

3 II/13 early cases of PD from normal [, 21, 58 60]. There is, however, still overlap between ipsilateral putamen I-β-CIT uptake and the normal range in patients with early unilateral PD [33], in contrast to F-dopa uptake when measured with PET in three-dimensional mode [48]. Putamen uptake of F-dopa, 11 C-nomifensine, I-β- CIT and I-FP-CIT in PD all show an inverse correlation with degree of locomotor disability [5, 7, 29, 30, 51, 59]. Only one study has formally compared the ability of PET and SPECT to discriminate PD from normal. In this study, F-dopa PET used in 2-dimensional mode and I-FP-CIT SPECT gave equivalent findings [22]. Fig. 2 Levels of putamen F-dopa uptake with three-dimensional PET in seven early cases of clinically unilateral Parkinson s disease. It can be seen that all asymptomatic putamen levels are reduced below the normal range tients with early hemi-pd, rather than in just 50% of cases as was thought previously (Fig. 2). Additionally, it is now possible to demonstrate significant reductions in striatal, nigral, and anterior cingulate levels of dopamine storage as the disease progresses [47, 48] (Fig. 3). 11 C-nomifensine and the tropane-based PET and SPECT tracers 11 C-CFT, F-CFT, 11 C-RTI-32, I-β-CIT, I-FP-CIT, and I-IPT all bind to dopamine uptake sites on nigro-striatal terminals and also provide a marker of integrity of nigro-striatal projections [, 21, 58 60, 64, 65]. I-β-CIT gives the highest striatal:cerebellar uptake ratio of all these tracers but has the disadvantage that it takes 20 h to equilibrate throughout the brain after injection, which means that SPECT has to be performed the following day. Paradoxically, the very low reference signal also increases variance in estimates of specific uptake. For this reason, SPECT tracers such as I-FP-CIT and I-IPT have become popular as, despite their lower striatal : cerebellar uptake ratios, a diagnostic scan can be performed within 1 3 h of tracer injection, although the uptake ratios obtained are time dependent. The PET tracer 11 C-dihydrotetrabenazine (DHTBZ) provides a marker of vesicle monoamine transporter function [23]. Like F-dopa PET, 11 C-CFT, F-CFT, 11 C-RTI-32, and 11 C-DHTBZ PET, I-β-CIT, I-FP-CIT, and I- IPT SPECT all appear to be capable of discriminating Detection of preclinical Parkinson s disease We have studied seven kindreds with documented familial PD and reported that 8 of 32 (25%) asymptomatic adult relatives had levels of putamen F-dopa uptake that were reduced more than 2.5 standard deviations below the normal mean [45]. This prevalence of dopaminergic dysfunction in asymptomatic relatives of familial PD cases is higher than the 15% prevalence of patients who give a positive family history. In another study involving monozygotic (MZ) twin pairs and 16 dizygotic (DZ) twin pairs (mean age 50 years), in which one twin had a clinical diagnosis of PD and the other was asymptomatic, putamen F-dopa uptake was reduced in 55% of MZ, and % of DZ cotwins [44]. Figure 4 shows reduced levels of putamen F-dopa uptake in an asymptomatic monozygotic PD cotwin at baseline. Five years later, the co-twin became symptomatic and showed a further decline in dopamine storage capacity. The significantly raised concordance (P = 0.03) for dopaminergic dysfunction in MZ co-twins of PD patients, and the 25% prevalence of dopaminergic dysfunction in adult relatives of familial cases, support a role of inheritance in PD. These findings do not, however, exclude nigral dysfunction arising as a consequence of exposure to an environmental agent in genetically susceptible individuals. Diagnosis of atypical parkinsonism As in PD, putamen F-dopa uptake is reduced to 50% of normal in cases of probable SND and individual uptake levels correlate with the degree of disability [5, 6]. Pa- Fig. 3 Statistical parametric mapping images of areas where F-dopa uptake is significantly reduced in advanced compared with early PD superimposed on an MRI template. (Picture courtesy of James Rakshi)

