Predicting Progression to Parkinson's Disease Dementia Using Multivariate Normative Comparisons.

OBJECTIVE: Parkinson's disease with mild cognitive impairment (PD-MCI) is a risk factor for progression to PD dementia (PDD) at a later stage of the disease. The consensus criteria of PD-MCI use a traditional test-by-test normative comparison. The aim of this study was to investigate whether a new multivariate statistical method provides a more sensitive tool for predicting dementia status at 3- and 5-year follow-ups. This method allows a formal evaluation of a patient's profile of test scores given a large aggregated database with regression-based norms. METHOD: The cognitive test results of 123 newly diagnosed PD patients from a previously published longitudinal study were analyzed with three different methods. First, the PD-MCI criteria were applied in the traditional way. Second, the PD-MCI criteria were applied using the large aggregated normative database. Last, multivariate normative comparisons (MNCs) were made using the same aggregated normative database. The outcome variable was progression to dementia within 3 and 5 years. RESULTS: The MNC was characterized by higher sensitivity and higher specificity in predicting progression to PDD at follow-up than the two PD-MCI criteria methods, although the difference in classification accuracy did not reach statistical significance. CONCLUSION: We conclude that MNCs could allow for a more accurate prediction of PDD than the traditional PD-MCI criteria, because there are encouraging trends in both increased sensitivity and increased specificity. (JINS, 2019, 25, 678-687).

Universal Scale of Intelligence Estimates (USIE): Representing Intelligence Estimated From Level of Education.

In clinical neuropsychology, it is often necessary to estimate a patient's premorbid level of cognitive functioning in order to evaluate whether his scores on cognitive tests should be considered abnormal. In practice, test results from before the onset of brain pathology are rarely available, and the patient's level of education is used instead as an estimate of his premorbid level. Unfortunately, level of education may be expressed on many different scales of education, which are difficult to use interchangeably. Here, we introduce a new scale that has the capacity to replace existing scales and can be used interchangeably with any of them: the Universal Scale of Intelligence Estimates (USIE). To achieve this, we propose to map all levels of existing educational scales to standard IQ scores. This USIE point estimate is supplemented with an estimation interval. We assert that USIE offers some important benefits for clinical practice and research.

Time course analyses of orthographic and phonological priming effects in developing readers.

It has been assumed that fluent reading requires efficient integration of orthographic and phonological codes. However, it is thus far unclear how this integration process develops when children learn to become fluent readers. Therefore, we used masked priming to investigate time courses of orthographic and phonological code activation in children at incremental levels of reading development (second, fourth and sixth grade). The first study used targets with small phonological differences between phonological and orthographic primes, which are typical in transparent orthographies. The second study manipulated the strength of the phonological difference between prime and target to clarify whether phonological difference influences phonological priming effects. Results in both studies showed that orthographic priming effects became facilitative at increasingly short durations during reading development, but phonological priming was absent. These results are taken to suggest that development of reading fluency is accompanied by increased automatization of orthographic representations. The absence of phonological priming suggests that developing readers cannot yet activate phonological codes automatically.

Effects of methylphenidate on executive functioning in attention-deficit/hyperactivity disorder across the lifespan: a meta-regression analysis.

Attention-deficit/hyperactivity disorder (ADHD) in childhood and adulthood is often treated with the psychostimulant methylphenidate (MPH). However, it is unknown whether cognitive effects of MPH depend on age in individuals with ADHD, while animal studies have suggested age-related effects. In this meta-analysis, we first determined the effects of MPH on response inhibition, working memory and sustained attention, but our main goal was to examine whether these effects are moderated by age. A systematic literature search using PubMed, PsycINFO, Web of Science and MEDLINE for double-blind, placebo-controlled studies with MPH resulted in 25 studies on response inhibition (n = 775), 13 studies on working memory (n = 559) and 29 studies on sustained attention (n = 956) (mean age range 4.8-50.1 years). The effects of MPH on response inhibition [effect size (ES) = 0.40, p < 0.0001, 95% confidence interval (CI) 0.22-0.58], working memory (ES = 0.24, p = 0.053, 95% CI 0.00-0.48) and sustained attention (ES = 0.42, p < 0.0001, 95% CI 26-0.59) were small to moderate. No linear or quadratic age-dependencies were observed, indicating that effects of MPH on executive functions are independent of age in children and adults with ADHD. However, adolescent studies are lacking and needed to conclude a lack of an age-dependency across the lifespan.

