L‐DOPA‐induced dyskinesia in a rat model of Parkinson's disease is associated with the fluctuational release of norepinephrine in the sensorimotor striatum

L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced dyskinesia (LID) is the most common complication of standard L‐DOPA therapy for Parkinson's disease experienced by most parkinsonian patients. LID is associated with disruption of dopaminergic homeostasis in basal ganglia following L‐DOPA administration. Norepinephrine (NE) is another important catecholaminergic neurotransmitter that is also believed to be involved in the pathogenesis of LID. This study compared NE release in the ipsilateral sensorimotor striatum of dyskinetic and nondyskinetic 6‐hydroxydopamine‐lesioned hemiparkinsonian rats treated chronically with L‐DOPA. After L‐DOPA injection, the time‐course curves of NE levels in the sensorimotor striatum were significantly different between dyskinetic and nondyskinetic rats. Several metabolic kinetic parameters of NE levels were also differentially expressed between the two groups. In comparison with nondyskinetic rats, the ΔC_max of NE was significantly higher in dyskinetic rats, whereas T_max and t_1/2 of NE were significantly shorter. Intrastriatal perfusion of NE into the lesioned sensorimotor striatum revealed a moderate dyskinesia in dyskinetic rats, which was similar to the dyskinetic behavior after L‐DOPA administration. The L‐DOPA‐related dyskinetic behavior was inhibited significantly by a further pretreatment of noradrenergic neurotoxin N‐?(2‐?chloroethyl)?‐?N‐?ethyl‐?2‐?bromobenzylamine or intrastriatal administration of the α₂‐adrenoceptor antagonist idazoxan, accompanied by significant changes in metabolic kinetic parameters of NE in the sensorimotor striatum. The results provide evidence to support the correlation between abnormal NE neurotransmission and the induction of LID and suggest that the aberrant change of the quantitative and temporal releasing of NE in the sensorimotor striatum might play an important role in the pathogenesis of LID. © 2014 Wiley Periodicals, Inc.     

Central dopamine deficiency in pure autonomic failure

Objective Pure autonomic failure (PAF) and Parkinson’s disease (PD) share several clinical laboratory abnormalities; however, PAF is not associated with parkinsonism. In this study, we tested the hypothesis that preservation of nigrostriatal dopaminergic innervation explains the absence of motor dysfunction in PAF. Methods Patients with PAF (N = 5) or PD (N = 21) and control subjects (N = 14) had brain 6-[¹⁸F]fluorodopa positron emission tomographic scanning and cerebrospinal fluid catechol measurements. A patient with PAF and another with PD had rapid postmortem striatal, nigral, and sympathetic ganglion sampling, with assays of catechols and tyrosine hydroxylase activity. Results The PAF and PD groups had similarly low mean substantia nigra (SN):occipital (OCC) ratios of 6-[¹⁸F]fluorodopa-derived radioactivity and similarly low cerebrospinal fluid dihydroxyphenylacetic acid and DOPA levels. Only the PD group, however, had low PUT:OCC, caudate:OCC, or PUT:SN ratios. The PAF and PD cases had similarly low SN tissue concentrations of dopamine and tyrosine hydroxylase activity, but the PD patient had tenfold lower PUT dopamine and the PAF patient 15-fold lower myocardial norepinephrine concentrations. Conclusions Surprisingly, PAF and PD entail similarly severe nigral and overall central dopaminergic denervation. There is more severe loss of striatal dopaminergic terminals in PD than in PAF and more severe loss of sympathetic noradrenergic terminals in PAF than in PD. These differences explain the distinctive clinical manifestations of the two Lewy body diseases. Parkinsonism appears to reflect striatal dopamine deficiency rather than loss of nigral dopaminergic neurons per se.     

