Striatal Fluorodopa Uptake Research Articles

Validation of nigrostriatal positron emission tomography measures: Critical limits

Molecular imaging and clinical endpoints are frequently discordant in Parkinson disease clinical trials, raising questions about validity of these imaging measures to reflect disease severity. We compared striatal uptake for 3 positron emission tomography (PET) tracers with in vitro measures of nigral cell counts and striatal dopamine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. Sixteen macaques had magnetic resonance imaging and baseline PETs using 6-[18F]fluorodopa (FD), [11C]dihydrotetrabenazine (DTBZ), and 2beta-[11 C]carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT). MPTP (0-0.31 mg/kg) infused unilaterally via the internal carotid artery produced stable hemiparkinsonism by 3 weeks. After 8 weeks, PETs were repeated and animals were euthanized for striatal dopamine measurements and unbiased counts of tyrosine hydroxylase-stained nigral cells. Striatal uptake for each radiotracer (FD, DTBZ, CFT) correlated with stereologic nigral cell counts only for nigral loss<50% (r2=0.84, r2=0.86, r2=0.87, p<0.001 respectively; n=10). In contrast, striatal uptake correlated with striatal dopamine over the full range of dopamine depletion (r2=0.95, r2=0.94, r2=0.94, p<0.001; n=16). Interestingly, indices of striatal uptake of FD, DTBZ, and CFT correlated strongly with each other (r2=0.98, p<0.001). Tracer uptake correlated with nigral neurons only when nigral loss was <50%. This along with previous work demonstrating that nigral cell counts correlate strongly with parkinsonism ratings may explain discordant results between neuroimaging and clinical endpoints. Furthermore, strong correlations among striatal uptake for these tracers support lack of differential regulation of decarboxylase activity (FD), vesicular monoamine transporter type 2 (DTBZ), and dopamine transporter (CFT) within 2 months after nigrostriatal injury.

Novel features in a patient homozygous for the L347P mutation in the PINK1 gene

The purpose of this study was to assess the genotype-phenotype of PINK1 mutations. We genotyped eight known mutations in three clinic-based cohorts with Parkinsonism and found one homozygous p.L347P mutation in PINK1. Clinically, hypo-osmia and profound diurnal variation of symptoms were identified as novel features; fluorodopa positron emission tomography revealed striking decline in striatal fluorodopa uptake. We suggest that it may be possible to clinically separate this form of Parkinsonism from dopa-responsive dystonia and Parkin-related Parkinsonism. Furthermore, as this mutation has only been reported in Filipinos (two originated from Luzon island), our results support the hypothesis of a common founder.

Neuroprotection in Parkinson's disease: clinical trials.

Advances in our understanding of the cause and pathogenesis of Parkinson's disease (PD) have permitted the rational selection of putative neuroprotective agents for study in PD. However, the list of agents that might provide neuroprotective effects derived from laboratory studies is daunting, and we face the challenge of determining which agents to bring to the clinic and how to find the resources (patients and funds) to properly study so many promising therapeutic opportunities.1 Appropriate outcome variables that are not confounded by any symptomatic effect of the drug and are acceptable to clinicians and regulatory authorities also remain to be defined. The first clinical trials designed to test the capacity of putative neuroprotective agents to alter the natural history of PD have now been performed and illustrate some of these problems. The DATATOP (Deprenyl and Tocopherol Antioxidant Therapy of PD) study used the time to reach a disease milestone in untreated PD patients (ie, need for levodopa) as the primary end point. However, interpretation of results was confounded by the drug's symptomatic effect. The SINDEPAR (Sinemet-Deprenyl-Parlodel) study used the change in motor score between initial visit and final visit after washout of all study medications as the primary end point. However, here too there were concerns about confounding symptomatic effects, because antiparkinsonian medications have now been shown to have a long duration response that can persist for weeks and perhaps even months after withdrawal. More recent studies have used surrogate markers of the integrity of nigrostriatal function such as striatal uptake of fluorodopa on positron emission tomography (PET) or beta-CIT-on single-photon emission computerized tomography (SPECT) as primary outcome measures. However, it has not yet been confirmed that striatal uptake of these isotopes does in fact correlate with the remaining number of dopamine neurons or terminals, and the possibility of a confounding pharmacological effect has not yet been completely excluded. To date, no drug has been established to have a neuroprotective effect in PD, and none has been approved for a neuroprotective indication. Furthermore, regulatory agencies have not yet agreed that any of the outcome measures currently used will be acceptable for approval of a new drug. Resolution of these issues is of critical importance to convince pharmaceutical companies to expend the hundreds of millions of dollars necessary to bring a new drug to market. Drugs that already have been approved in PD for their symptomatic effects, such as dopamine agonists or propargylamines (eg, selegiline), offer the best opportunity for establishing that a drug is neuroprotective in PD in the immediate future, but herein also lies the difficulty of establishing that any benefits observed are not solely because of the drug's symptomatic properties. Currently, this will most likely entail demonstrating that the drug provides benefit for PD patients for both imaging and clinical markers of disease progression.

