Different types of abstract concepts: evidence from two neurodegenerative patients.

The observation of neurological patients showing selective impairments for specific conceptual categories contributed in the development of semantic memory theories. Here, we studied two patients (P01, P02), affected, respectively, by the semantic variant of Primary Progressive Aphasia (sv-PPA) and Cortico-Basal Syndrome (CBS). An implicit lexical decision task, including concrete (animals, tools) and abstract (emotions, social, quantity) concepts, was administered to patients and healthy controls.P01 and P02 showed an abolished priming effect for social and quantity-related concepts, respectively. This double dissociation suggests a role of different brain areas in representing specific abstract categories, giving insights for current semantic memory theories.

The multidimensionality of abstract concepts: A systematic review.

The neuroscientific study of conceptual representation has largely focused on categories of concrete entities (biological entities, tools…), while abstract knowledge has been less extensively investigated. The possible presence of a categorical organization of abstract knowledge is a debated issue. An embodied cognition framework predicts an organization of the abstract domain into different dimensions, grounded in the brain regions engaged by the corresponding experience. Here we review the types of experience that have been proposed to characterize different categories of abstract concepts, and the evidence supporting a corresponding organization derived from behavioural, neuroimaging (i.e., fMRI, MRI, PET, SPECT), EEG, and neurostimulation (i.e., TMS) studies in healthy and clinical populations. The available data provide substantial converging evidence in favour of the presence of distinct neural representations of social and emotional knowledge, mental states and magnitude concepts, engaging brain systems involved in the corresponding experiences. This evidence is supporting an extension of embodied models of semantic memory organization to several types of abstract knowledge.

Early diagnosis of Alzheimer's disease: the role of biomarkers including advanced EEG signal analysis. Report from the IFCN-sponsored panel of experts.

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly with a progressive decline in cognitive function significantly affecting quality of life. Both the prevalence and emotional and financial burdens of AD on patients, their families, and society are predicted to grow significantly in the near future, due to a prolongation of the lifespan. Several lines of evidence suggest that modifications of risk-enhancing life styles and initiation of pharmacological and non-pharmacological treatments in the early stage of disease, although not able to modify its course, helps to maintain personal autonomy in daily activities and significantly reduces the total costs of disease management. Moreover, many clinical trials with potentially disease-modifying drugs are devoted to prodromal stages of AD. Thus, the identification of markers of conversion from prodromal form to clinically AD may be crucial for developing strategies of early interventions. The current available markers, including volumetric magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebral spinal fluid (CSF) analysis are expensive, poorly available in community health facilities, and relatively invasive. Taking into account its low cost, widespread availability and non-invasiveness, electroencephalography (EEG) would represent a candidate for tracking the prodromal phases of cognitive decline in routine clinical settings eventually in combination with other markers. In this scenario, the present paper provides an overview of epidemiology, genetic risk factors, neuropsychological, fluid and neuroimaging biomarkers in AD and describes the potential role of EEG in AD investigation, trying in particular to point out whether advanced analysis of EEG rhythms exploring brain function has sufficient specificity/sensitivity/accuracy for the early diagnosis of AD.

Italian consensus recommendations for a biomarker-based aetiological diagnosis in mild cognitive impairment patients.

