Maternal anxiety-driven modulation of fetal limbic connectivity designs a backbone linking neonatal brain functional topology to socio-emotional development in early childhood.

A link between maternal anxiety during pregnancy and adverse socio-emotional outcomes in childhood has been consistently sustained on the very early neurodevelopmental alteration of structural pathways between fetal limbic and cortical brain regions. In this study, we provide follow-up evidence for a feed-forward model linking (i) maternal anxiety, (ii) fetal functional neurodevelopment, (iii) neonatal functional network organization with (iv) socio-emotional neurobehavioral development in early childhood. Namely, we investigate a sample of 16 mother-fetus dyads and show how a maternal state-trait anxiety profile with pregnancy-specific worries can significantly influence functional synchronization patterns between regions of the fetal limbic system (i.e., hippocampus and amygdala) and the neocortex, as assessed through resting-state functional magnetic resonance imaging. Generalization of the findings was supported by leave-one-out cross-validation. We further show how this maternal-fetal cross-talk propagates to functional network topology in the neonate, specifically targeting connector hubs, and further maps onto socio-emotional profiles, assessed through Bayley-III socio-emotional scale in early childhood (i.e., in the 12-24 months range). Based on this evidence, we put forward the hypothesis of a "Maternal-Fetal-Neonatal Anxiety Backbone", through which neurobiological changes driven by maternal anxiety could trigger a divergence in the establishment of a cognitive-emotional development blueprint, in terms of the nascent functional homeostasis between bottom-up limbic and top-down higher-order neuronal circuitry.

The effects of the functional interplay between the Default Mode and Executive Control Resting State Networks on cognitive outcome in preterm born infants at 6 months of age.

Preterm birth can affect cognitive functions, such as attention or more generally executive control mechanisms, with severity in impairments proportional to prematurity. The functional cross-talk between the Default Mode (DMN) and Executive Control (ECN) networks mirrors the integrity of cognitive processing and is directly related to brain development. In this study, a cohort of 20 preterm-born infants was investigated using rs-fMRI. First, we addressed biological maturity of the DMN per se and its interplay with the ECN in terms of patterns of increased functional connectivity. Second, we assessed the impact of the degree of prematurity on the DMN-ECN functional interplay development in relation to cognitive outcome at six months. Our results highlighted the emergence of DMN in preterm neonates, with connectivity strength and synchronization between the anterior DMN hub and frontal areas increasing as a function of biological maturity. Further, cognitive scores at 6 months were predicted by mPFC-ECN connectivity strength with degree of prematurity impacting on mPFC-ECN connectivity and triggering differential patterns of functional maturation of the ECN for very early/early and moderate/late preterm neonates. Our findings suggest that the prematurity window allows to observe precursors of functional plasticity that may underlie different developmental trajectories in preterm children.

A hierarchical procedure to select intrauterine and extrauterine factors for methodological validation of preterm birth risk estimation.

BACKGROUND: Etiopathogenesis of preterm birth (PTB) is multifactorial, with a universe of risk factors interplaying between the mother and the environment. It is of utmost importance to identify the most informative factors in order to estimate the degree of PTB risk and trace an individualized profile. The aims of the present study were: 1) to identify all acknowledged risk factors for PTB and to select the most informative ones for defining an accurate model of risk prediction; 2) to verify predictive accuracy of the model and 3) to identify group profiles according to the degree of PTB risk based on the most informative factors. METHODS: The Maternal Frailty Inventory (MaFra) was created based on a systematic review of the literature including 174 identified intrauterine (IU) and extrauterine (EU) factors. A sample of 111 pregnant women previously categorized in low or high risk for PTB below 37 weeks, according to ACOG guidelines, underwent the MaFra Inventory. First, univariate logistic regression enabled p-value ordering and the Akaike Information Criterion (AIC) selected the model including the most informative MaFra factors. Second, random forest classifier verified the overall predictive accuracy of the model. Third, fuzzy c-means clustering assigned group membership based on the most informative MaFra factors. RESULTS: The most informative and parsimonious model selected through AIC included Placenta Previa, Pregnancy Induced Hypertension, Antibiotics, Cervix Length, Physical Exercise, Fetal Growth, Maternal Anxiety, Preeclampsia, Antihypertensives. The random forest classifier including only the most informative IU and EU factors achieved an overall accuracy of 81.08% and an AUC of 0.8122. The cluster analysis identified three groups of typical pregnant women, profiled on the basis of the most informative IU and EU risk factors from a lower to a higher degree of PTB risk, which paralleled time of birth delivery. CONCLUSIONS: This study establishes a generalized methodology for building-up an evidence-based holistic risk assessment for PTB to be used in clinical practice. Relevant and essential factors were selected and were able to provide an accurate estimation of degree of PTB risk based on the most informative constellation of IU and EU factors.

