The presymptomatic period in a patient with idiopathic parkinsonism

A 68-year-old, normal female volunteer was scanned by positron emission tomography (PET) with [(18)F]6-L-fluorodopa (FD). Striatal FD uptake was in the high normal range. Subsequently, she developed parkinsonism 3.7 years after the scan. A repeat FD PET scan revealed a significant reduction of FD uptake by 20% over the 5.2 year interval. Our observations suggest a relatively short presymptomatic period with fast initial losses of nigral neurons in idiopathic parkinsonism.     

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.     

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.     

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.     

Relatively spared mesocorticolimbic dopaminergic system in juvenile parkinsonism

This study aims to examine the function of the mesocorticolimbic dopaminergic system, including the amygdala, in recognizing emotions in juvenile parkinsonism (JP). Eleven patients with JP and 16 age-matched controls selected one basic emotion (happiness, sadness, anger, fear, surprise, or disgust) that best described the emotional state represented by visual and auditory stimuli. There was no significant difference between the patients and normal controls in their recognition of emotions. The spared emotion recognition in JP could be attributed to the absence of any pathological changes or the normal dopamine concentrations in the mesocorticolimbic system in this condition.     

Pattern of dopaminergic loss in the striatum of humans with MPTP induced parkinsonism

OBJECTIVES: To examine the distribution of striatal dopaminergic function in humans with parkinsonism induced by 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) to determine if there is a caudate-putamen gradient as is seen in idiopathic Parkinson's disease. METHODS: We scanned nine humans exposed to MPTP with parkinsonism ranging from minimal to severe using [(18)F]fluorodopa (FD) and high resolution PET. The results were compared with those of 10 patients with Parkinson's disease and six normal subjects. RESULTS: In the MPTP group there was an equal degree of reduction of dopaminergic function in the caudate and putamen. This was different from the greater putaminal than caudate loss in Parkinson's disease (p<0.001). CONCLUSIONS: Parkinson's disease is not caused by transient exposure to MPTP.     

Nigrostriatal dysfunction in patients with amyotrophic lateral sclerosis and parkinsonism

The pathomechanism of amyotrophic lateral sclerosis (ALS) with parkinsonism (ALS-P) has not been clarified. We report two patients with ALS-P who showed dysfunction of the nigrostriatal system. The first patient showed tremor dominant, asymmetric parkinsonism which was more severe on the right side, while the second patient exhibited predominant freezing of gait. Both patients showed reduced uptake of [1?F] N-(3-fluoropropyl)-2?-carbon ethoxy-3?-(4-iodophenyl) nortropane (1?F-FP-CIT) in the posterior parts of bilateral putamina on positron emission tomography (PET). Based on our PET findings, we suggest that presynaptic nigrostriatal dysfunction may be involved in the pathomechanism of parkinsonism combined with ALS.     

Juvenile parkinsonism

Juvenile parkinsonism (JP) is a clinically and etiologically heterogeneous entity. Unlike in the adult form, secondary causes, hereditary and metabolic conditions, are the predominant causes of JP. Idiopathic Parkinson's disease is very rare in this age group. In most cases of JP, parkinsonism is accompanied by other neurologic features, such as dystonia, cognitive impairment, seizures, oculomotor and visual dysfunction, and ataxia. Systemic findings, such as liver dysfunction or hepatosplenomegaly, may be present depending on the cause. This review article describes the clinical characteristics, classification, genetic basis, pathophysiology, biochemistry, pathology, and treatment of JP.     

Development of the nosological analysis of juvenile parkinsonism

In the nosological viewpoint concerning diseases with a pathophysiological dysfunction of the nigro-striatal dopaminergic system, juvenile parkinsonism (JP) is discussed in this paper in relation to hereditary progressive dystonia (HPD) and Parkinson's disease (PD). Most cases of JP have dystonia with parkinsonism, which is the main symptom of HPD. In the symptomatological analysis of complication with dystonia, an interesting observation arose as regards on the anatomical and functional development of the basal ganglia through patients with childhood onset HPD and JP. Genetic analysis revealed the disease entity of HPD to be an abnormality of the GTP-CH I gene. Consequently, it has been clarified that clinical differences between HPD and JP were not merely derived from differences in developmental processes. Furthermore, the autosomal recessive type of JP (AR-JP) was confirmed to be a disease entity by the detection of an abnormality of the 'parkin' gene. The nosological controversy about JP and PD in the clinical standpoint has been clarified. However, as more than half of patients with JP do not carry a mutation in the 'parkin' gene, more investigations concerning nosological entities should be carried out. The absence of Lewy bodies in most patients with AR-JP has been confirmed to be a characteristic neorupathological finding as compared with those with typical PD pathology. In this paper, we discuss the above findings.     

