Clinical Pregenetic Screening for Stroke Monogenic Diseases: Results From Lombardia GENS Registry.

BACKGROUND AND PURPOSE: Lombardia GENS is a multicentre prospective study aimed at diagnosing 5 single-gene disorders associated with stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], hereditary cerebral amyloid angiopathy, and Marfan syndrome) by applying diagnostic algorithms specific for each clinically suspected disease METHODS: We enrolled a consecutive series of patients with ischemic or hemorrhagic stroke or transient ischemic attack admitted in stroke units in the Lombardia region participating in the project. Patients were defined as probable when presenting with stroke or transient ischemic attack of unknown etiopathogenic causes, or in the presence of <3 conventional vascular risk factors or young age at onset, or positive familial history or of specific clinical features. Patients fulfilling diagnostic algorithms specific for each monogenic disease (suspected) were referred for genetic analysis. RESULTS: In 209 patients (57.4±14.7 years), the application of the disease-specific algorithm identified 227 patients with possible monogenic disease. Genetic testing identified pathogenic mutations in 7% of these cases. Familial history of stroke was the only significant specific feature that distinguished mutated patients from nonmutated ones. The presence of cerebrovascular risk factors did not exclude a genetic disease. CONCLUSIONS: In patients prescreened using a clinical algorithm for monogenic disorders, we identified monogenic causes of events in 7% of patients in comparison to the 1% to 5% prevalence reported in previous series.

Revised and extended norms for a picture naming test sensitive to category dissociations.

This study presents revised and extended norms for a picture naming test [Laiacona et al. (Arch Neurol Psicol Psichiatr 54:209-248, 1993)], based on 80 Snodgrass and Vanderwart (J Exp Psychol Human Learn Mem 6:174-215, 1980) pictures, devised to detect a categorical dissociation in the naming of items between biological and man-made categories. This survey is based on data from 215 healthy Italian participants. Since males are more frequently reported to have a disproportionate impairment of biological categories, norms have also been separately calculated for males and females and for the two categories of man-made objects and biological entities. Besides providing new normative values based on the Equivalent Scores approach, this study reappraises the interaction between categorical dissociations and sex in the normal population, and discusses some methodological aspects concerning the use of statistical norms.

Language disturbances associated to insular and entorhinal damage: study of a patient affected by herpetic encephalitis.

The herpes simplex encephalitis (HSE) patient reported in this study presented a left hemisphere lesion limited to the left insula and to the left anterior parahippocampal region. The patient was followed longitudinally, focusing on the aphasia type, the language recovery, and the integrity of semantic representations. The language deficit was of fluent type, without phonological impairment, and showed a good but incomplete recovery after four months. A semantic impairment was possible at the onset, but recovered quickly and did not present a disproportionate impairment of living categories.

Perceptual and response-related components of unilateral neglect may evolve independently of one another: evidence from five single-case studies.

The Milner Landmark Task allows the disentanglement of perceptual and response-related components of unilateral neglect. If these two components reflect separate functional systems, then cases should be observed in which the two components evolve differently across time. To test this hypothesis we surveyed a continuous series of 21 right hemisphere stroke patients. Five patients from the sample were affected by unilateral neglect at the outset and could be submitted to repeated administrations of the Landmark task in the first weeks post stroke. Two versions of the task were used, Landmark-Manual and Landmark-Verbal, differing in the type of response required. Two patients showed independent changes in the perceptual and the response-related component of neglect, hence confirming the view of separate functional systems underlying them. Dissociations between the task versions were found, witnessing a role of the type of response. Unexpectedly, one patient showed an initial leftward deviation of the subjective midpoint of the stimulus line, which later reversed to a classical rightward deviation. We interpreted such a pattern in terms of co-existing "productive" and "negative" components of perceptual neglect.

The assessment of colour perception, naming and knowledge: a new test device with a case study.

Besides ocular diseases, also cerebral damage may cause colour vision deficits; cerebral lesions may be associated with a variety of clinical conditions that impair colour processing. This study presents procedures and normative data for a rapid, comprehensive seven-test battery aimed at assessing colour perception, colour naming and object colour knowledge. The norms, obtained from 96 healthy Italian participants, allow normality/pathology judgements on the basis of one-sided tolerance limits, after adjusting the score of each test for the demographic variables of the proband subjects. We also report, as an example, use of the battery in a stroke patient; this patient was chosen because her lesion affected the left temporal-occipital cortex, an area sometimes associated with a deficit of colour processing. The patient resulted normal on colour perception and colour name retrieval, but defective on object colour knowledge probed using the stimulus name. For the sound definition of the functional locus of cognitive impairment at the single case level, a multi-faceted set of tasks is necessary.

