18F]fluorodopa uptake in the upper brainstem measured with positron emission tomography correlates with decreased REM sleep duration in early Parkinson's disease

Sleep disturbances are common in patients with Parkinson's disease (PD). Previous studies have shown alterations of polysomnographic sleep parameters in PD, such as overall diminution of slow-wave and REM sleep duration, absence of muscle atonia during REM and increased occurrence of periodic leg movements during sleep. The pathogenesis of sleep dysregulation in PD is unknown. The aim of this study was to determine relations of abnormal polysomnographic sleep parameters and the dopaminergic function of the striatum and the upper brainstem measured with the use of positron emission and magnetic resonance tomography in 10 early-stage PD patients with a history of sleep disturbances. Our data demonstrated a significant inverse correlation of absolute and percentage REM sleep duration with the mesopontine [18F]6-fluorodopa (FDOPA) uptake in PD patients. Therefore, the results point to a REM inhibiting effect of increased monaminergic transmission within the upper brainstem in early-stage PD. This finding emphasises the pathophysiological significance of a disturbed neurotransmitter equilibrium in the rostral brainstem for REM sleep alterations in PD.     

{18F}fluorodeoxyglucose positron emission tomography in refractory complex partial seizures

Positron emission tomography with simultaneous electroencephalographic monitoring was performed with {¹⁸F}fluorodeoxyglucose in 20 patients with complex partial seizures who had normal computed tomographic scans. Seven patients had only unilateral epileptiform discharges on the electroencephalogram, 3 had predominantly unilateral discharges, and 10 had nonlocalized epileptiform abnormalities. Positron emission tomography showed a hypometabolic lesion in 16 of the 20 patients. Pathological changes in the hypometabolic region were found in postoperative specimens in 4 of 5 patients studied. Positron emission tomography was unaffected by the seizure frequency, state of alertness, or number of spike discharges during the scan. There was a tendency for patients to have higher overall metabolic rates when taking less medication. Seizures occurring during {¹⁸F}fluorodeoxyglucose uptake in 3 patients produced a hypermetabolic area at the interictal hypometabolic focus. Positron emission tomography sometimes showed more widespread hypometabolism than suspected on the basis of the scalp-recorded electroencephalogram. The frontal lobe showed a greater degree of hypometabolism than the temporal lobe in 3 patients. Focal lesions may be identified by positron emission tomography even if the electroencephalographic abnormality is not well localized.     

Classification of schizophrenic patients and healthy controls using [18F] fluorodopa PET imaging

Striatal dopaminergic overactivity has been implicated in the pathophysiology of schizophrenia on the basis of in vivo neuroimaging studies. In particular, elevated striatal dopamine synthesis and storage has been repeatedly demonstrated in schizophrenia using the radiotracer 6-[18F] fluoro-l-DOPA ([18F] DOPA) and positron emission tomography (PET). Conventionally analysed [18F] DOPA PET imaging lacks the sensitivity or specificity to be used diagnostically. The aim of this study was to determine if the application of an Artificial Neural Network (ANN) would improve classification of images, and increase the sensitivity and specificity of [18F] DOPA as a potential diagnostic test for schizophrenia. We tested an ANN model in the discrimination of schizophrenic patients from normal controls using [18F] DOPA rate constants within the anterior-posterior subdivisions of the striatum, and compared the model with a general linear analysis of the same data. Participating in the study were 19 patients diagnosed with paranoid schizophrenia and 31 healthy subjects. Maximum classification was achieved using laterality quotients, - the ANN model correctly identified 94% of the controls and 89% of the patients, equivalent to 89% sensitivity and 94% specificity. Using all bilateral striatal regions correctly categorised 74% of the controls and 84% of the patients, equivalent to 84% sensitivity and 74% specificity. In comparison, the general linear analysis performed poorly, correctly classifying only 58% of the controls and 63% of the patients. Overall, these analyses have shown the potential utility of pattern recognition tools in the classification of psychiatric patients based upon molecular imaging of a single target.     

Inhibition of L-[18F]fluorodopa uptake into human brain by amino acids demonstrated by positron emission tomography

The brain uptake of L-[18F]fluorodopa was measured by positron emission tomography in a healthy male volunteer both under fasting conditions and during intravenous amino acid loading. A significant reduction of tracer uptake into the brain was demonstrated with amino acid loading. This finding represents the first direct evidence for competition between L-dopa and other amino acids for uptake across the blood-brain barrier obtained in vivo in a human subject. It underlines the possible importance of interference by dietary amino acids with the therapeutic actions of L-dopa in Parkinson's disease.     