Role of the dopaminergic system in chronic pain – a fluorodopa-PET study

Recent data from animal experiments suggest an important role for the basal ganglia in the processing and sensorimotor gating of nociceptive information. However, very little is known about their possible participation in human pain. Because of our previous finding of increased excitability of the blink reflex (a brainstem reflex under dopaminergic inhibitory control) in some burning mouth syndrome (BMS) patients, we have studied the dopaminergic function of the striatum (putamen and caudatus) of BMS patients with positron emission tomography (PET). 6-[ 18F]fluorodopa (FDOPA) PET scans were done on ten BMS patients and 14 healthy control subjects. The presynaptic dopaminergic function was significantly decreased in the right putamen (20%, P=0.04) of the BMS patients compared to control subjects. On the left side, the FDOPA uptake was decreased by 17% ( P=0.08). The mean FDOPA uptake was not significantly changed in the caudate nucleus of the patients. The finding of decreased striatal FDOPA uptake in the putamen supports our previous neurophysiological observations indicating decreased dopaminergic inhibition in BMS patients. The present result provides direct evidence of the involvement of the nigrostriatal dopaminergic system in pain for the first time in a clinical pain condition.

Depressive symptoms and presynaptic dopamine function in neuroleptic-naive schizophrenia

We have previously reported aberrations in the striatal presynaptic dopamine function in neuroleptic-naive schizophrenic patients compared to healthy controls (Hietala, J., Syvälahti, E., Vuorio, K. et al., 1995. Lancet 346, 1130–1131). In this extended study we explore whether the altered presynaptic dopamine function correlates with the clinical symptomatology in schizophrenia. Striatal dopamine synthesis capacity (6-[ 18 F ]fluorodopa (FDOPA) uptake, K i values) was studied with positron emission tomography in 10 neuroleptic-naive schizophrenic patients and 13 healthy controls. The clinical symptomatology was characterized with the Positive and Negative Symptom Scale (PANSS). The patients had an increased FDOPA uptake in striatum and lacked the asymmetry in caudate FDOPA uptake ( p=0.0005), confirming our earlier results. Left striatal FDOPA uptake ( K i) values correlated negatively with depressive symptoms in a highly significant manner. On the other hand, paranoid symptomatology correlated positively with right putamen FDOPA uptake at a trend level ( ρ=0.73, p<0.02). The lack of asymmetry in caudate K i values did not associate with any dimension of psychopathology. The major finding in this study is that depressive symptoms in neuroleptic-naive first-admission schizophrenia are associated with low presynaptic dopamine function. This link appears to be hemisphere-related and may have drug-treatment implications, e.g., in prediction of response to D2 receptor blocking antipsychotic drugs. A possible connection between paranoid symptomatology and subcortical hyperdopaminergia is suggested, but this remains to be further verified.

Hereditary form of parkinsonism--dementia.

In four generations of a family, 13 members were afflicted with an autosomal dominant disorder characterized by young age at onset, early weight loss, and rapidly progressive dopa-responsive parkinsonism, followed later by dementia and, in some, by hypotension. Intellectual dysfunction began with subjective memory loss and objective visuospatial dysfunction and was followed later by decline of frontal lobe cognitive and memory functions. Neuropathological examination in 4 autopsied cases showed neuronal loss in the substantia nigra and locus ceruleus and widespread Lewy bodies, many of them in the cerebral cortex; those in the hypothalamus and locus ceruleus were often of bizarre shapes. Other findings were vacuolation of the temporal cortex, unusual neuronal loss and gliosis in the hippocampus (CA 2/3), and neuronal loss in the nucleus basalis. There were no neuritic plaques, neurofibrillary tangles, or amyloid deposits. Positron emission tomography in 3 patients showed decreased striatal uptake of fluorodopa. Neurochemical analysis of an autopsied brain showed a pronounced decrease in choline acetyltransferase activity in the frontal and temporal cortices and hippocampus and a severe depletion of striatal dopamine with a pattern not typical of classic Parkinson's disease.