BACKGROUND AND PURPOSE: Biomarkers support the aetiological diagnosis of neurocognitive disorders in vivo. Incomplete evidence is available to drive clinical decisions; available diagnostic algorithms are generic and not very helpful in clinical practice. The aim was to develop a biomarker-based diagnostic algorithm for mild cognitive impairment patients, leveraging on knowledge from recognized national experts. METHODS: With a Delphi procedure, experienced clinicians making variable use of biomarkers in clinical practice and representing five Italian scientific societies (neurology - Società Italiana di Neurologia per le Demenze; neuroradiology - Associazione Italiana di Neuroradiologia; biochemistry - Società Italiana di Biochimica Clinica; psychogeriatrics - Associazione Italiana di Psicogeriatria; nuclear medicine - Associazione Italiana di Medicina Nucleare) defined the theoretical framework, relevant literature, the diagnostic issues to be addressed and the diagnostic algorithm. An N-1 majority defined consensus achievement. RESULTS: The panellists chose the 2011 National Institute on Aging and Alzheimer's Association diagnostic criteria as the reference theoretical framework and defined the algorithm in seven Delphi rounds. The algorithm includes baseline clinical and cognitive assessment, blood examination, and magnetic resonance imaging with exclusionary and inclusionary roles; dopamine transporter single-photon emission computed tomography (if no/unclear parkinsonism) or metaiodobenzylguanidine cardiac scintigraphy for suspected dementia with Lewy bodies with clear parkinsonism (round VII, votes (yes-no-abstained): 3-1-1); 18 F-fluorodeoxyglucose positron emission tomography for suspected frontotemporal lobar degeneration and low diagnostic confidence of Alzheimer's disease (round VII, 4-0-1); cerebrospinal fluid for suspected Alzheimer's disease (round IV, 4-1-0); and amyloid positron emission tomography if cerebrospinal fluid was not possible/accepted (round V, 4-1-0) or inconclusive (round VI, 5-0-0). CONCLUSIONS: These consensus recommendations can guide clinicians in the biomarker-based aetiological diagnosis of mild cognitive impairment, whilst guidelines cannot be defined with evidence-to-decision procedures due to incomplete evidence.

Involvement of TLR6 in the induction of COX-2, PGE2 and IL-10 in macrophages by lipids from virulent S2P and attenuated R1A Babesia bovis strains.

Toll like receptors (TLRs) are involved in the modulation of diverse host genes expression through a complex network of signalling events that allow for an appropriate response to a microbial pathogen. In the present work we used TLR6KO mice in order to study the role of TLR6 in the immune discrimination of lipids from two Babesia bovis strains, attenuated R1A (LA) and virulent S2P (LV), and the consequent macrophage activation. We demonstrated that TLR6 is required for lipid body induction in murine peritoneal macrophages by both LA and LV. Interestingly, as regards IL-10 and COX-2/PGE2 pathway induction by LA and LV, we observed differences in the biological effects produced by these lipid extracts. Our results indicate a role of TLR6 in the down-modulation of these immunoregulators only in the case of LA, whereas this receptor was not implicated in pro-inflammatory TNFα, IL-6 and KC release induced by LA. Remarkably, LV did not exert the down-modulatory effect observed for LA, supporting the notion that LA and LV possess different lipid composition that could correlate with the polar pathogenic effect of both B. bovis strains.

An updated Italian normative dataset for the Stroop color word test (SCWT).

The Stroop color and word test (SCWT) is widely used to evaluate attention, information processing speed, selective attention, and cognitive flexibility. Normative values for the Italian population are available only for selected age groups, or for the short version of the test. The aim of this study was to provide updated normal values for the full version, balancing groups across gender, age decades, and education. Two kinds of indexes were derived from the performance of 192 normal subjects, divided by decade (from 20 to 90) and level of education (4 levels: 3-5; 6-8; 9-13; >13 years). They were (i) the correct answers achieved for each table in the first 30 s (word items, WI; color items, CI; color word items, CWI) and (ii) the total time required for reading the three tables (word time, WT; color time, CT; color word time, CWT). For each index, the regression model was evaluated using age, education, and gender as independent variables. The normative data were then computed following the equivalent scores method. In the regression model, age and education significantly influenced the performance in each of the 6 indexes, whereas gender had no significant effect. This study confirms the effect of age and education on the main indexes of the Stroop test and provides updated normative data for an Italian healthy population, well balanced across age, education, and gender. It will be useful to Italian researchers studying attentional functions in health and disease.

A normative study of the Italian printed word version of the free and cued selective reminding test.

