Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

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

Parkinson's 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 Parkinson's 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 Parkinson's 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.

Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease.

The power of placebos has long been recognized for improving numerous medical conditions such as Parkinson's disease (PD). Little is known, however, about the mechanism underlying the placebo effect. Using the ability of endogenous dopamine to compete for [11C]raclopride binding as measured by positron emission tomography, we provide in vivo evidence for substantial release of endogenous dopamine in the striatum of PD patients in response to placebo. Our findings indicate that the placebo effect in PD is powerful and is mediated through activation of the damaged nigrostriatal dopamine system.

Neuroimaging in Parkinson's disease.

Structural imaging studies often reveal relatively limited findings in Parkinsonian disorders, as the most profound changes are neurochemical and hence better revealed by functional studies such as PET or SPECT. However, newer magnetic resonance techniques such as spectroscopy, diffusion weighted imaging, diffusion tensor imaging and magnetization transfer have shown promise in differentiating between idiopathic Parkinson's and the atypical parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy. We review here recent advances in functional imaging as well as in structural studies of basal ganglia disorders. Functional studies may give insights into mechanisms underlying disease pathogenesis, as well as neurochemical alterations.

Placebo effect and dopamine release.

The placebo effect can be encountered in a great variety of medical conditions, but is particularly prominent in pain, depression and Parkinson's disease. It has been shown that placebo responses play a part in the effect of any type of treatment for Parkinson's disease, including drug therapy, deep brain stimulation and dopamine tissue transplantation. Recent studies have demonstrated that the placebo effect in Parkinson's disease is related to the release of substantial amounts of endogenous dopamine in both the dorsal and ventral striatum. As the ventral striatum is involved in reward processing, these observations suggest that the placebo effect may be linked to reward mechanisms. In keeping with this placebo-reward model, most recent experiments have shown activation of the reward circuitry in association with placebo responses in other disorders. In addition, as dopamine is the major neurotransmitter in the reward circuitry, the model predicts that the release of dopamine in the ventral striatum could be involved in mediating placebo responses not only in Parkinson's but also in other medical conditions.

Controlling for cerebral atrophy in positron emission tomography data.

This article outlines a simple method for estimating the degree of cerebral atrophy and subsequent experimental control for the effects of cerebral atrophy on regional metabolic values measured with positron emission tomography. It is suggested that rather than correcting derived values for atrophy, less potential error is introduced by experimentally controlling for regional atrophy when possible. By treating the derived metabolic rates and the measure of atrophy as two separate variables, it is also possible to establish whether there actually is a demonstrable relationship between the two measures.

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.

Regression model for predicting dissociations of regional cerebral glucose metabolism in individuals at risk for Huntington's disease.

This article describes and partially validates a method for predicting whether an observed regional metabolic value is consistent with the observed value of another region. A regression equation was generated from a set of normal metabolic values, and then this equation was applied to patients with symptomatic Huntington's disease and patients at risk for this disorder. The results of the regression method were consistent with observations of the absolute rate for the normal subjects and Huntington's patients. For the at-risk patients, 6 of 18 were found to have reduced caudate metabolism relative to observed thalamic values. Since the initial scan, one of these identified at-risk individuals has developed symptomatic Huntington's disease. The method may be appropriate for other disorders where there are potential subgroups (e.g., schizophrenia) within a diagnostic category.

Analysis of four dopaminergic tracers kinetics using two different tissue input function methods.

The integrity of the dopaminergic system can be studied using positron emission tomography. The presynaptic tracers [11C]-methylphenidate and [11C]dihydrotetrabenazine (DTBZ) are used to investigate the dopamine transporter availability, the dopamine vesicular transporter integrity; the postsynaptic tracers [11C]-raclopride and [11C]-Schering 23990 (SCH) are used to probe the D2 and D1 receptors. These are reversible tracers, where the binding potential (BP) = Bmax/Kd often is used to quantify the amount of their specific binding to the sites of interest. The simplified tissue input methods to calculate BP are attractive, since they do not require a blood input function. The suitability and performance of two such methods were evaluated: the Logan graphical tissue method, and the Lammertsma reference tissue method (RTM). The BP estimates obtained with the two methods were nearly identical in most cases, with similar reliability and reproducibility indicating that all four tracers satisfy the assumptions required by each method. The correlations among the fitted parameters obtained from the RTM were estimated and were found not to introduce noticeable bias in the RTM BP and R1 estimates. R1 showed low intersubject and intrasubject variability. The k2 estimate showed good reliability for SCH with cerebellar input function and DTBZ with occipital input function.

Increase in dopamine turnover occurs early in Parkinson's disease: evidence from a new modeling approach to PET 18 F-fluorodopa data.

An increase in dopamine turnover has been hypothesized to occur early in Parkinson's disease (PD) as a compensatory mechanism for dopaminergic neuronal loss. A new approach to the determination of dopamine turnover was developed using 4-hour-long 18 F-fluorodopa (FD) positron emission tomography (PET) data. An effective dopamine turnover, an estimate of dopamine turnover, has been measured using its inverse, the effective dopamine distribution volume (EDV). This new method is based on a reversible tracer approach and determines the EDV using a graphical method. Six healthy subjects and 10 subjects with very early PD underwent a 4-hour-long FD scan. The EDV and the plasma uptake rate constant K(i), a marker of dopamine synthesis and storage, were compared according to their ability to separate the PD group from the healthy group. The EDV was the better discriminator (93.8% correct classification versus 81.3% for K(i)). Effective dopamine distribution volume decreased by 65% in the PD group relative to the healthy group, whereas the decrease in K(i) was 39%. These results show that changes in EDV are measurable with PET earlier than changes in the dopamine synthesis and storage rate, indicating that EDV is a sensitive marker for early PD and that a dopamine turnover increase likely serves as an early compensatory mechanism.

