The oral spelling profile of Posterior Cortical Atrophy and the nature of the graphemic representation

Spelling is a complex cognitive task where central and peripheral components are involved in engaging resources from many different cognitive processes. The present paper aims to both characterize the oral spelling deficit in a population of patients affected by a neurodegenerative condition and to clarify the nature of the graphemic representation within the currently available spelling models. Indeed, the nature of graphemic representation as a linear or multi-componential structure is still debated. Different hypotheses have been raised about its nature in the orthographic lexicon, with one positing that graphemes are complex objects whereby quantity and identity are separately represented in orthographic representations and can thus be selectively impaired. Posterior cortical atrophy (PCA) is a neurodegenerative condition that mainly affects visuoperceptual and visuospatial functions. Spelling impairments are considered part of the disease. Nonetheless the spelling deficit has received little attention so far and often it has been interpreted in relation to peripheral impairments such as writing difficulties associated with visuoperceptual and visuospatial deficits. In the present study we provide a detailed characterization of the oral spelling profile in PCA. The data suggest that multiple deficits underpin oral spelling problems in PCA, with elements of surface and phonological dysgraphia but also suggesting the involvement of the graphemic buffer. A large phenotypic individual variability is reported. Moreover, the larger proportion and the specific nature of errors involving geminate (i.e., double) as compared to non-geminate (i.e., non-double) letters suggest that a further central impairment might be associated with the abstract graphemic representation of letter numerosity. The present study contributes to the clinical characterization of PCA and to the current debate in the cognitive literature on spelling models. Findings despite not definitive, support the hypothesis that graphemic representations are multidimensional mental objects that separately encode information about grapheme identity and quantity

Stress in Context: Morpho-Syntactic Properties Affect Lexical Stress Assignment in Reading Aloud

Recent findings from English and Russian have shown that grammatical category plays a key role in stress assignment. In these languages, some grammatical categories have a typical stress pattern and this information is used by readers. However, whether readers are sensitive to smaller distributional differences and other morpho-syntactic properties (e.g., gender, number, person) remains unclear. We addressed this issue in word and non-word reading in Italian, a language in which: (1) nouns and verbs differ in the proportion of words with a dominant stress pattern; (2) information specified by words sharing morpho-syntactic properties may contrast with other sources of information, such as stress neighborhood. Both aspects were addressed in two experiments in which context words were used to induce the desired morpho-syntactic properties. Experiment 1 showed that the relatively different proportions of stress patterns between grammatical categories do not affect stress processing in word reading. In contrast, Experiment 2 showed that information specified by words sharing morpho-syntactic properties outweighs stress neighborhood in non-word reading. Thus, while general information specified by grammatical categories may not be used by Italian readers, stress neighbors with morpho-syntactic properties congruent with those of the target stimulus have a primary role in stress assignment. These results underscore the importance of expanding investigations of stress assignment beyond single words, as current models of single-word reading seem unable to account for our results

Evidence of semantic processing in parafoveal reading: a rapid parallel visual presentation (Rpvp) study

This study explores whether semantic processing in parafoveal reading in the Italian language is modulated by the perceptual and lexical features of stimuli by analyzing the results of the rapid parallel visual presentation (RPVP) paradigm experiment, which simultaneously presented two words, with one in the fovea and one in the parafovea. The words were randomly sampled from a set of semantically related and semantically unrelated pairs. The accuracy and reaction times in reading the words were measured as a function of the stimulus length and written word frequency. Fewer errors were observed in reading parafoveal words when they were semantically related to the foveal ones, and a larger semantic facilitatory effect was observed when the foveal word was highly frequent and the parafoveal word was short. Analysis of the reaction times suggests that the semantic relation between the two words sped up the naming of the foveal word when both words were short and highly frequent. Altogether, these results add further evidence in favor of the semantic processing of words in the parafovea during reading, modulated by the orthographic and lexical features of the stimuli. The results are discussed within the context of the most prominent models of word processing and eye movement controls in reading

