Spatial Resolution and Frequency Characteristics for Dose Modulation on the TrueBeam Medical Accelerator

Purpose: To study the spatial resolution achievable by dose modulation in a water phantom using a multi-leaf collimator, jaws and their combination. To estimate the power spectrum density of the useful signal (dose distribution) and statistical noise, evaluate the frequency interval containing the useful signal. Material and methods: Using the Gafchromic EBT2 radiochromic film, nested squares dose patterns formed in a water-equivalent phantom by 6 and 15 MV photon beams of the TrueBeam medical accelerator, jaws, a multi-leaf collimator, and a combination of these devices were measured. Dose response to step function (ESF) data was extracted from the penumbra and the linear photon source dose response function (LSF) was calculated. To move to frequency domain, fast Fourier transform was performed over the obtained datasets, as well as over individual LSF peaks, and then power spectra densities were calculated. The Nyquist frequency associated with data sampling was 1.42 mm-1, the Hann window was used to minimize leakage effect. Results: The shape of the obtained LSF peaks was approximated by a sum of two Gaussian distributions with the same center positions but different widths. The LSF peak width at half maximum (FWHM) was 1.7-3.9 mm depending on the modulation device. No significant difference was observed in the peak widths at energies of 6 and 15 MV. In most cases, the width of the peak along the X-axis was wider than along the Y-axis. The power spectrum of the useful signal had a maximum near zero frequency, a 50 % level was near 0.09 mm-1 and its high frequency limit was about 0.4 mm-1. Above this value, only the spectrum of statistical noise was recorded, uniformly distributed over frequency. Conclusion: The obtained values of the LSF peak width in the range 1.7-3.9 mm characterize the ability of dose modulation by the considered devices or their combination, which can be significant for treatment of small targets (less than 3-4 cm), where these limits of spatial resolution can be reached. The obtained relationships in frequency domain can be used for optimal removal of statistical noise using Wiener filters from profiles or two-dimensional dose distributions.

Summit: Automated Analysis of Arrayed Single-Cell Gel Electrophoresis

New pipelines are required to automate the quantitation of emerging high-throughput electrophoretic (EP) assessment of DNA damage, or proteoform expression in single cells. EP cytometry consists of thousands of Western blots performed on a microscope slide-sized gel microwell array for single cells. Thus, EP cytometry images pose an analysis challenge that blends requirements for accurate and reproducible analysis encountered for both standard Western blots and protein microarrays. Here, we introduce the Summit algorithm to automate array segmentation, peak background subtraction, and Gaussian fitting for EP cytometry. The data structure storage of parameters allows users to perform quality control on identically processed data, yielding a ~6.5% difference in coefficient of quartile variation (CQV) of protein peak area under the curve (AUC) distributions measured by four users. Further, inspired by investigations of background subtraction methods to reduce technical variation in protein microarray measurements, we aimed to understand the trade-offs between EP cytometry analysis throughput and variation. We found an 11%–50% increase in protein peaks that passed quality control with a subtraction method similar to microarray “average on-boundary” versus an axial subtraction method. The background subtraction method only mildly influences AUC CQV, which varies between 1% and 4.5%. Finally, we determined that the narrow confidence interval for peak location and peak width parameters from Gaussian fitting yield minimal uncertainty in protein sizing. The AUC CQV differed by only ~1%–2% when summed over the peak width bounds versus the 95% peak width confidence interval. We expect Summit to be broadly applicable to other arrayed EP separations, or traditional Western blot analysis.

Impact of white-mater mask selection on DTI histogram-based metrics as potential biomarkers in cerebral small vessel disease

Purpose Histogram-based metrics extracted from diffusion-tensor imaging (DTI) have been suggested as potential biomarkers for cerebral small vessel disease (SVD), but methods and results have varied across studies. This work aims to assess the impact of mask selection for extracting histogram-based metrics of fractional anisotropy (FA) and mean diffusivity (MD) on their sensitivity as SVD biomarkers.Methods DTI data were collected from 17 SVD patients and 12 healthy controls. For each participant, FA and MD maps were estimated; from these, histograms were computed on two alternative whole-brain white-matter masks: normal-appearing white-matter (NAWM) and mean FA tract skeleton (TBSS). Histogram-based metrics (median, peak height, peak width, peak value) were extracted from the FA and MD maps. These were compared between patients and controls, and correlated with the patients’ cognitive scores (executive function and processing speed).Results White matter mask selection significantly impacted FA and MD histogram metrics and affected their ability to discriminate between groups. Moreover, we observed that the mask can influence the correlations with cognitive measures. Nevertheless, the MD peak height and MD peak width metrics remained significantly correlated with executive function, regardless of the mask.Conclusion Our results corroborate previous reports and further support the value of DTI histogram-based metrics as SVD biomarkers. However, they also highlight the importance of the processing methodology, in particular the choice of white matter mask, as hence the urgent need to mitigate the lack of standardized MRI data-processing pipelines.

