PET studies of parkinsonism associated with mutation in the alpha-synuclein gene.

OBJECTIVE: To assess the pattern of dopaminergic abnormalities in a Greek-American kindred (family H) with autosomal dominantly inherited, levodopa-responsive parkinsonism caused by a mutation of the gene encoding alpha-synuclein. BACKGROUND: Mutations of alpha-synuclein have been associated recently with dominantly inherited, levodopa-responsive parkinsonism. The pattern of dopamine deficiency and status of postsynaptic dopamine receptors in this condition have not been reported previously. The authors followed a large, six-generation family in whom the affected members carry the recently reported G209A mutation in the gene encoding alpha-synuclein. METHODS: The authors studied four affected and two clinically unaffected gene-negative members of family H using [18F]-6-fluoro-L-dopa (FD) and [11C]-raclopride (RAC) PET to assess presynaptic dopaminergic function and dopamine D2 receptors. The results were compared with normal subjects and patients with sporadic, idiopathic PD (IP). RESULTS: In affected individuals, FD uptake was reduced in both the caudate and the putamen, but the putamen was affected more severely than the caudate, as seen in IP. RAC binding was within the normal range, but the ratio of RAC binding in the putamen to that in the caudate was increased in affected members of family H. This pattern is similar to that seen in IP. CONCLUSIONS: PET of the nigrostriatal system in parkinsonism associated with a mutation in the ac-synuclein gene indicates that it results in a pattern of dopamine deficiency, with preserved D2 binding, indistinguishable from IP.

Reproducibility studies with 11C-DTBZ, a monoamine vesicular transporter inhibitor in healthy human subjects.

UNLABELLED: The reproducibility of (+/-)-alpha-[11C] dihydrotetrabenazine (DTBZ) measures in PET was studied in 10 healthy human subjects, aged 22-76 y. METHODS: The scan-to-scan variation of several measures used in PET data analysis was determined, including the radioactivity ratio (target-to-reference), plasma-input Logan total distribution volume (DV), plasma-input Logan Bmax/Kd and tissue-input Logan Bmax/Kd values. RESULTS: The radioactivity ratios, plasma-input Bmax/Kd and tissue-input Bmax/Kd all have higher reliability than plasma-input total DV values. In addition, measures using the occipital cortex as the reference region have higher reliability than the same measures using the cerebellum as the reference region. CONCLUSION: Our results show that DTBZ is a reliable PET tracer that provides reproducible in vivo measurement of striatal vesicular monoamine transporter density. In the selection of reference regions for DTBZ PET data analysis, caution must be exercised in circumstances when DTBZ binding in the occipital cortex or the cerebellum may be altered.

Reproducibility of the distribution of carbon-11-SCH 23390, a dopamine D1 receptor tracer, in normal subjects.

UNLABELLED: The reproducibility of [11C]SCH 23390 in PET was studied in 10 normal human subjects. METHODS: The scan-to-scan variation of several measures used in PET data analysis, including the radioactivity ratio, plasma-input Logan total distribution volume (DV), plasma-input Logan DV ratio (DVR) and tissue-input Logan Bmax/Kd values, was determined. RESULTS: There were significant correlations among the radioactivity ratio, plasma-input DVR and tissue-input Bmax/Kd. With the cerebellum as the reference region, these three measures also had high reliability (86%-95%), high between-subject s.d. (7.7%-11.3%) and small within-subject s.d. (2.3%-3.6%), indicating that they are comparable and useful measures for the assessment of dopamine D1 receptor binding. CONCLUSION: The radioactivity ratio and the tissue-input Bmax/Kd may be preferred methods for the evaluation of dopamine D1 receptor binding because these two methods do not require arterial blood sampling and metabolite analysis. Our results show that cerebellum is a reliable reference region for SCH 23390. When the Logan plasma-input function method is used in data analysis for SCH 23390, DVRs rather than total DV values should be used because of the poor reliability of the DV values and their lack of correlation with other measures. Carbon-11-SCH 23390 is thus a reliable and reproducible ligand for the study of dopamine D1 receptor binding by PET.

Routes of administration and effect of carbidopa pretreatment on 6-[18F]fluoro-L-dopa/PET scans in non-human primates.

In 6-[18F]fluoro-L-dopa (Fdopa)/positron emission tomography (PET) studies, carbidopa pretreatment increases the Fdopa bioavailability to the brain and enhances the intensity of striatal PET images. Different PET research teams have used various carbidopa doses and routes of administration in non-human primate studies. The purpose of this study was to examine the plasma profiles of carbidopa and the effect of the route of administration of carbidopa on a Fdopa/PET scan. Cynomolgus monkeys were given carbidopa either orally (5 mg/kg), intraperitoneally (2.5 and 5 mg/kg) or intravenously (5 mg/kg) 60-90 min prior to the Fdopa injection. Carbidopa-treated monkeys were compared to monkeys without carbidopa treatment. No carbidopa was detected in the plasma samples when it was given orally, possibly due to poor absorption in the gastrointestinal tract. In addition, the striatal and cortical activities were not statistically different from those of the untreated monkeys, indicating that little or no inhibition of the peripheral decarboxylation of Fdopa by carbidopa had taken place. When carbidopa was given intraperitoneally at a dose of 2.5 and 5 mg/kg and intravenously at 5 mg/kg, plasma carbidopa concentrations at the time of Fdopa injection were 0.95 +/- 0.26, 2.22 +/- 0.23 and 2.79 +/- 0.26 micrograms/ml, respectively. Because of inhibition of peripheral decarboxylation of Fdopa by carbidopa, more Fdopa was available for transport into the brain and as a result, both the striatal and cortical activities were significantly higher than those of the untreated monkeys. Carbidopa administration had no effect on either the striatal-to-cortical activity ratio or the striatum uptake value.