Effect of catechol-O-methyltransferase inhibition on brain uptake of [18F]fluorodopa: Implications for compartmental modelling and clinical usefulness

The efficacy of levo-DOPA in the treatment of Parkinson's disease is potentiated by blockade of its peripheral metabolism with inhibitors of catechol-O-methyltransferase (COMT). Some COMT inhibitors may act entirely in the periphery (nitecapone, OR-462), while others may also have some activity in brain (entacapone, OR-611). We used positron emission tomography (PET) to test the effects of these two COMT inhibitors on the plasma kinetics and brain metabolism of the levo-DOPA analog 6-[¹⁸F]fluoro-L-dopa (FDOPA) in cynomolgus monkeys, employing a compartmental model for the assay of DOPA decarboxylase activity in living brain. Four monkeys each underwent two PET scans in the baseline condition, one PET scan after treatment with OR-462 (15 mg/ kg, i.v.), and one PET scan after treatment with OR-611 (15 mg/ kg, i.v.). Pharmacokinetic analysis of FDOPA metabolism in plasma indicated that these compounds blocked peripheral COMT activity by 80% for at least 60 minutes. Both COMT inhibitors increased the net availability of FDOPA in circulation, and increased the ratio of the radioactivity concentrations in striatum and occipital cortex, suggesting that [¹⁸F]fluorodopamine synthesis in striatum was potentiated. However, OR-611 treatment reduced the unidirectional (K) and net (K_i) blood-brain clearances of FDOPA, and also inhibited the rate of decarboxylation (k) of FDOPA in striatum. These observations suggest that high doses of OR-611 may partially antagonize the cerebral utilization of levo-DOPA. We used the present data to test the sensitivity of the compartmental model to the physiological constraint that the blood-brain permeabilities of the O-methylated plasma metabolite and FDOPA have a fixed ratio. In the groups with COMT inhibition, the estimates of k were insensitive to the magnitude of the permeability ratio. In the control group, the estimate of k increased by 40% as the magnitude of the constrained permeability ratio increased in the range of published estimates. Synapse 30:351–361, 1998. © 1998 Wiley-Liss, Inc.     

Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study

CONTEXT: The dopamine overactivity hypothesis of schizophrenia remains one of the most influential theories of the pathophysiology of the illness. Radiotracer brain imaging studies are now directly testing aspects of the overactivity hypothesis. OBJECTIVE: To assess presynaptic dopaminergic function in a large cohort of patients with schizophrenia by means of [18F]fluorodopa uptake and a high-sensitivity 3-dimensional positron emission tomograph. We predicted elevations in striatal [18F]fluorodopa uptake and reductions in prefrontal cortical [18F]fluorodopa uptake in patients with schizophrenia. DESIGN: Case-control study. SETTING: Research institute investigation recruiting hospital outpatients. PATIENTS: Sixteen male medicated hospital outpatients with a DSM-IV diagnosis of schizophrenia (mean age, 38 years) and 12 age-matched male volunteers free of psychiatric and neurologic illness. INTERVENTION: [18F]fluorodopa positron emission tomographic scanning. MAIN OUTDOME MEASURE: [18F]fluorodopa uptake constant Ki measured with statistical parametric mapping and region-of-interest analyses. RESULTS: Statistical parametric mapping (P<.05 corrected) and region-of-interest analyses (P<.01) showed increased [18F]fluorodopa uptake, confined primarily to the ventral striatum in patients with schizophrenia. No reductions in prefrontal cortical [18F]fluorodopa uptake Ki were seen in the statistical parametric mapping and region-of-interest analyses, although dorsal anterior cingulate [18F]fluorodopa Ki correlated with performance on the Stroop Color-Word Test in both groups. CONCLUSIONS: As in studies in unmedicated patients, presynaptic striatal dopamine dysfunction is present in medicated schizophrenic patients, adding further in vivo support for dopamine overactivity in the illness.     

Effect of dopamine loss and the metabolite 3-O-methyl-[18F]fluoro-dopa on the relation between the 18F-fluorodopa tissue input uptake rate constant Kocc and the [18F]fluorodopa plasma input uptake rate constant Ki.