Gray matter correlates of dopaminergic degeneration in Parkinson's disease: A hybrid PET/MR study using 18F‐FP‐CIT

Dopaminergic degeneration is a hallmark of Parkinson's disease (PD), which causes various symptoms affected by corticostriatal circuits. So far, the relationship between cortical changes and dopamine loss in the striatum is unclear. Here, we evaluate the gray matter (GM) changes in accordance with striatal dopaminergic degeneration in PD using hybrid PET/MR. Sixteen patients with idiopathic PD underwent ¹⁸F‐FP‐CIT PET/MR. To measure dopaminergic degeneration in PD, binding ratio (BR) of dopamine transporter in striatum was evaluated by ¹⁸F‐FP‐CIT. Voxel‐based morphometry (VBM) was used to evaluate GM density. We obtained voxelwise correlation maps of GM density according to the striatal BR. Voxel‐by‐voxel correlation between BR maps and GM density maps was done to evaluate region‐specific correlation of striatal dopaminergic degeneration. There was a trend of positive correlation between striatal BR and GM density in the cerebellum, parahippocampal gyri, and frontal cortex. A trend of negative correlation between striatal BR and GM density in the medial occipital cortex was found. Voxel‐by‐voxel correlation revealed that the positive correlation was mainly dependent on anterior striatal BR, while posterior striatal BR mostly showed negative correlation with GM density in occipital and temporal cortices. Decreased GM density related to anterior striatal dopaminergic degeneration might demonstrate degeneration of dopaminergic nonmotor circuits. Furthermore, the negative correlation could be related to the motor circuits of posterior striatum. Our integrated PET/MR study suggests that the widespread structural progressive changes in PD could denote the cortical functional correlates of the degeneration of striatal dopaminergic circuits. Hum Brain Mapp 37:1710–1721, 2016. © 2016 Wiley Periodicals, Inc .     

PET study of [(18)F]6-fluoro-L-dopa uptake in neuroleptic- and mood-stabilizer-naive first-episode nonpsychotic mania: effects of treatment with divalproex sodium

OBJECTIVE: Although dopaminergic hyperactivity has been implicated in mania, the precise location in the brain of the abnormality is unclear. This study assessed presynaptic dopamine function in neuroleptic- and mood-stabilizer-naive nonpsychotic first-episode manic patients before and after treatment with divalproex sodium by measuring [(18)F]6-fluoro-L-dopa ([(18)F]DOPA) uptake in the striatum with positron emission tomography (PET). METHOD: Thirteen patients with DSM-IV bipolar I disorder, manic episode, and 13 healthy comparison subjects underwent [(18)F]DOPA PET scans. Ten of the 13 patients had repeat PET scans 2-6 weeks after beginning treatment with divalproex sodium monotherapy. [(18)F]DOPA uptake rate constants (K(i) values) in the striatum were calculated by using graphical analysis with activity from the occipital cortex as the input function. RESULTS: No significant differences in [(18)F]DOPA uptake rate constants in the striatum were found between the manic patients and the comparison subjects. After treatment with divalproex sodium, [(18)F]DOPA rate constants were significantly reduced in the patients and were lower in the patients than in the comparison subjects. CONCLUSIONS: Although presynaptic dopamine function as reflected by [(18)F]DOPA uptake is not altered in mania, presynaptic dopamine function in manic patients was lower after treatment with divalproex sodium.     

Dopaminergic correlates of metabolic network activity in Parkinson's disease

Parkinson's disease (PD) is associated with distinct metabolic covariance patterns that relate to the motor and cognitive manifestations of the disorder. It is not known, however, how the expression of these patterns relates to measurements of nigrostriatal dopaminergic activity from the same individuals. To explore these associations, we studied 106 PD subjects who underwent cerebral PET with both ¹⁸F‐fluorodeoxyglucose (FDG) and ¹⁸F‐fluoro‐L‐dopa (FDOPA). Expression values for the PD motor‐ and cognition‐related metabolic patterns (PDRP and PDCP, respectively) were computed for each subject; these measures were correlated with FDOPA uptake on a voxel‐by‐voxel basis. To explore the relationship between dopaminergic function and local metabolic activity, caudate and putamen FDOPA PET signal was correlated voxel‐wise with FDG uptake over the entire brain. PDRP expression correlated with FDOPA uptake in caudate and putamen (P < 0.001), while PDCP expression correlated with uptake in the anterior striatum (P < 0.001). While statistically significant, the correlations were only of modest size, accounting for less than 20% of the overall variation in these measures. After controlling for PDCP expression, PDRP correlations were significant only in the posterior putamen. Of note, voxel‐wise correlations between caudate/putamen FDOPA uptake and whole‐brain FDG uptake were significant almost exclusively in PDRP regions. Overall, the data indicate that PDRP and PDCP expression correlates significantly with PET indices of presynaptic dopaminergic functioning obtained in the same individuals. Even so, the modest size of these correlations suggests that in PD patients, individual differences in network activity cannot be explained solely by nigrostriatal dopamine loss. Hum Brain Mapp 36:3575–3585, 2015. © 2015 Wiley Periodicals, Inc.     

