2-carbomethoxy-8-(3-fluoropropyl)-3-(4-iodophenyl)tropane and Nerve-Degeneration

[123I]FP-CIT (N-omega-fluoropropyl-2 beta-carbomethoxy-3 beta-(4-iodophenyl)nortropane) has been developed successfully as a radioligand for single-photon emission tomography (SPET) imaging of dopamine transporters, which are situated in the membrane of dopaminergic neurons. Imaging of these transporters has shown promise as a clinical tool to detect degeneration of the dopaminergic nigrostriatal pathway. Several "presynaptic parkinsonian" syndromes, such as Parkinson's disease or multiple system atrophy, are characterised by degeneration of the nigrostriatal pathway. [123I]FP-CIT SPET imaging studies have shown the ability to detect loss of striatal dopamine transporters in such syndromes. However, in clinical practice it is sometimes difficult, but important, to discriminate patients with "presynaptic parkinsonism" from those with other forms of parkinsonism not characterised by loss of presynaptic dopaminergic cells (e.g. psychogenic parkinsonism or drug-induced postsynaptic parkinsonism). In these inconclusive cases, it may be of value to confirm or exclude the existence of degeneration of nigrostriatal dopaminergic cells by using imaging techniques such as [123I]FP-CIT SPET. Using [123I]FP-CIT SPET, we have imaged the striatal dopamine transporters in a group of patients with inconclusive forms of parkinsonism, and, moreover, have been able to perform clinical follow-up of these patients 2-4 years after imaging. In 33 inconclusive cases, ratios of specific to non-specific binding were calculated for the caudate nucleus and putamen following [123I]FP-CIT SPET imaging and compared with ratios obtained in healthy controls. In nine of the patients, degeneration of the nigrostriatal pathway was found scintigraphically and in all these cases, presynaptic parkinsonism was confirmed by clinical follow-up. In the other 24 subjects no degeneration was found scintigraphically. Forms of parkinsonism other than the presynaptic were confirmed at follow-up in 19 cases, and in three cases no conclusive diagnosis was established, but presynaptic parkinsonism was excluded clinically. A clinical diagnosis of presynaptic parkinsonism was established in two cases: one case of multiple system atrophy (in this patient loss of dopamine D2 receptors was found with [123I]iodobenzamide SPET performed 2 weeks after [123I]FP-CIT imaging) and one case of Parkinson's disease. Our data suggest that the positive predictive value of [123I]FP-CIT imaging is very high, and although the

Topics: Adolescent; Adult; Aged; Carrier Proteins; Diagnosis, Differential; Dopamine Plasma Membrane Transport Proteins; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Neostriatum; Nerve Degeneration; Nerve Tissue Proteins; Parkinson Disease; Radiopharmaceuticals; Receptors, Presynaptic; Tomography, Emission-Computed, Single-Photon; Tropanes

This study used explainable artificial intelligence for data-driven identification of extrastriatal brain regions that can contribute to the interpretation of dopamine transporter SPECT with

Topics: Brain; Diagnosis, Differential; Dopamine Plasma Membrane Transport Proteins; Humans; Image Interpretation, Computer-Assisted; Nerve Degeneration; Neural Networks, Computer; Parkinson Disease; Predictive Value of Tests; Radiopharmaceuticals; Reproducibility of Results; Retrospective Studies; Tomography, Emission-Computed, Single-Photon; Tropanes

Parkinson's disease (PD) patients show cognitive deficits that are relevant in terms of prognosis and quality of life. Degeneration of striatal dopaminergic afferents proceeds from dorsal/caudal to anterior/ventral and is discussed to account for some of these symptoms. Treatment with dopamine (DA) has differential effects on cognitive dysfunctions, improving some and worsening others. We hypothesized that cognitive performance during the dopaminergic OFF state correlates with DAT availability in the associative striatum. 16 PD patients underwent motor and cognitive examination ON and OFF DA. Global cognition was measured using the Montréal Cognitive Assessment (MoCA) test and executive functioning using a Stroop test. Nigrostriatal dopaminergic innervation was characterized with [

