Logan Method Research Articles

NiftyPAD - Novel Python Package for Quantitative Analysis of Dynamic PET Data

Current PET datasets are becoming larger, thereby increasing the demand for fast and reproducible processing pipelines. This paper presents a freely available, open source, Python-based software package called NiftyPAD, for versatile analyses of static, full or dual-time window dynamic brain PET data. The key novelties of NiftyPAD are the analyses of dual-time window scans with reference input processing, pharmacokinetic modelling with shortened PET acquisitions through the incorporation of arterial spin labelling (ASL)-derived relative perfusion measures, as well as optional PET data-based motion correction. Results obtained with NiftyPAD were compared with the well-established software packages PPET and QModeling for a range of kinetic models. Clinical data from eight subjects scanned with four different amyloid tracers were used to validate the computational performance. NiftyPAD achieved R^2>0.999 correlation with PPET, with absolute difference sim 10^{-2} for linearised Logan and MRTM2 methods, and R^2>0.999999 correlation with QModeling, with absolute difference sim 10^{-4} for basis function based SRTM and SRTM2 models. For the recently published SRTM ASL method, which is unavailable in existing software packages, high correlations with negligible bias were observed with the full scan SRTM in terms of non-displaceable binding potential (R^2=0.96), indicating reliable model implementation in NiftyPAD. Together, these findings illustrate that NiftyPAD is versatile, flexible, and produces comparable results with established software packages for quantification of dynamic PET data. It is freely available (https://github.com/AMYPAD/NiftyPAD), and allows for multi-platform usage. The modular setup makes adding new functionalities easy, and the package is lightweight with minimal dependencies, making it easy to use and integrate into existing processing pipelines.

In vivo exploration of synaptic projections in frontotemporal dementia

The purpose of this exploratory research is to provide data on synaptopathy in the behavioral variant of frontotemporal dementia (bvFTD). Twelve patients with probable bvFTD were compared to 12 control participants and 12 patients with Alzheimer’s disease (AD). Loss of synaptic projections was assessed with [18F]UCBH-PET. Total distribution volume was obtained with Logan method using carotid artery derived input function. Neuroimages were analyzed with SPM12. Verbal fluency, episodic memory and awareness of cognitive impairment were equally impaired in patients groups. Compared to controls, [18F]UCBH uptake tended to decrease in the right anterior parahippocampal gyrus of bvFTD patients. Loss of synaptic projections was observed in the right hippocampus of AD participants, but there was no significant difference in [18F]UCBH brain uptake between patients groups. Anosognosia for clinical disorder was correlated with synaptic density in the caudate nucleus and the anteromedial prefrontal cortex. This study suggests that synaptopathy in bvFTD targets the temporal social brain and self-referential processes.

Dimensional Analysis of Transmissivity Equations and Comparison of Dependent Variables Using Birnin Gwari Aquifer Characteristics in Northern Nigeria

This study established relationship among three transmissivity equations using dimensional analysis, comparing three dependent variables inherent in the transmissivity equations, and use correlation analysis to examine the nature of interrelationship between drawdown and specific capacity in the Birnin-Gwari local government area of Kaduna State, Nigeria between October 2018 and October 2019. Relationship between three transmissivity equations, namely, Jacob, Logan and Babuskin was determined using dimensional analysis. The equations and the outcome were applied to the hydraulic data obtained from 26 producing boreholes in the study area. Comparison of the dependent variables, namely discharge, drawdown and hydraulic conductivity, was carried out to observe the relationship among them. The Correlation analysis was used to examine the nature of interrelationship between drawdown and specific capacity, while the plots of depth-to-water table and depth-to-basement were made to provide pictorial comparison between positions of water table and the underlying Basement. The results showed that the values computed from the Jacob method are the lowest among the three, while Logan method gave higher values, although they all trend in similar manner. The study revealed an inverse trend in the drawdown versus discharge and hydraulic conductivity. Correlation analysis between drawdown and specific capacity gave a regression coefficient of -0.593 and correlation coefficient of 0.352, indicating a weak relationship between them. The graphical relation of water level versus basement rock surfaces portend a near-parallel trend possibly determined by the underlying geology. Transmissivity values computed from the Babuskin method gave almost average values among the three methods. Both the regression and correlation coefficients gave low to average values between drawdown and specific capacity. The depth-to-basement versus depth-to-water plots showed that water table variations are probably controlled by the type and trend of basement topography.