Impaired mechanism of visual focal attention in posterior cortical atrophy

Objective: Simultanagnosia, a deficit in holistic visual perception, is among the most prominent features of posterior cortical atrophy (PCA). Deficits in visuoperceptual and attentional mechanisms could contribute to simultanagnosia. In the present study, we explored the impaired visual perception of global configuration with two main hypotheses: (a) It is due to a deficit in processing low-spatial frequency stimuli, and (b) it arises from deficits in adjusting attentional focus. Method: The visuoperceptual mechanism was explored by asking participants (5 PCA patients and 20 age- and education-matched healthy controls) to report the local and global elements of incongruent hierarchical letters. Stimuli were unbiased (black letters/white background) and parvocellular biased (red letters/green background). A cued T-detection task, where the stimulus onset asynchrony and the cues' features varied, was used to explore focal attention. Results: PCA patients systematically failed in reporting the global but not the local element. The parvocellular-biased condition partially improved the performance in only 1 patient. In the T-detection task, controls responded faster to targets cued by red dots and small cues as compared to no cues. Conversely, the cue's features did not affect patients' performance. Conclusions: Results only partially support the hypothesis according to which simultanagnosia is driven by an impairment in processing low-spatial frequencies. Data indicate a deficit in the flexibility of focal attention that prevents PCA patients from adapting the attentional window to the stimulus features. Simultanagnosia in PCA can be conceptualized as a complex result of a deficit involving visuoperceptual and exogenous attentional mechanisms. (PsycInfo Database Record (c) 2020 APA, all rights reserved)

The focal attention window size explains letter substitution errors in reading

Acquired Neglect Dyslexia is often associated with right-hemisphere brain damage and is mainly characterized by omissions and substitutions in reading single words. Martelli et al. proposed in 2011 that these two types of error are due to different mechanisms. Omissions should depend on neglect plus an oculomotor deficit, whilst substitutions on the difficulty with which the letters are perceptually segregated from each other (i.e., crowding phenomenon). In this study, we hypothesized that a deficit of focal attention could determine a pathological crowding effect, leading to imprecise letter identification and consequently substitution errors. In Experiment 1, three brain-damaged patients, suffering from peripheral dyslexia, mainly characterized by substitutions, underwent an assessment of error distribution in reading pseudowords and a T detection task as a function of cue size and timing, in order to measure focal attention. Each patient, when compared to a control group, showed a deficit in adjusting the attentional focus. In Experiment 2, a group of 17 right-brain-damaged patients were asked to perform the focal attention task and to read single words and pseudowords as a function of inter-letter spacing. The results allowed us to confirm a more general association between substitution-type reading errors and the performance in the focal attention task

Dissociation in optokinetic stimulation sensitivity between omission and substitution reading errors in neglect dyslexia

Although omission and substitution errors in neglect dyslexia (ND) patients have always been considered as different manifestations of the same acquired reading disorder, recently, we proposed a new dual mechanism model. While omissions are related to the exploratory disorder which characterizes unilateral spatial neglect (USN), substitutions are due to a perceptual integration mechanism. A consequence of this hypothesis is that spe- cific training for omission-type ND patients would aim at restoring the oculo-motor scanning and should not improve reading in substitution-type ND. With this aim we administered an optokinetic stimulation (OKS) to two brain-damaged patients with both USN and ND, MA and EP, who showed ND mainly characterized by omissions and substitutions, respectively. MA also showed an impairment in oculo-motor behavior with a non-reading task, while EP did not. The two patients presented a dissociation with respect to their sensitivity to OKS, so that, as expected, MA was positively affected, while EP was not. Our results confirm a dissociation between the two mechanisms underlying omission and substitution reading errors in ND patients. Moreover, they suggest that such a dissociation could possibly be extended to the effectiveness of rehabilitative procedures, and that patients who mainly omit contralesional-sided letters would benefit from OKS

Eyetracking metrics reveal impaired spatial anticipation in behavioural variant frontotemporal dementia.

Eyetracking technology has had limited application in the dementia field to date, with most studies attempting to discriminate syndrome subgroups on the basis of basic oculomotor functions rather than higher-order cognitive abilities. Eyetracking-based tasks may also offer opportunities to reduce or ameliorate problems associated with standard paper-and-pencil cognitive tests such as the complexity and linguistic demands of verbal test instructions, and the problems of tiredness and attention associated with lengthy tasks that generate few data points at a slow rate. In the present paper we adapted the Brixton spatial anticipation test to a computerized instruction-less version where oculomotor metrics, rather than overt verbal responses, were taken into account as indicators of high level cognitive functions. Twelve bvFTD (in whom spatial anticipation deficits were expected), six SD patients (in whom deficits were predicted to be less frequent) and 38 healthy controls were presented with a 10×7 matrix of white circles. During each trial (N=24) a black dot moved across seven positions on the screen, following 12 different patterns. Participants' eye movements were recorded. Frequentist statistical analysis of standard eye movement metrics were complemented by a Bayesian machine learning (ML) approach in which raw eyetracking time series datasets were examined to explore the ability to discriminate diagnostic group performance not only on the overall performance but also on individual trials. The original pen and paper Brixton test identified a spatial anticipation deficit in 7/12 (58%) of bvFTD and in 2/6 (33%) of SD patients. The eyetracking frequentist approach reported the deficit in 11/12 (92%) of bvFTD and in none (0%) of the SD patients. The machine learning approach had the main advantage of identifying significant differences from controls in 24/24 individual trials for bvFTD patients and in only 12/24 for SD patients. Results indicate that the fine grained rich datasets obtained from eyetacking metrics can inform us about high level cognitive functions in dementia, such as spatial anticipation. The ML approach can help identify conditions where subtle deficits are present and, potentially, contribute to test optimisation and the reduction of testing times. The absence of instructions also favoured a better distinction between different clinical groups of patients and can help provide valuable disease-specific markers

