P. K. Morrish

Measuring the rate of progression and estimating the preclinical period of Parkinson’s disease with [18F] dopa PET

OBJECTIVES To measure the rate of progression in striatal [18F]dopa metabolism in a large group (n=32) of patients with Parkinson’s disease, to estimate the average duration of preclinical period, and to examine the influence of the PET method on the assessment of rate of progression and preclinical period. METHODS Thirty two patients with Parkinson’s disease (mean age 58 (SD 13) years, mean duration 39 (SD 33) months) were assessed with [18F]dopa PET and UPDRS scoring on two occasions a mean of 18 (SD 6) months apart. PET data were sampled with separate caudate and putamen and total striatal regions of interest, and both graphical (Ki) and ratio methods of analysis. RESULTS The mean annual rate of deterioration in [18F]dopa uptake varied according to structure and method of analysis, with putamen Ki showing the most rapid mean rate of progression (4.7% of normal mean per year). The group showed a significant deterioration (p<0.0004, paired two tailed ttest) in UPDRS and in the putamen (p=0.008) and total striatal (p=0.012) [18F]dopa uptake measured using a graphical analysis, but no significant change in caudate or putamen uptake measured by a ratio approach. A study of sensitivity confirmed that putamen Ki was the most sensitive measure of disease progression, caudate ratio the least. Symptom onset in Parkinson’s disease was estimated at a mean putamen [18F]dopa uptake (Ki) of 75% of normal and a mean caudate [18F]dopa uptake (Ki) of 91% of normal. CONCLUSIONS Estimation of mean rate of progression varies according to the sensitivity of a functional imaging method to clinical severity. Sensitivity and reproducibility of method must be considered when designing studies of disease progression and neuroprotection. The mean preclinical period in Parkinson’s disease is unlikely to be longer than seven years.

Clinical and [18F] dopa PET findings in early Parkinson's disease.

Twenty seven patients with recent onset (mean symptom duration 22 (SD 14) months, Hoehn and Yahr score 1.8 (SD 0.7)) Parkinsons disease were studied with [18F]dopa PET. There was a correlation between putamen influx (Ki) and clinical rating, but not symptom duration. In 11 patients with hemi-Parkinsons disease of recent onset there were significant differences between normal (mean 0.0123 (SD 0.0023)), asymptomatic (mean 0.0099 (0.0020)) and symptomatic (mean 0.0070 (00.014)) putamen Kis. This suggests that Parkinsons disease has a widely variable rate of progression, and is most compatible with a short preclinical period. Symptom onset was estimated at a putamen Ki of between 57% and 80% of normal. Most ipsilateral putamen Ki values in early asymmetric Parkinsons disease fell within the normal range. The implication is that either the disease is not established in the ipsilateral putamen or that the technique is insufficiently sensitive to detect it. Discriminant analysis completely separated the normal and Parkinsons disease cohorts, but when a discriminant function from a previous study was used predictively four of the 27 patients with Parkinsons disease were incorrectly classified as normal.

The effect of entacapone (OR‐611) on brain [18F]‐6‐L‐fluorodopa metabolism Implications for levodopa therapy of Parkinson's disease

We used PET and [18F]-6-L-fluorodopa ([18F]dopa) to measure the effect of a peripheral COMT inhibitor, entacapone, on the extracerebral metabolism and subsequent striatal uptake of [18F]dopa. Four parkinsonian patients and six age-matched normal controls were each scanned twice, once after carbidopa (150 mg) plus placebo and once after carbidopa (150 mg) plus entacapone (400 mg or 800 mg). Without entacapone premedication, by 90 minutes from injection, only 22% of the [18F] signal in plasma represented unmetabolized [18F]dopa (the balance being 3-0-methyl[18F]dopa). After entacapone medication, this fraction increased to 56% of the [18F] signal (p < 0.0001). We did not find any significant differences between the changes observed in patients versus controls or between those subjects who received 400 mg entacapone versus 800 mg in either this or any of the other reported measures. PET image contrast increased in all cases, reflecting an increase in the specific striatal signal ([striatum-oceipitalhoccipital ratio increased 38% [p < 0.0001]). Entacapone did not alter the rate of striatal uptake and decarboxylation of [18F]dopa as estimated using a graphic approach with metabolite-corrected plasma as input function to calculate the influx constant, Ki(p) (p = NS). This confirms that such an analytic approach adequately corrects for the effect of extracerebral [18F]dopa methylation. In contrast, the influx constant Ki(o) (calculated using occipital counts as the input function) increased 45% after entacapone (p < 0.0001). This demonstrates the sensitivity of this analytic approach to the presence of peripheral 3-O-methyl[18F]dopa and provides an estimate of the percentage increase in brain free [18F]dopa resulting from entacapone premedication.