PET‐[18F]UCB‐H for assessing synaptic density in FTD

AbstractBackgroundThe behavioural variant of fronto‐temporal dementia (FTD) is characterized by clinical symptoms including behavioural and cognitive changes and by neurodegenerative involvement of the anterior part of the brain. The objective was to study the in vivo distribution of synaptic loss.Method12 patients with possible FTD and frontotemporal hypometabolism on FDG‐PET (mean disease duration of 4 years) were compared to 12 control participants and 12 patients with Alzheimer’s disease, matched for age, sex and education. Measures of verbal fluency, episodic memory and awareness of cognitive impairment did not differ between patients groups. We used [18F]UCBH‐PET to assess the regional loss of synaptic density. Total distribution volume was obtained with Logan method and carotid artery derived input function. SPM12 was used to analyze pve‐corrected PET and MRI images.ResultA significant decrease of [18F]UCBH uptake was observed in the right anterior parahippocampal gyrus of FTD patients, while atrophy was observed in the ventromedial prefrontal cortex. Loss of synaptic density was observed in the right hippocampus of AD participants, while atrophy extended from the right hippocampus to bilateral posterior associative cortices. AD patients showed lower [18F]UCBH uptake in the precuneus that FTD patients. Anosognosia for clinical symptoms was correlated with synaptic density in caudate nucleus and prefrontal cortex in FTD, and with synaptic density in posterior hippocampus in AD.ConclusionSynaptic loss was predominant in the anterior parahippocampal gyrus of our bvFTD patients. This region is part of the limbic network and the perceptive social brain. A validated measure of anosognosia (a characteristic but variable symptom in bvFTD) was related to synaptic density in two interconnected regions, caudate nucleus and anteromedial prefrontal cortex, the later being involved in self‐reference.

Repurposing radiotracers for myelin imaging: a study comparing 18F-florbetaben, 18F-florbetapir, 18F-flutemetamol,11C-MeDAS, and 11C-PiB.

Drugs promoting myelin repair represent a promising therapeutic approach in multiple sclerosis and several candidate molecules are currently being evaluated, fostering the need of a quantitative method to specifically measure myelin content in vivo. PET using the benzothiazole derivative 11C-PiB has been successfully used to quantify myelin content changes in humans. Stilbene derivatives, such as 11C-MeDAS, have also been shown to bind to myelin in animals and are considered a promising radiopharmaceutical class for myelin imaging. Fluorinated compounds from both classes are now commercially available and thus should constitute clinically useful myelin radiotracers. The aim of this study is to provide a head-to-head comparison of 18F-florbetaben, 18F-florbetapir, 18F-flutemetamol, 11C-MeDAS, and 11C-PiB with regard to brain kinetics and binding in white matter (WM). Four baboons underwent a 90-min dynamic PET scan for each radioligand. Arterial blood samples were collected during the exam for each radiotracer, except for 18F-florbetapir, to obtain a radiometabolite-corrected input function. Standardized uptake value ratio between 75 at 90min (SUVR75-90), binding potential (BP) estimated with Logan method with input function, and distribution volume ratio (DVR) estimated with Logan reference method (using cerebellar gray matter as reference region) were calculated in WM and compared between tracers using mixed effect models. In WM, 18F-florbetapir had the highest SUVR75-90 (1.38 ± 0.03), followed by 18F-flutemetamol (1.34 ± 0.02), 18F-florbetaben (1.32 ± 0.07), 11C-MeDAS (1.27 ± 0.04), and 11C-PiB (1.25 ± 0.07). With regard to BP, 18F-florbetaben had the highest value (0.32 ± 0.06) compared with 18F-flutemetamol (0.20 ± 0.03), 11C-MeDAS (0.17 ± 0.03), and 11C-PiB (0.16 ± 0.03). No difference in DVR was detected between 18F-florbetaben (1.26 ± 0.06) and 18F-florbetapir (1.27 ± 0.03), but both were significantly higher in DVR than 18F-flutemetamol (1.17 ± 0.02), 11C-MeDAS (1.16 ± 0.03), and 11C-PiB (1.14 ± 0.02). Given their higher binding and longer half-life, our study indicates that 18F-florbetapir and 18F-florbetaben are promising tracers for myelin imaging which are readily available for clinical application in demyelinating diseases.