Multitracer assessment of dopamine function after transplantation of embryonic stem cell‐derived neural stem cells in a primate model of Parkinson's disease

The ability of primate embryonic stem (ES) cells to differentiate into dopamine (DA)‐synthesizing neurons has raised hopes of creating novel cell therapies for Parkinson's disease (PD). As the primary purpose of cell transplantation in PD is restoration of dopaminergic neurotransmission in the striatum, in vivo assessment of DA function after grafting is necessary to achieve better therapeutic effects. A chronic model of PD was produced in two cynomolgus monkeys (M‐1 and M‐2) by systemic administration of neurotoxin. Neural stem cells (NSCs) derived from cynomolgus ES cells were implanted unilaterally in the putamen. To evaluate DA‐specific functions, we used multiple [¹¹C]‐labeled positron emission tomography (PET) tracers, including [β‐¹¹C]L ‐3,4‐dihydroxyphenylalanine (L ‐[β‐¹¹C]DOPA, DA precursor ligand), [¹¹C]‐2β‐carbomethoxy‐3β‐(4‐fluorophenyl)tropane ([¹¹C]β‐CFT, DA transporter ligand) and [¹¹C]raclopride (D₂ receptor ligand). At 12 weeks after grafting NSCs, PET demonstrated significantly increased uptake of L ‐[β‐¹¹C]DOPA (M‐1:41%, M‐2:61%) and [¹¹C]β‐CFT (M‐1:31%, M‐2:36%) uptake in the grafted putamen. In addition, methamphetamine challenge in M‐2 induced reduced [¹¹C]raclopride binding (16%) in the transplanted putamen, suggesting release of DA. These results show that transplantation of NSCs derived from cynomolgus monkey ES cells can restore DA function in the putamen of a primate model of PD. PET with multitracers is useful for functional studies in developing cell‐based therapies against PD. Synapse 63: 541‐548, 2009. © 2009 Wiley‐Liss, Inc.     

Enhancing Aromatic L‐amino Acid Decarboxylase Activity: Implications for L‐DOPA Treatment in Parkinson's Disease

Aromatic L‐amino acid decarboxylase (AAAD) is an essential enzyme for the formation of catecholamines, indolamines, and trace amines. Moreover, it is a required enzyme for converting L‐DOPA to dopamine when treating patients with Parkinson's disease (PD). There is now substantial evidence that the activity of AAAD in striatum is regulated by activation and induction, and second messengers play a role. Enzyme activity can be modulated by drugs acting on a number of neurotransmitter receptors including dopamine (D1–4), glutamate (NMDA), serotonin (5‐HT_1A, 5‐HT_2A) and nicotinic acetylcholine receptors. Generally, antagonists enhance AAAD activity; while, agonists may diminish it. Enhancement of AAAD activity is functional, as the formation of dopamine from exogenous L‐DOPA mirrors activity. Following a lesion of nigrostriatal dopaminergic neurons, AAAD in striatum responds more robustly to pharmacological manipulations, and this is true for the decarboxylation of exogenous L‐DOPA as well. We review the evidence for parallel modulation of AAAD activity and L‐DOPA decarboxylation and propose that this knowledge can be exploited to optimize the formation of dopamine from exogenous L‐DOPA. This information can be used as a blue print for the design of novel L‐DOPA treatment adjuvants to benefit patients with PD.     