The left inferior frontal gyrus: A neural crossroads between abstract and concrete knowledge.

Evidence from both neuropsychology and neuroimaging suggests that different types of information are necessary for representing and processing concrete and abstract word meanings. Both abstract and concrete concepts, however, conjointly rely on perceptual, verbal and contextual knowledge, with abstract concepts characterized by low values of imageability (IMG) (low sensory-motor grounding) and low context availability (CA) (more difficult to contextualize). Imaging studies supporting differences between abstract and concrete concepts show a greater recruitment of the left inferior frontal gyrus (LIFG) for abstract concepts, which has been attributed either to the representation of abstract-specific semantic knowledge or to the request for more executive control than in the case of concrete concepts. We conducted an fMRI study on 27 participants, using a lexical decision task involving both abstract and concrete words, whose IMG and CA values were explicitly modelled in separate parametric analyses. The LIFG was significantly more activated for abstract than for concrete words, and a conjunction analysis showed a common activation for words with low IMG or low CA only in the LIFG, in the same area reported for abstract words. A regional template map of brain activations was then traced for words with low IMG or low CA, and BOLD regional time-series were extracted and correlated with the specific LIFG neural activity elicited for abstract words. The regions associated to low IMG, which were functionally correlated with LIFG, were mainly in the left hemisphere, while those associated with low CA were in the right hemisphere. Finally, in order to reveal which LIFG-related network increased its connectivity with decreases of IMG or CA, we conducted generalized psychophysiological interaction analyses. The connectivity strength values extracted from each region connected with the LIFG were correlated with specific LIFG neural activity for abstract words, and a regression analysis was conducted to highlight which areas recruited by low IMG or low CA predicted the greater activation of the IFG for abstract concepts. Only the left middle temporal gyrus/angular gyrus, known to be involved in semantic processing, was a significant predictor of LIFG activity differentiating abstract from concrete words. The results show that the abstract conceptual processing requires the interplay of multiple brain regions, necessary for both the intrinsic and extrinsic properties of abstract knowledge. The LIFG can be thus identified as the neural crossroads between different types of information equally necessary for representing processing and differentiating abstract concepts from concrete ones.

Semantic interference and its control: A functional neuroimaging and connectivity study.

During picture naming, the ease with which humans generate words is dependent upon the context in which they are named. For instances, naming previously presented items results in facilitation. Instead, naming a picture semantically related to previous items displays persistent interference effects (i.e., cumulative semantic interference, CSI). The neural correlates of CSI are still unclear and it is a matter of debate whether semantic control, or cognitive control more in general, is necessary for the resolution of CSI. We carried out an event-related fMRI experiment to assess the neural underpinnings of the CSI effect and the involvement and nature of semantic control. Both left inferior frontal gyrus (LIFG) and the left caudate nucleus (LCN) showed a linear increase of BOLD response positively associated with the consecutive number of presentations of semantically related pictures independently of task-load. The generalized psychophysiological interaction analysis showed that LIFG demonstrated a quantitative neural connectivity difference with the left supramarginal and angular gyri for increases of task-load and with the fusiform gyri for linear CSI increases. Furthermore, seed-to-voxel functional connectivity showed that LIFG activity coupled with different regions involved in cognitive control and lexicosemantic processing when semantic interference was elicited to a minimum or maximum degree. Our results are consistent with the lexical-competitive nature of the CSI effect, and we provide novel evidence that semantic control lies upon a more general cognitive control network (i.e., LIFG and LCN) responsible for resolving interference between competing semantically related items through connectivity with different brain areas in order to guarantee the correct response. Hum Brain Mapp 37:4179-4196, 2016. © 2016 Wiley Periodicals, Inc.