According to the new research criteria for the diagnosis of Alzheimer's disease, episodic memory impairment, not significantly improved by cueing, is the core neuropsychological marker, even at a pre-dementia stage. The FCSRT assesses verbal learning and memory using semantic cues and is widely used in Europe. Standardization values for the Italian population are available for the colored picture version, but not for the 16-item printed word version. In this study, we present age- and education-adjusted normative data for FCSRT-16 obtained using linear regression techniques and generalized linear model, and critical values for classifying sub-test performance into equivalent scores. Six scores were derived from the performance of 194 normal subjects (MMSE score, range 27-30, mean 29.5 ± 0.5) divided per decade (from 20 to 90), per gender and per level of education (4 levels: 3-5, 6-8, 9-13, >13 years): immediate free recall (IFR), immediate total recall (ITR), recognition phase (RP), delayed free recall (DFR), delayed total recall (DTR), Index of Sensitivity of Cueing (ISC), number of intrusions. This study confirms the effect of age and education, but not of gender on immediate and delayed free and cued recall. The Italian version of the FCSRT-16 can be useful for both clinical and research purposes.

Motor neuron dysfunctions in the frontotemporal lobar degeneration spectrum: a clinical and neurophysiological study.

BACKGROUND: Although only a few frontotemporal lobar degeneration (FTLD) patients develop frank amyotrophic lateral sclerosis (ALS), motor neuron dysfunctions (MNDys) occur in a larger proportion of patients. The aim of this study is to evaluate MNDys and ALS in a sample of consecutively enrolled sporadic FTLD patients. METHODS: Clinical and neurophysiological evaluations (i.e. needle electromyography) assessed lower (LMN) and upper (UMN) motor neuron function at the baseline in 70 probable FTLD patients (i.e., 26 behavioural variant-bvFTD, 20 primary progressive aphasias-PPAs and 24 corticobasal syndrome-CBS). To obtain a more accurate estimation, quantitative scales were also applied (i.e. ALSFRS-r and UMN scale). Patients were screened for MAPT, GRN and C9orf72 mutations. A mean clinical follow-up of 27.8±22.4 months assessed MNDys progression and the clinical presentation of ALS. RESULTS: Five genetic cases were identified. Within the sample of sporadic patients, a relative low rate of FTLD patients was diagnosed as probable ALS (5%), while a higher proportion of patients (17%) showed clinical and neurophysiological MNDys. Thirteen patients (20%) presented with isolated clinical signs of LMN and/or UMN dysfunction, and 8 patients (12%) showed neurogenic changes at the electromyography. No differences in FTLD phenotype and disease duration were found between MNDys positive and negative patients. Clinical MNDys were highly associated with positive electromyographic findings. At follow-up, no MNDys positive patient developed ALS. CONCLUSION: Neurophysiological and clinical examinations revealed mild MNDys in FTLD patients not fulfilling criteria for ALS. This condition did not evolve at a mean follow-up of two years. These results, indicating a subclinical degeneration of corticospinal tracts and lower motor neurons, suggest that FTLD patients may be more at risk of MNDys than the general population.

Italian Frontotemporal Dementia Network (FTD Group-SINDEM): sharing clinical and diagnostic procedures in Frontotemporal Dementia in Italy.

In the prospect of improved disease management and future clinical trials in Frontotemporal Dementia, it is desirable to share common diagnostic procedures. To this aim, the Italian FTD Network, under the aegis of the Italian Neurological Society for Dementia, has been established. Currently, 85 Italian Centers involved in dementia care are part of the network. Each Center completed a questionnaire on the local clinical procedures, focused on (1) clinical assessment, (2) use of neuroimaging and genetics; (3) support for patients and caregivers; (4) an opinion about the prevalence of FTD. The analyses of the results documented a comprehensive clinical and instrumental approach to FTD patients and their caregivers in Italy, with about 1,000 newly diagnosed cases per year and 2,500 patients currently followed by the participating Centers. In analogy to other European FTD consortia, future aims will be devoted to collect data on epidemiology of FTD and its subtypes and to provide harmonization of procedures among Centers.

An improved DNA isolation technique for PCR detection of Strongyloides stercoralis in stool samples.

