Striatal and Extrastriatal Monoaminergic Disruption in Progressive Supranuclear Palsy.

BACKGROUND: As a biomarker targeting vesicular monoamine transporter 2 (VMAT2), 18F-9-fluoropropyldihydrotetrabenazine (18F-FP-DTBZ) positron emission tomography (PET) is highly accurate in diagnosing Parkinson's disease (PD) and assessing its severity. However, evidence is insufficient in patients with progressive supranuclear palsy (PSP). OBJECTIVE: We evaluated the striatal and extrastriatal monoaminergic disruption of PSP and differences in patterns between patients with PSP, PD, and healthy controls (HCs) using 18F-FP-DTBZ PET, as well as its correlations with the clinical characteristics of PSP. METHODS: We recruited 58 patients with PSP, 23 age- and duration-matched patients with PD, as well as 17 HCs. Patients were scanned using 18F-FP-DTBZ PET/computed tomography, and images were spatially normalized and analyzed based on the volume of interest. RESULTS: VMAT2 binding differed significantly in the striatum and substantia nigra among the groups (P < 0.001). A more severe disruption in the caudate was noted in the PSP group (P < 0.001) than in the PD group. However, no differences were found in the nucleus accumbens, hippocampus, amygdala, or raphe between the PD and PSP groups. Within the PSP group, striatal VMAT2 binding was significantly associated with the fall/postural stability subscore of the PSP Rating Scale, especially in the putamen. Furthermore, VMAT2 binding was correlated with Mini-Mental State Examination or Montreal Cognitive Assessment in the hippocampus. CONCLUSIONS: Caudate disruptions showed prominent differences among the groups. VAMT2 binding in the striatum and hippocampus reflects the severity of fall/postural stability and cognition, respectively. © 2024 International Parkinson and Movement Disorder Society.

18F-FP-DTBZ PET/CT detectable associations between monoaminergic depletion in the putamen with rigidity and the pallidus with tremor in Parkinson's disease.

INTRODUCTION: The motor subtypes of Parkinson's disease (PD) are widely accepted and implemented. However, the motor subtypes have been thought to represent different stages of PD recently because some patients experience tremor-dominant (TD) conversion to the non-tremor-dominant subtype, such as postural instability-gait difficulty (PIGD). In this study, we explore the monoaminergic denervation features of the striatal and extra-striatal areas in patients with different subtypes of PD with 18F-9-fluoropropyl-(+)-dihydrotetrabenazine (18F-FP-DTBZ) PET/CT. METHODS: Sixty-five patients diagnosed with PD were included and classified as TD (n = 25) and PIGD (n = 40). We evaluated the difference of monoaminergic features of each subregion of brain between motor subtypes of PD, as well as associations between these features and Parkinsonian motor symptoms. RESULTS: The striatal standardized uptake value ratios (SUVR) showed that dopaminergic disruption of patients with PIGD was more symmetrical in the posterior ventral putamen (p < 0.001) and more severe in the ipsilateral posterior dorsal putamen (p < 0.001 corrected) compared with that of patients with TD. The severity of PIGD scores was associated with striatal dopaminergic depletion, while tremor was associated with monoaminergic changes in extra-striatal areas, including pallidus, thalamus, and raphe nuclie. CONCLUSION: These results indicate that patients with different motor subtypes may have different underlying mechanisms of PD pathogenesis. Therefore, accurate diagnosis of PD subtypes can aid prognosis evaluation and treatment decision-making.

Respect or resect in Barlow disease.

Mitral regurgitation in Barlow disease may still be challenging to be repaired. Most often it involves the posterior leaflet. Many techniques and concepts are currently available; the main goal being to restore a good surface of coaptation. Basic principles such as thorough analysis is still required whatever the approach to assess excess tissue height, width, and prolapse. Nowadays it seems that two different ways of treating mitral prolapse coexist: the nonresection one and the resection one. Both will be discussed and analyzed. Similarly, the use of artificial chordae seems to have a preponderant role to support the free edge and correct a prolapse. Native secondary chord transfer are easy and reliable but seem abandoned by many. Anterior leaflet prolapse is also dealt with and fewer options are available to address this leaflet. Then commissural prolapse is mentioned. It is an important area of the valve which should deserve better treatment than commissuroplasty. Finally, a special entity will be described; mitro annular disjunction. The approach is not or no longer an issue as only good long-term results are important in an era where percutaneous therapy is the only noninvasive technique.