Positron emission tomographic studies of dopa-responsive dystonia and early-onset idiopathic parkinsonism

There are two major syndromes presenting in the early decades of life with dystonia and parkinsonism: dopa-responsive dystonia (DRD) and early-onset idiopathic parkinsonism (EOIP). DRD presents predominantly in childhood with prominent dystonia and lesser degrees of parkinsonism. EOIP presents before age 40 with parkinsonism (often with associated dystonia). Both disorders are exquisitely sensitive to levodopa, although the long-term prognosis in each appears to be different. Some have suggested, however, that DRD is a form of EOIP. We performed positron emission tomography with 6-fluorodopa in 10 patients with DRD and 18 patients with EOIP to study the integrity of their nigrostriatal dopaminergic systems. In DRD, we found normal striatal FD uptake. In contrast, patients with EOIP had reduced striatal FD uptake. We conclude that the pathophysiologies of DRD and EOIP are distinct. Although both disorders presumably represent a deficiency of striatal dopamine, the results suggest that in DRD dopa uptake, decarboxylation, and storage mechanisms are intact. This may explain the sustained response of DRD to low doses of levodopa. 6-Fluorodopa positron emission tomography distinguishes DRD from EOIP.     

Dopaminergic neuronal dysfunction associated with parkinsonism in both a Gaucher disease patient and a carrier

A clinical association between Gaucher disease and parkinsonism has been demonstrated. We herein report a Japanese patient with type 3 Gaucher disease who was compound heterozygous for F213I and L444P mutations in the glucocerebrosidase gene while his father was heterozygous for the L444P mutation. They both presented with parkinsonism characterized by a predominance of akinetic-rigid signs and a favorable response to anti-Parkinson therapies. We investigated the dopaminergic neuronal function using positron emission tomography (PET) with radioligands, [(11)C] CFT and [(11)C] raclopride. PET studies of both patients demonstrated the [(11)C] CFT uptake to be severely decreased in the putamen and the caudate nucleus, however, the [(11)C] raclopride uptake was normal in the basal ganglia. Although the majority of Gaucher disease patients with parkinsonism tend to be refractory to anti-Parkinson therapies. The clinical features and the findings of the PET studies suggest that patients with parkinsonism associated with the mutation in the glucocerebrosidase gene, even in heterozygosis, may be related to the presynaptic dopaminergic neuronal dysfunction reported in Parkinson's disease. A PET study to evaluate the dopaminergic neuronal function in Gaucher disease would provide both a better understanding of the effects of anti-Parkinson therapies and a help to improve our ability to make an early diagnosis of parkinsonism associated with Gaucher disease.     

Autosomal recessive juvenile parkinsonism: A key to understanding nigral degeneration in sporadic Parkinson's disease

The contribution of genetic factors to the pathogenesis of Parkinson's disease (PD) is supported by the demonstration of the high concordance in twins studies using positron emission tomography (PET), the increased risk among relatives of PD patients in case–control and family studies, and the existence of familial PD and parkinsonism by single gene defect. Recently several genes have been mapped and/or identified. α‐Synuclein is involved in a rare dominant form of familial PD with dopa‐responsive parkinsonism features and Lewy body‐positive pathology. In contrast, parkin is responsible for the autosomal recessive form (AR‐JP) of early onset PD with Lewy body‐negative pathology. The clinical features of this form include early onset (in the 20s), levodopa‐responsive parkinsonism, diurnal fluctuation, and slow progression of the disease. Parkin consists of 12 exons and the estimated size is over 1.5 Mb. To date, variable mutations such as deletions or point mutations resulting in missense and nonsense changes have been reported in AR‐JP patients. In addition, the localization of parkin indicates that parkin may be involved in the axonal transport system. More recently we have found that parkin interacts with the ubiquitin‐conjugating enzyme E2 and is functionally linked to the Ub‐proteasome pathway as a ubiquitin ligase, E3. These findings fit the characteristics of a lack of Lewy bodies (these are cytoplasmic inclusions that are considered to be a pathological hallmark). Our findings should enhance the exploration of the mechanisms of neuronal death in PD as well as other neurodegenerative disorders of which variable inclusion bodies are observed.     