The neural representation of abstract words: the role of emotion.

It is generally assumed that abstract concepts are linguistically coded, in line with imaging evidence of greater engagement of the left perisylvian language network for abstract than concrete words (Binder JR, Desai RH, Graves WW, Conant LL. 2009. Where is the semantic system? A critical review and meta-analysis of 120 functional neuroimaging studies. Cerebral Cortex. 19:2767-2796; Wang J, Conder JA, Blitzer DN, Shinkareva SV. 2010. Neural representation of abstract and concrete concepts: A meta-analysis of neuroimaging studies. Hum Brain Map. 31:1459-1468). Recent behavioral work, which used tighter matching of items than previous studies, however, suggests that abstract concepts also entail affective processing to a greater extent than concrete concepts (Kousta S-T, Vigliocco G, Vinson DP, Andrews M, Del Campo E. The representation of abstract words: Why emotion matters. J Exp Psychol Gen. 140:14-34). Here we report a functional magnetic resonance imaging experiment that shows greater engagement of the rostral anterior cingulate cortex, an area associated with emotion processing (e.g., Etkin A, Egner T, Peraza DM, Kandel ER, Hirsch J. 2006. Resolving emotional conflict: A role for the rostral anterior cingulate cortex in modulating activity in the amygdala. Neuron. 52:871), in abstract processing. For abstract words, activation in this area was modulated by the hedonic valence (degree of positive or negative affective association) of our items. A correlation analysis of more than 1,400 English words further showed that abstract words, in general, receive higher ratings for affective associations (both valence and arousal) than concrete words, supporting the view that engagement of emotional processing is generally required for processing abstract words. We argue that these results support embodiment views of semantic representation, according to which, whereas concrete concepts are grounded in our sensory-motor experience, affective experience is crucial in the grounding of abstract concepts.

Optimizing Performance of Transformer-based Models for Fetal Brain MR Image Segmentation.

"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology: Artificial Intelligence. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content. Purpose To test transformer-based models' performance when manipulating pretraining weights, dataset size, input size and comparing the best-model with reference standard and state-of-the-art models for a resting-state functional (rs-fMRI) fetal brain extraction task. Materials and Methods An internal retrospective dataset (fetuses = 172; images = 519; collected from 2018-2022) was used to investigate influence of dataset size, pretraining approaches and image input size on Swin-UNETR and UNETR models. The internal and an external (fetuses = 131; images = 561) datasets were used to cross-validate and to assess generalization capability of the best model against state-of-the-art models on different scanner types and number of gestational weeks (GW). The Dice similarity coefficient (DSC) and the Balanced average Hausdorff distance (BAHD) were used as segmentation performance metrics. GEE multifactorial models were used to assess significant model and interaction effects of interest. Results Swin-UNETR was not affected by pretraining approach and dataset size and performed best with the mean dataset image size, with a mean DSC of 0.92 and BAHD of 0.097. The Swin-UNETR was not affected by scanner type. Generalization results on the internal dataset showed that Swin-UNETR had lower performances compared with reference standard models and comparable performances on the external dataset. Cross-validation on internal and external test sets demonstrated better and comparable performance of Swin-UNETR versus convolutional neural network architectures during the late-fetal period (GWs > 25) but lower performance during the midfetal period (GWs ≤ 25). Conclusion Swin-UNTER showed flexibility in dealing with smaller datasets, regardless of pretraining approaches. For fetal brain extraction of rs-fMRI, Swin-UNTER showed comparable performance with reference standard models during the late-fetal period and lower performance during the early GW period. ©RSNA, 2024.

Increased interhemispheric functional connectivity after right anodal tDCS in chronic non-fluent aphasia: preliminary findings.