Strongyloides stercoralis is a nematode that causes severe infections in immunocompromised patients. The low parasitic burden of chronically infected patients makes diagnosis difficult to achieve by conventional methods. Here, an in-house (IH) method for the isolation of parasite DNA from stools and a PCR assay for the molecular diagnosis of S. stercoralis were optimized. DNA yield and purity improved with the IH method which included a step of incubation of stool samples with a glycine-SDS buffer and mechanical disruption prior to DNA extraction. For the PCR assay, the addition of bovine serum albumin was required to neutralize inhibitors present in stool. The analytical sensitivity of the PCR using DNA as template, isolated with the IH method, was superior to the commercial one. This study demonstrates that a combined method that adds the step of glycine-SDS buffer incubation plus mechanical disruption prior to DNA isolation with the commercial kit increased PCR sensitivity to levels of the IH method. Finally, our assay was tested on 17 clinical samples. With the IH method for DNA isolation, a S. stercoralis specific band was detected by PCR in the first stool sample in all patients (17/17), while with the commercial kit, our S. stercoralis-specific band was only observed in 7 samples. The superior efficiency of the IH and combined methods over the commercial kit was demonstrated when applied to clinical samples with low parasitic burden. These results show that the DNA extraction procedure is a key to increase sensitivity of the S. stercoralis PCR assay in stool samples. The method developed here could help to improve the molecular diagnosis of S. stercoralis.

Babesia bovis: lipids from virulent S2P and attenuated R1A strains trigger differential signalling and inflammatory responses in bovine macrophages.

The intra-erythrocytic protozoan Babesia bovis is an economically important pathogen that causes an acute and often fatal infection in adult cattle. Babesiosis limitation depends on the early activation of macrophages, essential cells of the host innate immunity, which can generate an inflammatory response mediated by cytokines and nitric oxide (NO). Herein, we demonstrate in bovine macrophages that lipids from B. bovis attenuated R1A strain (LA) produced a stronger NO release, an early TNFα mRNA induction and 2-fold higher IL-12p35 mRNA levels compared to the lipids of virulent S2P strain (LV). Neither LA nor LV induced anti-inflammatory IL-10. Regarding signalling pathways, we here report that LA induced a significant phosphorylation of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2) whereas LV only induced a reduced activation of ERK1/2. Besides, NF-κB was activated by LA and LV, but LA produced an early degradation of the inhibitor IκB. Interestingly, LV and the majority of its lipid fractions, exerted a significant inhibition of concanavalin A-induced peripheral blood mononuclear cell proliferation with respect to LA and its corresponding lipid fractions. In addition, we determined that animals infected with R1A developed a higher increase in IgM anti-phosphatidylcholine than those inoculated with S2P. Collectively, S2P lipids generated a decreased inflammatory response contributing to the evasion of innate immunity. Moreover, since R1A lipids induced a pro-inflammatory profile, we propose these molecules as good candidates for immunoprophylactic strategies against babesiosis.

Action-related semantic content and negation polarity modulate motor areas during sentence reading: an event-related desynchronization study.

Our study evaluated motor cortex involvement during silent reading of sentences referring to hand actions. We aimed at defining whether sentential polarity (affirmative vs. negative) would modulate motor cortex activation using the event-related desynchronization (ERD) analysis of the mu rhythm. Eleven healthy volunteers performed a reading task involving 160 sentences (80 affirmative: 40 hand-related, 40 abstract; 80 negative: 40 hand-related, 40 abstract). After reading each sentence, subjects had to decide whether the verb was high or low frequency in Italian. Electroencephalographic (EEG) activity was recorded with 32 surface electrodes and mu ERD analyses were performed for each subject. Hand-action related sentences induced a greater mu ERD over the left premotor and motor hand areas compared to abstract sentences. Mu ERD was greater and temporally delayed when the hand-related verbs were presented in the negative versus affirmative form. As predicted by the "embodied semantic" theory of language understanding, motor areas were activated during sentences referring to hand actions. In addition, motor cortex activation was larger for negative than affirmative motor sentences, a finding compatible with the hypothesis that comprehension is more demanding in the specific case of motor content negation.

