Spatiotemporal Power of Positron Emission Tomography: Pushing the Limits of Poisson Statistics in High-Resolution Human Neurotransmission Studies

Brain disorders involving dysfunctions in neurotransmissionconstitute one of the most prevalent health problems. Subtledisruptions in human neurotransmission can result in significantdysfunction of cognition, locomotion, or practically any facet ofhuman behaviour. In turn, homeostasis of a specific neurotransmitter system can often be retrieved through pharmacologicalor lifestyle interventions. At present, human neurotransmissioncan be best assayed using positron emission tomography (PET). To date, neurotransmitter-PET (nt-PET) has been employedto investigate neuroreceptor level phenomenon in human behavior/cognition as well as in treatment development. In thecurrent work the goal was to explore and enhance the temporalcapabilities of nt-PET, to allow better characterization of thetemporal facets of neurotransmission.Main obstacles limiting temporal characterization stem fromthe poor signal-to-noise-ratio of the PET measurement. Inparticular, the limitations related to image reconstruction algorithms and in turn the benefits obtained through regionalanalysis were in the focus of the investigations in this work. Themain finding was that the best temporal resolution achieved using a commonly recommended iterative reconstruction methodwas insufficient for temporal characterization, while a newlydeveloped algorithm allowing analytical reconstruction showedbetter temporal resolution without decreasing signal-to-noiseratio. Furthermore, a novel atlas-based regional analysis methodwas found superior to the currently employed manual region-ofinterest definition.The findings made through this work will directly assist theplanning of future neurotransmission studies, and it is wishedthat the observations in this work would spark new, more widespread interest on the application of nt-PET in e.g. cognitivestimulation studies

Individual parkinsonian motor signs and striatal dopamine transporter deficiency: a study with [I-123]FP-CIT SPECT

IntroductionTotal parkinsonian motor symptom severity correlates with presynaptic striatal dopamine function in patients with Parkinson's disease. There is a lack of studies that have investigated the associations between parkinsonian motor signs and striatal dopaminergic deficiency in patients with parkinsonism of an unknown origin. Identification of specific motor signs associated with the highest likelihood of striatal dopamine deficiency could aid the differential diagnostics of parkinsonian and tremor syndromes.MethodsIn this cross-sectional clinical and imaging study, detailed motor examinations were performed for 221 patients with parkinsonism or tremor of an unknown origin immediately before dopamine transporter (DAT) [I-123]FP-CIT SPECT imaging. Region-of-interest and voxel-based methods were used to investigate striatal DAT deficiency in relation to individual motor signs.ResultsUpper extremity rigidity and facial expression were the only motor signs that differentiated patients with normal and abnormal striatal DAT function. The presence of any upper extremity rigidity showed the highest likelihood of DAT deficiency (OR 4.79, 95% CI 1.56-14.75, P=0.006) followed by reduced facial expression (OR 2.14, 95% CI 1.14-4.00, P=0.018). In patients with DAT deficits, reduced facial expression was associated with DAT deficiency specifically in the caudate nucleus, and increased upper extremity rigidity was associated with DAT loss in the dorsal putamen (FWE-corrected PPeer reviewe

Comparison of manual and automatic techniques for substriatal segmentation in C-11-raclopride high-resolution PET studies

Background: The striatum is the primary target in regional C-11-raclopride-PET studies, and despite its small volume, it contains several functional and anatomical subregions. The outcome of the quantitative dopamine receptor study using C-11-raclopride-PET depends heavily on the quality of the region-of-interest (ROI) definition of these subregions. The aim of this study was to evaluate subregional analysis techniques because new approaches have emerged, but have not yet been compared directly.Materials and methods: In this paper, we compared manual ROI delineation with several automatic methods. The automatic methods used either direct clustering of the PET image or individualization of chosen brain atlases on the basis of MRI or PET image normalization. State-of-the-art normalization methods and atlases were applied, including those provided in the FreeSurfer, Statistical Parametric Mapping8, and FSL software packages. Evaluation of the automatic methods was based on voxel-wise congruity with the manual delineations and the test-retest variability and reliability of the outcome measures using data from seven healthy male participants who were scanned twice with C-11-raclopride-PET on the same day.Results: The results show that both manual and automatic methods can be used to define striatal subregions. Although most of the methods performed well with respect to the test-retest variability and reliability of binding potential, the smallest average test-retest variability and SEM were obtained using a connectivity-based atlas and PET normalization (test-retest variability=4.5%, SEM=0.17).Conclusion: The current state-of-the-art automatic ROI methods can be considered good alternatives for subjective and laborious manual segmentation in C-11-raclopride-PET studies.Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.</div