Corrigendum: Diagnostic value of striatal 18F-FP-DTBZ PET in Parkinson's disease.

[This corrects the article DOI: 10.3389/fnagi.2022.931015.].

Diagnostic value of striatal 18F-FP-DTBZ PET in Parkinson's disease.

Background: 18F-FP-DTBZ has been proven as a biomarker for quantifying the concentration of presynaptic vesicular monoamine transporter 2 (VMAT2). However, its clinical application is still limited. Objectives: To evaluate the difference in dopaminergic integrity between patients with Parkinson's disease (PD) and healthy controls (HC) using 18F-FP-DTBZ PET in vivo and to determine the diagnostic value of standardized uptake value ratios (SUVRs) using the Receiver Operating Characteristic (ROC) curve. Methods: A total of 34 PD and 31 HC participants were enrolled in the PET/MR derivation cohort, while 89 PD and 18 HC participants were recruited in the PET/CT validation cohort. The Hoehn-Yahr Scale and the third part of the MDS-Unified Parkinson's Disease Rating Scale (MDSUPDRS-III) were used to evaluate the disease staging and severity. All assessments and PET scanning were performed in drug-off states. The striatum was segmented into five subregions as follows: caudate, anterior dorsal putamen (ADP), anterior ventral putamen (AVP), posterior dorsal putamen (PDP), and posterior ventral putamen (PVP) using automatic pipeline built with the PMOD software (version 4.105). The SUVRs of the targeted subregions were calculated using the bilateral occipital cortex as the reference region. Results: Regarding the diagnostic value, ROC curve and blind validation showed that the contralateral PDP (SUVR = 3.43) had the best diagnostic accuracy (AUC = 0.973; P < 0.05), with a sensitivity of 97.1% (95% CI: 82.9-99.8%), specificity of 100% (95% CI: 86.3-100%), positive predictive value (PPV) of 100% (95% CI: 87.0-100%), negative predictive value (NPV) of 96.9% (95% CI: 82.0-99.8%), and an accuracy of 98.5% for the diagnosis of PD in the derivation cohort. Blind validation of 18F-FP-DTBZ PET imaging diagnosis was done using the PET/CT cohort, where participants with a SUVR of the PDP <3.43 were defined as PD. Kappa test showed a consistency of 0.933 (P < 0.05) between clinical diagnosis and imaging diagnosis, with a sensitivity of 98.9% (95% CI: 93.0-99.9%), specificity of 94.4% (95% CI: 70.6-99.7%), PPV of 98.9% (95% CI: 93.0-99.9%), NPV of 94.4% (95% CI: 70.6-99.7%), and a diagnostic accuracy of 98.1%. Conclusions: Our results showed that an SUVR threshold of 3.43 in the PDP could effectively distinguish patients with PD from HC.

Brain microglia activation and peripheral adaptive immunity in Parkinson's disease: a multimodal PET study.