White matter damage in frontotemporal lobar degeneration spectrum.

White matter (WM) tract damage was assessed in patients with the behavioral variant frontotemporal dementia (bvFTD) and the 3 primary progressive aphasia (PPA) variants and compared with the corresponding brain atrophy patterns. Thirteen bvFTD and 20 PPA patients were studied. Tract-based spatial statistics and voxel-based morphometry were used. Patients with bvFTD showed widespread diffusion tensor magnetic resonance imaging (DT MRI) abnormalities affecting most of the WM bilaterally. In PPA patients, WM damage was more focal and varied across the 3 syndromes: left frontotemporoparietal in nonfluent, left frontotemporal in semantic, and left frontoparietal in logopenic patients. In each syndrome, DT MRI changes extended beyond the topography of gray matter loss. Left uncinate damage was the best predictor of frontotemporal lobar degeneration diagnosis versus controls. DT MRI measures of the anterior corpus callosum and left superior longitudinal fasciculus differentiated bvFTD from nonfluent cases. The best predictors of semantic PPA compared with both bvFTD and nonfluent cases were diffusivity abnormalities of the left uncinate and inferior longitudinal fasciculus. This study provides insights into the similarities and differences of WM damage in bvFTD and PPA variants. DT MRI metrics hold promise to serve as early markers of WM integrity loss that only at a later stage may be detectable by volumetric measures.

Education and occupation provide reserve in both ApoE ε4 carrier and noncarrier patients with probable Alzheimer's disease.

According to the reserve hypothesis, a high educational/occupational attainment can modulate Alzheimer's disease (AD) clinical expression. The impact of the Apolipoprotein E (ApoE) ε4 allele on the reserve mechanism in AD has not been assessed. Aim of this European multicenter study was to evaluate the metabolic correlates of reserve and ApoE genotype in early probable AD. 51 AD subjects, 27 ε4 carriers, and 24 noncarriers, underwent FDG-PET brain imaging. We used the general linear model as implemented in SPM2 to test for the linear correlation of a reserve index, accounting for both educational and occupational level, with brain glucose metabolism, controlling for demographic variables (age and gender) and for cognitive performance. We found an inverse correlation between a reserve index, accounting for educational/occupational level, and metabolism in the posterior cingulate cortex and precuneus in both ε4 carriers and noncarriers, and no significant difference between the groups. We show that education and occupation act as proxies for reserve in ε4 carriers, compensating for an unfavorable genetic background; we also show that the degree of compensation does not differ significantly by ApoE ε4 status.

Free and Cued Selective Reminding Test: an Italian normative study.

The presence of episodic memory impairment is required for the diagnosis of Alzheimer's dementia by all current diagnostic criteria. The new research criteria proposed by Dubois et al. (Lancet Neurol 6:734-746, 2007) require that the impairment should not improve significantly with cueing, recognition testing nor after the control of effective encoding. This is considered to be the core deficit of "prodromal Alzheimer's disease". The Free and Cued Selective Reminding Test (FCSRT) is a memory test that allows in assessing these specific features of memory impairment. Here, we report normative data for an Italian version of the FCSRT. The test is based on the 12 pictorial stimuli, 6 belonging to the living domain, and 6 to the non-living domain. Six scores were derived from the performance of 227 healthy Italian adults, with age, sex and education homogenously distributed across subgroups: immediate free recall (IFR), immediate total recall (ITR), delayed-free recall (DFR), delayed total recall (DTR), Index of Sensitivity of Cueing (ISC), number of intrusions. In multiple regression analyses, age emerged as an influencing factor for both IFR and DFR, with older people obtaining lower scores. Education and gender appear to influence only IFR, with better performance by more educated subjects and females. Adjusted scores were used to determine inferential cutoff scores and to compute equivalent scores.

Classification of primary progressive aphasia and its variants.