How flatbed scanners upset accurate film dosimetry.

Film is an excellent dosimeter for verification of dose distributions due to its high spatial resolution. Irradiated film can be digitized with low-cost, transmission, flatbed scanners. However, a disadvantage is their lateral scan effect (LSE): a scanner readout change over its lateral scan axis. Although anisotropic light scattering was presented as the origin of the LSE, this paper presents an alternative cause. Hereto, LSE for two flatbed scanners (Epson 1680 Expression Pro and Epson 10000XL), and Gafchromic film (EBT, EBT2, EBT3) was investigated, focused on three effects: cross talk, optical path length and polarization. Cross talk was examined using triangular sheets of various optical densities. The optical path length effect was studied using absorptive and reflective neutral density filters with well-defined optical characteristics (OD range 0.2-2.0). Linear polarizer sheets were used to investigate light polarization on the CCD signal in absence and presence of (un)irradiated Gafchromic film. Film dose values ranged between 0.2 to 9 Gy, i.e. an optical density range between 0.25 to 1.1. Measurements were performed in the scanner's transmission mode, with red-green-blue channels. LSE was found to depend on scanner construction and film type. Its magnitude depends on dose: for 9 Gy increasing up to 14% at maximum lateral position. Cross talk was only significant in high contrast regions, up to 2% for very small fields. The optical path length effect introduced by film on the scanner causes 3% for pixels in the extreme lateral position. Light polarization due to film and the scanner's optical mirror system is the main contributor, different in magnitude for the red, green and blue channel. We concluded that any Gafchromic EBT type film scanned with a flatbed scanner will face these optical effects. Accurate dosimetry requires correction of LSE, therefore, determination of the LSE per color channel and dose delivered to the film.

Time course analyses of orthographic and phonological priming effects during word recognition in a transparent orthography.

In opaque orthographies, the activation of orthographic and phonological codes follows distinct time courses during visual word recognition. However, it is unclear how orthography and phonology are accessed in more transparent orthographies. Therefore, we conducted time course analyses of masked priming effects in the transparent Dutch orthography. The first study used targets with small phonological differences between phonological and orthographic primes, which are typical in transparent orthographies. Results showed consistent orthographic priming effects, yet phonological priming effects were absent. The second study explicitly manipulated the strength of the phonological difference and revealed that both orthographic and phonological priming effects became identifiable when phonological differences were strong enough. This suggests that, similar to opaque orthographies, strong phonological differences are a prerequisite to separate orthographic and phonological priming effects in transparent orthographies. Orthographic and phonological priming appeared to follow distinct time courses, with orthographic codes being quickly translated into phonological codes and phonology dominating the remainder of the lexical access phase.

Inhibition deficits in individuals with intellectual disability: a meta-regression analysis.

BACKGROUND: Individuals with intellectual disabilities (ID) are characterised by inhibition deficits; however, the magnitude of these deficits is still subject to debate. This meta-analytic study therefore has two aims: first to assess the magnitude of inhibition deficits in ID, and second to investigate inhibition type, age, IQ and the presence/absence of comorbid problems as potential moderators of effect sizes. METHOD: Twenty-eight effect sizes comparing ID and age matched normal controls on inhibition tasks were included in a random effects meta-regression. Moderators were age, IQ, inhibition type and presence/absence of comorbid disorder. RESULTS: The analysis showed a medium to large inhibition deficit in ID. Inhibition type significantly moderated effect size, whereas age and comorbid disorder did not. IQ significantly moderated effect size indicating increasing effect size with decreasing IQ, but only in studies that included a sample of ID participants with mean IQ > 70. The analysis indicated comparable deficits in behavioural inhibition and interference control, but no significant deficits in cognitive inhibition and motivational inhibition. CONCLUSIONS: These results indicate that ID is characterised by a medium to large inhibition deficit in individuals with ID. ID seems not to be characterised by deficits in cognitive and motivational inhibition, which might indicate that distinct processes underlie distinct inhibition capacities.

Meta-analysis of CSF and MRI biomarkers for detecting preclinical Alzheimer's disease.