Introduction: Anodal transcranial Direct Current Stimulation (tDCS) is a non-invasive, low-cost and environment-friendly brain neuromodulation technique that increases cortical excitability. In post-stroke aphasia, the role of the right hemisphere in language recovery remains debated. In this preliminary study, we aimed to investigate the efficacy of excitatory tDCS on the right hemisphere in chronic aphasic patients. Methods: We applied anodal tDCS to the right homologous region of Broca's area in four chronic aphasic patients while performing a one-month naming rehabilitation treatment. Longitudinal data on language assessment and naming performance were collected. Resting-state fMRI images were acquired before and after treatment to measure changes in functional connectivity. Results: Results showed enhanced positive functional connectivity of the right Broca homologous with the left middle frontal and middle temporal gyri. Every patient showed improvements in language functions, but no major changes in naming performance. Conclusion: These preliminary findings suggest that tDCS applied over the unaffected hemisphere may result in longitudinal inter-hemispheric functional neuroplastic changes that could specifically improve language recovery and could potentially be included in therapeutic neurorehabilitative plans.

Bilingualism tunes the anterior cingulate cortex for conflict monitoring.

Monitoring and controlling 2 language systems is fundamental to language use in bilinguals. Here, we reveal in a combined functional (event-related functional magnetic resonance imaging) and structural neuroimaging (voxel-based morphometry) study that dorsal anterior cingulate cortex (ACC), a structure tightly bound to domain-general executive control functions, is a common locus for language control and resolving nonverbal conflict. We also show an experience-dependent effect in the same region: Bilinguals use this structure more efficiently than monolinguals to monitor nonlinguistic cognitive conflicts. They adapted better to conflicting situations showing less ACC activity while outperforming monolinguals. Importantly, for bilinguals, brain activity in the ACC, as well as behavioral measures, also correlated positively with local gray matter volume. These results suggest that early learning and lifelong practice of 2 languages exert a strong impact upon human neocortical development. The bilingual brain adapts better to resolve cognitive conflicts in domain-general cognitive tasks.

Continuity of care for patients with dementia during COVID-19 pandemic: flexibility and integration between in-person and remote visits.

Introduction: During the pandemic, the Cognitive Disorders Unit of San Raffaele Hospital (Milan, Italy) offered patients the opportunity to undergo neuropsychological evaluations and cognitive training through telemedicine. Method: We conducted an investigation to assess how patients responded to this option and to determine if telemedicine could ensure continuity of care. Results: Between October 2019 and May 2022, a total of 5,768 telemedicine appointments and 8,190 in-person outpatient appointments were conducted, resulting in an increase in the rate of telemedicine activity from 16.81% in January 2020 to 23.21% in May 2022. Peaks in telemedicine activity reached 85.64% in May 2020 and 83.65% in February 2021, both representing a significant portion of the total activity. Interestingly, there was a notable positive correlation between telemedicine activity and the worsening of the Italian pandemic (r = 0.433, p = 0.027). Discussion: During the peaks of contagion, the total number of visits remained stable, highlighting that telemedicine effectively served as a valuable and efficient tool to ensure continuity of care for vulnerable patients. This was evident from the integration of remote visits with in-person appointments.

In search of different categories of abstract concepts: a fMRI adaptation study.

Concrete conceptual knowledge is supported by a distributed neural network representing different semantic features according to the neuroanatomy of sensory and motor systems. If and how this framework applies to abstract knowledge is currently debated. Here we investigated the specific brain correlates of different abstract categories. After a systematic a priori selection of brain regions involved in semantic cognition, i.e. responsible of, respectively, semantic representations and cognitive control, we used a fMRI-adaptation paradigm with a passive reading task, in order to modulate the neural response to abstract (emotions, cognitions, attitudes, human actions) and concrete (biological entities, artefacts) categories. Different portions of the left anterior temporal lobe responded selectively to abstract and concrete concepts. Emotions and attitudes adapted the left middle temporal gyrus, whereas concrete items adapted the left fusiform gyrus. Our results suggest that, similarly to concrete concepts, some categories of abstract knowledge have specific brain correlates corresponding to the prevalent semantic dimensions involved in their representation.

Uncertain Effectiveness of Prophylactic Anticonvulsive Medication in Predicting Cognitive Outcome of Neurosurgical Patients.