Multi-Modal Signatures of Tau Pathology, Neuronal Fiber Integrity, and Functional Connectivity in Traumatic Brain Injury.

[18F]AV-1451 (aka 18F-Flortaucipir, [18F]T807) was developed for positron-emission tomography (PET) imaging of paired helical filaments of hyperphosphorylated tau, which are of interest in a range of neuropathologies, including traumatic brain injury (TBI). Magnetic resonance imaging (MRI) techniques like diffusion tensor imaging (DTI) and resting state functional connectivity assess structural and functional characteristics of the brain, complementing the molecular information that can be obtained by PET. The goal herein was to explore the utility of such multi-modal imaging in a case series based on a population of TBI subjects. This study probes the interrelationship between tau deposition, white matter integrity, and gray matter functional connectivity across the spectrum of TBI. Nineteen subjects (11 controls, five former contact sports athletes, one automotive accident, and two with military-related injury) underwent [18F]AV-1451 PET and magnetic resonance scanning procedures. [18F]AV-1451 distribution volume ratio (DVR) was estimated using the Logan method and the cerebellum as a reference region. Diffusion tractography images and fractional anisotropy (FA) images were generated using diffusion toolkit and FSL. Resting-state functional MRI (fMRI) analysis was based on a graph theory metric, namely weighted degree centrality. TBI subjects showed greater heterogeneity in [18F]AV-1451 DVR when compared with control subjects. In a subset of TBI subjects, areas with high [18F]AV-1451 binding corresponded with increased FA and diminished white matter tract density in DTI. Functional MRI results exhibited an increase in functional connectivity, particularly among local connections, in the areas where tau aggregates were more prevalent. In a case series of a diverse group of TBI subjects, brain regions with elevated tau burden exhibited increased functional connectivity as well as decreased white matter integrity. These findings portray molecular, microstructural, and functional corollaries of TBI that spatially coincide and can be measured in the living human brain using noninvasive neuroimaging techniques.

Reproducible quantification of cardiac sympathetic innervation using graphical modeling of carbon-11-meta-hydroxyephedrine kinetics with dynamic PET-CT imaging

BackgroundGraphical methods of radiotracer kinetic modeling in PET are ideal for parametric imaging and data quality assurance but can suffer from noise bias. This study compared the Logan and Multilinear Analysis-1 (MA1) graphical models to the standard one-tissue-compartment (1TC) model, including correction for partial-volume effects, in dynamic PET-CT studies of myocardial sympathetic innervation in the left ventricle (LV) using [11C]HED.MethodsTest and retest [11C]HED PET imaging (47 ± 22 days apart) was performed in 18 subjects with heart failure symptoms. Myocardial tissue volume of distribution (VT) was estimated using Logan and MA1 graphical methods and compared to the 1TC standard model values using intraclass correlation (ICC) and Bland-Altman analysis of the non-parametric reproducibility coefficient (NPC).ResultsA modeling start-time of t* = 5 min gave the best fit for both Logan and MA1 (R2 = 0.95) methods. Logan slightly underestimated VT relative to 1TC (p = 0.002), whereas MA1 did not (p = 0.96). Both the MA1 and Logan models exhibited good-to-excellent agreement with the 1TC (MA1-1TC ICC = 0.96; Logan-1TC ICC = 0.93) with no significant differences in NPC between the two comparisons (p = 0.92). All methods exhibited good-to-excellent test-retest repeatability with no significant differences in NPC (p = 0.57).ConclusionsLogan and MA1 models exhibited similar agreement and variability compared to the 1TC for modeling of [11C]HED kinetics. Using t* = 5 min and partial-volume correction produced accurate estimates of VT as an index of myocardial sympathetic innervation.

Reference tissue models in the assessment of 11 C-DTBZ binding to the VMAT2 in rat striatum: A test-retest reproducibility study.

