Thomas J. Ruth

In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease

Clinical symptoms of Parkinsons disease (PD) do not manifest until dopamine (DA) neuronal loss reaches a symptomatic threshold. To explore the mechanisms of functional compensation that occur in presynaptic DA nerve terminals in PD, we compared striatal positron emission tomographic (PET) measurements by using [11C]dihydrotetrabenazine ([11C]DTBZ; labeling the vesicular monoamine transporter type 2), [11C]methylphenidate (labeling the plasma membrane DA transporter), and [18F]dopa (reflecting synthesis and storage of DA). Three consecutive PET scans were performed in three‐dimensional mode by using each tracer on 35 patients and 16 age‐matched, normal controls. PET measurements by the three tracers were compared between subgroups of earlier and later stages of PD, between drug‐naive and drug‐treated subgroups of PD, and between subregions of the parkinsonian striatum. The quantitative relationships of [18F]dopa and [11C]DTBZ, and of [11C]methylphenidate and [11C]DTBZ, were compared between the PD and the normal control subjects. We found that [18F]dopa Ki was reduced less than the binding potential (Bmax/Kd) for [11C]DTBZ in the parkinsonian striatum, whereas the [11C]methylphenidate binding potential was reduced more than [11C]DTBZ binding potential. These observations suggest that the activity of aromatic L‐amino acid decarboxylase is up‐regulated, whereas the plasma membrane DA transporter is down‐regulated in the striatum of patients with PD. Ann Neurol 2000;47:493–503.

Dopamine release in human ventral striatum and expectation of reward.

Using the ability of [11C]raclopride to compete with dopamine for D(2)/D(3) receptors, we investigated by positron emission tomography the effect of placebo (saline) injection on dopamine release in the ventral striatum of patients with Parkinsons disease. We found evidence for placebo-induced dopamine release of similar magnitude to that reported in healthy volunteers after amphetamine administration. However, in contrast to the dorsal striatum, there were no differences in [11C]raclopride binding potential changes between patients who experienced the reward (those who reported placebo-induced clinical benefit) and those who did not. We conclude that the release of dopamine in the ventral striatum (nucleus accumbens) is related to the expectation of reward and not to the reward itself. These observations have potential implications for the treatment of drug addiction.

Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson's disease: PET evidence of increased dopamine turnover

Motor fluctuations are a major disabling complication in the treatment of Parkinsons disease. To investigate whether such oscillations in mobility can be attributed to changes in the synaptic levels of dopamine, we studied prospectively patients in the early stages of Parkinsons disease with a follow‐up after at least 3 years of levodopa treatment. At baseline, 3 positron emission tomography (PET) scans using [11C]raclopride before and after (1 hour and 4 hours) orally administered levodopa were performed on the same day for each patient. Patients who developed “wearing‐off” fluctuations during the follow‐up period had a different pattern of levodopa‐induced changes in [11C]raclopride binding potential (BP) from that observed in patients who were still stable by the end of the follow‐up. Thus, 1 hour post‐levodopa the estimated increase in the synaptic level of dopamine was 3 times higher in fluctuators than in stable responders. By contrast, only stable responders maintained increased levels of synaptic dopamine in the PET scan performed after 4 hours. These results indicate that fluctuations in the synaptic concentration of dopamine precede clinically apparent “wearing‐off” phenomena. The rapid increase in synaptic levels of dopamine observed in fluctuators suggests that increased dopamine turnover might play a relevant role in levodopa‐related motor complications. Ann Neurol 2001;49:298–303

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. Synapse 30:56–61, 1998. Published 1998 Wiley‐Liss, Inc.

Positron emission tomography in the early diagnosis of Huntington's disease

We studied 10 patients with early Huntingtons disease and 7 normal age-matched controls with positron emission tomography (PET) using fluorodeoxyglucose. Subjects had little or no caudate nucleus atrophy and had not received any medications. The results demonstrated that hypometabolism of glucose preceded tissue loss. Furthermore, patients with minimal neurologic or psychiatric symptoms and no obvious CT changes may be differentiated from normal persons with high accuracy by PET. PET is helpful in the early diagnosis of Huntingtons disease irrespective of the mode of presentation. PET may also be useful for preclinical detection and may supplement information from DNA studies.