Non-Parametric Mixture Modelling and its Application to Disease Progression Modelling

Dementia is characterised by its progressive degeneration of cognitive abilities. In research cohorts, detailed neuropsychological test batteries are often administered to better understand how cognition changes over time. Understanding cognitive changes in dementia is of great importance, particularly in determining how structural changes in the brain may affect cognition and in facilitating earlier detection of symptomatic changes. Disease progression models are often applied to these data to understand how a disease changes over time from cross-sectional data or to disease trajectories from large numbers of individuals. Previous disease progression models used to build longitudinal models from cross-sectional data have focused on brain imaging data; however, these models are not directly applicable to cognitive data. Here we use the novel, non-parametric, Kernel Density Estimation Mixture Modelling (KDEMM) approach and demonstrate accurate modelling of the progression of cognitive test data. We found that using KDEMM resulted in more accurate models of disease progression in simulated data compared to Gaussian Mixture Models (GMMs) for the majority of parameters used to simulate the data. When comparing KDEMM and GMM to cognitive data collected in different Alzheimer's Disease subtypes, we found the KDEMM resulted in a model much more in line with clinical phenotype. We anticipate that the KDEMM will be used to integrate cognitive test data, and other non-normally distributed datasets into complex disease progression models

Eyetracking Metrics in Young Onset Alzheimer’s Disease: A Window into Cognitive Visual Functions

Young onset Alzheimer’s disease (YOAD) is defined as symptom onset before the age of 65 years and is particularly associated with phenotypic heterogeneity. Atypical presentations, such as the clinic-radiological visual syndrome posterior cortical atrophy (PCA), often lead to delays in accurate diagnosis. Eyetracking has been used to demonstrate basic oculomotor impairments in individuals with dementia. In the present study, we aim to explore the relationship between eyetracking metrics and standard tests of visual cognition in individuals with YOAD. Fifty-seven participants were included: 36 individuals with YOAD (n =  26 typical AD; n =  10 PCA) and 21 age-matched healthy controls. Participants completed three eyetracking experiments: fixation, pro-saccade, and smooth pursuit tasks. Summary metrics were used as outcome measures and their predictive value explored looking at correlations with visuoperceptual and visuospatial metrics. Significant correlations between eyetracking metrics and standard visual cognitive estimates are reported. A machine-learning approach using a classification method based on the smooth pursuit raw eyetracking data discriminates with approximately 95% accuracy patients and controls in cross-validation tests. Results suggest that the eyetracking paradigms of a relatively simple and specific nature provide measures not only reflecting basic oculomotor characteristics but also predicting higher order visuospatial and visuoperceptual impairments. Eyetracking measures can represent extremely useful markers during the diagnostic phase and may be exploited as potential outcome measures for clinical trials

CYP1A1 Variability In Human Populations

The human cytochrome P4501A1 (CYP1A1) enzyme plays an important role in the metabolism of xenobiotics and endogenous substrates. Because polymorphisms within the CYP1A1 gene have been shown to be associated with various cancer risks and with the predicting clinical efficacy of some chemotherapies in different populations, most studies focus on their clinical significance. We, however, were interested in evaluating whether the polymorphisms could be used to distinguish human populations. Four single nucleotide CYP1A1 polymorphisms (rs4646903/ g.75011641; rs1048943/g.75012985; g.75012235; and rs1799814/ g.75012987) were analysed via PCR-RFLP assay in 1,195 individuals of various human groups from all over the world. In order to gain a more complete view of the genetic variability of the CYP1A1 gene, different statistical analyses were performed upon the populations of the present study and upon the limited data gleaned from previously studied populations. The allele and haplotype frequencies vary among populations: the rs4646903 (C) and rs1048943 (G) have been found to be nearly always linked and were found at the highest frequencies in Native Americans, while the variant associated to the position g.75012235 was only detected in certain African populations. Our work clearly indicates that the CYP1A1 polymorphisms differ among populations and that the prediction of genotypes constitutes an important aspect of precision medicine since some variants were associated with certain cancers and rs1048943 show strong association with optimized chemotherapy. Moreover, the CYP1A1 gene plays an important role in the metabolism of xenobiotics and it is likely that its frequencies could be strongly influenced by environmental factors