A.J. Stoessl

PET demonstrates reduced dopamine transporter expression in PD with dyskinesias

Objective: Dyskinesias are common in Parkinson disease (PD). Prior investigations suggest that dopamine (DA) terminals compensate for abnormal DA transmission. We verified whether similar adaptations could be related to the development of treatment-related complications. Methods: Thirty-six patients with PD with motor fluctuations were assessed with PET using [11C]-d-threo-methylphenidate (MP) and [11C]-(±) dihydrotetrabenazine (DTBZ). The expression of DA transporter relative to DA nerve terminal density was estimated by determining the MP/DTBZ ratio. Age, treatment, and disease severity were also taken into account in the evaluation of our data. Results: Twenty-seven of the 36 patients had dyskinesias. Nine individuals had motor fluctuations without dyskinesia. The two patient groups were comparable in terms of age, disease duration and severity, medication, and striatal MP and DTBZ binding potentials. The MP/DTBZ ratio in the caudate was not different between groups (nondyskinesia 1.54 ± 0.36, dyskinesia 1.39 ± 0.28; mean ± SD, p = 0.23). Putaminal MP/DTBZ was decreased in individuals with dyskinesia (1.18 ± 0.24), compared to those who had motor fluctuations without dyskinesia (1.52 ± 0.24, p = 0.019). The relationship between putaminal MP/DTBZ ratio and the presence of dyskinesias was not altered after correcting for age, treatment, and measures of disease severity. Conclusions: This investigation supports the role of presynaptic alterations in the appearance of dyskinesias. Dopamine (DA) transporter downregulation may minimize symptoms by contributing to increased synaptic DA levels in early Parkinson disease, but at the expense of leading to increased extracellular DA catabolism and oscillating levels of DA. Such oscillations might ultimately facilitate the appearance of dyskinesias. BP = binding potential; COMTi = catechol-O-methyl transferase inhibitors; CR = controlled release; DA = dopamine; DAT = DA transporter; DTBZ = [11C]-(±) dihydrotetrabenazine; DVR = distribution volume; MF = motor fluctuation; MP = [11C]-d-threo-methylphenidate; PD = Parkinson disease; ROI = region of interest; UPDRS = Unified Parkinson’s Disease Rating Scale.

Evidence for impaired presynaptic dopamine function in parkinsonian patients with motor fluctuations.

Summary. We used [18F]6-fluorodopa (FD) positron emission tomography (PET) to examine the severity of nigrostriatal dopaminergic dysfunction in 67 patients with Idiopathic Parkinsonism (IP), 52 with fluctuations and 15 with a stable response to levodopa. FD uptake (Ki) was reduced by 12% in the caudate (p = 0.08) and by 28% in the putamen (p = 0.0004) of patients with fluctuations compared to those with a stable response. However, there was considerable overlap of FD Ki values between the two groups. The fluctuators had a longer symptom duration (11.6 ± 5.7 years) than the patients with a stable response to levodopa (4.3 ± 2.4 years; p < 0.0001) and the age of onset of symptoms was earlier in the fluctuators (43.9 ± 8.9 versus 54.1 ± 10.4; p = 0.0004). Similar reductions in FD Ki in the fluctuators persisted following adjustment for these variables (7.5% in the caudate and 26% in the putamen; p = n.s. and 0.007, respectively). When smaller groups (n = 15 each) were matched for duration of symptoms, the reduction in caudate Ki in the fluctuators was only 1.9% (p = n.s.), but there was still a 24% reduction in putamen Ki (p = 0.05). These findings suggest that fluctuators and non-fluctuators may differ in the severity of their nigrostriatal damage and provide modest support for the hypothesis that fluctuations may in part reflect altered buffering capacity of dopaminergic nerve terminals. However, the considerable overlap between groups suggests that other factors such as altered postsynaptic mechanisms and/or increased turnover of dopamine may make a substantial contribution to the development of motor fluctuations.

Striatal D2 receptors in symptomatic and asymptomatic carriers of dopa-responsive dystonia measured with [11C]-raclopride and positron-emission tomography

We tested the hypothesis that asymptomatic carriers of dopa-responsive dystonia (DRD) have increased dopamine D2 receptors in the striatum that protect them from the clinical manifestations of dopaminergic deficiency. We examined striatal D2-receptor binding in (1) symptomatic subjects (treated and untreated) and (2) asymptomatic gene carriers. Using[11C]-raclopride PET, we found elevated striatal D2-receptor binding in both groups. In one of our drug-naive symptomatic subjects, 7 months of treatment with levodopa/carbidopa did not affect the receptor binding as measured on a second scan. We conclude that increased D2-receptor binding in DRD may be a homeostatic response to the dopaminergic deficit in subjects carrying the DRD gene, but is not the sole factor determining the clinical state of these individuals.