PET study of striatal fluorodopa uptake and dopamine D2 receptor binding in a patient with juvenile parkinsonism.

We studied pre-synaptic and post-synaptic function in the striatum of a patient with juvenile parkinsonism (JP) using positron emission tomography (PET). [18F]6-fluorodopa (18FDOPA), 11C-YM-09151-2 and [18F]fluoro-2-deoxy-d-glucose (18FDG) were used to measure fluorodopa uptake, dopamine D2 receptor binding and glucose metabolism, respectively. In this patient, 18FDOPA accumulation was decreased markedly in the caudate nucleus and the putamen bilaterally. In the images of 11C-YM-09151-2 and 18FDG, in contrast, no conspicuous changes were observed in the striatum. Thus our PET studies using 18FDOPA, 11C-YM-09151-2 and 18FDG provide a useful approach for assisting the diagnosis of JP, because the present findings are different from the results in patients with dopa-responsive dystonia and hereditary progressive dystonia with marked diurnal fluctuation. Furthermore, our findings are of particular interest in relation to the pathogenesis of JP.Copyright Lippincott-Raven Publishers

2-30-06 Striatal fluorodopa uptake and dopamine D2 receptor bindings in early and late onset of Parkinson's disease studied by positron emission tomography

2-30-06 Striatal fluorodopa uptake and dopamine D2 receptor bindings in early and late onset of Parkinson's disease studied by positron emission tomography

Presynaptic nigrostriatal function in genetically tested asymptomatic relatives from the pallido-ponto-nigral degeneration family.

Pallido-ponto-nigral degeneration (PPND) is a dominantly inherited disorder with parkinsonism. We performed PET with [18F]fluorodopa (FD) and, later, gene testing in 12 asymptomatic relatives at risk from a family with PPND and compared the striatal FD uptake constant (Ki) in them with 4 symptomatic individuals and 10 normal control subjects. Four relatives with positive linkage had a significantly reduced Ki from the normal control subjects but to a lesser degree than the symptomatic patients. The mean Ki in the relatives with negative linkage (n = 8) did not differ from normal control subjects. In conclusion, we identified reduced dopaminergic function in asymptomatic relatives with positive genetic linkage from the PPND family. Most of the reduction in this disorder occurs in the fifth decade, when the disease manifests clinically.

Nigrostriatal dopaminergic function in familial amyotrophic lateral sclerosis patients with and without copper/zinc superoxide dismutase mutations.

Some cases of familial amyotrophic lateral sclerosis (FALS) are associated with copper/zinc superoxide dismutase (Cu/Zn-SOD) mutations, which are implicated in the death of motor neurons. Because Cu/Zn-SOD is present in high amounts in nigrostriatal dopaminergic neurons, we considered the possibility that FALS may be associated with subclinical nigrostriatal dopaminergic dysfunction. We used [18F]fluorodopa (FDOPA) and PET to study 14 FALS patients (50 +/- 11 years [mean +/- SD]): seven with (FALS-1) and seven without (FALS-0) Cu/Zn-SOD mutations. Fourteen age-matched normal volunteers (48 +/- 18 years) served as controls. Striato-occipital ratios (SORs) for the caudate and the putamen were calculated. Five of the 14 FALS patients had reduced striatal FDOPA uptake in the caudate nucleus, putamen, or both. Mean caudate SOR did not differ among FALS-1, FALS-0, and control subjects. Mean putamen SOR was significantly abnormal in FALS-0 but not in FALS-1 patients. These findings indicate that subclinical nigrostriatal dopaminergic dysfunction is present in some FALS patients and that FDOPA/PET abnormalities are more likely to be associated with FALS-0 status. This suggests that SOD mutations are less cytotoxic to dopaminergic than to motor neurons.

A 61-Year-Old Man With Parkinson's Disease

To the Editor. —I must take exception to the discussion by Dr Olanow 1 of the presumed clinical benefits and improvements that resulted from fetal tissue transplantation in patients with PD. Landau 2 has addressed this topic. The clinical improvement described in the patients who received transplants, based almost exclusively on clinical criteria, differs very little from that reported earlier with adrenal gland grafting. This technology has subsequently proven to be of no value. Olanow mentions the measured increases in striatal fluorodopa uptake, using positron-emission tomography (PET) scanning, but, at present, it is not known whether this is indicative of dopamine production by the graft or is an irritative effect on the surrounding brain. He reinforces his belief in the success of this method by mentioning the single autopsy case 3 that demonstrated some cellular survival in the fetal brain graft. No neuropathologist would argue that this was evidence of robust graft survival,

Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson's disease.