Parkinson disease is characterized by the loss of dopaminergic neurons, thus decreasing the system's ability to produce and store dopamine (DA). Such ability is often investigated using 18F-fluorodopa (FD) positron emission tomography. A commonly used model to investigate the DA synthesis and storage rate is the modified Patlak graphical approach. This approach allows for both plasma and tissue input functions, yielding the respective uptake rate constants K(i) and K(occ). This method requires the presence of an irreversible compartment and the absence of any nontrapped tracer metabolite. In the case of K(occ), this last assumption is violated by the presence of the FD metabolite 3-O-methyl-[18F]fluoro-dopa (3OMFD), which makes the K(occ) evaluation susceptible to a downward bias. It was found that both K(i) and K(occ) are influenced by DA loss and thus are not pure measures of DA synthesis and storage. In the case of K(occ), the presence of 3OMFD exacerbates the effect of DA egress, thus introducing a disease-dependent bias in the K(occ) determination. These findings imply that K(i) and K(occ) provide different assessments of disease severity and that, as disease progresses, K(i) and especially K(occ) become more related to DA storage capacity and less to the DA synthesis rate.     

Levodopa effect on [18F]fluorodopa influx to brain: normal volunteers and patients with Parkinson's disease

OBJECTIVES: Levodopa is the immediate precursor of dopamine and the substrate for DOPA decarboxylase, an enzyme subject to regulation in living brain. To test whether this regulation changes in disease, we used Positron Emission Tomography (PET) with parametric mapping to measure the effect of levodopa on the net clearance of [(18)F]fluorodopa to brain (K, ml/g/min). METHODS: Five patients with early Parkinson's disease with pause of medication for 3 days and six age-matched healthy volunteers were studied in a baseline condition and after levodopa challenge. RESULTS: Levodopa (200 mg as Sinemet) increased the magnitude of the net clearance K in the left and right putamen of the healthy volunteers by 11% relative to the baseline condition. In contrast, resumption of medication with levodopa did not significantly alter the magnitude of K in putamen of the Parkinson's disease patients. Compartmental analysis was used to probe the physiological basis of the activation of K: levodopa treatment increased by 15% the apparent distribution volume of [(18)F]fluorodopa in cerebellum (, ml/g) of both patients and control subjects, without significantly altering the unidirectional blood-brain clearance (, ml/g/min) or the relative activity of DOPA decarboxylase (, min(-1)) in putamen. CONCLUSION: We conclude that levodopa treatment increases the distribution volume of [(18)F]fluorodopa in brain, increasing its availability for utilization in dopamine terminals. We speculate that levodopa act as a direct beta-adrenergic agonist at receptors regulating the permeability of the blood-brain barrier to levodopa. However, the PET analytical method was without sufficient power to detect the consequent increase in magnitude of K in brain of only five Parkinson's disease subjects.     

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.     

[18F]fluorodopa PET shows striatal dopaminergic dysfunction in juvenile neuronal ceroid lipofuscinosis.

OBJECTIVES: To investigate whether nigrostriatal dopaminergic hypofunction is related to the extrapyramidal symptoms in patients with juvenile neuronal ceroid lipofuscinosis (JNCL). METHODS: Nine patients with JNCL and seven healthy controls were studied using [18F]fluorodopa PET. RESULTS: In the patients with JNCL [18F]fluorodopa uptake (K[i][occ]) in the putamen was 60% of the control mean and the corresponding figure in the caudate nucleus was 79%. There was a weak correlation between putamen K(i)(occ) values and extrapyramidal symptoms of the patients evaluated by the motor part of the unified Parkinson's disease rating scale (r = -0.57, P < 0.05). The overall severity of the disease also displayed a negative correlation with the K(i)(occ) values in the putamen (r = -0.71, P < 0.05). CONCLUSION: In patients with JNCL there was reduced striatal [18F]fluorodopa uptake, which had a modest correlation with extrapyramidal symptoms. Dysfunction of nigrostriatal dopaminergic neurons is therefore not the only cause of the patients' extrapyramidal symptoms, but degenerative changes in other brain areas are also contributory.     