Topics: Adult; Aged; Brain Mapping; Cognition; Cognitive Dysfunction; Cohort Studies; Corpus Striatum; Dopamine; Dopamine Plasma Membrane Transport Proteins; Executive Function; Female; Humans; Male; Middle Aged; Nerve Degeneration; Neuropsychological Tests; Parkinson Disease; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon; Tropanes

This study sought to precisely evaluate striatal oxidative stress and its relationship with the disease severity in Parkinson's disease (PD) using double brain imaging, 62Cu-diacetyl-bis (N4-methylthiosemicarbazone) (62Cu-ATSM) PET and 123I-FP-CIT SPECT.. Nine PD patients were studied with brain 62Cu-ATSM PET for oxidative stress and 123I-FP-CIT SPECT for the density of striatal dopamine transporter. Standardized uptake values (SUVs) were obtained from the delayed phase of dynamic 62Cu-ATSM PET, and striatum-to-cerebellum SUV ratio (SUVR) was calculated. To correct the effect of neuronal loss in the striatum, 62Cu-ATSM SUVR was corrected for striatal specific binding ratio (SBR) values of 123I-FP-CIT (SUVR/SBR).. 62Cu-ATSM SUVR without correction was not significantly correlated with disease severity estimated by the Unified Parkinson's Disease Rating Scale (UPDRS) scores or 123I-FP-CIT SBR. In contrast, the SUVR/SBR showed significant correlations with the UPDRS total and motor scores, and 123I-FP-CIT SBR.. Oxidative stress in the remaining striatal dopaminergic neurons estimated by SUVR/SBR was increased with disease severity in PD patients, suggesting that oxidative stress based on mitochondrial dysfunction contributes to promoting dopaminergic neuronal degeneration in PD. 62Cu-ATSM PET with 123I-FP-CIT SPECT correction would be a promising tool to evaluate dopaminergic neuronal oxidative stress in PD.

Topics: Aged; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Male; Middle Aged; Nerve Degeneration; Neuroimaging; Oxidative Stress; Parkinson Disease; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon; Tropanes

This study analyzed data from dopamine transporter (DAT) positron emission tomographic scans of 282 male patients with de novo Parkinson disease to investigate whether smoking impacts striatal dopamine neuronal degeneration. Mean DAT activity in the posterior (p = 0.016) and ventral putamen (p = 0.028) was higher in 44 current smokers in comparison to 105 ex-smokers and 133 never-smokers. The severity of baseline motor deficits and the longitudinal increases in levodopa-equivalent doses during follow-up were similar among the 3 groups. These results suggest that current smoking, but not past smoking, protects dopamine neuronal degeneration in the sensorimotor striatum with no additional clinical benefits. Ann Neurol 2017;82:850-854.

Topics: Aged; Case-Control Studies; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Functional Neuroimaging; Humans; Male; Middle Aged; Nerve Degeneration; Parkinson Disease; Positron-Emission Tomography; Protective Factors; Smoking; Tropanes

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 (18) F-FP-CIT PET/MR. To measure dopaminergic degeneration in PD, binding ratio (BR) of dopamine transporter in striatum was evaluated by (18) F-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.

Topics: Adult; Aged; Brain Mapping; Dopamine; Dopamine Plasma Membrane Transport Proteins; Female; Gray Matter; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Degeneration; Parkinson Disease; Positron-Emission Tomography; Prospective Studies; Tropanes

To verify if (123)I-FP-CIT, DaTSCAN(®) can differentiate early stages of Parkinson's disease (PD) as well as patients with Atypical Parkinsonian syndromes (APS) from manifest Parkinson's disease.. 128 consecutive patients were investigated with (123)I-FP-CIT SPECT during a 4-year period. All patients were diagnosed according to the established consensus criteria for diagnosis of PD (n = 53) and APS (n = 19). Remaining patients were grouped early PD (before onset of L-DOPA medication), (n = 20), vascular PD (n = 6), and non-PD syndromes (n = 30) and SWEDD (n = 1). SPECT images were analyzed visually according to a predefined ranking scale of dopaminergic nerve cell degeneration, distinguishing a posterior-anterior degeneration pattern (egg shape) from a more global and severe degeneration pattern (burst striatum). Striatum uptake ratios were quantitatively analyzed with the 3D software, EXINI.. In the group of APS patients, the burst striatum pattern was most frequent and found in 61 % (11/18 patients). In PD patients, the egg shape pattern was dominating, especially in early PD where it was present in 95 % (19/20 patients). The positive predictive value for the egg shape pattern to diagnose PD was 92 % in this material (APS and all PD patients) and the specificity 90 % for the burst striatum pattern to exclude APS. The uptake ratios were reduced in both PD and APS patients and closely related to the image ranking.. In this study, we found that in more than half of the patients it was possible to differentiate between PD and APS by visual interpretation only. Similar results were obtained using semi-quantitative uptake ratios. Combining visual assessment with uptake ratios did not add to the discriminating power of DaTSCAN(®) SPECT in this material.