This article provides a classification of primary progressive aphasia (PPA) and its 3 main variants to improve the uniformity of case reporting and the reliability of research results. Criteria for the 3 variants of PPA--nonfluent/agrammatic, semantic, and logopenic--were developed by an international group of PPA investigators who convened on 3 occasions to operationalize earlier published clinical descriptions for PPA subtypes. Patients are first diagnosed with PPA and are then divided into clinical variants based on specific speech and language features characteristic of each subtype. Classification can then be further specified as "imaging-supported" if the expected pattern of atrophy is found and "with definite pathology" if pathologic or genetic data are available. The working recommendations are presented in lists of features, and suggested assessment tasks are also provided. These recommendations have been widely agreed upon by a large group of experts and should be used to ensure consistency of PPA classification in future studies. Future collaborations will collect prospective data to identify relationships between each of these syndromes and specific biomarkers for a more detailed understanding of clinicopathologic correlations.

Generalization of the effects of phonological training for anomia using structural equation modelling: a multiple single-case study.

Structural Equation Modelling analysis of three longitudinal er-fMRI sessions was used to test the impact of phonological training and of the generalization process on the pattern of brain connectivity during overt picture naming in two chronic anomic patients. Phonological training yielded a positive effect on the trained material. Six months after the training, a generalization of the positive impact on the untrained items was also observed. Connectivity analysis showed that training and generalization effects shared paralleled cortical patterns of functional integration. These findings may represent the neurophysiological correlate of the training-induced cognitive strategies for the compensation of anomia.

Lipids from attenuated and virulent Babesia bovis strains induce differential TLR2-mediated macrophage activation.

Babesia bovis is an intraerythrocytic apicomplexan protozoa of cattle that causes an acute infection with parasite persistence. Babesiosis limitation depends on macrophages, essential effector cells of the host innate defense, which generate inflammatory cytokines and nitric oxide. Herein, we report quantitative differences in the lipid composition of merozoites from two B. bovis strains with polar behaviour: attenuated R1A and virulent S2P. Accordingly, we observed a distinct inflammatory response induced by the total lipids of R1A (L(A)) and S2P (L(V)) in murine peritoneal macrophages. L(A) and particularly its fractions phosphatidic acid and phosphatidylserine+phosphatidylinositol (PS+PI), produced a strong activation of these cells with lipid body formation, cyclooxygenase-2 expression and pro-inflammatory TNFalpha, IL-6 and KC secretion. Although L(V) did not activate these cells, the corresponding PS+PI fraction induced TNFalpha, IL-6 and KC release. Therefore, these facts might be suggesting the presence of an inhibitor in L(V). Furthermore, the employment of wild type and toll like receptor 2 knockout (TLR2KO) mice allowed us to demonstrate that macrophage activation by the stimulating lipid fractions was mediated through TLR2. Interestingly, only L(A) activated the extracellular signal-regulated kinases 1 and 2 (ERK1/2). Inhibitory studies employing UO126, indicated that the ERK pathway was required for TNFalpha, IL-6 and KC release. In conclusion, the absence of inflammatory response observed with the lipids of S2P virulent strain could constitute an evasion mechanism of the innate immune response enabling parasite establishment in the host.

Gender-related differences in moral judgments.

The moral sense is among the most complex aspects of the human mind. Despite substantial evidence confirming gender-related neurobiological and behavioral differences, and psychological research suggesting gender specificities in moral development, whether these differences arise from cultural effects or are innate remains unclear. In this study, we investigated the role of gender, education (general education and health education) and religious belief (Catholic and non-Catholic) on moral choices by testing 50 men and 50 women with a moral judgment task. Whereas we found no differences between the two genders in utilitarian responses to non-moral dilemmas and to impersonal moral dilemmas, men gave significantly more utilitarian answers to personal moral (PM) dilemmas (i.e., those courses of action whose endorsement involves highly emotional decisions). Cultural factors such as education and religion had no effect on performance in the moral judgment task. These findings suggest that the cognitive-emotional processes involved in evaluating PM dilemmas differ in men and in women, possibly reflecting differences in the underlying neural mechanisms. Gender-related determinants of moral behavior may partly explain gender differences in real-life involving power management, economic decision-making, leadership and possibly also aggressive and criminal behaviors.