Dopaminergic PET imaging is a useful tool to assess the dopaminergic integrity and to follow-up longitudinal studies. The aim of this study was to evaluate the reliability and reproducibility of different reference tissue-based methods to determine the non-displaceable binding potential (BPND ) as a quantitative measure of 11 C-DTBZ binding to the VMAT2 in rat striatum using cerebellum as reference region. Eight healthy Wistar rats underwent two microPET scans at the age of 12 (test) and 20 weeks (retest). BPND was determined using the simplified reference tissue model, Logan reference tissue model, and multilinear reference tissue models (MRTMo and MRTM2). Additionally, a striatal-to-cerebellar-ratio (SCR) analysis was performed. The reproducibility between the two scans was assessed using the interclass correlation coefficients (ICC) and the variability index. Repeatability indices showed acceptable ICC = 0.66 (SCR) to excellent ICC = 0.98 (MRTM2) reliability for this study and a variability ranging from 12.26% (SCR) to 3.28% (MRTM2). To the best of our knowledge, this is the first report on longitudinal studies for 11 C-DTBZ in rats using reference tissue methods. Excellent intersubject and intrasubject reproducibility was obtained with the multilinear reference MRTM2, suggesting this as the best method to compare longitudinal studies, whereas the SCR method had poor reliability. Logan method, however, is a method simple to compute that shows accurate reproducibility with a reasonable level of inter- and intra-subject variability allowing crossover studies to follow-up the uptake of 11 C-DTBZ in rat striatum.

The distribution of the alpha7 nicotinic acetylcholine receptor in healthy aging: An in vivo positron emission tomography study with [18F]ASEM

Altered function of the alpha7 nicotinic acetylcholine receptor (α7-nAChR) is implicated in several neuropsychiatric diseases. Nevertheless, studies of the human cerebral α7-nAChR even in healthy aging are limited in number and to postmortem tissue. MethodsThe distribution of the cerebral α7-nAChR was estimated in nine brain regions in 25 healthy volunteers (ages 21–86 years; median 57 years, interquartile range 52 years) using [18F]ASEM with positron emission tomography (PET) imaging. Regional total distribution volume (VT) measurements were calculated using the Logan method from each subject's 90 min dynamic PET data and their metabolite-corrected plasma input function. Spearman's rank or Pearson's correlation analysis was used depending on the normality of the data. Correlation between age and regional 1) volume relative to intracranial volume (volume ratio) and 2) [18F]ASEM VT was tested. Correlation between regional volume ratio and [18F]ASEM VT was also evaluated. Finally, the relationship between [18F]ASEM VT and neuropsychological measures was investigated in a subpopulation of 15 elderly healthy participants (those 50 years of age and older). Bonferroni correction for multiple comparisons was applied to statistical analyses. ResultsA negative correlation between tissue volume ratio and age was observed in six of the nine brain regions including striatum and five cortical (temporal, occipital, cingulate, frontal, or parietal) regions. A positive correlation between [18F]ASEM VT and age was observed in all nine brain regions of interest (ROIs). There was no correlation between [18F]ASEM VT and volume ratio in any ROI after controlling for age. Regional [18F]ASEM VT and neuropsychological performance on each of eight representative subtests were not correlated among the well-performing subpopulation of elderly healthy participants. ConclusionsOur results suggest an increase in cerebral α7-nAChR distribution over the course of healthy aging that should be tested in future longitudinal studies. The preservation of the α7-nAChR in the aging human brain supports the development of therapeutic agents that target this receptor for use in the elderly. Further study of the relationship between α7-nAChR availability and cognitive impairment over aging is needed.

Assessment of dental plaque coverage by Quantitative Light-induced Fluorescence (QLF) in domestic short-haired cats