BACKGROUND: Abnormal activation of immune system is an important pathogenesis of Parkinson's disease, but the relationship between peripheral inflammation, central microglia activation and dopaminergic degeneration remains unclear. OBJECTIVES: To evaluate the brain regional microglia activation and its relationship with clinical severity, dopaminergic presynaptic function, and peripheral inflammatory biomarkers related to adaptive immunity. METHODS: In this case-control study, we recruited 23 healthy participants and 24 participants with early-stage Parkinson's disease. 18F-PBR06 PET/MR for microglia activation, 18F-FP-DTBZ for dopaminergic denervation, total account of T cells and subpopulations of T helper (Th1/Th2/Th17) cells, and the levels of serum inflammatory cytokines were assessed. Sanger sequencing was used to exclude the mix-affinity binders of 18F-PBR06-PET. RESULTS: Compared to healthy controls, patients with Parkinson's disease had an increased 18F-PBR06-PET standardized uptake value ratio (SUVR) in the putamen, particularly in the ipsilateral side of the motor onset. 18F-PBR06-PET SUVR was positively associated with 18F-FP-DTBZ-PET SUVR in the brainstem and not associated with disease severity measured by Hoehn and Yahr stage, MDS-UPDRS III scores. Patients with Parkinson's disease had elevated frequencies of Th1 cells and serum levels of IL10 and IL17A as compared to healthy controls. No significant association between peripheral inflammation markers and microglia activation in the brain of PD was observed. CONCLUSION: Parkinson's disease is associated with early putaminal microglial activation and peripheral phenotypic Th1 bias. Peripheral adaptive immunity might be involved in microglia activation in the process of neurodegeneration in PD indirectly, which may be a potential biomarker for the early detection and the target for immunomodulating therapy.

Tricuspid valve replacement: The old and the new.

Tricuspid regurgitation is a frequent and serious condition but tricuspid valve (TV) surgery, that may be a valve replacement when a repair is not feasible, is rarely performed. Recent development of transcatheter TV interventions offers new options for those high-surgical risk patients, especially TV replacement for patients who are not eligible for transcatheter TV repair. In this review, we describe indications and outcome after surgical TV replacement, and devices available or in development for transcatheter TV replacement.

Experimental Assessment of Workplace Radiation Exposure in Diagnostic X-ray Medical Imaging Centres in Benin from 2019 to 2020.

The ease of prescribing radiological examinations has prompted an expansion in radiological procedures and, consequently, an increase of occupational dose to medical imaging workers. However, little is known about radiation exposure in the workplace of medical radiology professionals in many countries, and in Benin particularly. The purpose of this study was to assess ambient radiation doses in diagnostic X-ray medical facilities in Benin and to observe whether exposure levels are below reference levels. A total of 72 public and private medical imaging centres participated in a cross-sectional study carried out from June 2019 to February 2020 in Benin. These centres had 59 X-ray, four chest and six computed tomography (CT) scan rooms. A calibrated radiameter able to measure short, pulsed or continuous X fields and gamma/beta (50 nSv to 10 Sv) was used to measure exposure levels in these functional rooms. Scattered X-ray doses and exposure time from radiological examinations both behind the lead glass of the control area to assess the levels of exposure of professionals and outside of the examination room to evaluate the level of exposure of the public (including non-exposed workers) have been provided. Equivalent doses estimated per hour were compared with the reference levels of 7.50 and 0.05 µSv per hour for workers and the public, respectively. At the control area, the mean/median (min-max) equivalent doses were 0.09/0.07 (0.00-0.21), 2.39/0.13 (0.00-75.67), and 228.39/28.65 (0.39-869.75) µSv per hour for the chest, X-ray, and CT-scan rooms, respectively. Among 69 examination rooms, 13.04% of the equivalent dose estimated in the workplace behind the lead glass was greater than 7.50 µSv per hour; 65 out of 69 examination rooms showed that 40.00% of the equivalent dose estimated behind the doors was greater than 0.05 µSv per hour. These results demonstrated that current controls, including leaded glass separating the control panel and leaded doors between the examination room and the corridor, are inadequate to limit radiation exposures. The controls must be upgraded and a dosimetry program should be implemented to monitor exposures of employees, patients, and visitors.

Outcome of consistent guideline-based tricuspid management in patients undergoing degenerative mitral regurgitation correction.