Effects of Expectation on Placebo-Induced Dopamine Release in Parkinson Disease

CONTEXT Expectations play a central role in the mechanism of the placebo effect. In Parkinson disease (PD), the placebo effect is associated with release of endogenous dopamine in both nigrostriatal and mesoaccumbens projections, yet the factors that control this dopamine release are undetermined. OBJECTIVE To determine how the strength of expectation of clinical improvement influences the degree of striatal dopamine release in response to placebo in patients with moderate PD. DESIGN Randomized, repeated-measures study with perceived expectation as the independent between-subjects variable. SETTING University of British Columbia Hospital, Vancouver, British Columbia, Canada. Patients Thirty-five patients with mild to moderate PD undergoing levodopa treatment. Intervention Verbal manipulation was used to modulate the expectations of patients, who were told that they had a particular probability (25%, 50%, 75%, or 100%) of receiving active medication when they in fact received placebo. MAIN OUTCOME MEASURES The dopaminergic response to placebo was measured using [11C]raclopride positron emission tomography. The clinical response was also measured (Unified Parkinson Disease Rating Scale) and subjective responses were ascertained using patient self-report. RESULTS Significant dopamine release occurred when the declared probability of receiving active medication was 75%, but not at other probabilities. Placebo-induced dopamine release in all regions of the striatum was also highly correlated with the dopaminergic response to open administration of active medication. Whereas response to prior medication was the major determinant of placebo-induced dopamine release in the motor striatum, expectation of clinical improvement was additionally required to drive dopamine release in the ventral striatum. CONCLUSIONS The strength of belief of improvement can directly modulate dopamine release in patients with PD. Our findings demonstrate the importance of uncertainty and/or salience over and above a patients prior treatment response in regulating the placebo effect and have important implications for the interpretation and design of clinical trials.

Feedback Regulation of Nitrate Influx in Barley Roots by Nitrate, Nitrite, and Ammonium

The short-lived radiotracer 13N was used to study feedback regulation of nitrate influx through the inducible high-affinity transport system of barley (Hordeum vulgare L. cv Steptoe) roots. Both wild-type plants and the mutant line Az12:Az70 (genotype nar1a;nar7w), which is deficient in the NADH-specific and NAD(P)H-bispecific nitrate reductases (R.L. Warner, R.C. Huffaker [1989] Plant Physiol 91: 947–953) showed strong feedback inhibition of nitrate influx within approximately 5 d of exposure to 100 fmu]M nitrate. The result with the mutant, in which the flux of nitrogen into reduced products is greatly reduced, indicated that nitrate itself was capable of exercising feedback regulation upon its own influx. This conclusion was supported by the observation that feedback in wild-type plants occurred in both the presence and absence of L-methionine sulfoximine, an inhibitor of ammonium assimilation. Nitrite and ammonium were also found to be capable of exerting feedback inhibition upon nitrate influx, although it was not determined whether these ions themselves or subsequent metabolites were responsible for the effect. It is suggested that feed-back regulation of nitrate influx is potentially mediated through several nitrogen pools, including that of nitrate itself.

Longitudinal progression of sporadic Parkinson's disease: a multi-tracer positron emission tomography study

Parkinsons disease is a heterogeneous disorder with multiple factors contributing to disease initiation and progression. Using serial, multi-tracer positron emission tomography imaging, we studied a cohort of 78 subjects with sporadic Parkinsons disease to understand the disease course better. Subjects were scanned with radiotracers of presynaptic dopaminergic integrity at baseline and again after 4 and 8 years of follow-up. Non-linear multivariate regression analyses, using random effects, of the form BP(ND)(t) or K(occ)(t) = a*e((-)(bt)(-d)(A) + c, where BP(ND) = tracer binding potential (nondispaceable), K(OCC) = tracer uptake constant a, b, c and d are regression parameters, t is the symptom duration and A is the age at onset, were utilized to model the longitudinal progression of radiotracer binding/uptake. We found that the initial tracer binding/uptake was significantly different in anterior versus posterior striatal subregions, indicating that the degree of denervation at disease onset was different between regions. However, the relative rate of decline in tracer binding/uptake was similar between the striatal subregions. While an antero-posterior gradient of severity was maintained for dopamine synthesis, storage and reuptake, the asymmetry between the more and less affected striatum became less prominent over the disease course. Our study suggests that the mechanisms underlying Parkinsons disease initiation and progression are probably different. Whereas factors responsible for disease initiation affect striatal subregions differently, those factors contributing to disease progression affect all striatal subregions to a similar degree and may therefore reflect non-specific mechanisms such as oxidative stress, inflammation or excitotoxicity.

Age-specific progression of nigrostriatal dysfunction in Parkinson's disease

To investigate in vivo the impact of age on nigrostriatal dopamine dysfunction in Parkinsons disease (PD).

Dopamine transporter relation to dopamine turnover in Parkinson's disease: a positron emission tomography study.

To investigate the role of the dopamine transporter (DAT) in the regulation of synaptic dopamine (DA) levels in Parkinsons disease and its role in the preservation of DA in presynaptic terminals.