Dietary means of reducing plaque and calculus deposits are frequently sought for the maintenance of oral health in cats and dogs. In the development of such products sensitive, reliable, reproducible methods of measuring plaque and calculus are key. The aim of this study was to assess Quantitative Light-induced Fluorescence (QLF™) for the detection of dental plaque coverage in cats compared to the modified Logan and Boyce technique. The techniques were utilised in a crossover study, which compared two diets for their effect on plaque deposition in a cohort of 24 adult cats. Analysis of the effect of diet on plaque coverage by both the modified Logan and Boyce technique and QLF showed a significant effect of feeding regime (p=0.024 and p≤0.0001, respectively) with good agreement between the techniques in the percentage reduction of plaque accumulation. A within study assessment of QLF demonstrated excellent intra-operator repeatability (coefficient of variation 2.2%). Similarly, inter-operator reproducibility was also good (coefficient of variation 2.3%). A retrospective analysis, using the data to estimate the sample size required for at least 90% power to detect a 15% difference between treatments in a two-way crossover study, established that 10 cats would be sufficient for plaque measurement by QLF, while assessment by the modified Logan and Boyce method required over 30 cats. QLF was determined to be a reliable, reproducible method for the assessment of plaque deposition in cats and requires fewer subjects for the detection of differences between treatment effects compared to the modified Logan and Boyce method.

Quantification of Canine Dental Plaque Using Quantitative Light-Induced Fluorescence.

The aim of this work was to evaluate Quantitative Light-induced Fluorescence (QLF) as an alternative to the established Logan and Boyce method for determining plaque coverage of dogs' teeth. In a series of studies in conscious and anesthetized dogs, QLF showed good intra-photographer repeatability (coefficient of variation [CV] of 7.5% for undisclosed teeth) and inter-photographer reproducibility (CV of 3.2% for undisclosed teeth and 8.5% for disclosed teeth). The QLF software accurately identifies areas of plaque as demonstrated by comparison to the variability of 5 human scorers, manually marking plaque on QLF-acquired images (P = 0.1). There was good agreement with the modified Logan and Boyce method in the percentage reduction in plaque accumulation measured when dogs were fed an oral care chew versus no chew. To see a 15% difference in plaque accumulation, which is considered sufficient by the Veterinary Oral Health Council to differentiate between 2 treatments, a retrospective power analysis (90%) of the data established that only 7 dogs would be required, compared to 19 dogs for the modified Logan and Boyce method. QLF is a reliable method for measuring dental plaque in dogs with the added advantage that it is not subjective and requires fewer animals.

Correlation between Vitamin C Deficiency and Hydroxyproline Amino Acid in Young Children of Northern Part in Palestine

Vitamin C is a water soluble vitamin found in many natural sources, citric fruits, vegetables, particularly as antioxidants and as a factor to catabolism and metabolism. The aim of this article is to correlate the level of vitamin C and the hydroxyproline level in urine samples among young palestinian children from age 5 - 14 years. Materials and Methods: Urine samples of 34 individuals of both sexes, their ages ranged from 5 - 14 years were collected and analyzed for determination of Urinary Hydroxyproline by using Modified Neuman and Logan Method. The result of this study shows a significant correlation between Vitamin C and Hydroxyproline at level 0.01. The conclusion of this study was that low vitamin C intake was found among young palestinian children from age 5 - 14 years, Vitamin C should be supplemented in the drinks taken by young palestinian children from age 5 - 14 years as well as further research and investigation with large samples required to include all children from middle and southern Palestine.

Retest imaging of [11C]NOP-1A binding to nociceptin/orphanin FQ peptide (NOP) receptors in the brain of healthy humans

[11C]NOP-1A is a novel high-affinity PET ligand for imaging nociceptin/orphanin FQ peptide (NOP) receptors. Here, we report reproducibility and reliability measures of binding parameter estimates for [11C]NOP-1A binding in the brain of healthy humans.After intravenous injection of [11C]NOP-1A, PET scans were conducted twice on eleven healthy volunteers on the same (10/11 subjects) or different (1/11 subjects) days. Subjects underwent serial sampling of radial arterial blood to measure parent radioligand concentrations. Distribution volume (VT; a measure of receptor density) was determined by compartmental (one- and two-tissue) modeling in large regions and by simpler regression methods (graphical Logan and bilinear MA1) in both large regions and voxel data. Retest variability and intraclass correlation coefficient (ICC) of VT were determined as measures of reproducibility and reliability respectively.Regional [11C]NOP-1A uptake in the brain was high, with a peak radioactivity concentration of 4–7 SUV (standardized uptake value) and a rank order of putamen>cingulate cortex>cerebellum. Brain time–activity curves fitted well in 10 of 11 subjects by unconstrained two-tissue compartmental model. The retest variability of VT was moderately good across brain regions except cerebellum, and was similar across different modeling methods, averaging 12% for large regions and 14% for voxel-based methods. The retest reliability of VT was also moderately good in most brain regions, except thalamus and cerebellum, and was similar across different modeling methods averaging 0.46 for large regions and 0.48 for voxels having gray matter probability >20%. The lowest retest variability and highest retest reliability of VT were achieved by compartmental modeling for large regions, and by the parametric Logan method for voxel-based methods.Moderately good reproducibility and reliability measures of VT for [11C]NOP-1A make it a useful PET ligand for comparing NOP receptor binding between different subject groups or under different conditions in the same subject.