Objectives: Despite coherent guidelines, management of functional tricuspid regurgitation (FTR) consequences on outcome in the context of degenerative mitral regurgitation (DMR) remains controversial due to lacking series of large magnitude with rigorous application of tricuspid guidelines and strict long-term echocardiographic follow-up. Thus, we aimed at gathering such a cohort to examine outcomes of patients undergoing DMR surgery following tricuspid surgery guidelines. Methods: All consecutive patients with isolated DMR 2005-2015 operated on with baseline FTR assessment and tricuspid annulus diameter measurement were identified. Operative complications, postoperative tricuspid regurgitation incidence, and survival were assessed overall and stratified by guideline-based tricuspid annuloplasty (TA) indication (severe FTR or tricuspid annulus diameter ≥40 mm). Results: Among 441 patients with DMR undergoing mitral repair (66 ± 13 years, 30% female, ejection fraction 66 ± 10%, systolic pulmonary artery pressures 39 ± 12 mm Hg) followed 6 [3-9] years, patients with TA (n = 234, 53%) had generally similar presentation versus without TA (n = 207, 47%; all P ≥ .2) except for more atrial fibrillation and larger left ventricle (both P ≥ .0003). Patients with TA showed longer bypass time, more maze procedures (all P ≤ .001), but hospital stay, renal-failure, pacemaker implantation, and operative mortality (overall 0.9%) were comparable (all P ≥ .2). Postoperative incidence of moderate/severe FTR (0% at 1 year) became over time greater among patients without TA (5-year 8% [4%-13%] vs 3% [1%-11%] and 10-year 10% [6%-16%] vs 4% [1%-16%], P = .01). Survival (95% confidence interval) throughout follow-up was 85% (77%-89%) at 10 years, with hazard ratio 0.57 (0.29-1.10), P = .09. for patients with TA versus without. Conclusions: In this large surgical DMR cohort, guideline-based FTR management was safe and effective. While long-term mortality did not reach significance, postoperative incidence of moderate/severe FTR, overall low, was nevertheless greater in patients who did not appear to require TA at surgery and linked to tricuspid annular dimension. Thus, future multicenter prospective cohorts with long-term follow-up are warranted to re-examine thresholds for TA performance and impact on survival.

Rapidly (and Successfully) Translating Novel Brain Radiotracers From Animal Research Into Clinical Use.

The advent of preclinical research scanners for in vivo imaging of small animals has added confidence into the multi-step decision-making process of radiotracer discovery and development. Furthermore, it has expanded the utility of imaging techniques available to dissect clinical questions, fostering a cyclic interaction between the clinical and the preclinical worlds. Significant efforts from medicinal chemistry have also made available several high-affinity and selective compounds amenable for radiolabeling, that target different receptors, transporters and enzymes in vivo. This substantially increased the range of applications of molecular imaging using positron emission tomography (PET) or single photon emission computed tomography (SPECT). However, the process of developing novel radiotracers for in vivo imaging of the human brain is a multi-step process that has several inherent pitfalls and technical difficulties, which often hampers the successful translation of novel imaging agents from preclinical research into clinical use. In this paper, the process of radiotracer development and its relevance in brain research is discussed; as well as, its pitfalls, technical challenges and future promises. Examples of successful and unsuccessful translation of brain radiotracers will be presented.

A systematic review of occupational radiation individual dose monitoring among healthcare workers exposed in Africa.

Dosimetric monitoring is useful to limit exposures to ionising radiation in medical occupational settings, and reduce subsequent health risks. Scientific literatures, such as the UNSCEAR report 2017 and International Atomic Energy Agency Report 2014b, updated information on this subject; however, few African works have been found. This is the reason why we undertook this study, which summarises existing information on monitoring external radiation exposure doses for the whole body, using data from medical workers on this continent. Using standard terms and combining different keyword searches for radiation dose monitoring among radiology healthcare workers in Africa, from the titles, abstracts, and full texts, we found 3139 articles in the PubMed/MEDLINE, Google Scholar and INIS databases. Two reviewers screened the retrieved publications based on predefined eligibility criteria to identify relevant studies, extract key information from each, and summarise the data in table form. A total of 20 potentially relevant articles were identified. Among these 20 articles, 15 reported the overall average annual effective dose. Studies included in this systematic review represent an inventory of the radiation protection of medical workers in various African countries, with a focus on the monitoring of occupational radiation exposure. The size of studied populations ranged between 81 and 5152 occupational exposed workers. The mean annual effective doses ranged from 0.44 to 8.20 mSv in all specialities of medical sectors, while diagnostic radiology ranged from 0.07 to 4.37 mSv. For the nuclear medicine and radiotherapy from medical groups, the mean annual effective dose varied between 0.56 and 6.30 mSv. Industrial and research/teaching sectors data varied between 0.38 to 19.40 mSv. In conclusion, more studies implemented on dosimetric monitoring in Africa are needed to get a real picture of occupational exposure in the continent.