OBJECTIVES: To evaluate the influence of prophylactic anticonvulsive medication, above all levetiracetam monotherapy, in predicting the cognitive outcome of neurosurgical patients with post-traumatic brain injury, intracerebral hemorrhage, and encephalic tumors. METHODS: We examined data concerning 232 of 327 adult patients admitted to the Neurorehabilitation Department of the San Raffaele Hospital (Milan, Italy) after discharge from the Neurosurgery Department. Cognitive status was evaluated by means of the "Mini-Mental State" examination and the Functional Independence Measure at baseline and at the end of a rehabilitation care with an average duration of about four weeks. RESULTS: The vast majority of the patients were treated with levetiracetam. Our data showed a negative role of antiepileptic drugs on cognitive recovery in a cohort of neurosurgical patients. CONCLUSIONS: Knowing thoroughly the effects of antiepileptic drugs in rehabilitation outcome is of fundamental importance. This study represents the only large series analyzing these aspects in the rehabilitation of neurosurgical patients. Antiepileptic drugs should be managed to ensure patients the best possible cognitive outcome. Further evidence from good-quality trials is required to assess the clinical effectiveness of prophylactic anticonvulsive medication in predicting the cognitive outcome of neurosurgical patients who are treated with rehabilitation.

Anterior cingulate cortex sulcation and its differential effects on conflict monitoring in bilinguals and monolinguals.

The role of the anterior cingulate cortex (ACC) in modulating the effect of bilingual experience on cognitive control has been reported at both functional and structural neural levels. Individual differences in the ACC sulcal patterns have been recently correlated with cognitive control efficiency in monolinguals. We aimed to investigate whether differences of ACC sulcation mediate the effect of bilingualism on cognitive control efficiency. We contrasted the performance of bilinguals and monolinguals during a cognitive control task (i.e., the Flanker Task) using a stratification based on the participants' ACC sulcal features. We found that performance of the two groups was differentially affected by ACC sulcation. Our findings provide the first evidence that early neurodevelopmental mechanisms may modulate the effect of different environmental backgrounds - here, bilingual vs monolingual experience - on cognitive efficiency.

Statistical Voxel-Based Methods and [18F]FDG PET Brain Imaging: Frontiers for the Diagnosis of AD.

Recommended guidelines for the diagnosis of dementia due to Alzheimer's Disease (AD) were revised in recent years, including Positron Emission Tomography (PET) as an in-vivo diagnostic imaging technique for the diagnosis of neurodegeneration. In particular PET, using 18Ffluorodeoxiglucouse ([18F]FDG), is able to detect very early changes of glucose consumption at the synaptic level, enabling to support both early and differential diagnosis of AD. In standard clinical practice, interpretation of [18F] FDG-PET images is usually achieved through qualitative assessment. Visual inspection although only reveals information visible at human eyes resolution, while information at a higher resolution is missed. Furthermore, qualitative assessment depends on the degree of expertise of the clinician, preventing from the definition of accurate and standardized imaging biomarkers. Automated and computerized image processing methods have been proposed to support the in-vivo assessment of brain PET studies. In particular, objective statistical image analyses, enabling the comparison of one patient's images to a group of control images have been shown to carry important advantages for detecting significant metabolic changes, including the availability of more objective, cross-center reliable metrics and the detectability of brain subtle functional changes, as occurring in prodromal AD. The purpose of the current review is to provide a systematic overview encompassing the frontiers recently reached by quantitative approaches for the statistical analysis of PET brain images in the study of AD, with a particular focus on Statistical Parametric Mapping. Main achievements, e.g. in terms of standardized biomarkers of AD as well as of sensitivity and specificity, will be discussed.

Brain changes within the visuo-spatial attentional network in posterior cortical atrophy.

Posterior cortical atrophy (PCA) is characterized by basic visual and high order visual-spatial dysfunctions. In this study, we investigated long-distance deafferentation processes within the frontal-parietal-occipital network in ten PCA patients using a MRI-PET combined approach. Objective voxel-based [18F]FDG-PET imaging measured metabolic changes in single patients. Comprehensive investigation of diffusion tensor imaging (DTI) metrics and grey-matter density with voxel-based morphometry were obtained in a subgroup of 6 patients. Fractional anisotropy in the superior longitudinal fasciculus correlated with the PET metabolic changes within the inferior parietal and frontal eye field regions. [18F]FDG-PET analysis showed in each PCA case the typical bilateral hypometabolic pattern, involving posterior temporal, parietal, and occipital cortex, with additional hypometabolic foci in the frontal eye fields. Voxel-based morphometry showed right-sided atrophy in the parieto-occipital cortex, as well as a limited temporal involvement. DTI revealed extensive degeneration of the major anterior-posterior connecting fiber bundles and of commissural frontal lobe tracts. Microstructural measures in the superior longitudinal fasciculus were correlated with the PET metabolic changes within the inferior parietal and frontal eye field regions. Our results confirmed the predominant occipital-temporal and occipital-parietal degeneration in PCA patients. [18F]FDG-PET and DTI-MRI combined approaches revealed neurodegeneration effects well beyond the classical posterior cortical involvement, most likely as a consequence of deafferentation processes within the occipital-parietal-frontal network that could be at the basis of visuo-perceptual, visuo-spatial integration and attention deficits in PCA.