Apomorphine-induced changes in synaptic dopamine levels: positron emission tomography evidence for presynaptic inhibition.

The authors developed a novel positron emission tomography method to estimate changes in the synaptic level of dopamine ([DA]) induced by direct dopamine agonists (for example, apomorphine) in patients with Parkinson disease. The method is based on the typical asymmetry of the nigrostriatal lesion that often occurs in Parkinson disease. Using the between-side difference (ipsilateral (I) and contralateral (C) putamen to the more affected body side) of the inverse of the putamen [11C]raclopride binding potential (BP), the authors obtained [equation: see text] at baseline (that is, before apomorphine administration) and [equation: see text] after apomorphine administration (assuming the concentration of apomorphine is equal in both putamina). The between-side difference in the estimated synaptic concentration of dopamine (diff[DA]) should remain constant unless apomorphine affects dopamine release differently between the two sides. The authors found that apomorphine given subcutaneously at doses of 0.03 and 0.06 mg/kg induced significant changes in their estimate of diff[DA] (P < 0.05). Such changes were more pronounced when only patients with a stable response to levodopa were considered (P < 0.01). These findings provide in vivo evidence that direct dopamine agonists can inhibit the release of endogenous dopamine. The authors propose that this effect is mainly mediated by the activation of presynaptic D2/D3 dopamine receptors.

Nemaline myopathy with associated cardiomyopathy. Report of clinical and detailed autopsy findings.

We describe the clinical features and autopsy findings of an adult patient who had nemaline myopathy and an associated progressive cardiomyopathy. The spinal cord and the results of morphometric analysis of multiple peripheral nerves were normal. There was probable intrafusal fiber involvement, in addition to the typical histopathologic features of extrafusal fibers. Cardiac dysfunction was a prominent clinical and autopsy feature, but it has been infrequently recognized in this entity. Our findings suggest that there is a poor correlation between clinical and pathologic features in this disorder, and they support the need for careful cardiac evaluation of affected patients. Furthermore, the constellation of features favors a myopathic basis for the disease, in contradistinction to some previously expressed views.

The combined use of positron emission tomography and DNA polymorphisms for preclinical detection of Huntington's disease.

Twenty-three persons at risk for Huntington's disease (HD) have been studied using a polymorphic human linked DNA marker (D4S10) and positron emission tomography (PET). We determined the likelihood of inheritance of the gene for HD in 13 persons, using DNA polymorphism studies. Of these, eight persons had a greater than 90% probability of being presymptomatic heterozygotes for HD. Three of these eight subjects had caudate glucose utilization detected by PET that was more than 2 standard deviations (SD) below the age-matched control mean. Measurement of caudate glucose utilization in the other five presumed presymptomatic heterozygotes revealed results between 1 and 2 SD below the mean. Five persons had a less than 10% likelihood of having inherited the abnormal gene for HD. Of these, four had normal rates of glucose utilization in the caudate nuclei. However, one individual with DNA results indicating a low risk of developing HD had abnormally low measures of caudate glucose utilization. This suggests that a recombination had occurred between the linked marker and the gene in this person. These studies suggest that PET studies of caudate glucose utilization may help to confirm results of DNA studies in some persons, and may provide an opportunity to detect when DNA results may be incorrect due to recombination.

Cortical glucose metabolism in Huntington's disease.

We measured cortical glucose metabolism with positron emission tomography in 39 patients with Huntington's disease (HD) and in 34 controls. In the 23 patients with symptoms for less than 5 years, there was a 15% decrease in metabolism in frontal and inferior parietal cortex. In 16 patients with symptoms for more than 5 years, all cortical areas (except temporal) were significantly involved, with metabolic rates 25 to 30% below those of controls. These data indicate the presence of a diffuse abnormality of cortical function with early involvement of frontal lobes in HD, suggesting that the clinical manifestations may not be related solely to basal ganglia pathology, even in early disease.

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

We studied 10 patients with early Huntington's 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 Huntington's disease irrespective of the mode of presentation. PET may also be useful for preclinical detection and may supplement information from DNA studies.

Lesions of the putamen: their relevance to dystonia.

Two patients with acquired dystonia were studied by computed imaging techniques and found to have lesions predominantly involving the putamen. The implications of these findings are discussed, and it is concluded that, for the genesis of dystonia, a relative increase of other inputs to the pallidum may be important, such as those from the caudate and subthalamic nuclei.

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.

PET studies of cerebral glucose metabolism in idiopathic torticollis.

Regional cerebral glucose metabolism was studied in 16 patients with idiopathic torticollis, using positron emission tomography. Analysis of subcortical regions revealed no consistent focal abnormality of cerebral metabolic rate for glucose, but there was a bilateral breakdown of the normal relationships between the thalamus and basal ganglia. The findings suggest disruption of the pallidothalamic projections in this focal dystonia and may imply a disturbance of GABA.

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.

SCA-2 presenting as parkinsonism in an Alberta family: clinical, genetic, and PET findings.

The authors describe an Alberta family with levodopa-responsive parkinsonism without cerebellar abnormalities. Genetic testing showed expanded repeats for SCA-2; other mutations for parkinsonism were excluded. The expanded allele shows interruption of the CAG repeat with CAA. PET in two affected members showed reduced fluorodopa uptake in striatum and normal raclopride binding. Families with autosomal dominant, levodopa-responsive parkinsonism should be tested for the SCA-2 mutation.