Tricuspid Regurgitation: Predicting the Need for Intervention, Procedural Success, and Recurrence of Disease.

Interest in tricuspid valve pathology has rapidly expanded in response to reported poor clinical outcome for functional tricuspid regurgitation and the limited indications and options for treatment. In the past few years, different transcatheter technologies have emerged as alternatives to conventional surgery to serve this untreated high-risk population. In this review, the authors explore the indications for intervention in tricuspid regurgitation according to current guidelines, the published research to support the expansion of these indications including the role of transcatheter interventions, and the risk factors for therapy failure, which may help define the appropriate patient population for treatment.

Development and In Vivo Preclinical Imaging of Fluorine-18-Labeled Synaptic Vesicle Protein 2A (SV2A) PET Tracers.

PURPOSE: Synaptic vesicle protein 2A (SV2A) serves as a biomarker of synaptic density and positron emission tomography (PET) imaging of SV2A could provide a tool to assess progression of neurodegenerative diseases. Two tracers have primarily been reported and characterized in vivo: [11C]UCB-J and [18F]UCB-H. In early human studies, [11C]UCB-J showed promising results, while its F-18-labeled analogue [18F]UCB-H showed suboptimal specific signal in comparison to [11C]UCB-J. Considering the limited use of [11C]UCB-J to facilities with a cyclotron, having a F-18 variant would facilitate large, multicenter imaging trials. We have screened several F-18 derivatives of UCB-J in non-human primates and identified a promising F-18 PET candidate, [18F]MNI-1126, with additional investigations of the racemate [18F]MNI-1038, affording a signal comparable to [11C]UCB-J. PROCEDURES: F-18 derivatives of UCB-J and UCB-H were synthesized and administered to non-human primates for microPET imaging. Following screenings, [18F]MNI-1038 (racemate) and [18F]MNI-1126 (R-enantiomer) were identified with the highest signal and favorable kinetics and were selected for further imaging. Kinetic modeling with one- and two-tissue compartmental models, and linear methods were applied to PET data using metabolite-corrected arterial input function. Pre-block scans with levetiracetam (LEV, 10, 30 mg/kg, iv) were performed to determine the tracers' in vivo specificity for SV2A. Two whole-body PET studies were performed with [18F]MNI-1038 in one male and one female rhesus, and radiation absorbed dose estimates and effective dose (ED, ICRP-103) were estimated with OLINDA/EXM 2.0. RESULTS: All compounds screened displayed very good brain penetration, with a plasma-free fraction of ~ 40 %. [18F]MNI-1126 and [18F]MNI-1038 showed uptake and distribution the most consistent with UCB-J, while the other derivatives showed suboptimal results, with similar or lower uptake than [18F]UCB-H. VT of [18F]MNI-1126 and [18F]MNI-1038 was high in all gray matter regions (within animal averages ~ 30 ml/cm3) and highly correlated with [11C]UCB-J (r > 0.99). Pre-blocking of [18F]MNI-1126 or [18F]MNI-1038 with LEV showed robust occupancy across all gray matter regions, similar to that reported with [11C]UCB-J (~ 85 % at 30 mg/kg, ~ 65 % at 10 mg/kg). Using the centrum semiovale as a reference region, BPND of [18F]MNI-1126 reached values of up to ~ 30 to 40 % higher than those reported for [11C]UCB-J. From whole-body imaging average ED of [18F]MNI-1038 was estimated to be 22.3 µSv/MBq, with tracer being eliminated via both urinary and hepatobiliary pathways. CONCLUSIONS: We have identified a F-18-labeled tracer ([18F]MNI-1126) that exhibits comparable in vivo characteristics and specificity for SV2A to [11C]UCB-J in non-human primates, which makes [18F]MNI-1126 a promising PET radiotracer for imaging SV2A in human trials.