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.

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.

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.

Ordinary least squares dipole localization is influenced by the reference.

It is shown empirically, analytically and in simulations that common and average referenced recordings differentially affect the accuracy of equivalent source estimates. This effect is mediated by the influence of the reference on noise correlations. The general conclusion of this analysis is that, if software only allows for ordinary least squares estimation (OLS), then average referencing should be preferred, although these estimates will still be sub-optimal. Optimal estimates are derived by generalized least squares (GLS) which accounts for correlated noise. With GLS, average and common referenced recordings give rise to comparable accuracy.

Equivalent source estimation of scalp potential fields contaminated by heteroscedastic and correlated noise.

The customary ordinary least squares (OLS) approach to the estimation of equivalent sources of scalp potential fields relies on the assumption that noise in the potential measurements has an equal variance and is uncorrelated over leads. It is shown that this assumption is likely to be violated in practice, for instance by the use of a common reference lead. We describe tests to detect these violations and we propose several versions of an alternative estimation method called iterated generalised least squares (IGLS), which accounts for heteroscedastic or correlated noise by incorporating an estimate of the covariance matrix of the noise derived from single trial OLS residuals. Simulation results indicate that these alternatives give a considerable increase in the accuracy of both the parameter and the standard error and confidence interval estimates. The proposed tests and methods are finally integrated into a stepwise approach to equivalent source estimation, which incorporates in addition a test on the goodness of fit of the model, an assessment of the confidence intervals of the parameters and a powerful test of differences between experimental conditions. This stepwise approach is applied to the modelling of equivalent sources of early visual potentials elicited in a spatial attention task.

Estimating and Testing the Sources of Evoked Potentials in the Brain.

The source of an event related brain potential (ERP) is estimated from multivariate measurements of this ERP on the head under several mathematical and physical constraints on the parameters of the source model. We will discuss statistical aspects of standard methods to estimate these parameters and their confidence intervals. In addition new principled tests of the goodness of fit as well as of differences between estimated sources are proposed and compared with customary approaches in psychophysiology. Several factors which influence the statistical analysis, in particular the number of measurement leads, will be discussed.