Topics: Adult; Aged; Aged, 80 and over; Dopaminergic Neurons; Female; Humans; Imaging, Three-Dimensional; Male; Middle Aged; Nerve Degeneration; Parkinson Disease; Radiopharmaceuticals; Severity of Illness Index; Software; Tomography, Emission-Computed, Single-Photon; Tropanes

The aim of this study was to investigate whether visual assessment of (123)I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropan ((123)I-FP-CIT) single photon emission computed tomography (SPECT) in addition to quantitative analyses can help to differentiate idiopathic Parkinson's disease (PD) from atypical parkinsonian syndromes (APS). From a consecutive series of patients examined with (123)I-FP-CIT SPECT (n = 190) over a three-year period we identified 165 patients with a clinical diagnosis of PD (n = 120) or APS (n = 45). (123)I-FP-CIT SPECT results were analysed visually and quantitatively and compared for PD and APS and for the subgroup of patients with early PD and APS (disease duration <5 years). According to predefined visual patterns of dopaminergic degeneration the results were graded as normal (grade 5) or abnormal (grade 1-4), distinguishing a posterior-anterior degeneration pattern ("egg shape") from a global and severe degeneration pattern ("burst striatum"). Visual assessment of (123)I-FP-CIT SPECT showed significant different dopaminergic degeneration patterns for PD and APS patients. A grade 1 ("burst striatum") degeneration pattern was predominantly associated with APS patients. In contrast to that, a grade 2 (egg shape) degeneration pattern was the characteristic finding in PD patients. In a subgroup of patients with early disease, visual assessment with identification of the burst striatum degeneration pattern provided 90% positive predictive value and 99% specificity for the diagnosis of APS. Quantitative analysis of striatal binding ratios failed to depict these different degeneration patterns in PD and APS patients. Visual assessment of the pattern of dopaminergic loss in (123)I-FP-CIT SPECT shows different patterns of dopaminergic degeneration for PD and APS patients. Therefore, it could provide valuable information to distinguish APS from PD patients, especially in early stages of disease. Within the first 5 years of disease, the occurrence of a burst striatum degeneration pattern has a high positive predictive value of APS.

Topics: Aged; Brain; Dopaminergic Neurons; Female; Humans; Male; Middle Aged; Nerve Degeneration; Parkinson Disease; Parkinsonian Disorders; Radiopharmaceuticals; Sensitivity and Specificity; Tomography, Emission-Computed, Single-Photon; Tropanes

The pathogenesis of rapid eye movement (REM) sleep behavior disorder (RBD) is not clear despite its frequent association with Parkinson's disease (PD). We investigated whether the nigrostriatal dopaminergic system is involved in the development of idiopathic RBD.. Fourteen patients with RBD, 14 patients with PD and 12 normal controls were included in the study. The diagnosis of RBD was confirmed on polysomnography. All the participants performed single-photon emission computed tomography imaging 3 h after injection of [(123)I]FP-CIT. During REM sleep of the RBD patients, each 30-s epoch was rated as 'tonic' when there was at least 50% of tonically maintained chin electromyography (EMG) activity in the epoch. Phasic EMG activities were calculated as the percentage of 3-s mini-epoch containing phasic EMG events (leg and chin, separately).. The RBD patients showed a trend of lower binding in the striatum than the normal controls (P = 0.07), and the significance was revealed in the putamen (P = 0.02). However, in 11 individual cases of the 14 RBD patients, the dopamine transporter (DAT) densities in the putamen still remained within the normal range. In the RBD patients, there was no correlation between EMG activities and DAT densities.. Nigrostriatal dopaminergic degeneration could be a part of the pathogenesis of RBD, but not essential for the development of RBD. The lack of correlation between RBD severity and DAT densities suggests that another pathogenic process not related to nigrostriatal dopaminergic transmission may be implicated in RBD.