BACKGROUND: Abnormal levels of biomarkers in cerebrospinal fluid (CSF) and atrophy of medial temporal lobe (MTL) structures on magnetic resonance imaging (MRI) are being used increasingly to diagnose early Alzheimer's disease (AD). We evaluated the claim that these biomarkers can detect preclinical AD before behavioural (i.e. memory) symptoms arise. METHOD: We included all relevant longitudinal studies of CSF and MRI biomarkers published between January 2003 and November 2008. Subjects were not demented at baseline but some declined to mild cognitive impairment (MCI) or to AD during follow-up. Measures of tau and beta-amyloid in CSF, MTL atrophy on MRI, and performance on delayed memory tasks were extracted from the papers or obtained from the investigators. RESULTS: Twenty-one MRI studies and 14 CSF studies were retrieved. The effect sizes of total tau (t-tau), phosphorylated tau (p-tau) and amyloid beta 42 (a beta 42) ranged from 0.91 to 1.11. The effect size of MTL atrophy was 0.75. Memory performance had an effect size of 1.06. MTL atrophy and memory impairment tended to increase when assessed closer to the moment of diagnosis, whereas effect sizes of CSF biomarkers tended to increase when assessed longer before the diagnosis. CONCLUSIONS: Memory impairment is a more accurate predictor of early AD than atrophy of MTL on MRI, whereas CSF abnormalities and memory impairment are about equally predictive. Consequently, the CSF and MRI biomarkers are not very sensitive to preclinical AD. CSF markers remain promising, but studies with long follow-up periods in elderly subjects who are normal at baseline are needed to evaluate this promise.

Profiling Fragile X Syndrome in males: strengths and weaknesses in cognitive abilities.

The present study examined the cognitive profile in Fragile X Syndrome (FXS) males, and investigated whether cognitive profiles are similar for FXS males at different levels of intellectual functioning. Cognitive abilities in non-verbal, verbal, memory and executive functioning domains were contrasted to both a non-verbal and verbal mental age reference. Model-based cluster analyses revealed three distinct subgroups which differed in level of functioning, but showed similar cognitive profiles. Results showed that cognitive performance is particularly weak on measures of reasoning- and performal abilities confined to abstract item content, but relatively strong on measures of visuo-perceptual recognition and vocabulary. Further, a significant weakness was found for verbal short-term memory. Finally, these results indicated that the choice of an appropriate reference is critically important in examining cognitive profiles. The pattern of findings that emerged from the current cognitive profiling of FXS males was interpreted to suggest a fundamental deficit in executive control.

The curvature of sensitometric curves for Kodak XV-2 film irradiated with photon and electron beams.

Sensitometric curves of Kodak XV-2 film, obtained in a time period of ten years with various types of equipment, have been analyzed both for photon and electron beams. The sensitometric slope in the dataset varies more than a factor of 2, which is attributed mainly to variations in developer conditions. In the literature, the single hit equation has been proposed as a model for the sensitometric curve, as with the parameters of the sensitivity and maximum optical density. In this work, the single hit equation has been translated into a polynomial like function as with the parameters of the sensitometric slope and curvature. The model has been applied to fit the sensitometric data. If the dataset is fitted for each single sensitometric curve separately, a large variation is observed for both fit parameters. When sensitometric curves are fitted simultaneously it appears that all curves can be fitted adequately with a sensitometric curvature that is related to the sensitometric slope. When fitting each curve separately, apparently measurement uncertainty hides this relation. This relation appears to be dependent only on the type of densitometer used. No significant differences between beam energies or beam modalities are observed. Using the intrinsic relation between slope and curvature in fitting sensitometric data, e.g., for pretreatment verification of intensity-modulated radiotherapy, will increase the accuracy of the sensitometric curve. A calibration at a single dose point, together with a predetermined densitometer-dependent parameter ODmax will be adequate to find the actual relation between optical density and dose.

Scattered radiation from applicators in clinical electron beams.