Fluorine‐19 magnetic resonance imaging probe for the detection of tau pathology in female rTg4510 mice

Aggregation of tau into neurofibrillary tangles (NFTs) is characteristic of tauopathies, including Alzheimer's disease. Recent advances in tau imaging have attracted much attention because of its potential contributions to early diagnosis and monitoring of disease progress. Fluorine‐19 magnetic resonance imaging (¹⁹F‐MRI) may be extremely useful for tau imaging once a high‐quality probe has been formulated. In this investigation, a novel fluorine‐19–labeling compound has been developed as a probe for tau imaging using ¹⁹F‐MRI. This compound is a buta‐1,3‐diene derivative with a polyethylene glycol side chain bearing a CF₃ group and is known as Shiga‐X35. Female rTg4510 mice (a mouse model of tauopathy) and wild‐type mice were intravenously injected with Shiga‐X35, and magnetic resonance imaging of each mouse's head was conducted in a 7.0‐T horizontal‐bore magnetic resonance scanner. The ¹⁹F‐MRI in rTg4510 mice showed an intense signal in the forebrain region. Analysis of the signal intensity in the forebrain region revealed a significant accumulation of fluorine‐19 magnetic resonance signal in the rTg4510 mice compared with the wild‐type mice. Histological analysis showed fluorescent signals of Shiga‐X35 binding to the NFTs in the brain sections of rTg4510 mice. Data collected as part of this investigation indicate that ¹⁹F‐MRI using Shiga‐X35 could be a promising tool to evaluate tau pathology in the brain.     

Variability of presynaptic nigrostriatal dopaminergic function and clinical heterogeneity in a dopa-responsive dystonia family with GCH-1 gene mutation

We studied the presynaptic nigrostriatal dopaminergic function using single photon emission computed tomography (SPECT) imaging of a ^99mTc-TRODAT-1 (TRODAT) scan in a dopa-responsive dystonia (DRD) family with the guanosine triphosphate cyclohydrolase 1 (GCH-1) gene mutation. Clinically, there was presentation of intrafamilial variability in the DRD family. The index patient was a 10-year-old girl with classic DRD and normal presynaptic nigrostriatal dopaminergic function. However, her grandmother, a 79-year-old woman, presented with slowly progressive Parkinson’s disease (PD) without dystonic symptoms and excellent response to dopaminergic therapy for 21 years. Her brain TRODAT SPECT imaging revealed a markedly and asymmetrically reduced uptake of dopamine transporter at the bilateral striatum. Her father, a 54-year-old man, was an asymptomatic gene carrier and his brain TRODAT SPECT imaging revealed asymmetrically reduced nigrostriatal dopaminergic transmission in the bilateral striatum. We conclude variability of presynaptic nigrostriatal dopaminergic function in patients with DRD is related to their clinical heterogeneity. Significantly, impairment of presynaptic dopamine function actually occurs in the asymptomatic gene carrier.     

In vitro autoradiography and in vivo evaluation in cynomolgus monkey of [18F]FE‐PE2I,a new dopamine transporter PET radioligand

This study evaluated the in vitro and in vivo characteristics of a new dopamine transporter (DAT) radioligand, [¹⁸F]fluoroethyl(FE)PE2I, by autoradiography from postmortem human brain and by positron emission tomography (PET) in three cynomolgus monkeys. In the autoradiography experiments, high [¹⁸F]FE‐PE2I accumulation was observed in caudate and putamen that was selectively abolished by GBR12909 or β‐CIT but not by maprotiline. High doses of citalopram (>5 μM) also inhibited [¹⁸F]FE‐PE2I binding in the striatum. In vitro K_i of the radioligand was 12 nM at rodent dopamine transporter. [¹⁸F]FE‐PE2I brain uptake measured by PET was ～4–5% of the injected dose, with highest uptake in striatum followed by midbrain and thalamus, lower uptake in neocortex, and lowest in cerebellum. Peak specific binding in striatum was reached ～40 min and in midbrain 20–30 min postinjection. The ratio‐to‐cerebellum was 7–10 in striatum and 1.5–2.3 in midbrain. BP_ND measured with simplified reference tissue method using the cerebellum as reference region was 4.5 in striatum and 0.6 in midbrain. No displacement was shown after citalopram or maprotiline administration, while GBR12909 decreased the binding in striatum and midbrain to the level of cerebellum. [¹⁸F]FE‐PE2I showed relatively fast elimination and metabolism with the presence of two metabolite peaks with similar retention time as the labeled metabolites of [¹¹C]PE2I. [¹⁸F]FE‐PE2I showed in vivo selectivity for the DAT and compared with [¹¹C]PE2I, it showed faster kinetics and earlier peak equilibrium. The potential influence of the two radiometabolites on PET quantification requires further evaluation. Synapse 63:871–880, 2009. © 2009 Wiley‐Liss, Inc.     