SPECT imaging of the dopamine transporter in juvenile-onset dystonia

Juvenile-onset dystonia that improves after levodopa may occur in both dopa-responsive dystonia (DRD) and juvenile parkinsonism (JP), clinically similar conditions with different prognoses and management goals. The authors show normal striatal uptake of the dopamine transporter ligand FP-CIT with SPECT in a clinically atypical case of DRD, in contrast to the reduced uptake observed in JP.     

The nigrostriatal dopaminergic pathway in Wilson''s disease studied with positron emission tomography.

Movement disorders, including Parkinsonism, are prominent features of neurological Wilson's disease (WD). This suggests there may be dysfunction of the nigrostriatal dopaminergic pathway. To explore this possibility, five patients were studied using positron emission tomography (PET) with 18F-6-fluorodopa (6FD), and magnetic resonance imaging (MRI). We calculated striatal 6FD uptake rate constants by a graphical method and compared the results with those of 18 normal subjects. It was found that four patients with symptoms all had abnormally low 6FD uptake, and the one asymptomatic patient had normal uptake. PET evidence for nigrostriatal dopaminergic dysfunction was present even after many years of penicillamine treatment. It is concluded that the nigrostriatal dopaminergic pathway is involved in neurological WD.     

18F]FDOPA PET and clinical features in parkinsonism due to manganism.

Manganese exposure reportedly causes a clinically and pathophysiologically distinct syndrome from idiopathic Parkinson's disease (PD). We describe the clinical features and results of positron emission tomography with 6-[18F]fluorodopa ([18F]FDOPA PET) of a patient with parkinsonism occurring in the setting of elevated blood manganese. The patient developed parkinsonism associated with elevated serum manganese from hepatic dysfunction. [18F]FDOPA PET demonstrated relatively symmetric and severely reduced [18F]FDOPA levels in the posterior putamen compared to controls. The globus pallidum interna had increased signal on T1-weighted magnetic resonance imaging (MRI) images. We conclude that elevated manganese exposure may be associated with reduced striatal [18F]FDOPA uptake, and MRI may reveal selective abnormality within the internal segment of the pallidum. This case suggests that the clinical and pathophysiological features of manganese-associated parkinsonism may overlap with that of PD.     

Mutation analysis of ATP13A2 in early-onset parkinsonism patients☆○

BACKGROUND： A recent study has found that ATP13A2 is the causative gene for PARK9-linked autosomal recessive early-onset parkinsonism, described previously in Jordanian and Chilean families （Kufor-Rakeb syndrome）. OBJECTIVE： To screen eastern Asian patients with early-onset parkinsonism for mutations in ATP13A2 and to describe positron emission tomography （PET） findings of PARK9-linked parkinsonism. DESIGN, TIME AND SETTING： In total, 117 patients were selected from the Department of Neurology, Juntendo University, from February 2003 to October 2006, for this molecular genetics and case-control study. PARTICIPANTS： The patients with parkinsonism consist of two cohorts. Ninety four patients with onset age of less than 30 years were selected for the first cohort. They included 49 males and 44 females, comprising 73 Japanese, 9 Korean, 8 Taiwanese, and 4 Mainland Chinese. Eleven patients had parkinsonism complicated with dementia, 15 patients had family histories of parkinsonism （including 2 families）, and 5 patients were from consanguineous parents （including one family）. The second cohort of 23 patients was composed of patients with consanguineous parents （n = 15） or who had affected siblings （n = 6） or both （n = 2）, but the age at onset ranged from 30 to 50 years. METHODS： In 117 patients with parkinsonism, direct sequencing of ATP13A2 exons 13, 16, and 26, in which mutations had been reported previously, were performed. Sequencing was also performed in all 29 exons, including splice sites, in 28 probands who showed homozygosity at the PARK9 locus by haplotype analysis. Mutation analysis was also performed in 150 normal people. Linkage analysis was performed on all 3 parkinsonism families using short tandem repeat markers flanking the PARK9 locus. For patients who had ATP13A2 mutation, we performed brain MRI and ^18F-dopa PET scans. MAIN OUTCOME MEASURES： ATP13A2 DNA sequence, ^18F-dopa PET scan and brain MRI findings. RESULTS： A novel F182L mutation in a consanguineous J     

Diagnostic considerations in juvenile parkinsonism.