Associated impairment of the categories of conspecifics and biological entities: cognitive and neuroanatomical aspects of a new case.

Case A.C.A. presented an associated impairment of visual recognition and semantic knowledge for celebrities and biological objects. This case was relevant for (a) the neuroanatomical correlations, and (b) the relationship between visual recognition and semantics within the biological domain and the conspecifics domain. A.C.A. was not affected by anterior temporal damage. Her bilateral vascular lesions were localized on the medial and inferior temporal gyrus on the right and on the intermediate fusiform gyrus on the left, without concomitant lesions of the parahippocampal gyrus or posterior fusiform. Data analysis was based on a novel methodology developed to estimate the rate of stored items in the visual structural description system (SDS) or in the face recognition unit. For each biological object, no particular correlation was found between the visual information accessed through the semantic system and that tapped by the picture reality judgement. Findings are discussed with reference to whether a putative resource commonality is likely between biological objects and conspecifics, and whether or not either category may depend on an exclusive neural substrate.

Posterior cerebral artery infarcts and semantic category dissociations: a study of 28 patients.

In this study we analysed the relationship between damage in the territory of the posterior cerebral artery and semantic knowledge, with special reference to category dissociations. Twenty-eight posterior cerebral artery stroke patients (18 left, 8 right and 2 bilateral posterior cerebral artery infarctions) completed a neuropsychological battery aimed at assessing semantic knowledge. The battery included picture naming, word-picture matching, a verbal semantic questionnaire and a picture reality decision task. For each participant, the lesion was reconstructed on the basis of MRI images, and was classified according to the involvement of the areas supplied by posterior cerebral artery. Defective naming scores were observed in 12 of 18 left posterior cerebral artery cases (67%), four of eight right posterior cerebral artery cases (50%), and one of two bilateral posterior cerebral artery cases (50%). Only in the bilateral posterior cerebral artery lesion case did we observe the pattern expected in pure visual agnosia, i.e. poor picture naming, poor picture reality decision, and normal verbal semantic questionnaire. Nine left posterior cerebral artery cases and two right posterior cerebral artery cases presented with poor performance on both the picture naming task and the verbal semantic questionnaire, thus suggesting semantic impairment. For 5 of the 12 left posterior cerebral artery patients who fared poorly on the naming task, biological stimuli (overall) were significantly more impaired than artifacts. In three of these five subjects, performance on plant-life stimuli was significantly less accurate than that on animals. A further left posterior cerebral artery patient presented a disproportionate impairment on plant-life stimuli only on the word-picture matching and on the questionnaire. The patterns of performance in these subjects suggest that the observed dissociations originated at the semantic level. Among left posterior cerebral artery patients, a naming deficit only occurred when damage to the fusiform gyrus extended anterior to Talairach's y-coordinate -50, and a disproportionate impairment of biological categories only when the lesion extended anterior to y = -32.5. Results show that the semantic deficit for the category of plant life is a genuine cognitive pattern, and does not depend on loss of colour knowledge. The contrast of left posterior cerebral artery strokes and herpes simplex encephalitis cases shows that the neural substrates for the semantic representation of plant life and animals are, at least in part, distinct. Middle and posterior portions of the left fusiform are crucial for the representation of plant-life knowledge, whereas left anterior temporal areas are more crucial than left posterior and basal temporal areas for the representation of knowledge about animals.

Brain damage and semantic category dissociations: is the animals category easier for males?

Semantic dissociations show that biological stimuli present a further dissociation between animals and plant life. Almost all cases of greater impairment of plant life knowledge were males, suggesting a higher male familiarity with animals possibly derived from different daily activities. To verify this hypothesis, we collected familiarity ratings for normal males and females, for 288 animals, subdivided according to whether they were hunted/fished, or were used as food. The overall familiarity was almost identical between males and females. Males were more familiar with hunted animals, but for them also food animals were more familiar. There was not a consistent effect of hunting/fishing independently of the food/not food classification. The claim that males are generally more proficient with animals knowledge because most hunters/fishers are males seems rather simplistic, and the familiarity structure of the animals category is more complex. An evolution-based account is suggested for the category by sex interaction.

Mirror asymmetry of Category and Letter fluency in traumatic brain injury and Alzheimer's patients.