Fibrillar amyloid correlates of preclinical cognitive decline

BackgroundIt is not known whether preclinical cognitive decline is associated with fibrillar β-amyloid (Aβ) deposition irrespective of apolipoprotein E (APOE) ε4 status. MethodsFrom a prospective observational study of 623 cognitively normal individuals, we identified all subjects who showed preclinical decline of at least 2 standard deviations beyond the decline of the entire group in memory or executive function. Fourteen decliners were matched by APOE ε4 gene dose, age, sex, and education with 14 nondecliners. Dynamic Pittsburgh compound B (PiB) positron emission tomography (PET) scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest were used to characterize and compare cerebral-to-cerebellar PiB distribution volume ratios (DVRs), reflecting fibrillar Aβ burden. ResultsAt P < .005 (uncorrected), decliners had significantly greater DVRs in comparison to nondecliners. ConclusionsAsymptomatic longitudinal neuropsychological decline is associated with subsequent increased fibrillar amyloid deposition, even when controlling for APOE ε4 genotype.

In-vivo Measurement of LDOPA Uptake, Dopamine Reserve and Turnover in the Rat Brain Using [18F]FDOPA PET

Longitudinal measurements of dopamine (DA) uptake and turnover in transgenic rodents may be critical when developing disease-modifying therapies for Parkinson's disease (PD). We demonstrate methodology for such measurements using [(18)F]fluoro-3,4-dihydroxyphenyl-L-alanine ([(18)F]FDOPA) positron emission tomography (PET). The method was applied to 6-hydroxydopamine lesioned rats, providing the first PET-derived estimates of DA turnover for this species. Control (n=4) and unilaterally lesioned (n=11) rats were imaged multiple times. Kinetic modeling was performed using extended Patlak, incorporating a k(loss) term for metabolite washout, and modified Logan methods. Dopaminergic terminal loss was measured via [(11)C]-(+)-dihydrotetrabenazine (DTBZ) PET. Clear striatal [(18)F]FDOPA uptake was observed. In the lesioned striatum the effective DA turnover increased, shown by a reduced effective distribution volume ratio (EDVR) for [(18)F]FDOPA. Effective distribution volume ratio correlated (r>0.9) with the [(11)C]DTBZ binding potential (BP(ND)). The uptake and trapping rate (k(ref)) decreased after lesioning, but relatively less so than [(11)C]DTBZ BP(ND). For normal controls, striatal estimates were k(ref)=0.037±0.005 per minute, EDVR=1.07±0.22 and k(loss)=0.024±0.003 per minute (30 minutes turnover half-time), with repeatability (coefficient of variation) ≤11%. [(18)F]fluoro-3,4-dihydroxyphenyl-L-alanine PET enables measurements of DA turnover in the rat, which is useful for developing novel therapies for PD.