We performed fetal nigral transplantations in 4 Parkinson's disease (PD) patients. Solid grafts were bilaterally implanted into the postcommissural putamen using 3 to 4 donors per side aged 6 1/2 to 9 weeks postconception. Transplant deposits were separated by no more than 5 mm in three dimensions. Cyclosporine was employed for a total of 6 months. Patients were evaluated at baseline and at 1, 3, and 6 months postoperatively. Striatal 18-fluorodopa uptake was assessed by positron emission tomography at baseline and at 6 months postoperatively. The procedure was well tolerated in all patients. One patient had a clinically asymptomatic superficial cortical hemorrhage along the needle tract and a second had transient postoperative confusion and hallucinations. All patients experienced clinically meaningful benefit. Significant improvement (p < 0.05) was detected in total UPDRS score during the "off" state, Schwab-England disability score during the "off" state, percent "off" time, and percent "on" time with dyskinesia. Increased striatal fluorodopa uptake was observed bilaterally in each patient, with mean increases of 53% on the right (p = 0.01) and 33% on the left (p = 0.08). Our study demonstrated clear and consistent improvement in clinical features and striatal fluorodopa uptake following fetal tissue transplantation in patients with advanced PD whose condition was not improved preoperatively by drug manipulation. These preliminary results are encouraging and support further studies to evaluate grafting strategies as a therapy for PD.

Resting tremor only: a variant of Parkinson's disease or of essential tremor

Resting tremor is one of the characteristic features of Parkinson's disease. However, there are a number of patients who typically have resting tremor alone for at least 5 years without development of other parkinsonian signs or symptoms. The etiology of an isolated resting tremor is still obscure. Recently, positron emission tomography was used to study these patients with isolated resting tremor, and demonstrated a markedly decreased striatal uptake of fluoro-dopa to the range of Parkinson's disease. These findings suggested the existence of a separate subtype, namely, tremulous Parkinson's disease with a manifestation of resting tremor alone. In order to confirm the existence of this subgroup of tremulous Parkinson's disease and further investigate its morphological changes and the usefulness of magnetic resonance imaging, we collected 5 patients who typically have resting tremor for at least 8 years in the absence of other features of Parkinson's disease. MRI was performed and the results of the images showed typical findings of Parkinson's disease with smudging or decreased distance between substantia nigra and red nucleus. Quantitative analysis also demonstrated a significant decrease of the above-noted distance when the resting tremor group was compared to the essential tremor group. Therefore, patients with an isolated resting tremor can have morphological abnormalities in addition to functional disturbances shown by positron emission tomography. To our knowledge, this is the first paper to report that resting tremor is a variant of Parkinson's disease rather than essential tremor, by using a double-blind method, with magnetic resonance imaging to support.

An Aging Effect in Striatal Fluorodopa Uptake? Large versus Small Rois

To the Editor: We read with interest the paper by Eidelberg et ai. (1993), in which the authors state that they ana­ lyzed the scans according to our method. Unfortu­ nately, they did not. We used elliptical striatal regions of interest (ROIs) in our original paper and found a clear aging effect (Martin et aI., 1989). Eidelberg et ai. used rectangular ROIs in their attempt to replicate our method. The difference may be critical, as rectan­ gular ROIs would necessarily include more ventri­ cle, where there is no background activity, than el­ liptical ROIs; the error introduced by this may ob­ scure any aging effect. Eidelberg et ai. concede in their article that their failure to demonstrate an ef­ fect of age may be explained by excess variability. The issue is important, as the Eidelberg et ai. paper attempts to resolve disparate findings of an age re­ lationship in fluorodopa uptake using different ROIs (Martin et aI., 1989; Sawle et aI., 1990). We have recently shown in a new data set that using total striatal ROIs reveals an aging effect in fluorodopa uptake, while using small (8.8-mm­ diameter) ROIs does not (Vingerhoets et aI., 1994). These findings reconcile the differing conclusions of Martin et ai. (1989) (who used total striatal ROIs and found an age effect) and Sawle et ai. (1990) (who used small ROIs and did not). The difference between the methods does not relate just to the size of the ROIs; large ROIs measure the total striatal fluorodopa uptake, while small ROIs measure the concentration of fluorodopa uptake per milliliter of striatum. Eidelberg et ai. are confused by this point when they state that the total striatal ROI method is sensitive to the known age-related striatal atrophy (Murphy et aI., 1992). In fact, the opposite is true, because dopaminergic neurons make up a minimal part of the volume of the striatum. Any atrophy of the nondopaminergic elements would alter the con­ centration of fluorodopa uptake but not the total uptake, which is therefore the true measure of ni­ grostriatal dopaminergic function. Eidelberg et ai. could have contributed to the dis­ cussion by applying the methods of both Martin et ai. and Sawle et ai. to the same data set. U nfortu­ nately they did not replicate the methods, and