In this study we contrasted the Category fluency and Letter fluency performance of 198 normal subjects, 57 Alzheimer's patients and 57 patients affected by traumatic brain injury (TBI). The aim was to check whether, besides the prevalence of Category fluency deficit often reported among Alzheimer's patients, the TBI group presented the opposite dissociation. According to some recent claims, in fact, the deficit of TBI would be equally severe for both fluency types. The inquiry followed different approaches for data analysis, including the evaluation of a unique index (Fluency Type Index or FTI), independent of the overall fluency and aimed at expressing at individual subject level the relationship between Category and Letter fluency. The results confirmed that Alzheimer's patients are more defective on Category than Letter fluency, and also clearly indicated that an opposite pattern applies to TBI patients. TBI seems to cause a relatively more severe impairment of Letter than Category fluency, probably due to its impact on the frontal lobe structures. We discuss whether, on the basis of the statistical distribution of our data, it is worth considering as homogeneous populations broadly defined groups as Alzheimer's or TBI patients.

Integration of lexical and sublexical processing in the spelling of regular words: a multiple single-case study in Italian dysgraphic patients.

In this study we investigated 12 cases of "mixed dysgraphia", a spelling impairment where regular words are spelt better than either ambiguous words or regular non-words. Two explanations of mixed dysgraphia were formerly offered by Luzzatti et al. (1998): (i) a double functional lesion of the orthographic output lexicon (or damage to its access) and of the acoustic-to-phonological conversion; and (ii) some kind of interaction/summation between lexical and sublexical spelling routes when processing regular words. We first analysed whether a double functional lesion was sufficient to explain the mixed dysgraphia, checking acoustic-to-phonological conversion by means of the repetition of words and non-words: the answer was positive in five cases and uncertain in three. We tested the remaining four cases to see if there was an interaction between lexical and sublexical processing of regular words, quantifying for each patient, on a probabilistic basis, the separate contribution of the residual lexical and sublexical resources. We investigated whether the processing along these routes was simultaneous but independent ("independent cooperation") or if instead there was "interaction", i.e., the simultaneous activity led to an added increase of efficiency over and above the mere combination of separate success probabilities. For one case the processing along the two routes was independent, in the other three cases an interaction resulted. Following the same approach, we found that for the five cases with a double functional lesion, the observed success on regular word spelling was higher than that expected on a probabilistic basis, but the interpretation of this finding was different.

Modelling picture naming in aphasia: The relationship between consistency and predictability of responses.

OBJECTIVE: Two aspects of aphasic picture naming were examined: response consistency, that is, the extent to which the accuracy of the response to the same stimulus is replicated in a successive examination, and response predictability, that is, the extent to which accuracy depends on the characteristics of each stimulus. METHODS: Thirty-eight aphasic participants were examined twice. The response pattern was the same across the 2 presentations (response stability) for 36 participants, who were classified into 3 groups according to the prevailing error-type (lexical-semantic, phonological, or a balance between the two error-types): Their item-consistency was quantified with Cohen's kappa. In each case the roles played by lexical frequency, precocity of acquisition and length of the target word, and visual complexity and image agreement of the stimulus picture were examined; the ability to predict response accuracy of a model simultaneously including these 5 variables was quantified by means of the McFadden index. Finally, the relationship between predictability (McFadden index) and consistency (Cohen's kappa) was analyzed. RESULTS: For 34 of 36 participants, consistency was higher than chance. Consistency was directly correlated to the prevalence of lexical-semantic errors. On regression analysis, the relationship between consistency and predictability was significant. CONCLUSIONS: Response consistency reflects the existence of a clear difficulty gradient within the items of a battery. The significant relationship between consistency and error type suggests that, in principle, lexical-semantic errors might be more predictable than phonological errors based on the characteristics of each stimulus. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Different variables predict anomia in different subjects: a longitudinal study of two Alzheimer's patients.

Two Alzheimer's patients participated in a longitudinal study of picture naming aimed at analysing the effect of lexical frequency, age of acquisition, stimulus familiarity, word length, name imageability, visual complexity and semantic category membership on naming success. The results were analysed with a new method [Capitani, E., & Laiacona, M. (2004). A method for studying the evolution of naming error types in the recovery of acute aphasia: A single-patient and single-stimulus approach. Neuropsychologia, 42, 613-623] that allows us to consider the consistency of responses to stimuli over repeated testing within clinical stages. The experiment was carried out as a longitudinal study of single cases, and the effect of each variable was estimated after removing the overlap with the other predictors. The semantic category of stimuli was not an influential factor for either patient. Other findings sharply distinguished between the two patients. In one case, disease-related decline consistently affected mainly late acquired names, whereas in the other case the decline affected names corresponding to low-familiarity items. To interpret this contrast, we further analysed the quality of the errors produced by each patient. This study shows that the psycholinguistic characteristics of a stimulus may exert varying influence in different patients, warranting further development of this line of inquiry.