Positron emission tomography in pallido-ponto-nigral degeneration (PPND) family (frontotemporal dementia with parkinsonism linked to chromosome 17 and point mutation in tau gene).

Pallido-ponto-nigral degeneration (PPND) is a rapidly progressive disorder characterized by frontotemporal dementia with parkinsonism unresponsive to levodopa therapy. In this study, we have further characterized the regional abnormalities of cerebral function using PET with 6-[18F]fluoro-L-dopa (FD), [11C] raclopride (RAC), and 2-deoxy-2-fluoro-[18F]-D-glucose (FDG). FD and RAC scans were performed in 3 patients-2 new patients and a previously reported asymptomatic at-risk individual who became symptomatic 2years after the first FD scan. Cerebral glucose metabolism was studied by FDG in 2 other patients. In keeping with previous reports, there was a severe reduction of FD uptake, which affected both caudate and putamen to a similar degree in all 3 patients. RAC scans showed normal to elevated striatal D2-receptor binding in all patients. Cerebral glucose metabolism was globally reduced (>2 SD below control mean) in one patient, with maximal involvement of frontal regions, and to a lesser degree in the other patient. Our study showed severe presynaptic dopaminergic dysfunction with intact striatal D2 receptors in PPND patients, implying that the dopa unresponsiveness is probably a result of pathology downstream to the striatum. The pattern of presynaptic dysfunction contrasts with that seen in idiopathic parkinsonism, where the putamen is affected more than the caudate nucleus. The pattern of glucose hypometabolism correlates well with the presence of frontotemporal dementia.

Alternating two finger tapping with contralateral activation is an objective measure of clinical severity in Parkinson's disease and correlates with PET

We explored an objective method of measuring clinical severity of Parkinson's disease. Eighty-six patients with PD and 136 healthy subjects were studied. We serially carried out four types of finger tapping (FT) using a computerized drum machine: (i) repetitive one-finger tapping with an index-finger (F1K1); (ii) one-finger tapping on two keys separated by 20cm (F1K2); (iii) alternate tapping with index and middle fingers on two adjacent keys (F2K2); and (iv) F2K2 with contralateral activation (aF2K2). Analyses on FT included: (i) age and gender effects in healthy volunteers and Parkinson's disease; (ii) comparison between Parkinson patients and controls of similar age distribution; (iii) correlation with the Purdue Pegboard and Modified Columbia Scale in Disease; and (iv) in a subset of patients in whom PET scans were performed (n=30), correlation with 18F-DOPA uptake constant (Ki). In healthy subjects, there was a negative age effect on FT scores and a gender effect, with males scoring higher than females. All FT scores were significantly lower in the Parkinson patients, correlated with Purdue Peg Board, and inversely with the duration of illness, and with the Modified Columbia Scale. The 18F-DOPA Ki correlated significantly with aF2K2 (p=0.024), less so with PPB (p=0.038), but not with the Modified Columbia Scale. We conclude that alternating two-finger tapping with contralateral hand activation is a simple, objective test for measuring the severity of Parkinson's disease.

Age-dependent decline of dopamine D1 receptors in human brain: a PET study.

Radioligand binding studies in animals have demonstrated age-related loss of dopamine receptors in the caudate and putamen. In humans, while age-related declines in dopamine D2 receptors have been consistently reported, the effects of ageing on D1 receptors have been controversial. We used positron emission tomography (PET) with [11C]SCH 23390 to investigate dopamine D1 receptor binding in 21 normal volunteers aged 22-74 years. We also assessed their motor function with a Modified Columbia Score (MCS) and the Purdue Pegboard Test (PPBT). D1 binding potentials were derived using a graphical analysis with a cerebellar tissue input function. Standard linear regression techniques were used to determine the age-related rate of decline of D1 binding. We found an age-dependent decrease of D1 receptor binding in the caudate (6.9% per decade) and putamen (7.4% per decade). There was also a significant inverse correlation between [11C]SCH 23390 binding in the occipital cortex and age (8.6% decline per decade). PPBT score also decreased with age (P = 0.007). There was a direct correlation between PPBT score and D1 binding potential. We conclude that dopamine D1 receptor density declines with age and that the effects of physiological ageing may play a role in the expression of extrapyramidal disorders in the elderly.