Correlation of striatal fluorodopa uptake in the MPTP Monkey with dopaminergic indices

Striatal 18F-6-fluorodopa (FD) uptake constants were measured by positron emission tomography in (1) normal cynomolgus monkeys and (2) a series of cynomolgus and rhesus monkeys that had received intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). After the animals were killed, the number and average size of dopaminergic neurons in the substantia nigra pars compacta were measured. Striatal levels of dopamine and its metabolites, and the striatal activities of the dopaminergic synthetic enzymes, were also determined. The striatal FD uptake constants showed highly significant positive correlations with both number and size of dopaminergic neurons, indicating atrophy of surviving neurons in MPTP-treated animals. The uptake constants also showed significant positive correlations with striatal levels of dopamine, total catecholamines, and the activities of the synthetic enzymes. Both histochemical and biochemical data on tyrosine hydroxylase suggested some contralateral enzyme loss in these MPTP-treated monkeys, as well as decreased enzyme activity in surviving neurons on the lesioned side. However, residual enzyme activities were apparently not rate limiting to striatal FD uptake. It is concluded that PET-FD measurements by positron emission tomography provide a good index of the integrity of the nigrostriatal pathway.

Administration of the new COMT inhibitor OR-611 increases striatal uptake of fluorodopa.

L-Dopa is metabolized to 3-O-methyldopa (3OMD) by catechol-O-methyltransferase (COMT). This reduces the amount of L-dopa available for entry into brain. We studied the effect of OR-611, a new COMT inhibitor, on plasma and brain 6-[18F]-fluoro-L-dopa (6FD) metabolism in cynomolgus monkeys with positron emission tomography (PET). OR-611 pretreatment substantially reduced plasma 6FD metabolism to 3-O-methylfluorodopa (3OMFD). PET measurements of striatal 6FD concentrations showed an average 2.3-fold increase following OR-611 pretreatment, compared to the same animals in the control state. OR-611 inhibits plasma metabolism of 6FD and increases brain uptake of this L-dopa analog. OR-611 appears to be a promising agent as an adjunct to L-dopa for the treatment of patients with Parkinson's disease.

The metabolic anatomy of Parkinson's disease: Complementary [18F]fluorodeoxyglucose and [18F]fluorodopa positron emission tomographic studies

We studied the metabolic anatomy of typical Parkinson's disease (PD) using [18F]fluorodeoxyglucose (FDG) and [18F]fluorodopa (FDOPA) and positron emission tomography (PET). Fourteen PD patients (mean age 49 years) had FDG/PET scans, of which 11 were scanned with both FDOPA and FDG. After the injection of FDOPA, brain uptake and arterial plasma radioactivity were monitored for 2 h. Striatal FDOPA uptake was analyzed with regard to a two-compartment model, and target-to-background ratios (TBRs) and TBR-versus-time slopes were also calculated. Regional patterns of metabolic covariation were extracted from FDG/PET data using the Scaled Subprofile Model (SSM). SSM pattern weights, FDOPA uptake constants (Ki), TBRs, and TBR slopes were correlated with clinical measures for bradykinesia, rigidity, tremor, gait disturbance, left-right asymmetry, dementia, and overall disease severity. In PD patients, rate constants for FDOPA uptake correlated with individual measures of bradykinesia (p = 0.001) and gait disability (p less than 0.05). SSM analysis revealed a distinct pattern of regional metabolic asymmetries, which correlated with motor asymmetries (p less than 0.001) and left-right differences in Ki (p less than 0.01). Our data suggest that in PD patients, FDG/PET and FDOPA/PET may provide unique and complementary information about underlying disease processes.