In radiotherapy with high-energy (4-25 MeV) electron beams, scattered radiation from the electron applicator influences the dose distribution in the patient. In most currently available treatment planning systems for radiotherapy this component is not explicitly included and handled only by a slight change of the intensity of the primary beam. The scattered radiation from an applicator changes with the field size and distance from the applicator. The amount of scattered radiation is dependent on the applicator design and on the formation of the electron beam in the treatment head. Electron applicators currently applied in most treatment machines are essentially a set of diaphragms, but still do produce scattered radiation. This paper investigates the present level of scattered dose from electron applicators, and as such provides an extensive set of measured data. The data provided could for instance serve as example input data or benchmark data for advanced treatment planning algorithms which employ a parametrized initial phase space to characterize the clinical electron beam. Central axis depth dose curves of the electron beams have been measured with and without applicators in place, for various applicator sizes and energies, for a Siemens Primus, a Varian 2300 C/D and an Elekta SLi accelerator. Scattered radiation generated by the applicator has been found by subtraction of the central axis depth dose curves, obtained with and without applicator. Scattered radiation from Siemens, Varian and Elekta electron applicators is still significant and cannot be neglected in advanced treatment planning. Scattered radiation at the surface of a water phantom can be as high as 12%. Scattered radiation decreases almost linearly with depth. Scattered radiation from Varian applicators shows clear dependence on beam energy. The Elekta applicators produce less scattered radiation than those of Varian and Siemens, but feature a higher effective angular variance. The scattered radiation decreases somewhat with increasing field size and is spread uniformly over the aperture. Experimental results comply with the results of simulations of the treatment head and electron applicator, using the BEAM Monte Carlo code, and Siemens, but feature a higher effective angular variance. The scattered radiation decreases somewhat with increasing field size and is spread uniformly over the aperture. Experimental results comply with the results of simulations of the treatment head and electron applicator, using the BEAM Monte Carlo code.

Simultaneous MEG and EEG source analysis.

A method is described to derive source and conductivity estimates in a simultaneous MEG and EEG source analysis. In addition the covariance matrix of the estimates is derived. Simulation studies with a concentric spheres model and a more realistic boundary element model indicate that this method has several advantages, even if only a few EEG sensors are added to a MEG configuration. First, a simultaneous analysis profits from the 'preferred' location directions of MEG and EEG. Second, deep sources can be estimated quite accurately, which is an advantage compared to MEG. Third, superficial sources profit from accurate MEG location and from accurate EEG moment. Fourth, the radial source component can be estimated, which is an advantage compared to MEG. Fifth, the conductivities can be estimated. It is shown that conductivity estimation gives a substantial increase in precision, even if the conductivities are not identified appropriately. An illustrative analysis of empirical data supports these findings.

Estimated generalized least squares electromagnetic source analysis based on a parametric noise covariance model.

Estimated generalized least squares (EGLS) electromagnetic source analysis is used to downweight noisy and correlated data. Standard EGLS requires many trials to accurately estimate the noise covariances and, thus, the source parameters. Alternatively, the noise covariances can be modeled parametrically. Only the parameters of the model describing the noise covariances need to be estimated and, therefore, less trials are required. This method is referred to as parametric egls (PEGLS). In this paper, PEGLS is developed and its performance is tested in a simulation study and in a pseudoempirical study.

Effectiveness of couch height-based patient set-up and an off-line correction protocol in prostate cancer radiotherapy.

PURPOSE: To investigate set-up improvement caused by applying a couch height-based patient set-up method in combination with a technologist-driven off-line correction protocol in nonimmobilized radiotherapy of prostate patients. METHODS AND MATERIALS: A three-dimensional shrinking action level correction protocol is applied in two consecutive patient cohorts with different set-up methods: the traditional "laser set-up" group (n = 43) and the "couch height set-up" group (n = 112). For all directions, left-right, ventro-dorsal, and cranio-caudal, random and systematic set-up deviations were measured. RESULTS: The couch height set-up method improves the patient positioning compared to the laser set-up method. Without application of the correction protocol, both systematic and random errors reduced to 2.2-2.4 mm (1 SD) and 1.7-2.2 mm (1 SD), respectively. By using the correction protocol, systematic errors reduced further to 1.3-1.6 mm (1 SD). One-dimensional deviations were within 5 mm for >90% of the measured fractions. The required number of corrections per patient in the off-line correction protocol was reduced significantly during the course of treatment from 1.1 to 0.6 by the couch height set-up method. The treatment time was not prolonged by application of the correction protocol. CONCLUSIONS: The couch height set-up method improves the set-up significantly, especially in the ventro-dorsal direction. Combination of this set-up method with an off-line correction strategy, executed by technologists, reduces the number of set-up corrections required.