4 II/14 Fig. 4 PET images of striatal F-dopa uptake in a normal subject and an asymptomatic MZ co-twin of an affected PD patient. The co-twin shows reduced putamen F-dopa uptake at base line and more severely 5 years later when symptomatic. (Picture courtesy of Paola Piccini) tients with MSA (rigidity, ataxia, and autonomic failure) show significantly lower mean caudate F-dopa uptake compared with equivalently disabled PD patients. The PD and SND caudate ranges overlap, so relative levels of reduced caudate F-dopa uptake only discriminate SND and PD with 70% specificity [5, 8, 41]. Striatal dopamine D 1 and D 2 receptor binding has been studied using PET in parkinsonian patients thought to have SND due to their lack of a levodopa response [4, 61, 62]. However, since the SND, PD, and normal ranges overlapped, this has not proved to be a sensitive discriminator. In an I-IBZM SPECT series it was noted that only two-thirds of de novo PD patients later found to be poorly responsive to apomorphine showed reduced levels of striatal D 2 binding [55]. Additionally, 20% of early PD cases with normal striatal D 2 binding showed a poor apomorphine response; therefore the presence of normal striatal I-IBZM uptake does not reliably exclude an atypical syndrome. Among patients with clinically probable SND, 80% show reduced resting levels of striatal glucose metabolism, unlike PD patients where resting striatal metabolism is normal or elevated [11, 14, 41]. Frontal glucose metabolism may also be impaired in SND, and cerebellar metabolism is reduced in MSA with ataxia. Proton MRS also provides a potential means of discriminating SND from PD. N-acetylaspartate (NAA) is found in high concentrations in neurones and is believed to be a metabolic marker of neuronal integrity. Reduced NAA : creatinine ratios in the proton MRS signal from the lentiform nucleus were found in six out of seven cases of clinically probable SND, while eight out of nine clinically probable PD cases had normal levels of putamen NAA [10]. Unlike PD, putamen and caudate F-dopa uptake are uniformly reduced in PSP, and 90% of patients can be classified as being atypical on the basis of their severe caudate involvement alone [5, 8]. Similar findings have been reported with I-β-CIT SPECT [35]. Mean caudate and putamen D 2 binding is also significantly reduced in PSP (1, 4, 56), but there is an overlap with the normal range. PET studies in patients with probable PSP have revealed depressed basal ganglia metabolism [3, 17, 20, 26, 42]. Proton MRS studies have also found reduced lentiform nucleus NAA : creatinine ratios in seven out of nine patients with PSP [9]. Cortical metabolism is globally depressed in PSP but posterior frontal areas are particularly targeted [3]. Although these techniques can sensitively distinguish PSP from PD, they are unable to discriminate between PSP and SND.

5 II/15 Objective measurement of PD progression Two problems confound the use of clinical rating scales for measuring Parkinson s disease progression. Firstly, subjective rating scores and objective task performance times are both influenced by medication, and uncertainty remains about the washout time required to obtain a true off state following cessation of treatment. Secondly, different aspects of the disease can progress at varying rates, and any clinical rating must take this heterogeneity into account. F-dopa PET provides a means of monitoring loss of dopaminergic function in PD objectively and is free from the confounding effects of symptomatic therapy. The decline of whole striatal F-dopa uptake in PD is more rapid than in controls [66] and an average annual decline in baseline putamen F-dopa K i value of 9 12% has been reported [36, 38, 40]. Individual rises in clinical severity rated with the Unified Parkinson s Disease Rating Scale (UPDRS) in the Morrish series did not correlate well with individual reductions in putamen F-dopa uptake, but this was not surprising since the UPDRS does not only reflect dopaminergic dysfunction. Patients were scored after ceasing medication for 12 hours and the washout achieved in practice may have varied considerably from patient to patient. The poor correlation between changes in F-dopa PET and UPDRS suggests that both measures should be used as independent markers of PD progression. Assuming a linear relationship between decline in putamen F-dopa uptake and disease duration, the preclinical window for PD was estimated to be 6 ± 3 years with clinical symptoms arising after a 30% loss of terminal dopaminergic function [36]. In fact, loss of putamen F-dopa storage appears to progress non-linearly since the earliest PD cases (clinical duration < 2 years) had an annual rate of putamen K i loss four times faster than those with more established disease. This suggests that the mean preclinical disease window may be shorter than 6 years. These findings are in agreement with the reported exponential relationship between nigral cell counts and pre-mortem clinical disease duration, which suggested a mean preclinical disease period of 4.6 years [15]. I-β-CIT, I-FP-CIT, and I-IPT SPECT have been used to monitor the rate of loss of striatal dopamine transporters in PD. Marek and colleagues [32] reported a mean 12% annual loss of striatal I-β-CIT uptake in 24 early PD patients followed for an average of 15 months. Assuming a linear relationship between loss of striatal I-β-CIT uptake and disease duration, it was estimated that PD had a mean preclinical window of 4 years. These findings are in good agreement with Morrish and coworkers F-dopa PET findings [36]. In a follow-up study, this group has noted that rate of disease progression correlated with initial levels of striatal I-β-CIT binding [31]. Those PD patients with symptoms for less than 2 years progressed four times faster than those with more established disease a similar finding to the Morrish series. In contrast, Schwarz and co-workers [57] reported only a 3% mean annual decline in striatal I-IPT binding in 11 PD cases followed over 12 months. The Schwarz series, however, contained both early and late cases and this may have biased their cohort towards a slower rate of loss of dopaminergic function. Conclusions Clinical assessment, although highly sensitive, cannot detect preclinical disease or reliably discriminate PD from atypical variants. Measurement of dopamine terminal function with PET and SPECT provides a sensitive marker of the presence of active PD and enables any preclinical dopaminergic dysfunction to be detected in at-risk relatives of patients with familial disease and asymptomatic co-twins. Concomitant measurement of striatal function with PET, SPECT, and proton MRS can help discriminate atypical parkinsonian syndromes from PD with up to 80% specificity. F-dopa PET and I-β-CIT SPECT have both been successfully used to monitor the rate of loss of dopamine terminal function in PD objectively. In the future, as genetic markers for PD and its atypical variants become available, functional imaging is likely to play an increasingly important role in establishing the presence of disease activity in gene carriers and in determining the efficacy of putative neuroprotective and restorative agents in the treatment of these disorders. References 1. 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