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).

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.

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.

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.

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.

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.

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.

Film dosimetry of clinical electron beams.

Film dosimetry is used widely to obtain relative dose distributions of clinical electron beams in phantoms. Nevertheless, measurement results obtained with film dosimetry may lack precision and reliability. In this paper well defined and reproducible methods in film dosimetry are discussed. By application of these methods, film dosimetry appears to be adequate in measuring relative dose distributions of clinically applied electron beams, with an accuracy of 1% to 2% of the dose maximum, in water and plastics as well as in heterogeneously composed material.

Performance of a prototype fluoroscopic radiotherapy imaging system.

An increasing demand exists for the implementation of radiotherapy imaging during routine patient treatment, not only for quality assurance of field alignment, but also to obtain full documentation of the actual radiation treatments given. As the method using conventional portal films has distinct disadvantages, alternative methods are required which preferably are faster and produce images of better quality. This paper describes the performance of a prototype fluoroscopic system in terms of spatial resolution and contrast resolution as well as imaging of patients during routine treatments. The system described appears to be suitable for patient set-up and treatment verification and documentation.

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.

Quality assurance using portal imaging: the accuracy of patient positioning in irradiation of breast cancer.

PURPOSE: To study the accuracy of patient positioning in irradiation of breast cancer. METHODS AND MATERIALS: Megavolt portal images were obtained using a fast electronic megavoltage radiotherapy imaging system in 17 breast cancer patients immobilized with plastic fixation masks on a flat board with arm support and in 14 patients positioned without a mask on either a flat or a wedge-shaped board. Quantitative analysis of 510 megavolt portal images and comparison to 66 digitized simulation films was performed. Differences between the positioning techniques were evaluated. RESULTS: For the position of the patient in the field, standard deviations of the difference between simulation and treatment images were 3.2 mm and 4.6 mm for irradiation with and without masks, respectively. Larger standard deviations were found for the field width and length (5-7 mm), for collimator rotation (1.5-2 degrees), and for the position of the lung shielding block for patients positioned on the flat board (10-16 mm). The changes in field size and collimator rotation appeared to be largely due to the inclination of the technologists to slightly adapt fields in order to obtain a seemingly better congruity of the field with the skin or mask markings. Comparison of the accuracy of patient positioning with and without masks yielded similar error rates; standard deviations and extremes tended to be somewhat larger in positioning without a mask. The wedge-shaped board was preferred because of the ease of patient set-up and because the use of a lung block is avoided. The transition from simulation to treatment set-up yielded larger deviations than repeated treatment set-ups. CONCLUSION: These results emphasize again the continuous need for focusing attention on the accuracy of patient positioning in order to achieve maximal precision in radiotherapy. The electronic portal imaging system is very suitable for both quick on-line treatment verification and off-line analyses.

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.

A quality control study of the accuracy of patient positioning in irradiation of pelvic fields.

PURPOSE: Determining and improving the accuracy of patient positioning in pelvic fields. METHODS AND MATERIALS: Small pelvic fields were studied in 16 patients treated for urological cancers using a three-field isocentric technique. Large pelvic fields were studied in 17 gynecological cancer patients treated with anterior and posterior (AP-PA) parallel opposed fields. Quantitative analysis of 645 megavolt images and comparison to 82 simulation images were carried out. RESULTS: Small pelvic fields: for the position of the patient in the field, standard deviations of the difference between simulation (SIM) and treatment (MV) images were 3.4 mm in the lateral direction, 5.3 mm in the cranio-caudal direction, and 4.8 mm in the ventro-dorsal direction. Alterations in the positioning technique were made and tested. Large pelvic fields: differences between simulation and treatment images for the position of the patient in the field were 4 mm [1 standard deviation (SD)] in the lateral direction and 6.5 mm in the cranio-caudal direction. A systematic shift of the treatment field in the cranial direction had occurred in the majority of patients. A positioning technique using laser lines and marking of the caudal field border was shown to be more accurate. CONCLUSIONS: Studies of positioning accuracy in routine irradiation techniques are needed to obtain data for definition of the margins for each treatment site at each institution. Random variations should be kept at a minimum by monitoring and improving positioning techniques. Treatment verification by megavolt imaging or film should be used to detect and correct systematic variations early in the treatment series.

Isolation and partial characterization of a surface glycoconjugate of Entamoeba histolytica.

To study surface molecules of Entamoeba histolytica we produced monoclonal antibodies from mice immunized with lysates from the pathogenic amebic strain HM1:IMSS, and screened them for the ability to inhibit E. histolytica adhesion. One monoclonal antibody, CC 8.6, was a potent inhibitor of amebic adhesion to a Chinese hamster ovary cell line, and was capable of inhibiting HM1:IMSS mediated cytotoxicity by 50%. We found that monoclonal antibody CC 8.6 bound to an amebic glycoconjugate. The glycoconjugate is present only in E. histolytica and not in other Entamoeba sp. It migrates as a polydisperse band on SDS-PAGE, and can be metabolically radiolabeled with [14C]glucose, [32P]phosphate, and [3H]palmitate. The glycoconjugate can be purified by hydrophobic interaction chromatography on octyl-Sepharose; enzymatic hydrolysis with phosphatidylinositol-specific phospholipase C alters the hydrophobic properties of the molecule. HPLC analysis of [14C]glucose-labeled glycoconjugate saccharides revealed that approximately 82% of the incorporated label was in glucose and 12% in galactose. Our studies demonstrate that one of the immunogenic surface molecules of E. histolytica is a phosphorylated, lipid-containing, glycoconjugate, and that antibodies to this antigen may have the potential to protect against E. histolytica adhesion and cytotoxicity.