A model to determine the initial phase space of a clinical electron beam from measured beam data.

Advanced electron beam dose calculation models for radiation oncology require as input an initial phase space (IPS) that describes a clinical electron beam. The IPS is a distribution in position, energy and direction of electrons and photons in a plane in front of the patient. A method is presented to derive the IPS of a clinical electron beam from a limited set of measured beam data. The electron beam is modelled by a sum of four beam components: a main diverging beam, applicator edge scatter, applicator transmission and a second diverging beam. The two diverging beam components are described by weighted sums of monoenergetic diverging electron and photon beams. The weight factors of these monoenergetic beams are determined by the method of simulated annealing such that a best fit is obtained with depth-dose curves measured for several field sizes at two source-surface distances. The resulting IPSs are applied by the phase-space evolution electron beam dose calculation model to calculate absolute 3D dose distributions. The accuracy of the calculated results is in general within 1.5% or 1.5 mm; worst cases show differences of up to 3% or 3 mm. The method presented here to describe clinical electron beams yields accurate results, requires only a limited set of measurements and might be considered as an alternative to the use of Monte Carlo methods to generate full initial phase spaces.

Optimization of multileaf collimator settings for radiotherapy treatment planning.

Multileaf collimators have become available in many radiotherapy treatment centres. The cross section of a beam can be shaped to a projection of the target area by moving the leaves of the multileaf collimator into the beam. In this paper, a method is described to optimize the positions of the individual leaves automatically, once the beam directions and weights have been chosen. The individual positions of the leaves are optimized using the variable metric method. Changes in dose resulting from small leaf movements are computed efficiently using a special method. The optimization method was tested on a treatment plan for a phantom patient. It was found that the unnecessary edges of the beams were trimmed efficiently.

Accuracy of the phase space evolution dose calculation model for clinical 25 MeV electron beams.

The phase space evolution (PSE) model is a dose calculation model for electron beams in radiation oncology developed with the aim of a higher accuracy than the commonly used pencil beam (PB) models and with shorter calculation times than needed for Monte Carlo (MC) calculations. In this paper the accuracy of the PSE model has been investigated for 25 MeV electron beams of a MM50 racetrack microtron (Scanditronix Medical AB, Sweden) and compared with the results of a PB model. Measurements have been performed for tests like non-standard SSD, irregularly shaped fields, oblique incidence and in phantoms with heterogeneities of air, bone and lung. MC calculations have been performed as well, to reveal possible errors in the measurements and/or possible inaccuracies in the interaction data used for the bone and lung substitute materials. Results show a good agreement between PSE calculated dose distributions and measurements. For all points the differences--in absolute dose--were generally well within 3% and 3 mm. However, the PSE model was found to be less accurate in large regions of low-density material and errors of up to 6% were found for the lung phantom. Results of the PB model show larger deviations, with differences of up to 6% and 6 mm and of up to 10% for the lung phantom; at shortened SSDs the dose was overestimated by up to 6%. The agreement between MC calculations and measurement was good. For the bone and the lung phantom maximum deviations of 4% and 3% were found, caused by uncertainties about the actual interaction data. In conclusion, using the phase space evolution model, absolute 3D dose distributions of 25 MeV electron beams can be calculated with sufficient accuracy in most cases. The accuracy is significantly better than for a pencil beam model. In regions of lung tissue, a Monte Carlo model yields more accurate results than the current implementation of the PSE model.

On the initial angular variances of clinical electron beams.