Does sex influence the age of acquisition of common names? A contrast of different semantic categories.

The literature reports a sex-related asymmetry in the ability to process different semantic categories: women are more proficient with biological categories and men with man-made objects. The origin of this asymmetry is still debated. In this study, we directly checked whether the acquisition of names belonging to different semantic categories differs according to sex. We carried out our inquiry on 202 children aged 3-5 years, who were given a coloured picture naming task using a battery of 60 stimuli belonging to different semantic categories. Boys differed from girls only on naming of stimuli belonging to the categories of tools and vehicles, where they showed an earlier name acquisition. No sex differences were found for animals or plant life, notwithstanding evidence in the literature of an overrepresentation of males among patients affected by biological categories impairment. Our findings suggest that the male advantage for tools and vehicles reported in the literature on verbal fluency and naming tasks is strongly related to the earlier age in males of name acquisition for these categories, and possibly to their higher familiarity. On the contrary, the female advantage for plant life knowledge, which becomes evident later in life, has a still undefined nature and only a dubious relationship to familiarity, although it is sufficient to cause an overrepresentation of males among patients affected by a category specific impairment of biological categories, especially of plant life knowledge.

Recollection of public events in healthy people: a latent-variable stochastic approach to disentangling retrieval and storage.

Recollection of media-mediated past events was examined in 96 healthy participants to investigate the interaction between the age of the subject and the "age" of memories. The results provided evidence that people older than 75 years recall recent events significantly worse than remote ones. Younger participants (47-60 years old) showed the reverse pattern. The implementation of a Markov chains latent-variable stochastic model suggested that reduced efficiency of retrieval rather than storage processes accounts for these results. The findings were interpreted with reference to models of memory trace consolidation, assuming that memory for past public events is dependent on hippocampal structures.

Outer and inner tolerance limits: their usefulness for the construction of norms and the standardization of neuropsychological tests.

OBJECTIVES: After adjustment of scores for demographic variables, especially when test scales have an upper limit that causes a ceiling effect, the original score variability is deeply altered and the scale properties degenerate. We present a method for fixing normality thresholds on scores previously adjusted for demographic variables that overcomes these problems. METHODS: We suggest to fix norms using non-parametric tolerance limits. These limits, valid even for asymmetrical distributions and adjusted scores, can also be used as a basis for a non-parametric standardization of adjusted scores. Non-parametric tolerance limits permit to fix, with controlled risk, the threshold under which there is at most 5% of the normal population (outer tolerance limit); this approach also permits to fix, still with a stringent risk control, the inner tolerance limit, i.e. the threshold under which there is at least 5% of the normal population. Separate limits are needed to control not only against falsely declaring that an individual is 'not normal' (outer tolerance limit), but also against falsely declaring that an individual is 'normal' (inner tolerance limit). RESULTS: We provide examples of the calculations necessary and some tables useful for clinical practice, both for the normality judgment and for a standardization method called Equivalent Scores. CONCLUSIONS: This approach has been followed for about 80 neuropsychological tests studied in the Italian population. Besides the intrinsic value of this method, its extension to a wider audience of neuropsychologists could provide a way to gain from the experimental and clinical practice carried out in different countries.

Qualitative features of semantic fluency performance in mesial and lateral frontal patients.

Semantic verbal fluency is widely used in clinical and experimental studies. This task is highly sensitive to the presence of brain pathology and is frequently impaired after frontal lesions. Besides the total number of words generated, a qualitative analysis of their sequence can add valuable information about the impaired cognitive components. Thirty-four frontal patients and a group of matched controls were examined. Besides the number of words and subcategories retrieved by each group, we analysed two distinct aspects of the word sequence: the search strategy through a semantically organised store and the ability to switch from one subcategory to another. We checked whether the pattern of impairment changed according to the lesion site within the frontal lobe. Overall, patients produced fewer words than controls. However, only lateral frontal patients presented a reduced semantic relatedness between contiguously produced words and a specifically increased proportion of switches to different subcategories. The performance of lateral frontal patients was in line with the hypothesis of a search strategy impairment and cannot be attributed to a switching deficit. The performance of mesial frontal patients could be ascribed to a general deficit of activation.