New methods for quantifying rapidity of action potential onset differentiate neuron types

Two new methods for quantifying the rapidity of action potential onset have lower relative standard deviations and better distinguish neuron cell types than current methods. Action potentials (APs) in most central mammalian neurons exhibit sharp onset dynamics. The main views explaining such an abrupt onset differ. Some studies suggest sharp onsets reflect cooperative sodium channels activation, while others suggest they reflect AP backpropagation from the axon initial segment. However, AP onset rapidity is defined subjectively in these studies, often using the slope at an arbitrary value on the phase plot. Thus, we proposed more systematic methods using the membrane potential’s second-time derivative (V¨m) peak width. Here, the AP rapidity was measured for four different cortical and hippocampal neuron types using four quantification methods: the inverse of full-width at the half maximum of the V¨m peak (IFWd2), the inverse of half-width at the half maximum of the V¨m peak (IHWd2), the phase plot slope, and the error ratio method. The IFWd2 and IHWd2 methods show the smallest variation among neurons of the same type. Furthermore, the AP rapidity, using the V¨m peak width methods, significantly differentiates between different types of neurons, indicating that AP rapidity can be used to classify neuron types. The AP rapidity measured using the IFWd2 method was able to differentiate between all four neuron types analyzed. Therefore, the V¨m peak width methods provide another sensitive tool to investigate the mechanisms impacting the AP onset dynamics.

Abstract 9: Peak Width of Skeletonized Mean Diffusivity and Cognition in Cerebral Amyloid Angiopathy

Background: We hypothesized that Peak Width of Skeletonized Mean Diffusivity (PSMD), an automated marker of cerebral microangiopathy representing microstructural disruption of white matter (WM), would be increased in patients with cerebral amyloid angiopathy (CAA) compared to healthy controls (HCs) and increased PSMD would be associated with lower processing speed scores (PSSs) in patients with CAA. Methods: Seventy-two nondemented probable CAA patients and 23 HCs prospectively underwent high-resolution brain MRIs and cognitive tests. PSMD scores were quantified from a probabilistic skeleton of the WM tracts as previously validated (http://www.psmd-marker.com). In subjects with intracerebral hemorrhage (ICH, n=27), ICH regions were masked and removed from the PSMD pipeline. The analyses were repeated in the non-ICH hemisphere. Raw scores of Trail Making Test-B and Symbol Substitution Test were transformed into standardized z -scores and averaged to obtain PSSs. Results: The mean age (p=0.366) and sex (p=0.811) were similar between CAA patients and HCs. PSMD was higher in the CAA group [(3.95±0.9) х 10 –4 mm 2 /s] compared to HCs [(3.32±0.6) х 10 –4 mm 2 /s] (p=0.003). This association remained significant in a linear regression model corrected for age and sex (β=0.700, 95%CI 0.3-1, p=0.001). Within the CAA cohort, higher PSMD was associated with higher WM hyperintensity volume in a multiple regression model adjusted for all relevant variables (β=0.890, 95%CI 0.7-1, p<0.001). In a regression model corrected for age, sex, years of education and presence of ICH, a lower PSS was independently associated with increased PSMD (β=-0.405, 95%CI {-0.6}-{-0.2}, p<0.001). These results did not change when the non-ICH hemisphere was used for PSMD processing. Conclusion: PSMD is increased in CAA and is associated with worse PSSs supporting the view that disruption of white matter has a significant role in cognitive impairment in CAA.

Abstract P59: Peak Width of Skeletonized Mean Diffusivity Outperforms Other Diffusion Tensor Imaging Metrics as Biomarker for Cognition in Memory-Clinic Subjects With Cerebral Amyloid Angiopathy

Introduction: Peak width of skeletonized mean diffusivity (PSMD) is a novel fully automated diffusion tensor imaging (DTI) marker that has been consistently associated with cognition in cerebral small vessel disease (SVD) cohorts, including cerebral amyloid angiopathy (CAA). We hypothesized that PSMD would be more strongly associated with cognitive performance compared to other conventional DTI metrics in our CAA sample. Methods: We recruited non-demented subjects with probable-CAA from a single-center memory-clinic cohort. We analyzed structural MRIs to compute a validated CAA burden score (0-6 points scale, based on the following MRI features: lobar microbleeds, superficial siderosis, perivascular spaces in centrum semiovale, and white matter hyperintensities). PSMD was obtained using a freely available script ( www.psmd-marker.com ). We used the same skeleton-mask to compute: mean of skeletonized mean diffusivity (mean MD) and mean of skeletonized fractional anisotropy (mean FA). We used linear regression analyses to explore relationships with CAA burden score and cognitive composite scores (processing speed, executive function, memory, and language - z-scores adjusted for age, sex and education level). Results: We included 43 subjects (mean age 74.4 ± 5.9 years; 48.8% female; PSMD median [IQR]: 4.05 [3.58 - 4.80] x 10 -4 mm 2 /s). In linear regression models adjusting for age, DTI metrics were significantly associated with CAA burden score (mean FA: β = -0.563, Adj. R 2 : 0.27; p < 0.001; mean MD: β = 0.581; Adj. R 2 : 0.32; p < 0.001; PSMD: β = 0.364, Adj. R 2 : 0.12; p = 0.018). PSMD was significantly associated with cognitive performance, specifically in the domains of executive function ( β = -0.568; Adj. R 2 : 0.25; p < 0.001) and processing speed ( β = -0.447; Adj. R 2 : 0.19; p = 0.004). Other DTI metrics were not significantly associated with cognitive scores. Conclusion: In this CAA sample, all DTI metrics were associated with CAA burden scores, however, only PSMD was significantly associated with cognition, in domains that are commonly affected in vascular cognitive impairment. Our results warrant confirmation in larger samples, but support PSMD as biomarker for cognition in CAA, outperforming other conventional DTI metrics.

Terbium Doping Graphitic Carbon Nitride Endows Highly Sensitive Ratiometric Fluorescence Assay of Alkaline Phosphatase

Terbium doping graphitic carbon nitride (g-C3N4:Tb) gives rise to two exceptional emissions at λex/λem=290/490 nm and 290/546 nm, with extremely narrow peak width of FWHM <12 nm as well as...