Brain metabolic maps in Mild Cognitive Impairment predict heterogeneity of progression to dementia.

[(18)F]FDG-PET imaging has been recognized as a crucial diagnostic marker in Mild Cognitive Impairment (MCI), supporting the presence or the exclusion of Alzheimer's Disease (AD) pathology. A clinical heterogeneity, however, underlies MCI definition. In this study, we aimed to evaluate the predictive role of single-subject voxel-based maps of [(18)F]FDG distribution generated through statistical parametric mapping (SPM) in the progression to different dementia subtypes in a sample of 45 MCI. Their scans were compared to a large normal reference dataset developed and validated for comparison at single-subject level. Additionally, Aß42 and Tau CSF values were available in 34 MCI subjects. Clinical follow-up (mean 28.5 ± 7.8 months) assessed subsequent progression to AD or non-AD dementias. The SPM analysis showed: 1) normal brain metabolism in 14 MCI cases, none of them progressing to dementia; 2) the typical temporo-parietal pattern suggestive for prodromal AD in 15 cases, 11 of them progressing to AD; 3) brain hypometabolism suggestive of frontotemporal lobar degeneration (FTLD) subtypes in 7 and dementia with Lewy bodies (DLB) in 2 subjects (all fulfilled FTLD or DLB clinical criteria at follow-up); and 4) 7 MCI cases showed a selective unilateral or bilateral temporo-medial hypometabolism without the typical AD pattern, and they all remained stable. In our sample, objective voxel-based analysis of [(18)F]FDG-PET scans showed high predictive prognostic value, by identifying either normal brain metabolism or hypometabolic patterns suggestive of different underlying pathologies, as confirmed by progression at follow-up. These data support the potential usefulness of this SPM [(18)F]FDG PET analysis in the early dementia diagnosis and for improving subject selection in clinical trials based on MCI definition.

The semantic variant of primary progressive aphasia: clinical and neuroimaging evidence in single subjects.

BACKGROUND/AIM: We present a clinical-neuroimaging study in a series of patients with a clinical diagnosis of semantic variant of primary progressive aphasia (svPPA), with the aim to provide clinical-functional correlations of the cognitive and behavioral manifestations at the single-subject level. METHODS: We performed neuropsychological investigations, 18F-FDG-PET single-subject and group analysis, with an optimized SPM voxel-based approach, and correlation analyses. A measurement of white matter integrity by means of diffusion tensor imaging (DTI) was also available for a subgroup of patients. RESULTS: Cognitive assessment confirmed the presence of typical semantic memory deficits in all patients, with a relative sparing of executive, attentional, visuo-constructional, and episodic memory domains. 18F-FDG-PET showed a consistent pattern of cerebral hypometabolism across all patients, which correlated with performance in semantic memory tasks. In addition, a majority of patients also presented with behavioral disturbances associated with metabolic dysfunction in limbic structures. In a subgroup of cases the DTI analysis showed FA abnormalities in the inferior longitudinal and uncinate fasciculi. DISCUSSION: Each svPPA individual had functional derangement involving an extended, connected system within the left temporal lobe, a crucial part of the verbal semantic network, as well as an involvement of limbic structures. The latter was associated with behavioral manifestations and extended beyond the area of atrophy shown by CT scan. CONCLUSION: Single-subject 18F-FDG-PET analysis can account for both cognitive and behavioral alterations in svPPA. This provides useful support to the clinical diagnosis.

Simultaneous PET-MRI Studies of the Concordance of Atrophy and Hypometabolism in Syndromic Variants of Alzheimer's Disease and Frontotemporal Dementia: An Extended Case Series.