Nigral Pathology Contributes to Microstructural Integrity of Striatal and Frontal Tracts in Parkinson's Disease

Background

Motor and cognitive impairment in Parkinson's disease (PD) is associated with dopaminergic dysfunction that stems from substantia nigra (SN) degeneration and concomitant α-synuclein accumulation. Diffusion magnetic resonance imaging (MRI) can detect microstructural alterations of the SN and its tracts to (sub)cortical regions, but their pathological sensitivity is still poorly understood.

Objective

To unravel the pathological substrate(s) underlying microstructural alterations of SN, and its tracts to the dorsal striatum and dorsolateral prefrontal cortex (DLPFC) in PD.

Methods

Combining post-mortem in situ MRI and histopathology, T1-weighted and diffusion MRI, and neuropathological samples of nine PD, six PD with dementia (PDD), five dementia with Lewy bodies (DLB), and 10 control donors were collected. From diffusion MRI, mean diffusivity (MD) and fractional anisotropy (FA) were derived from the SN, and tracts between the SN and caudate nucleus, putamen, and DLPFC. Phosphorylated-Ser129-α-synuclein and tyrosine hydroxylase immunohistochemistry was included to quantify nigral Lewy pathology and dopaminergic degeneration, respectively.

Results

Compared to controls, PD and PDD/DLB showed increased MD of the SN and SN-DLPFC tract, as well as increased FA of the SN-caudate nucleus tract. Both PD and PDD/DLB showed nigral Lewy pathology and dopaminergic loss compared to controls. Increased MD of the SN and FA of SN-caudate nucleus tract were associated with SN dopaminergic loss. Whereas increased MD of the SN-DLPFC tract was associated with increased SN Lewy neurite load.

Conclusions

In PD and PDD/DLB, diffusion MRI captures microstructural alterations of the SN and tracts to the dorsal striatum and DLPFC, which differentially associates with SN dopaminergic degeneration and Lewy neurite pathology. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

In vivo imaging of inflammation in the peripheral nervous system by (19)F MRI

Visualization of neuroinflammation is still a major task in neuroscience and neurology since inflammatory processes play a central pathophysiological role in many disorders of the nervous system but are not yet covered by conventional imaging techniques.Recently, ¹⁹F magnetic resonance imaging (MRI) was introduced as a new cellular imaging technology. In the present study, we established ¹⁹F high field MRI for cell tracking in the peripheral nervous system (PNS) of rats using dedicated MR coils. To mimic focal neuroinflammation, lysolecithin was locally injected into the left sciatic nerve inducing demyelination followed by severe infiltration of monocytes/macrophages from the circulation. Systemic administration of perfluorocarbons (PFC) led to a fluorine signal along the proximal stretch of the affected sciatic nerves in in vivo¹⁹F MRI which was not seen on the right healthy side. The preferential in vivo uptake of PFC by circulating mononuclear cells was confirmed by density gradient centrifugation of the blood. Removal of nerves with consecutive ex vivo¹⁹F MRI and additional ¹⁹F spectroscopy for quantification corroborated the localization of the ¹⁹F marker within the injured nerves (1.07 × 10¹⁸ ± 1.00 × 10¹⁸ mean detectable fluorine spins) while contralateral naive nerves did not exhibit any detectable fluorine signal. Histological assessment confirmed the presence of numerous ED1-positive macrophages within the nerve lesions. Control experiments showed that intraneural application of saline led to an inflammatory reaction restricted to the perineurium which could also be detected by ¹⁹F MRI. In conclusion, we show that ¹⁹F MRI is a promising new technology to visualize hematogenous macrophage responses in the nervous system.     