Evaluation of the short Parkinson's evaluation scale : A new friendly scale for the evaluation of Parkinson's disease in clinical drug trials

The extensive use of the Unified Parkinsons Disease Rating Scale (UPDRS) has revealed low interrater reliability in some items and redundancy in others. In view of these shortcomings, we have structured a new scale that includes a zero-to three-point scale for each item in the evaluation of PD. The mental axis includes memory, thought disorders, and depression. Activities of daily living (ADL) includes eight items: speech, eating, feeding, dressing, hygiene, handwriting, walking, and turning in bed. The motor examination includes eight items: speech, tremor, rest and posture, rigidity, finger tapping, arising from chair, gait, and postural stability. Complications of therapy were also included: dyskinesias, dystonia, motor fluctuations, and freezing episodes, collected by history. In addition, a global scoring for motor fluctuations that should complement the Hoehn and Yahr Scale was incorporated. In this report, we present a statistical analysis of the ADL, motor evaluation, and complications of therapy sections. Concerning the interrater reliability mean, Kendalls W values were >0.9 for most of the items in the Short Parkinsons Evaluation Scale (SPES). Kendalls W <0.8 (motor evaluation) was found for two items of the SPES and nine items of the UPDRS. The mean interrater reliability for both scales across all seven centers (seven Kendalls W for seven centers) (Mann-Whitney test) showed no statistical differences between the scales. Spearmans correlations between items of both scales were significant. Factor analysis of the SPES and UPDRS data revealed a four-factor solution that explained approximately 60% of the data. All participating centers found the SPES easier to apply and quicker to complete, when compared with the UPDRS. The results obtained strongly favor the introduction of SPES for clinical practice.

Statistical parametric mapping with 18F-dopa PET shows bilaterally reduced striatal and nigral dopaminergic function in early Parkinson's disease.

OBJECTIVE To apply statistical parametric mapping to 18F-dopa PET data sets, to examine the regional distribution of changes in dopaminergic metabolism in early asymmetric Parkinson’s disease. METHODS Thirteen normal volunteers (age 57.7 (SD 16.5) years; four women, nine men ) and six patients (age 50.3 (SD 13.5) years; three women, three men) with asymmetric (right sided) Parkinson’s disease were studied. Images from each dynamic dopa PET dataset were aligned and parametric images of18F-dopa influx (Ki) were created for each subject. The Ki images were transformed into standard stereotactic space. The Ki values of the caudate and putamen on spatially normalised images were compared with the Ki values before normalisation. The application of statistical parametric mapping (SPM) allowed statistical comparison of regional Ki values on a voxel by voxel basis between healthy volunteers and patients with Parkinson’s disease. RESULTS There was a strong correlation between the Ki values before and after spatial normalisation (r=0.898, p=0.0001). Significant decreases in the Ki values were found for the Parkinson’s desease group throughout the entire left putamen (p< 0.001) and focally in the dorsal right putamen (p< 0.001). Decreased Ki values were also shown bilaterally in the substantia nigra (p< 0.01). CONCLUSION Using (SPM) and 18F-dopa PET, reductions in both striatal and nigral brain dopaminergic function could be demonstrated in early Parkinson’s disease.

CHAPTER 17 – Implementation of 3D Acquisition, Reconstruction, and Analysis of Dynamic [18F]Fluorodopa Studies

The aim of this chapter is to implement quantitative 3D positron emission tomography (PET) [ 18 F]fluorodopa studies, present the obtained results, and compare the results with a previous protocol using 2D PET. 3D data sets were acquired on an ECAT 953B.The energy window used in all studies is 380–850 keV. Reconstruction is done by using a 3D filtered back-projection/reprojection algorithm. To test the accuracy of the entire process of 3D data acquisition, reconstruction, and analysis, a validation experiment to simulate a patient study is performed on the ECAT 953B. Analysis of data is performed on Sun Sparc workstations using in-house software written in Interactive Data Language (IDL). Region of interest (ROI) analysis was performed using standardized regions of a 10 mm diameter circular ROI for each caudate, and a 10 × 24 mm elliptical ROI for each putamen sample aligned to the long axis of the putamen. These regions are placed manually by visual inspection with reference to a stereotaxic atlas on three combined planes encompassing the striatum in 3D and two combined planes in 2D, which gives approximately equivalent total axial coverage. Two circular regions of 32 mm diameter are defined for the tissue input function in the occipital lobes in the same planes as those used for the striatal regions and averaged. Mean counts per pixel were measured for each region of interest in the last 14 frames, corresponding to the period 25–94 min after injection, for the striatal regions, and for the entire study for the tissue input function. The [ 18 F]fluorodopa influx rate constant is then calculated for caudate and putamen using the multiple time graphical analysis method.

Modifying the Progression of Parkinson’s Disease

Parkinson’s disease (PD) is a progressive and severely disabling movement disorder of unknown aetiology. The prevalence of the disease increases with advancing age, from approximately 0.5% at age 60 to 2% at age 85. As social and medical changes increase the average life span, the prevalence and hence the financial and social costs of the disease are likely to rise. Despite decades of laboratory and clinical research at present there is no therapy that has been shown conclusively to retard the progression of PD. A number of interventions have been suggested to influence disease progression but design faults in the relevant clinical trials have led to difficulties interpreting their findings [1]. This chapter will discuss firstly the rationale for the development of neuroprotective therapy in PD and the problems that are faced by clinical trials of the effect of medication on disease progression.