Decreased single-photon emission computed tomographic {123I}β-CIT striatal uptake correlates with symptom severity in parkinson's disease

Previous studies have utilized single-photon emission computed tomography (SPECT) to demonstrate decreased {¹²³I}β-CIT striatal uptake in idiopathic Parkinson disease (PD) patients. The present study extendss this work by examining SPECT outcome measures in a larger group of PD patients with varying disease severity. Twenty-eight l-dopa-responsive PD patients (Hoehn-Yahr stages 1–4) and 27 healthy controls had SPECT scans at 18 to 24 hours after injection of {¹²³I}β-CIT. Specific to nondisplaceable striatal uptake ratios (designated V_3″) were correlated with Hoehn-Yahr stage and Unified Parkinson's Disease Rating Scale (UPDRS) subscores. Linear discriminant function analyses utilizing striatal uptakes, putamen-to-caudate ratios, and ipsilateral-contralateral asymmetry indices were performed. Decreased striatal tracer uptake (V_3″) was correlated with total UPDRS score for both contralateral and ipsilateral striatum. Putamen uptake was relatively more reduced than caudate with mean putamen:caudate ratios of 0.50 ± 0.17 and 0.82 ± 0.09 for PD patients and controls, respectively. Ipsilateral:contralateral asymmetry was significantly greater in PD patients than controls. Discriminant function analysis utilizing V_3″ for ipsilateral and contralateral caudate and putamen correctly classified all 55 cases. These data demonstrate Marchked differences in {¹²³I}β-CIT SPECT measures in healthy controls and PD patients. The significant correlation of SPECT measures with motor severity suggests {¹²³I}β-CIT may be a useful Marchker of disease severity in PD.     

Nonlinear progression of Parkinson disease as determined by serial positron emission tomographic imaging of striatal fluorodopa F 18 activity

BACKGROUND: The investigation of disease progression provides important information on the dynamics of cell death in Parkinson disease (PD). OBJECTIVE: To determine the progression of dopaminergic impairment in PD with the use of positron emission tomography (PET). DESIGN: Longitudinal prospective cohort study with a follow-up period of 64.5 +/- 22.6 months (mean +/- SD). SETTING: University hospital. PATIENTS: A consecutive sample of patients with PD (N = 31; age at symptom onset, 53.6 +/- 11.3 years) with a wide range of symptom duration and severity at the time of study entry. INTERVENTIONS: Investigation by serial fluorodopa F 18 ([(18)F]fluorodopa) PET as a marker for striatal dopaminergic function. MAIN OUTCOME MEASURES: Changes in caudate and putaminal [(18)F]fluorodopa influx constant (K(i)) values. RESULTS: In patients with PD, the decline rate of putaminal [(18)F]fluorodopa K(i) correlated inversely with disease duration before study inclusion (r = -0.46, P = .01) and positively with baseline K(i) values (r = 0.44, P = .01), indicating a negative exponential loss of dopamine neurons. Annual disease progression rates ranged from 4.4% in the caudate nucleus to 6.3% in the putamen. A mean preclinical period of 5.6 +/- 3.2 years was calculated with symptom onset at a putaminal K(i) threshold of 69% from controls. Assuming nonlinear progression kinetics, the required sample size to prove neuroprotection with the use of [(18)F]fluorodopa PET was found to increase strongly with the preceding symptom duration of study subjects. CONCLUSION: These data suggest that the neurodegenerative process in PD follows a negative exponential course and slows down with increasing symptom duration, contradicting the long-latency hypothesis of PD.     

Somatomotor mu rhythm amplitude correlates with rigidity during deep brain stimulation in Parkinsonian patients

Objective

Parkinsonian patients have abnormal oscillatory activity within the basal ganglia-thalamocortical circuitry. Particularly, excessive beta band oscillations are thought to be associated with akinesia. We studied whether cortical spontaneous activity is modified by deep brain stimulation (DBS) in advanced Parkinson’s disease and if the modifications are related to the clinical symptoms.

Methods

We studied the effects of bilateral electrical stimulation of subthalamic nucleus (STN) on cortical spontaneous activity by magnetoencephalography (MEG) in 11 Parkinsonian patients. The artifacts produced by DBS were suppressed by tSSS algorithm.

Results

During DBS, UPDRS (Unified Parkinson’s Disease Rating Scale) rigidity scores correlated with 6-10 Hz and 12-20 Hz somatomotor source strengths when eyes were open. When DBS was off UPDRS action tremor scores correlated with pericentral 6-10 Hz and 21-30 Hz and occipital alpha source strengths when eyes open.Occipital alpha strength decreased during DBS when eyes closed. The peak frequency of occipital alpha rhythm correlated negatively with total UPDRS motor scores and with rigidity subscores, when eyes closed.

Conclusion

STN DBS modulates brain oscillations both in alpha and beta bands and these oscillations reflect the clinical condition during DBS.

Significance

MEG combined with an appropriate artifact rejection method enables studies of DBS effects in Parkinson’s disease and presumably also in the other emerging DBS indications.     