Synthesis and In Vitro Evaluation of a Set of 6-Deoxy-6-thio- carboranyl D-Glucoconjugates Shed Light on the Substrate Specificity of the GLUT1 Transporter

Glucose-and sodium-dependent glucose transporters (GLUTs and SGLTs) play vital roles in human biology. Of the 14 GLUTs and 12 SGLTs, the GLUT1 transporter has gained t h e most widespread recognition because GLUT1 is overexpressed in several cancers and is a clinically valid therapeutic target. We have been pursuing a GLUT1-targeting approach in boron neutron capture therapy (BNCT). Here, we report on surprising findings encountered w i t h a set of 6-deoxy-6-thio-carbora n y l D-glucoconjugates. In more detail, we show that even subtle structural changes in t h e carborane cluster, and the linker, may significantly reduce the delivery capacity of GLUT1-based boron carriers. In addition to providing new insights on the substrate specificity of this important transporter, we reach a fresh perspec t i v e on the boundaries within which a GLUT1-targeting approach in BNCT can be further refined.Peer reviewe

Exploring the Biochemical Foundations of a Successful GLUT1-Targeting Strategy to BNCT: Chemical Synthesis and In Vitro Evaluation of the Entire Positional Isomer Library of ortho-Carboranylmethyl-Bearing Glucoconjugates

Boron neutron capture therapy (BNCT) is a noninvasive binary therapeutic modality applicable to the treatment of cancers. While BNCT offers a tumor-targeting selectivity that is difficult to match by other means, the last obstacles preventing the full harness of this potential come in the form of the suboptimal boron delivery strategies presently used in the clinics. To address these challenges, we have developed delivery agents that target the glucose transporter GLUT1. Here, we present the chemical synthesis of a number of ortho-carboranylmethyl-substituted glucoconjugates and the biological assessment of all positional isomers. Altogether, the study provides protocols for the synthesis and structural characterization of such glucoconjugates and insights into their essential properties, for example, cytotoxicity, GLUT1-affinity, metabolism, and boron delivery capacity. In addition to solidifying the biochemical foundations of a successful GLUT1-targeting approach to BNCT, we identify the most promising modification sites in d-glucose, which are critical in order to further develop this strategy toward clinical use.Peer reviewe

Change in brain amyloid load and cognition in patients with amnestic mild cognitive impairment: a 3-year follow-up study

Background Our aim was to investigate the discriminative value of F-18-Flutemetamol PET in longitudinal assessment of amyloid beta accumulation in amnestic mild cognitive impairment (aMCI) patients, in relation to longitudinal cognitive changes. Methods We investigated the change in F-18-Flutemetamol uptake and cognitive impairment in aMCI patients over time up to 3 years which enabled us to investigate possible association between changes in brain amyloid load and cognition over time. Thirty-four patients with aMCI (mean age 73.4 years, SD 6.6) were examined with F-18-Flutemetamol PET scan, brain MRI and cognitive tests at baseline and after 3-year follow-up or earlier if the patient had converted to Alzheimer ' s disease (AD). F-18-Flutemetamol data were analyzed both with automated region-of-interest analysis and voxel-based statistical parametric mapping. Results F-18-flutemetamol uptake increased during the follow-up, and the increase was significantly higher in patients who were amyloid positive at baseline as compared to the amyloid-negative ones. At follow-up, there was a significant association between F-18-Flutemetamol uptake and MMSE, logical memory I (immediate recall), logical memory II (delayed recall) and verbal fluency. An association was seen between the increase in F-18-Flutemetamol uptake and decline in MMSE and logical memory I scores. Conclusions In the early phase of aMCI, presence of amyloid pathology at baseline strongly predicted amyloid accumulation during follow-up, which was further paralleled by cognitive declines. Inversely, some of our patients remained amyloid negative also at the end of the study without significant change in F-18-Flutemetamol uptake or cognition. Future studies with longer follow-up are needed to distinguish whether the underlying pathophysiology of aMCI in such patients is other than AD.</p