Perseveration during verbal fluency in traumatic brain injury reflects impairments in working memory.

OBJECTIVE: Previous studies of verbal fluency have reported higher rates of perseverative responses in both Alzheimer's disease (AD) and traumatic brain injury (TBI) relative to control groups. These perseverations could arise from a number of impairments-for example, failures in working memory, inhibitory control, or word retrieval-and different clinical populations may show an increase in perseveration because of different underlying deficits. The objective of the current report is to investigate the cause of perseveration in verbal fluency in individuals with TBI and compare those results to a recent study of individuals with AD. METHOD: In a previous study, conducted by Miozzo, Fischer-Baum, and Caccappolo-van Vliet (2013), perseveration errors produced by individuals with AD were shown to have long lags between the 1st occurrence of a word and its repetition in verbal fluency, suggesting that perseverations were caused by a failure of the working memory mechanisms that control response monitoring. In the present investigation, we applied the same analysis to the perseveration errors produced during 197 administrations of the verbal fluency task with 143 individuals with TBI. RESULTS: The perseverations of individuals with TBI showed a lag distribution similar to that of the AD population, with the lag between the 1st occurrence of a word and its repetition systematically longer than would be expected by chance. CONCLUSIONS: These results suggest that the perseverations produced during verbal fluency in individuals with TBI stem from the same working memory mechanism proposed in AD, rather than inhibitory control or word retrieval deficits. (PsycINFO Database Record

The dissociability of lexical retrieval and morphosyntactic processes for nouns and verbs: A functional and anatomoclinical study.

Nouns and verbs can dissociate following brain damage, at both lexical retrieval and morphosyntactic processing levels. In order to document the range and the neural underpinnings of behavioral dissociations, twelve aphasics with disproportionate difficulty naming objects or actions were asked to apply phonologically identical morphosyntactic transformations to nouns and verbs. Two subjects with poor object naming and 2/10 with poor action naming made no morphosyntactic errors at all. Six of 10 subjects with poor action naming showed disproportionate or no morphosyntactic difficulties for verbs. Morphological errors on nouns and verbs correlated at the group level, but in individual cases a selective impairment of verb morphology was observed. Poor object and action naming with spared morphosyntax were associated with non-overlapping lesions (inferior occipitotemporal and fronto-temporal, respectively). Poor verb morphosyntax was observed with frontal-temporal lesions affecting white matter tracts deep to the insula, possibly disrupting the interaction of nodes in a fronto-temporal network.

Patterns of comprehension performance in agrammatic Broca's aphasia: a test of the Trace Deletion Hypothesis.

We tested the core prediction of the Trace Deletion Hypothesis (TDH) of agrammatic Broca's aphasia, which contends that such patients' comprehension performance is normal for active reversible sentences but at chance level for passive reversible sentences. We analyzed the comprehension performance of 38 Italian Broca's aphasics with verified damage to Broca's area, who completed sentence-to-picture matching tasks using active and passive reversible sentences as stimuli. The results failed to confirm the predictions made by TDH: only a small minority (15%) performed at chance on passive sentences and better than chance on active sentences. Furthermore, the distribution of the 38 subjects' performance on passive sentences differed from that predicted by the TDH since many more subjects performed at better-than-chance levels than expected. We discuss the implication of these results for claims about the distribution of language processing mechanisms in the brain.

A method for studying the evolution of naming error types in the recovery of acute aphasia: a single-patient and single-stimulus approach.

In this study, we present a method for analysing the evolution of picture naming errors in the follow-up of single patients affected by acute aphasia. In particular, we have based our analysis on the presence of response type inconsistency, as patients often fail to give the same type of response to the same stimulus at a task repetition attempted after a short time. Due to the uncertain definition of the type of response associated to a given stimulus for each stage of the clinical course, the investigation of the factors underlying the transition between different types of response is a serious methodological challenge. The solution presented here is based on a multiple presentation of the same naming battery at different stages of the clinical course, on the estimation of the probability associated with each response type at each stage, and on the estimation of the transition probability between different response types from one clinical stage to another. The basic idea was to use the set of probabilities referred to above as single stimuli weights in the study of linear models; these permit to compare different types of responses and different types of transitions. We present the application of this method to the study of a single case, a woman affected by fluent aphasia examined twice in the first 2 weeks following stroke. Besides discussing empirical findings, we comment on the usefulness of this method for wider fields of inquiry.