Juvenile parkinsonism (JP) describes patients in whom the clinical features of parkinsonism manifest before 21 years of age. Many reported cases that had a good response to levodopa have proved to have autosomal recessive juvenile parkinsonism (AR-JP) due to mutations in the parkin gene. With the exception of parkin mutations and dopa-responsive dystonia, most causes are associated with the presence of additional neurological signs, resulting from additional lesions outside of the basal ganglia. Lewy body pathology has only been reported in one case, suggesting that a juvenile form of idiopathic Parkinson's disease may be extremely rare.     

Functional brain imaging in glucocerebrosidase mutation carriers with and without Parkinsonism

Mutations in the glucocerebrosidase gene (GBA) increase the risk for Parkinson's disease and are also associated with an earlier onset of the disease and an akinetic parkinsonian phenotype. To investigate the underlying pathogenesis of this condition, we assessed cerebral metabolism using positron emission tomography (PET) in GBA mutation carriers with and without parkinsonism. [¹⁸F]‐fluorodeoxyglucose (FDG)‐PET using a three‐dimensional stereotactic surface projection analysis was used to measure the cerebral metabolic rates of glucose (CMRGlc) in a patient with parkinsonism and Gaucher disease (GD) and five subjects with a heterozygous GBA mutation, including three patients with parkinsonism and three asymptomatic carriers in comparison to 10 healthy controls in the same age range. Dopaminergic neuronal activity was investigated using [¹¹C] CFT‐ and [¹¹C] raclopride‐PET. All GBA mutation carriers displayed a significant CMRGlc decrease in the supplemental motor area (SMA). The carriers with parkinsonism showed additional hypometabolism in the parietooccipital cortices. The CFT and raclopride PET images in the asymptomatic carriers demonstrated the CFT binding to be within normal values in the putamen and a significant increase was observed in the caudate nucleus while raclopride binding in the striatum was in the normal range. An advanced parkinsonian carrier showed decreased CFT binding and increased raclopride binding in the striatum. The decreased CMRGlc in the SMA was characteristic of the GBA mutation carriers. The hypometabolism in the SMA may, therefore, be involved in the clinical characteristics of parkinsonism associated with GBA mutations when the carriers manifest parkinsonism. © 2010 Movement Disorder Society     

Rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration.

We describe a family with nearly 300 members over 8 generations with 32 affected individuals who have an autosomal dominant neurodegenerative disease characterized by progressive parkinsonism with dystonia unrelated to medications, dementia, ocular motility abnormalities, pyramidal tract dysfunction, frontal lobe release signs, perseverative vocalizations, and urinary incontinence. The course is exceptionally aggressive; symptom onset and death consistently occur in the fifth decade. Positron emission tomographic studies with [18F]6-fluoro-L-dopa (6FD) were performed in 4 patients and 7 individuals at risk for development of the disease. All affected subjects had markedly reduced striatal uptake of 6FD (p less than 0.001). All individuals at risk had normal striatal uptake, but high 6FD uptake rate constants were noted in 3 of the 7 studied. Autopsy findings revealed severe neuronal loss with gliosis in substantia nigra, pontine tegmentum, and globus pallidus, with less involvement of the caudate and the putamen. There were no plaques, tangles, Lewy bodies, or amyloid bodies. This kindred appears to represent a neurodegenerative disease not heretofore described. We propose the following name for this new genetic disease: autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration.     

Molecular imaging in Parkinsonism: The essential for clinical practice and future perspectives

Nuclear medicine with positron emission tomography (PET) and single photon emission computed tomography (SPECT) develops powerful tools in molecular imaging to help clinicians in the challenging diagnosis of parkinsonism. These techniques can provide biomarkers for neurodegenerative parkinsonism and to distinguish Parkinson disease (PD) from atypical parkinsonism. This review summarizes the main SPECT and PET contributions to the diagnosis of parkinsonism. We will also discuss new technologies in the field of nuclear imaging and their potential contribution to the diagnosis of parkinsonian syndromes.