Increased dopamine release after working-memory updating training: Neurochemical correlates of transfer

AbstractPrevious work demonstrates that working-memory (WM) updating training results in improved performance on a letter-memory criterion task, transfers to an untrained n-back task, and increases striatal dopamine (DA) activity during the criterion task. Here, we sought to replicate and extend these findings by also examining neurochemical correlates of transfer. Four positron emission tomography (PET) scans using the radioligand raclopride were performed. Two of these assessed DAD2 binding (letter memory; n-back) before 5 weeks of updating training, and the same two scans were performed post training. Key findings were (a) pronounced training-related behavioral gains in the letter-memory criterion task, (b) altered striatal DAD2 binding potential after training during letter-memory performance, suggesting training-induced increases in DA release, and (c) increased striatal DA activity also during the n-back transfer task after the intervention, but no concomitant behavioral transfer. The fact that the training-related DA alterations during the transfer task were not accompanied by behavioral transfer suggests that increased DA release may be a necessary, but not sufficient, condition for behavioral transfer to occur.</div

Opinion: Insights into updating Ambient Air Quality Directive 2008/50/EC

As evidence of adverse health effects due to air pollution continues to increase, the World Health Organization (WHO) recently published its latest edition of the global air quality guidelines (World Health Organization, 2021). Although not legally binding, the guidelines aim to provide a framework in which policymakers can combat air pollution by formulating evidence-based air quality management strategies. In the light of this, the European Union has stated its intent to revise the current ambient air quality directive (2008/50/EC) to more closely resemble the newly published WHO guidelines (European Commission, 2020). This article provides an informed opinion on selected features of the air quality directive that we believe would benefit from a reassessment. The selected features include discussion about (1) air quality sensors as a part of a hierarchical observation network, (2) the number of minimum sampling points and their siting criteria, and (3) new target air pollution parameters for future consideration.Peer reviewe

Individual parkinsonian motor signs and striatal dopamine transporter deficiency: a study with [I-123]FP-CIT SPECT

IntroductionTotal parkinsonian motor symptom severity correlates with presynaptic striatal dopamine function in patients with Parkinson’s disease. There is a lack of studies that have investigated the associations between parkinsonian motor signs and striatal dopaminergic deficiency in patients with parkinsonism of an unknown origin. Identification of specific motor signs associated with the highest likelihood of striatal dopamine deficiency could aid the differential diagnostics of parkinsonian and tremor syndromes.MethodsIn this cross-sectional clinical and imaging study, detailed motor examinations were performed for 221 patients with parkinsonism or tremor of an unknown origin immediately before dopamine transporter (DAT) [I-123]FP-CIT SPECT imaging. Region-of-interest and voxel-based methods were used to investigate striatal DAT deficiency in relation to individual motor signs.ResultsUpper extremity rigidity and facial expression were the only motor signs that differentiated patients with normal and abnormal striatal DAT function. The presence of any upper extremity rigidity showed the highest likelihood of DAT deficiency (OR 4.79, 95% CI 1.56–14.75, P = 0.006) followed by reduced facial expression (OR 2.14, 95% CI 1.14–4.00, P = 0.018). In patients with DAT deficits, reduced facial expression was associated with DAT deficiency specifically in the caudate nucleus, and increased upper extremity rigidity was associated with DAT loss in the dorsal putamen (FWE-corrected P ConclusionsIncreased upper extremity muscle tone and hypomimia are independently associated with a higher likelihood of striatal hypodopaminergic imaging finding. This information can be used as a factor when the clinical need of auxiliary investigations, such as DAT SPECT, is considered for patients with parkinsonism.</div