Topics: Aged; Ascorbic Acid; Caudate Nucleus; Chin; Cholecalciferol; Corpus Striatum; Dehydroepiandrosterone; Dopamine; Dopamine Plasma Membrane Transport Proteins; Electromyography; Facial Muscles; Female; Humans; Male; Middle Aged; Nerve Degeneration; Nicotinic Acids; Plant Extracts; Polysomnography; Putamen; REM Sleep Behavior Disorder; Tomography, Emission-Computed, Single-Photon; Tropanes

We used 123I-Ioflupane SPECT to study striatal dopamine transporter (DAT) binding in 36 Parkinson's disease (PD) patients with history of severe occupational exposure to hydrocarbons. Data were compared with 38 PD patients without exposure history as well as healthy controls. Both PD cohorts showed significant striatal uptake decrements compared with controls. We found significantly lower values in the whole striatum of exposed compared with non-exposed patients (0.83 +/- 0.25 vs. 1.05 +/- 0.39; P = 0.004), more pronounced in the putamen (0.61 +/- 0.24 vs. 0.85 +/- 0.42; P = 0.004). We conclude that severe occupational exposure to hydrocarbons may modify disease course and ultimately accelerate nigro-striatal denervation.

Topics: Aged; Binding, Competitive; Corpus Striatum; Disease Progression; Dopamine; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Hydrocarbons; Male; Middle Aged; Nerve Degeneration; Nortropanes; Occupational Exposure; Parkinson Disease; Tomography, Emission-Computed, Single-Photon

Parkinson's disease (PD) is characterized neuropathologically by degeneration of the nigrostriatal dopaminergic pathway. With natural aging there is loss of dopaminergic cells in the substantia nigra and, consequently, loss of dopamine transporters in the striatum. It has been suggested that PD is caused by an accelerated rate of cell death. Conceptually, symptoms in idiopathic PD become apparent after a critical level of cell loss, the "symptom threshold." It has been suggested that this symptom threshold is independent of age. In this study, [123I]FP-CIT SPECT was used to assess the effect of aging on the density of striatal dopamine transporters in vivo in controls (n = 36) and early, drug-naive, patients with PD (n = 32). We found a significant age-associated decline of [123I]FP-CIT binding to striatal dopamine transporters in controls, but not in parkinsonian patients. This finding might give further support for the existence of an age-independent threshold in PD. In a subgroup of patients with hemi-PD, we found a significant loss of dopamine transporters bilaterally in the caudate nucleus and putamen. This loss was more pronounced in the putamen than in the caudate nucleus and the contralateral binding was significantly lower than the ipsilateral binding. By using age-corrected data, we estimated that in our particular patient group motor signs started when the loss of [123I]FP-CIT binding ratios in the putamen was 46-64%.

Topics: Adult; Age Factors; Aged; Aging; Carrier Proteins; Disease Progression; Dopamine; Dopamine Plasma Membrane Transport Proteins; Female; Humans; Iodine Radioisotopes; Male; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Neostriatum; Nerve Degeneration; Nerve Tissue Proteins; Neural Pathways; Neurons; Parkinson Disease; Sex Factors; Substantia Nigra; Tomography, Emission-Computed, Single-Photon; Tropanes

With the dopaminergic presynaptic ligand FP-CIT and single photon emission tomography we have shown a severe dopaminergic degeneration in a patient with a necropsy confirmed diagnosis of dementia with Lewy bodies (DLB). We suggest that functional imaging of the nigrostriatal dopamine pathway helps to distinguish DLB from Alzheimer's disease during life.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Dementia; Diagnosis, Differential; Dopamine; Humans; Lewy Bodies; Male; Nerve Degeneration; Neurons; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon; Tropanes