A comparison of the progression of early Parkinson's disease in patients started on ropinirole or L-dopa: an 18F-dopa PET study.

OBJECTIVE: To study the relative rates of progression of early Parkinson's disease (PD) in patients started on a dopamine agonist, ropinirole, or L-dopa. METHODS: A double-blind study of 45 early PD patients [mean age 61 +/- 9.8 SD and mean symptom duration, 26 +/- 16 SD months] randomized 2 : 1 (ropinirole : L-dopa). Supplementary L-dopa was allowed if, during the trial, there was lack of a therapeutic effect. (18)F-dopa PET scans were performed at baseline (n = 45) and 2 years (n = 37). RESULTS: At two years, the mean percentage reduction in putamen (18)F-dopa uptake (Ki(o)) was not significantly different between the two groups (13% ropinirole, n = 28 versus 18% L-dopa, n = 9). CONCLUSIONS: We found no significant overall difference in underlying PD progression, after two years treatment, between patients groups. In summary, (18)F-dopa PET can be employed to objectively evaluate the effect of potential neuroprotective agents on dopaminergic function.

Frontal, midbrain and striatal dopaminergic function in early and advanced Parkinson's disease A 3D [(18)F]dopa-PET study.

We have studied focal changes in dopaminergic function throughout the brain volume in early and advanced Parkinson's disease by applying statistical parametric mapping (SPM) to 3D [(18)F]dopa-PET. Data from seven early hemi-Parkinson's disease and seven advanced bilateral Parkinson's disease patients were compared with that from 12 normal controls. Parametric images of [(18)F]dopa influx rate constant (K(i)(o)) were generated for each subject from dynamic 3D [(18)F]dopa datasets and transformed into standard stereotactic space. Significant changes in mean voxel [(18)F]dopa K(i)(o) values between the normal control group and each Parkinson's disease group were localized with SPM. Conventional region of interest analysis was also applied to comparable regions on the untransformed image datasets. In early left hemi-Parkinson's disease, significant extrastriatal increases in [(18)F]dopa K(i)(o) were observed in the left anterior cingulate gyrus and the dorsal midbrain region (P < 0.05, corrected) along with decreases in striatal [(18)F]dopa K(i)(o). In advanced Parkinson's disease, significant extrastriatal decreases in [(18)F]dopa K(i)(o) were observed in the ventral and dorsal midbrain regions (P < 0.05, corrected). No significant changes in [(18)F]dopa K(i)(o) were observed in the anterior cingulate region. In a direct comparison between the early and late Parkinson's disease groups, we observed relative [(18)F]dopa K(i)(o) reductions in ventral and dorsal midbrain, and dorsal pontine regions along with striatal [(18)F]dopa K(i)(o) reductions. Similiar results were found with a region of interest approach, on non-transformed data, except for the focal midbrain [(18)F]dopa K(i)(o) increase seen in early Parkinson's disease. In conclusion, using SPM with [(18)F]dopa-PET, we have objectively localized changes in extrastriatal, pre-synaptic dopaminergic function in Parkinson's disease. The significance of the increased dopaminergic activity of anterior cingulate in early Parkinson's disease remains unclear, but may be compensatory. The [(18)F]dopa signal in dorsal midbrain and pontine regions suggests that [(18)F]dopa is taken up by serotonergic and noradrenergic neurons which also degenerate in advanced Parkinson's disease. This suggests, therefore, that Parkinson's disease is a monoaminergic neurodegenerative disorder.

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 of 18F-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.

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 t test) 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.

Dopaminergic function in familial Parkinson's disease: a clinical and 18F-dopa positron emission tomography study.

There is increasing evidence for familial aggregation in Parkinson's disease (PD). It is possible that some asymptomatic relatives of PD patients have subclinical nigral Lewy body pathology and their identification could help determine the true prevalence of the disease. We used 18F-dopa positron emission tomography to investigate nigrostriatal dopaminergic terminal function in asymptomatic members of 7 unrelated kindreds in which at least 2 members had parkinsonism. Eight (25%) of the 32 asymptomatic relatives showed abnormal putamen 18F-dopa uptake (2.5 standard deviations below the normal mean). When discriminant function analysis was applied, all of these 8 subjects plus another 3 were classified with high probability as having PD. On neurological examination, 5 of the 32 relatives scanned had an isolated mild postural tremor and 2 of these 5 had reduced putamen uptake. Our findings provide further support for a role of inheritance in the etiology of PD and suggest that the penetrance for nigrostriatal dopaminergic dysfunction in familial clusters of PD is higher than the prevalence of clinical parkinsonism reported in epidemiological surveys.

Regional changes in [18F]dopa metabolism in the striatum in Parkinson's disease.

We have investigated regional changes in dopamine metabolism within the basal ganglia with clinical progression of idiopathic Parkinson's disease, using coregistration of [18F]dopa-PET and MRI images and comparing six normal subjects with 15 Parkinson's disease patients in a cross-sectional study. We have demonstrated that [18F]dopa metabolism in the dorsal putamen is reduced to almost 50% of normal both caudally and rostrally early in the disease whilst the ventral putamen is not significantly affected. With progression of symptoms there is loss of dopa metabolism from the ventral putamen, the ventrocaudal putamen in advance of the ventrorostral putamen. Throughout the disease the ventrorostral putamen is relatively preserved; even in the most advanced group [18F]dopa uptake is reduced here by only 30%. We conclude that the progression of Parkinson's disease is associated with a focal process affecting only the dorsal putamen in its early (and preclinical) phase then affecting the ventral putamen with increasing disease severity.

An [18F]dopa-PET and clinical study of the rate of progression in Parkinson's disease.

We have studied disease progression in a group of 10 patients with recent onset idiopathic Parkinson's disease [mean age 53.7 +/- 12.6 years, mean duration 18.3 +/- 6.5 months, mean unified Parkinson's disease rating scale (UPDRS) 19.0 +/- 9.5], and a group of seven patients with established Parkinson's disease (mean age 60.1 +/- 15.1 years, mean duration 70.8 +/- 35.5 months, mean UPDRS 47.9 +/- 18.1), using both clinical assessment and [18F]dopa-PET. Results were compared with those of a group of 10 normal subjects (age 66 +/- 16 years). Mean putamen [18F]dopa influx constant (Ki) was a reliable measurement (R = 0.82) and the most sensitive marker of disease progression (r = -0.85, P < 0.0001). The mean annual rate of reduction in mean putamen Ki in the Parkinson's disease patients was 12.5% per annum, whereas the control group showed no significant change in Ki over a mean of 32 months follow up. The rate of progression was more rapid in the recent onset compared with the established disease group but this did not reach statistical significance. Assuming a linear progression for the entire group we estimate symptom onset at a mean putamen Ki 79% of normal with a mean preclinical period of 3.1 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)) Parkinson's 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-Parkinson's 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 Parkinson's 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 Parkinson's 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 Parkinson's disease cohorts, but when a discriminant function from a previous study was used predictively four of the 27 patients with Parkinson's 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-O-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-occipital]:occipital 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.