Daytime somnolence in patients with Parkinson's disease

We studied daytime sleepiness in 160 patients with Parkinsons disease and 40 normal subjects. We compared the prevalence of daytime sleepiness in patients who were taking levodopa alone, levodopa with bromocriptine, levodopa with ropinirole, and levodopa with pramipexole. We found that (1) all these anti-Parkinson drugs can cause daytime sleepiness; (2) dozing off correlated highly with falling asleep without warning; (3) after statistical adjustment for confounding variables there was no significant difference among the risks for any of these anti-Parkinson drugs causing daytime somnolence.

Alternating two finger tapping with contralateral activation is an objective measure of clinical severity in Parkinson's disease and correlates with PET [18F]-DOPA Ki

We explored an objective method of measuring clinical severity of Parkinsons 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 Parkinsons 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 Parkinsons disease.

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.

Positron emission tomography of dopamine pathways in familial Parkinsonian syndromes

Positron emission tomography (PET) scan is considered to be the most useful tool with which to assess the integrity of nigrostriatal function in the living brain. Recently, different genetic defects have been associated with a variety of familial parkinsonian syndromes, the clinical phenotypes of which have varying degrees of similarities to idiopathic parkinsonism (IP), (sporadic Parkinsons disease). This review summarizes: (1) the PET scan findings (fluorodopa uptake and raclopride binding) in both familial parkinsonian syndromes and IP; and (2) the similarities and differences of the clinical and PET features between familial parkinsonian syndromes and IP. This analysis demonstrates that more similarities than differences exist in PET scan findings in the different familial parkinsonian syndromes with the exception of pallido-ponto-nigral degeneration (PPND), that is perhaps best considered as multisystem degeneration. As a result of this analysis, we believe that while different genetic defects may underlie different mechanisms of nigrostriatal degeneration, the final pattern of nigrostriatal dysfunction is essentially similar to that of IP. Parkinsons disease, therefore, may not represent a single disease entity, but rather the final manifestation of different pathogenetic mechanisms-mediated by genetic or environmental factors, or an interaction of genetic and environmental factors.

Effect of age on caudate dopaminergic function in idiopathic Parkinsonism

Aging has long been implicated in the pathogenesis of Idiopathic Parkinsonism (IP). However, postmortem studies have demonstrated that the pathological changes in aging and IP affect the dopaminergic function in putamen and caudate nuclei differently. This has been considered by some authors as evidence against the role of aging in IP. We performed fluorodopa (FD) positron emission tomography (PET) in 36 patients with IP and 25 normal controls to test the hypothesis that the effect of aging on the striatal dopaminergic function in IP differs from the effect of aging in normal controls. We found that the FD uptake constant (Ki) in the caudate nucleus of patients with IP declines with both age (p = 0.002) and duration (p = 0.05) of symptoms. This effect was over and above that of normal aging (p = 0.007). We did not find a similar superimposed effect of age in the putamen. We conclude that the effect of aging on the dopaminergic function in the caudate nucleus in IP differs from that in normal aging. Whether this abnormal aging precedes and even predisposes to IP or is triggered by pathogenetic factors in IP is unclear.

Impact of the spatial normalization template and realignment procedure on the SPM analysis of [11C]Raclopride PET studies

Background/Objectives: In this paper, we address the issue of how the preprocessing steps of a typical neuroreceptor PET study may influence the outcome of a statistical parametric mapping (SPM) analysis examining intercondition differences. Two preprocessing steps and their possible interaction were investigated: 1) the realignment of dynamic images to correct for patients motion and 2) the effect of the template in the spatial normalization step required by SPM. Methods : The impact of different realignment methods was tested by performing the SPM analysis on a six patient-two conditions /sup 11/C-raclopride (RAC) study where the dynamic images of each subject were re-aligned with four methods. Once realigned, the images were spatially normalized to the standard cerebral blood flow (CBF) template, available in SPM, and to a RAC template. The SPM pattern showing the intercondition differences obtained in each case was compared with the expected one. The accuracy of the four realignment methods used was further tested using a set of motion-free RAC studies. Results/Conclusion: We found that: 1) different realignment methods may create different intercondition difference patterns; 2) such differences in the results may be due to a failure in accuracy of some realignment methods; and 3) the use of a template that closely matches the spatial distribution of the tracer under investigation can minimize these problems.

New concepts and tools in imaging for the study of neurodegenerative disease

Existing technologies permit the detection of changes in neurotransmitter and/or neuroreceptor expression. This may be useful for diagnosis, for monitoring disease progression, and for assessing the pathogenesis of complications associated with long-term treatment. Although the binding of [11C]raclopride to D2 receptors is subject to competition from endogenous dopamine, this can be exploited to estimate changes in synaptic levels of dopamine. Assessment of processes downstream to the receptor will require the development of new approaches.