Possible leakage radiation during malfunctioning of a Sagittaire accelerator.

A non-fatal accident with a CGR-Sagittaire accelerator in the Dr Daniel den Hoed Cancer Center (DDHCC) in Rotterdam in 1988 is described. In a period with frequently occurring technical problems, a patient, undergoing fractionated treatment at this accelerator for prostatic cancer, developed severe skin reactions on the right half ventral part of thorax, head and upper arm. The skin reactions suggested an irradiation with a dose of up to 10-20 Gy, so it was likely that a radiation accident had occurred caused by leakage radiation. A number of experiments were performed in attempting to explain the estimated large dose rates of leakage radiation. Under rather extreme malfunctioning conditions, a high leakage dose rate (4 Gy/min) could be obtained during therapy use. This condition might have occurred during this period of technical difficulty.

Effect of set-up uncertainties on the dose distribution in the match region of supraclavicular and tangential breast fields.

BACKGROUND: The objective of this paper is to illustrate the effect of a gap of 5 mm, an overlap of 5 mm and a perfect match on the dose distribution across the junction of tangential breast fields and adjacent supraclavicular and axillary fields. MATERIALS AND METHODS: For this purpose film dosimetry was applied to measure relative dose distributions in two sagittal planes in an anthropomorphic breast phantom having cork lungs, simulating a radiation therapy treatment of the breast and adjacent supraclavicular lymph nodes. Two different treatment techniques, an SSD match technique and a geometrically exact isocentric match technique, as routinely applied in the two institutes were examined. The three-dimensional treatment planning system of each institute was used to calculate the dose distribution in the match region of the supraclavicular fields and the two opposing tangential fields. The measured and calculated dose distributions were evaluated and compared along lines in two sagittal planes from the supraclavicular fields down to the tangential fields crossing the match planes. These dose distributions in the match region were extremely dependent on the set-up of the fields. RESULTS: Although the reproducibility of the film measurements was within 2%, it became clear that the set-up of the fields to achieve a gap of 5 mm, a perfect match or an overlap of 5 mm required a lot of attention, even when using a phantom. CONCLUSIONS: It can be concluded that in clinical practice, these set-up difficulties do influence the dose distribution in the match region much more than the systematic uncertainties in the dose calculation algorithms of the treatment planning systems and the type of treatment technique.

Accuracy in radiation field alignment in head and neck cancer: a prospective study.

A prospective study has been performed to determine the accuracy of radiation field alignment for a group of 22 patients with tumors in the head and neck. The accuracy was assessed by an analysis of 138 megavolt portal films in comparison to 55 simulation films. The distance (at the patient midplane) between corresponding points at the field edges on verification film and simulation film appeared to be 5 mm on the average and the standard deviation 5 mm. The analysis was extended by translational and rotational matching of the fields in order to separate each error in a translation error of the field with respect to the patient and an error in field size or shape. Translation errors appear to be somewhat larger than field size or shape errors. From an analysis of a series of megavolt films taken every third radiotherapy session, it was concluded that treatment-to-treatment variations are as large as the errors due to the transition from simulation to treatment situation. Further analysis showed that variation of the patient's position within the cast is clearly one of the error sources.

Film dosimetry for radiotherapy treatment planning verification of a 6 MV tangential breast irradiation.

Film dosimetry has been applied to measure relative dose distributions in an anthropomorphic polystyrene breast phantom having cork lungs, simulating a radiation therapy treatment with 6 MV opposing tangential beams. Measured relative dose distributions showed good reproducibility (about 1.5%, 1 SD) and good agreement (< 2%) with calculations performed with a three-dimensional treatment planning system. These results demonstrate that film dosimetry is a useful tool for treatment planning verification.

Sharpening the penumbra of high energy electron beams with low weight narrow photon beams.

BACKGROUND AND PURPOSE: High energy (20-50 MeV) electron beams, available from the MM50 Racetrack Microtron, can be used for the treatment of deep-seated tumors. A disadvantage is the increasing penumbra width as a function of depth. By the addition of a narrow (typically 1 cm wide) photon beam near the field edge, the 50-90% penumbra width of the electron beam is reduced, yielding a significantly increased effective field size. MATERIALS AND METHODS: For rectangular electron beams in a water phantom (energies 25 and 40 MeV, field sizes 5 x 5-15 x 15 cm2) a computer program was used to optimize the photon beam parameters (position, weight and width) to obtain a combined beam with the sharpest penumbra at the optimization depth and a beam flatness within certain constraints. The study furthermore included penumbra sharpening of an irregular multileaf collimator-shaped field. RESULTS AND CONCLUSION: At optimization depths near R90, photon beam addition reduces the penumbra width by 40-50% (from 15-20 mm to 8-10 mm). Beam flatness at the optimization depth is within +/-5% and hot-spots are < or =120% for all depths. By the addition of narrow photon beams around the rectangular or irregular field, the electron field width can be reduced by 1-3 cm, while the effective field size is maintained.