Carbon monoxide poisoning-induced nigrostriatal dopaminergic dysfunction detected using positron emission tomography (PET)

A malfunctioning heater caused a severe carbon monoxide (CO) intoxication leading to unconsciousness and predominantly right-sided extrapyramidal syndrome in a 29-year-old man. Follow-up included thorough clinical monitoring, and brain MRI and PET studies. Nine days after the poisoning, brain MRI showed symmetrical necrosis in the globus pallidi, but no abnormality was found in the substantia nigra. In addition, white matter periventricular lesions were seen. In a control scan 14 months later the white matter changes had subsided but small necrotic lesions were still noted bilaterally in the globus pallidi. A 6-[¹⁸F]fluoro-l-dopa PET examination performed 5 weeks after the intoxication revealed impaired presynaptic dopaminergic function in the left putamen whereas in the right putamen the dopaminergic activity was within normal limits. [¹¹C] raclopride PET imaging 4 months after the poisoning showed no abnormality in postsynaptic D2 binding in the striatum. Clinically, the parkinsonian symptoms resolved 1.5 years after the poisoning. The final outcome of the recovery was excellent, and the patient returned to work. This is the first case reported where unilateral presynaptic, dopaminergic hypofunction in putamen could be confirmed with fluoro-l-dopa PET imaging on a patient with extrapyramidal syndrome caused by CO poisoning. Our results emphasize that CO intoxication can lead to striatal dopaminergic hypofunction, and that PET is a sensitive tool in evaluating extrapyramidal system after sudden neurotoxic insult.     

Induction of GAP‐43 modulates neuroplasticity in PBSC (CD34+) implanted‐Parkinson's model

As a result of the progressive decrease in efficacy of drugs used to treat Parkinson's disease (PD) and the rapid development of motor complications, effective alternative treatments for PD are required. In a 6‐hydroxydopamine (6‐OHDA)‐induced Parkinson's rat model, intracerebral peripheral blood stem cell (CD34⁺) (PBSC) transplantation significantly protected dopaminergic neurons from 6‐OHDA‐induced neurotoxicity, enhanced neural repair of tyrosine hydroxylase neurons through up‐regulation of Bcl‐2, facilitated stem cell plasticity, and attenuated activation of microglia, in comparison with vehicle‐control rats. The 6‐OHDA‐lesioned hemi‐Parkinsonian rats receiving intrastriatal transplantation of PBSCs also showed: 1) enhanced glucose metabolism in the lesioned striatum and thalamus, demonstrated by [¹⁸F]fluoro‐2‐deoxyglucose positron emission tomography (FDG‐PET), 2) improved neurochemical activity as shown by proton magnetic resonance spectroscopy (¹H‐MRS), and 3) significantly reduced rotational behavior in comparison with control lesioned rats. These observations might be explained by an up‐regulation of growth‐associated protein 43 (GAP‐43) expression because improvements in neurological dysfunction were blocked by injection of MK‐801 in the PBSC‐treated group. In addition, a significant increase in neurotrophic factor expression was found in the ipsilateral hemisphere of the PBSC‐treated group. In summary, this protocol may be a useful strategy for the treatment of clinical PD. © 2009 Wiley‐Liss, Inc.     

Dopamine transporter binding in chronic manganese intoxication

Abstract. Chronic exposure to manganese may induce parkinsonism similar to idiopathic Parkinsons disease (PD). However, clinical manifestations of manganism also have some features different from PD. The mechanisms of manganese-induced parkinsonism remain not fully understood. ^99mTc-TRODAT-1 is a cocaine analogue that can bind to the dopamine transporter (DAT) site reflecting the function of presynaptic dopaminergic terminals. The purpose of this study was to evaluate DAT function using ^99mTc-TRODAT-1 to investigate the integrity of the presynaptic dopaminergic terminals in manganese-induced parkinsonism. Brain ^99mTc-TRODAT-1 single photon emission computed tomography was performed in 4 patients with chronic manganese intoxication in a ferromanganese smelting plant in Taiwan. Twelve PD patients and 12 healthy volunteers served as abnormal and normal controls, respectively. Clinically, all manganism patients had a bradykinetic-rigid syndrome. The scores of the Unified Parkinsons Disease Rating Scale ranged between 19 and 64. The uptake values of the ^99mTc-TRODAT-1 were 0.868±0.136 in the right corpus striatum and 0.865±0.118 in the left, as compared with 0.951±0.059 and 0.956±0.058, respectively for the normal controls. The data were significantly higher than 0.250±0.070 and 0.317±0.066 respectively for the PD patients. Interestingly, there was a mild decrease in the uptake of ^99mTc-TRODAT-1 in the putamen and the ratio of putamen and caudate when compared with the normal controls. Although the DAT shows a slight decrease in the putamen of manganism patients as compared with that of the normal controls, the data indicate that the presynaptic dopaminergic terminals are not the main target of chronic manganese intoxication. In addition ^99mTc-TRODAT-1 SPECT can provide a useful, convenient and inexpensive tool for differentiation between chronic manganism and PD.     