BACKGROUND: Simultaneous PET-MRI is used to compare patterns of cerebral hypometabolism and atrophy in six different dementia syndromes. OBJECTIVES: The primary objective was to conduct an initial exploratory study regarding the concordance of atrophy and hypometabolism in syndromic variants of Alzheimer's disease (AD) and frontotemporal dementia (FTD). The secondary objective was to determine the effect of image analysis methods on determination of atrophy and hypometabolism. METHOD: PET and MRI data were acquired simultaneously on 24 subjects with six variants of AD and FTD (n = 4 per group). Atrophy was rated visually and also quantified with measures of cortical thickness. Hypometabolism was rated visually and also quantified using atlas- and SPM-based approaches. Concordance was measured using weighted Cohen's kappa. RESULTS: Atrophy-hypometabolism concordance differed markedly between patient groups; kappa scores ranged from 0.13 (nonfluent/agrammatic variant of primary progressive aphasia, nfvPPA) to 0.49 (posterior cortical variant of AD, PCA). Heterogeneity was also observed within groups; the confidence intervals of kappa scores ranging from 0-0.25 for PCA to 0.29-0.61 for nfvPPA. More widespread MRI and PET changes were identified using quantitative methods than on visual rating. CONCLUSION: The marked differences in concordance identified in this initial study may reflect differences in the molecular pathologies underlying AD and FTD syndromic variants but also operational differences in the methods used to diagnose these syndromes. The superior ability of quantitative methodologies to detect changes on PET and MRI, if confirmed on larger cohorts, may favor their usage over qualitative visual inspection in future clinical diagnostic practice.

How to assess abstract conceptual knowledge: construction, standardization and validation of a new battery of semantic memory tests.

The neuropsychological investigation of semantic memory has mainly focused on concrete concepts, while abstract concepts have been relatively neglected. We describe a new battery for assessing abstract concepts in brain-damaged patients. The battery includes three different tests: an association task, a multiplechoice naming-to-description task and a sentence completion task. The three tasks are based on the same 40 stimuli belonging to different categories of abstract concepts and they are tightly controlled for variables that can account for quantitative differences between abstract concepts (i.e. concreteness, imageability, context availability, familiarity, age of acquisition, mode of acquisition, emotional valence and arousal). The three tasks showed high reliability. Normative data were collected from 108 healthy Italian adults. To assess its sensitivity, the battery was administered to 13 patients with probable Alzheimer's disease who performed worse than matched controls. Significant correlations were also found between the tests and other semantic memory tests, supporting the validity of the battery.

Integration of mRNA expression profile, copy number alterations, and microRNA expression levels in breast cancer to improve grade definition.

Defining the aggressiveness and growth rate of a malignant cell population is a key step in the clinical approach to treating tumor disease. The correct grading of breast cancer (BC) is a fundamental part in determining the appropriate treatment. Biological variables can make it difficult to elucidate the mechanisms underlying BC development. To identify potential markers that can be used for BC classification, we analyzed mRNAs expression profiles, gene copy numbers, microRNAs expression and their association with tumor grade in BC microarray-derived datasets. From mRNA expression results, we found that grade 2 BC is most likely a mixture of grade 1 and grade 3 that have been misclassified, being described by the gene signature of either grade 1 or grade 3. We assessed the potential of the new approach of integrating mRNA expression profile, copy number alterations, and microRNA expression levels to select a limited number of genomic BC biomarkers. The combination of mRNA profile analysis and copy number data with microRNA expression levels led to the identification of two gene signatures of 42 and 4 altered genes (FOXM1, KPNA4, H2AFV and DDX19A) respectively, the latter obtained through a meta-analytical procedure. The 42-based gene signature identifies 4 classes of up- or down-regulated microRNAs (17 microRNAs) and of their 17 target mRNA, and the 4-based genes signature identified 4 microRNAs (Hsa-miR-320d, Hsa-miR-139-5p, Hsa-miR-567 and Hsa-let-7c). These results are discussed from a biological point of view with respect to pathological features of BC. Our identified mRNAs and microRNAs were validated as prognostic factors of BC disease progression, and could potentially facilitate the implementation of assays for laboratory validation, due to their reduced number.