Improved kinetic analysis of dynamic PET data with optimized HYPR‐LR

Highly constrained backprojection-local reconstruction (HYPR-LR) has made a dramatic impact on magnetic resonance angiography (MRA) and shows promise for positron emission tomography (PET) because of the improvements in the signal-to-noise ratio (SNR) it provides dynamic images. For PET in particular, HYPR-LR could improve kinetic analysis methods that are sensitive to noise. In this work, the authors closely examine the performance of HYPR-LR in the context of kinetic analysis, they develop an implementation of the algorithm that can be tailored to specific PET imaging tasks to minimize bias and maximize improvement in variance, and they provide a framework for validating the use of HYPR-LR processing for a particular imaging task. HYPR-LR can introduce errors into non sparse PET studies that might bias kinetic parameter estimates. An implementation of HYPR-LR is proposed that uses multiple temporally summed composite images that are formed based on the kinetics of the tracer being studied (HYPR-LR-MC). The effects of HYPR-LR-MC and of HYPR-LR using a full composite formed with all the frames in the study (HYPR-LR-FC) on the kinetic analysis of Pittsburgh compound-B ([11C]-PIB) are studied. HYPR-LR processing is compared to spatial smoothing. HYPR-LR processing was evaluated using both simulated and human studies. Nondisplaceable binding potential (BP(ND)) parametric images were generated from fifty noise realizations of the same numerical phantom and eight [(11)C]-PIB positive human scans before and after HYPR-LR processing or smoothing using the reference region Logan graphical method and receptor parametric mapping (RPM2). The bias and coefficient of variation in the frontal and parietal cortex in the simulated parametric images were calculated to evaluate the absolute performance of HYPR-LR processing. Bias in the human data was evaluated by comparing parametric image BP(ND) values averaged over large regions of interest (ROIs) to Logan estimates of the BP(ND) from TACs averaged over the same ROIs. Variance was assessed qualitatively in the parametric images and semiquantitatively by studying the correlation between voxel BP(ND) estimates from Logan analysis and RPM2. Both the simulated and human data show that HYPR-LR-FC overestimates BP(ND) values in regions of high [(11)C]-PIB uptake. HYPR-LR-MC virtually eliminates this bias. Both implementations of HYPR-LR reduce variance in the parametric images generated with both Logan analysis and RPM2, and HYPR-LR-FC provides a greater reduction in variance. This reduction in variance nearly eliminates the noise-dependent Logan bias. The variance reduction is greater for the Logan method, particularly for HYPR-LR-MC, and the variance in the resulting Logan images is comparable to that in the RPM2 images. HYPR-LR processing compares favorably with spatial smoothing, particularly when the data are analyzed with the Logan method, as it provides a reduction in variance with no loss of spatial resolution. HYPR-LR processing shows significant potential for reducing variance in parametric images, and can eliminate the noise-dependent Logan bias. HYPR-LR-FC processing provides the greatest reduction in variance but introduces a positive bias into the BP(ND) of high-uptake border regions. The proposed method for forming HYPR composite images, HYPR-LR-MC, eliminates this bias at the cost of less variance reduction.

Sparse Clustering with Resampling for Subject Classification in PET Amyloid Imaging Studies.

A dataset of n=60 observations (3 groups of 20) and p=500 variables was generated for each simulation run; only 50 variables were truly different across groups. The dataset was resampled 20 times, Sparse_kM was applied to each sample and average variable weights were calculated. Probabilities of cluster membership, also called confidence levels, were computed (n=60). Simulations were performed 250 times. The 50 truly different variables were identified by variable weights that were 13-32 times greater than those for the 450 uninformative variables. For the PiB PET dataset, images (ECAT HR+, 10-15 mCi, 90 min) were acquired for 64 cognitively normal subjects (74.1±5.4 yrs). Parametric PiB distribution volume ratio images were generated (Logan method, cerebellum reference) and normalized to the MNI template (SPM8) to produce a dataset of n=64 subjects and p=343,099 voxels/image. The dataset was resampled 10 times and Sparse_kM was applied. An average voxel weight image was computed that indicated cortical areas of greatest interest that included precuneus and frontal cortex; these are key areas linked to early amyloid deposition. Seven of 64 subjects were identified as PiB(+) and 47 as PiB(-) with confidence ≥ 90%, where another subject was PiB(+) at lower confidence (80%) and the other 9 subjects were PiB(-) at confidence in the range of 50-70%. In conclusion, Sparse_kM with resampling can help to establish confidence levels for clustering when p≫n and may be a promising method for revealing informative voxels/spatial patterns that distinguish levels of amyloid load, including that at the transitional amyloid +/- boundary.