Diagnostic value of brain MRI and 18F‐FDG PET in the differentiation of parkinsonian type multiple system atrophy from Parkinson’s disease

Background and purpose: Differentiation between parkinsonian type multiple system atrophy (MSA‐P) and Parkinson’s disease (PD) is important but often difficult. We investigated the diagnostic value of brain magnetic resonance imaging (MRI) and ¹⁸F‐fluorodeoxyglucose positron emission tomography (¹⁸F‐FDG PET) in differentiating MSA‐P from PD. Methods: Twenty‐four patients with MSA‐P (16 probable and 8 possible) and eight patients with PD were included in this study. Results: For analysis using the putaminal findings, the sensitivities were 58.3% by visual analysis of brain MRI, 95.8% by visual analysis of ¹⁸F‐FDG PET, and 79.2% by statistical parametric mapping (SPM) analysis of ¹⁸F‐FDG PET in differentiating MSA‐P from PD; the specificity was 100% for each analysis. Using the putaminal findings, visual analysis of ¹⁸F‐FDG PET had a higher sensitivity compared with brain MRI (P = 0.004) and SPM analysis of ¹⁸F‐FDG PET revealed a tendency towards higher sensitivity compared with brain MRI (P = 0.063). For analysis using both putaminal and infratentorial findings, the sensitivities were 79.2% by visual analysis of brain MRI, 95.8% by visual analysis of ¹⁸F‐FDG PET, 95.8% by SPM analysis of ¹⁸F‐FDG PET in differentiating MSA‐P from PD; the specificity was 100% for each analysis. Conclusion: Both brain MRI and ¹⁸F‐FDG PET showed diagnostic usefulness in differentiating MSA‐P from PD, with ¹⁸F‐FDG PET being more sensitive than brain MRI.     

High Presynaptic Dopaminergic Activity in Children With Tourette's Disorder

ObjectiveTourette's disorder is characterized by chronic fluctuating motor and vocal tics. Despite extensive investigation of the neuropathophysiology of the disorder by a wide array of methodologies, its neurobiochemical substrate is still unclear. Converging evidence, however, suggests a primary role of the dopaminergic system, particularly within the basal ganglia.MethodThis study examined the integrity of presynaptic dopaminergic function in children with Tourette's disorder, using positron emission tomography and the tracer [¹⁸F]fluorodopa (FDOPA). Accumulation of FDOPA in synaptic terminals, a measure of DOPA decarboxylase activity, was quantified in caudate nucleus, putamen, frontal cortex, and midbrain (i.e., substantia nigra and ventral tegmentum).ResultsSubjects with Tourette's disorder showed higher FDOPA accumulation than controls in the left caudate nucleus (by 25%; p = .03) and right midbrain (by 53%; p = .08).ConclusionThese findings provide evidence of dopaminergic dysfunction in children with Tourette's disorder which affects both cell nuclei and nerve terminals. Based on the known regulation of DOPA decarboxylase activity by post- and presynaptic receptors, and by extracellular dopamine concentration, abnormal activity in this enzyme may reflect deficits in a variety of functional elements of the dopamine system. The precise mechanism underlying an up-regulation of DOPA decarboxylase activity needs to be identified in future studies. J. Am. Acad. Child Adolesc. Psychiatry, 1999, 38(1):86–94     

Relationship between dopamine deficit and the expression of depressive behavior resulted from alteration of serotonin system