Electron beam radiotherapy treatment planning systems need to be fed with the characteristics of the high-energy electron beams (4-50 MeV) from the specifically applied accelerator. Beams can be characterized by their mean initial energy, effective initial angular variance, virtual source position and the resulting central axis depth dose distribution in water. This information is the only input to pencil beam dose calculation models. Newer calculation models like macro Monte Carlo, voxel Monte Carlo and phase space evolution require as input the full initial phase space or a parametrization of that initial phase space, generally consisting of a primary beam component and one or more scatter components. This primary beam component is often characterized by initial energy, primary beam initial angular variance and virtual source distance. The purpose of the present investigation was to investigate to what extent standard values can be used both for the effective initial angular variance as input to pencil beam models and for the primary beam initial angular variance. Comprehensive benchmark data were obtained on the initial angular variance of various types of accelerator, for various energies and field sizes. The initial angular variance sigma2theta(x) has been derived from penumbra measurements in air by means of film dosimetry at various distances from the lower collimator. For the types of accelerator used in radiotherapy nowadays the measurements show values for sigma2theta(x)/T(E) of around 13 cm where T(E) is the ICRU-35 linear angular scattering power in air. This value can be chosen as standard value for the primary beam initial angular variance, only slightly compromising the dose calculation accuracy. As input to pencil beam models, an effective sigma2theta(x)/T(E) should be used incorporating the scatter from the lower collimator. For the case that the air gaps between lower collimator and patient are small (5-10 cm) an effective sigma2theata(x)/T(E) of 20 cm has been found and is recommended as the standard input for pencil beam models. Of the accelerators investigated, a different value was found only for the Elekta SL15, i.e. 50% higher for the effective sigma2theta(x)/T(E).

Mixing intensity modulated electron and photon beams: combining a steep dose fall-off at depth with sharp and depth-independent penumbras and flat beam profiles.

For application in radiotherapy, intensity modulated high-energy electron and photon beams were mixed to create dose distributions that feature: (a) a steep dose fall-off at larger depths, similar to pure electron beams, (b) flat beam profiles and sharp and depth-independent beam penumbras, as in photon beams, and (c) a selectable skin dose that is lower than for pure electron beams. To determine the required electron and photon beam fluence profiles, an inverse treatment planning algorithm was used. Mixed beams were realized at a MM50 racetrack microtron (Scanditronix Medical AB, Sweden), and evaluated by the dose distributions measured in a water phantom. The multileaf collimator of the MM50 was used in a static mode to shape overlapping electron beam segments, and the dynamic multileaf collimation mode was used to realize the intensity modulated photon beam profiles. Examples of mixed beams were generated at electron energies of up to 40 MeV. The intensity modulated electron beam component consists of two overlapping concentric fields with optimized field sizes, yielding broad, fairly depth-independent overall beam penumbras. The matched intensity modulated photon beam component has high fluence peaks at the field edges to sharpen this penumbra. The combination of the electron and the photon beams yields dose distributions with the characteristics (a)-(c) mentioned above.

Inclusion of geometrical uncertainties in radiotherapy treatment planning by means of coverage probability.

PURPOSE: Following the ICRU-50 recommendations, geometrical uncertainties in tumor position during radiotherapy treatments are generally included in the treatment planning by adding a margin to the clinical target volume (CTV) to yield the planning target volume (PTV). We have developed a method for automatic calculation of this margin. METHODS AND MATERIALS: Geometrical uncertainties of a specific patient group can normally be characterized by the standard deviation of the distribution of systematic deviations in the patient group (Sigma) and by the average standard deviation of the distribution of random deviations (sigma). The CTV of a patient to be planned can be represented in a 3D matrix in the treatment room coordinate system with voxel values one inside and zero outside the CTV. Convolution of this matrix with the appropriate probability distributions for translations and rotations yields a matrix with coverage probabilities (CPs) which is defined as the probability for each point to be covered by the CTV. The PTV can then be chosen as a volume corresponding to a certain iso-probability level. Separate calculations are performed for systematic and random deviations. Iso-probability volumes are selected in such a way that a high percentage of the CTV volume (on average > 99%) receives a high dose (> 95%). The consequences of systematic deviations on the dose distribution in the CTV can be estimated by calculation of dose histograms of the CP matrix for systematic deviations, resulting in a so-called dose probability histogram (DPH). A DPH represents the average dose volume histogram (DVH) for all systematic deviations in the patient group. The consequences of random deviations can be calculated by convolution of the dose distribution with the probability distributions for random deviations. Using the convolved dose matrix in the DPH calculation yields full information about the influence of geometrical uncertainties on the dose in the CTV. RESULTS: The model is demonstrated to be fast and accurate for a prostate, cervix, and lung cancer case. A CTV-to-PTV margin size which ensures at least 95% dose to (on average) 99% of the CTV, appears to be equal to about 2Sigma + 0.7sigma for three all cases. Because rotational deviations are included, the resulting margins can be anisotropic, as shown for the prostate cancer case. CONCLUSION: A method has been developed for calculation of CTV-to-PTV margins based on the assumption that the CTV should be adequately irradiated with a high probability.