Cognitive impairment and the brain dopaminergic system in Parkinson disease: [18F]fluorodopa positron emission tomographic study

OBJECTIVE: To investigate the role of the brain dopaminergic system in cognitive impairment in patients with Parkinson disease (PD). DESIGN: We studied 28 patients with PD and 16 age-matched healthy control subjects using [18F] fluorodopa (fluorodopa F 18) positron emission tomography. Patients with PD showed a variable degree of cognitive impairment, which was assessed using the Mini-Mental State Examination and detailed neuropsychologic assessment, including tests sensitive for frontal lobe function. RESULTS: [18F] Fluorodopa uptake was reduced in the putamen (to 36% of the control mean; P<.001), the caudate nucleus (to 61% of the control mean; P<.001), and the frontal cortex (to 45% of the control mean; P<.001) in patients with PD compared with controls. There was no significant association between the degree of overall cognitive impairment of patients and [18F] fluorodopa uptake values. The influx constant (Ki(occ)) in the caudate nucleus had a negative association with performance in the attention-demanding Stroop interference task, especially with the interference time. The Ki(occ) in the frontal cortex had a positive correlation with performance in the digit span (backwards), verbal fluency, and verbal immediate recall tests. Thus, the better the patient performed in tasks demanding immediate and working memory and executive strategies, the better the [18F] fluorodopa uptake in the frontal cortex. In the putamen, no significant correlation was seen between the Ki(occ) value and any of the cognitive tests. The severity of the motor symptoms of PD and [18F]fluorodopa uptake showed a negative correlation in the putamen (r = -0.38; P = .04), and in the caudate nucleus a similar trend was seen (r = -0.36; P = .06). CONCLUSIONS: Reduced [18F]fluorodopa uptake in PD in the caudate nucleus (and frontal cortex) is related to impairment in neuropsychologic tests measuring verbal fluency, working memory, and attentional functioning reflecting frontal lobe function. This indicates that dysfunction of the dopamine system has an impact on the cognitive impairment of patients with PD. However, our results do not exclude the possibility of more generalized cognitive impairment in PD, the pathophysiology of which is probably different and more generalized.     

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.     

Clinical correlates of Parkinsonian signs in community- dwelling Chinese older persons: a population based study

BACKGROUND AND OBJECTIVE: This study examined the clinical correlates of parkinsonian signs including neuropsychiatric symptoms, cognitive impairment and medical illness burden in the community-dwelling non-demented Chinese elderly. METHODS: A random sample of 765 Chinese elderly subjects from a thematic household survey was recruited. There were 389 normal elderly controls (Clinical Dementia Rating [CDR] 0) (NC) and 376 subjects with questionable dementia (CDR 0.5). The subjects with questionable dementia (CDR 0.5) were categorized into two groups: a MCI group (n = 291) and a very mild dementia (VMD) group (n = 85). Parkinsonian signs were measured by Unified Parkinson Disease Rating Scale- motor scale (UPDRS). The clinical correlates were investigated in each group. RESULTS: UPDRS motor score was associated with age, cumulative medical illness burden and cerebrovascular accidents in the normal control and MCI groups. It correlated negatively with MMSE scores in the NC group. It was associated with presence of soft signs in the NC and MCI groups; and apathy in the VMD group. CONCLUSION: Neuropsychiatric symptoms, cognitive impairment and vascular risk factors had different patterns of associations with parkinsonian signs in the older persons with different degree of cognitive impairment.     

Haloperidol blocks the uptake of [18F]N-methylspiroperidol by extrastriatal dopamine receptors in schizophrenic patients

We had previously demonstrated extrastriatal uptake of [¹⁸F]N-methyl-spiroperidol (¹⁸F-NMS) in the human brain. This study evaluates the effect of haloperidol on ¹⁸F-NMS binding in extrastriatal brain regions. Six schizophrenic patients on haloperidol underwent two PET scans with ¹⁸F-NMS at 12 h and at 6 days after haloperidol withdrawal. There was a significant increase in ¹⁸F-NMS uptake in striatal, thalamic, and temporal regions but not in frontal, occipital, or cerebellar regions, following drug withdrawal. Haloperidol's ability to block the uptake of ¹⁸F-NMS is an indication of the specificity of the radioligand's binding in these regions and supports the postmortem data demonstrating the presence of dopamine D₂ receptors in the thalamus and temporal cortex of the human brain. © 1995 Wiley-Liss, Inc.