Sensitivity of kinetic macro parameters to changes in dopamine synthesis, storage, and metabolism: A simulation study for [18F]FDOPA PET by a model with detailed dopamine pathway

Quantitative interpretation of brain [¹⁸F]FDOPA PET data has been made possible by several kinetic modeling approaches, which are based on different assumptions about complex [¹⁸F]FDOPA metabolic pathways in brain tissue. Simple kinetic macro parameters are often utilized to quantitatively evaluate metabolic and physiological processes of interest, which may include DDC activity, vesicular storage, and catabolism from (18) F-labeled dopamine to DOPAC and HVA. A macro parameter most sensitive to the changes of these processes would be potentially beneficial to identify impaired processes in a neurodegenerative disorder such as Parkinson's disease. The purpose of this study is a systematic comparison of several [¹⁸F]FDOPA macro parameters in terms of sensitivities to process-specific changes in simulated time-activity curve (TAC) data of [¹⁸F]FDOPA PET. We introduced a multiple-compartment kinetic model to simulate PET TACs with physiological changes in the dopamine pathway. TACs in the alteration of dopamine synthesis, storage, and metabolism were simulated with a plasma input function obtained by a non-human primate [¹⁸F]FDOPA PET study. Kinetic macro parameters were calculated using three conventional linear approaches (Gjedde-Patlak, Logan, and Kumakura methods). For simulated changes in dopamine storage and metabolism, the slow clearance rate (k(loss) ) as calculated by the Kumakura method showed the highest sensitivity to these changes. Although k(loss) performed well at typical ROI noise levels, there was large bias at high noise level. In contrast, for simulated changes in DDC activity it was found that K(i) and V(T), estimated by Gjedde-Patlak and Logan method respectively, have better performance than k(loss).

Chronological versus dental age in subjects from 5 to 19 years: a comparative study with forensic implications

Objectives: This study evaluated six methods used in estimating the age of patients attending the Dental School at Universidad del Valle, evaluating dental development by using panoramic radiographs. Additionally, the study determined the sexual identity of the person and the bilateral symmetry of development, the maturity and the chronological eruption of permanent teeth. Materials and methods: This is a descriptive, quantitative and transversal study that evaluated which of the six methods (Logan & Kronfeld; Schour & Massler; Moorrees, Fanning & Hunt; Demirjian, Goldstein & Tanner; Ubelaker & Smith) for estimating the age of a patient through radiographic evaluation of dental development is the most correlated with the chronological age of the patient, so it can be used for forensic purposes. Results: The Moorrees, Fanning & Hunt and the Smith methods showed high correlation (0.7874 and 0.7808, respectively). The Logan & Kronfeld methods presented low correlation (0.6879). The sample studied did not show sexual dimorphism or bilateral asymmetry. Conclusions: All methods evaluated have a high correlation coefficient between the dental age and the radiographic age. However, the Moorrees, Fanning & Hunt, and Smith methods presented higher correlation coefficients between dental and chronological age.

Evaluation of a bolus/infusion protocol for 11C-ABP688, a PET tracer for mGluR5

(11)C-ABP-688 is a selective tracer for the mGluR5 receptor. Its kinetics is fast and thus favourable for an equilibrium approach to determine receptor-related parameters. The purpose of this study was to test the hypothesis that the pattern of the (11)C-ABP688 uptake using a bolus-plus-infusion (B/I) protocol at early time points corresponds to the perfusion and at a later time point to the total distribution volume. A bolus and a B/I study (1 h each) was performed in five healthy male volunteers. With the B/I protocol, early and late scans were normalized to gray matter, cerebellum and white matter. The same normalization was done on the maps of the total distribution volume (Vt) and K(1) which were calculated in the study with bolus only injection and the Logan method (Vt) and a two-tissue compartment model (K(1)). There was an excellent correlation close to the identity line between the pattern of the late uptake in the B/I study and Vt of the bolus-only study for all three normalizations. The pattern of the early uptake in the B/I study correlated well with the K(1) maps, but only when normalized to gray matter and cerebellum, not to white matter. It is demonstrated that with a B/I protocol the (11)C-ABP688 distribution in late scans reflects the pattern of the total distribution volume and is therefore a measure for the density pattern of mGluR5. The early scans following injection are related to blood flow, although not in a fully quantitative manner. The advantage of the B/I protocol is that no arterial blood sampling is required, which is advantageous in clinical studies.