Depression frequently accompanies in Parkinson's disease (PD). Previous research suggested that dopamine (DA) and serotonin systems are closely linked with depression in PD. However, comprehensive studies about the relationship between these two neurotransmitter systems are limited. Therefore, the purpose of this study is to evaluate the effect of dopaminergic destruction on the serotonin system. The interconnection between motor and depression was also examined. Two PET scans were performed in the 6‐hydroxydopamine (6‐OHDA) lesioned and sham operated rats: [¹⁸F]FP‐CIT for DA transporters and [¹⁸F]Mefway for serotonin 1A (5‐HT_1A) receptors. Here, 6‐OHDA is a neurotoxin for dopaminergic neurons. Behavioral tests were used to evaluate the severity of symptoms: rotational number for motor impairment and immobility time, acquired from the forced swim test for depression. Region‐of‐interests were drawn in the striatum and cerebellum for the DA system and hippocampus and cerebellum for the 5‐HT system. The cerebellum was chosen as a reference region. Nondisplaceable binding potential in the striatum and hippocampus were compared between 6‐OHDA and sham groups. As a result, the degree of DA depletion was negatively correlated with rotational behavior (R² = 0.79, P = 0.003). In 6‐OHDA lesioned rats, binding values for 5‐HT_1A receptors was 22% lower than the sham operated group. This decrement of 5‐HT_1A receptor binding was also correlated with the severity of depression (R² = 0.81, P = 0.006). Taken together, this research demonstrated that the destruction of dopaminergic system causes the reduction of the serotonergic system resulting in the expression of depressive behavior. The degree of dopaminergic dysfunction was positively correlated with the impairment of the serotonin system. Severity of motor symptoms was also closely related to depressive behavior. Synapse 69:453–460, 2015. © 2015 Wiley Periodicals, Inc.     

Axon responses of embryonic stem cell‐derived dopaminergic neurons to semaphorins 3A and 3C

Class 3 Semaphorins are a subfamily of chemotropic molecules implicated in the projection of dopaminergic neurons from the ventral mesencephalon and in the formation of the nigrostriatal pathway (NSP) during embryonic development. In humans, loss of mesencephalic dopaminergic neurons leads to Parkinson's disease (PD). Cell replacement therapy with dopaminergic neurons generated from embryonic stem cells (ES‐TH⁺) is being actively explored in models of PD. Among several requisites for this approach to work are adequate reconstruction of the NSP and correct innervation of normal striatal targets by dopaminergic axons. In this work, we characterized the response of ES‐TH⁺ neurons to semaphorins 3A, 3C, and 3F and compared it with that of tyrosine hidroxylase‐positive neurons (TH⁺) obtained from embryonic ventral mesencephalon (VM‐TH⁺). We observed that similar proportions of ES‐TH⁺ and VM‐TH⁺ neurons express semaphorin receptors neuropilins 1 and 2. Furthermore, the axons of both populations responded very similarly to semaphorin exposure: semaphorin 3A increased axon length, and semaphorin 3C attracted axons and increased their length. These effects were mediated by neuropilins, insofar as addition of blocking antibodies against these proteins reduced the effects on axonal growth and attraction, and only TH⁺ axons expressing neuropilins responded to the semaphorins analyzed. The observations reported here show phenotypic similarities between VM‐TH⁺ and ES‐TH⁺ neurons and suggest that semaphorins 3A and 3C could be employed to guide axons of grafted ES‐TH⁺ in therapeutic protocols for PD. © 2009 Wiley‐Liss, Inc.     

Comparison of the subregional distributions of the monoamine vesicular transporter and dopamine uptake complex in the rat striatum and changes during aging

Summary We have studied the heterogeneous distribution of the vesicular monoamine transporter, labelled with³H dihydrotetrabenazine (³H TBZOH) and the dopamine uptake complex, labelled with³H GBR12783 in the rat striatum. The ratio TBZOH/GBR12783 was higher in the anterior part of the striatum than in the caudal part. This discrepancy could not be explained by the contribution of serotoninergic innervation to³H TBZOH binding, since the ratio TBZOH/citalopram was also higher in the anterior striatum than in the caudal striatum. The monoamine vesicular transporter and the dopamine uptake complex were more abundant in the lateral regions than in the regions situated near the midline. In the caudal striatum, the ventral part was richer in vesicular transporter than the dorsal part. In aged rats (30 months), a significant decrease in the density of both transporters was noticed in the middle part of the striatum. In the anterior part of the striatum, the ratio TBZOH/GBR12783 was elevated in aged rats compared to adult ones. This could participate in a functional adaptation of the partially diminished population of dopaminergic neurons during aging.