Dopaminergic Neuronal Imaging in Genetic Parkinson's Disease: Insights into Pathogenesis

Objectives:To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease.Methods:A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated for bilateral caudate and putamen for each case. The right:left asymmetry index and striatal asymmetry index was calculated.Results:Scans were available from 37 cases of monogenetic Parkinson's disease (7 glucocerebrosidase (GBA) mutations, 8 alpha-synuclein, 3 LRRK2, 7 PINK1, 12 Parkin). The asymmetry of radioligand uptake for Parkinson's disease with GBA or LRRK2 mutations was greater than that for Parkinson's disease with alpha synuclein, PINK1 or Parkin mutations.Conclusions:The asymmetry of radioligand uptake in Parkinsons disease associated with GBA or LRRK2 mutations suggests that interactions with additional genetic or environmental factors may be associated with dopaminergic neuronal loss

Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine

Characterization of the Novel P2X7 Receptor Radioligand [³H]JNJ-64413739 in Human Brain Tissue

Radioligands targeting microglia cells have been developed to identify and determine neuroinflammation in the living brain. One recently discovered ligand is JNJ-64413739 that binds selectively to the purinergic receptor P2X7R. The expression of P2X7R is increased under inflammation; hence, the ligand is considered useful in the detection of neuroinflammation in the brain. [18F]JNJ-64413739 has been evaluated in healthy subjects with positron emission tomography; however, the in vitro binding properties of the ligand in human brain tissue have not been investigated. Therefore, the purpose of this study was to measure Bmax and Kd of [3H]JNJ-64413739 using autoradiography on human cortical tissue sections resected from a total of 48 patients with treatment-resistant epilepsy. Correlations between the specific binding of [3H]JNJ-64413739 with age, sex, and duration of disease were explored. Finally, to examine the relationship between P2X7R and TSPO availability, specific binding of [3H]JNJ-64413739 and [123I]CLINDE was examined in the same tissue. The binding was measured in both cortical gray and subcortical white matter. Saturation revealed a Kd (5 nM) value similar between gray and white matter but a larger Bmax in the white than in the gray matter. The binding was completely displaced by the cold ligand and structurally different P2X7R ligands. The variability in saturable binding among the samples was found to be 38% in gray and white matter but was not correlated to either age, sex, or the duration of the disease. Interestingly, there was no significant correlation between [3H]JNJ-64413739 and [123I]CLINDE binding. These data demonstrate that [3H]JNJ-64413739 is a suitable radioligand for evaluating the distribution and expression of the P2X7R in the human brain.</p

Sex correction improves the accuracy of clinical dopamine transporter imaging

Background In clinical diagnostic imaging, dopamine transporter (DAT) SPECT scans are commonly evaluated using automated semiquantitative analysis software. Age correction is routinely implemented, but usually no sex correction of DAT binding is performed. Since there are sex differences in presynaptic dopaminergic function, we investigated the effect of DAT sex correction in a sample of healthy volunteers who underwent brain [I-123]-FP-CIT SPECT. Methods Forty healthy elderly individuals (21 men and 19 women) underwent brain [I-123]-FP-CIT SPECT, and each subject was examined clinically for motor and non-motor parkinsonian symptoms and signs. Regional specific DAT binding ratios (SBR = [ROI-occ]/occ) were calculated using age correction, and the results were compared to those in normal databases with and without sex correction. The level of regional abnormality was set at 2 standard deviations below the mean values of the reference databases. Results In the analysis without sex correction, compared to the mean ratio of the reference database, ten healthy individuals (8 men and 2 women) had abnormally low DAT binding ratios, and four individuals (3 men and 1 woman) had borderline low DAT binding ratios in at least one striatal region. When sex correction was implemented, the ratio of one individual was abnormal, and the ratio of one individual was borderline (both males). There were no clinically significant differences in motor or non-motor symptoms between healthy volunteers with abnormal and normal binding. Conclusions A considerable number of elderly healthy male subjects can be interpreted to be dopaminergically abnormal if no sex correction of DAT binding is performed. Sex differences in striatal dopaminergic function should be taken into account when DAT imaging is used to assist clinical diagnostics in patients with suspected neurological disorders.</p

Glia Imaging Differentiates Multiple System Atrophy from Parkinson's Disease: A Positron Emission Tomography Study with [C-11]PBR28 and Machine Learning Analysis

Background The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA. Objective In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA.Methods We analyzed [C-11]PBR28 binding to TSPO using imaging data of 66 patients with MSA and 24 patients with PD. Group comparisons were based on regional analysis of parametric images. The diagnostic readout included visual reading of PET images against clinical diagnosis and machine learning analyses. Sensitivity, specificity, and receiver operating curves were used to discriminate MSA from PD and cerebellar from parkinsonian variant MSA. Results We observed a conspicuous pattern of elevated regional [C-11]PBR28 binding to TSPO in MSA as compared with PD, with "hotspots" in the lentiform nucleus and cerebellar white matter. Visual reading discriminated MSA from PD with 100% specificity and 83% sensitivity. The machine learning approach improved sensitivity to 96%. We identified MSA subtype-specific TSPO binding patterns. Conclusions We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an alpha-synucleinopathy that remains strikingly incurable. </p

Imaging of neuroinflammation: TSPO and beyond

Editorial, no abstract availabl

Dopamine transporter binding in symptomatic controls and healthy volunteers : Considerations for neuroimaging trials

Publisher Copyright: © 2021 The Author(s)Objective: To evaluate possible differences between brain dopamine transporter (DAT) binding in a group of symptomatic parkinsonism patients without dopaminergic degeneration and healthy individuals. Background: Dopaminergic neuroimaging studies of Parkinson's disease (PD) have often used control groups formed from symptomatic patients with apparently normal striatal dopamine function. We sought to investigate whether symptomatic patients can be used to represent dopaminergically normal healthy controls. Methods: Forty healthy elderly individuals were scanned with DAT [123I]FP-CIT SPECT and compared to 69 age- and sex-matched symptomatic patients with nondegenerative conditions (including essential tremor, drug-induced parkinsonism and vascular parkinsonism). An automated region-of-interest based analysis of the caudate nucleus and the anterior/posterior putamen was performed. Specific binding ratios (SBR = [ROI-occ]/occ) were compared between the groups. Results: DAT binding in symptomatic patients was 8.6% higher in the posterior putamen than in healthy controls (p = 0.03). Binding correlated negatively with age in both groups but not with motor symptom severity, cognitive function or depression ratings. Conclusions: Putaminal DAT binding, as measured with [123I]FP-CIT SPECT, was higher in symptomatic controls than in healthy individuals. The reason for the difference is unclear but can include selection bias when DAT binding is used to aid clinical diagnosis and possible self-selection bias in healthy volunteerism. This effect should be taken into consideration when designing and interpreting neuroimaging trials investigating the dopamine system with [123I]FP-CIT SPECT.Peer reviewe