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.

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.

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.

The neural bases of word encoding and retrieval: A fMRI-guided transcranial magnetic stimulation study.

There is evidence that the human prefrontal cortex is asymmetrically involved in long-term episodic memory processing. Moreover, abstract and concrete words processing has been reported to differentially involve prefrontal and parietal areas. We implemented a two-stages functional magnetic resonance imaging (fMRI)-repetitive transcranial magnetic stimulation (rTMS) paradigm to investigate the role of the dorsolateral prefrontal cortices (DLPFCs) and parietal cortices (PARCs) in encoding and retrieval of abstract and concrete words. Using this paradigm we could select areas to be stimulated on the basis of single-subject (SS) anatomical and functional data, investigating the usefulness of this integration approach. With respect to fMRI, abstract and concrete words differed only for a greater left fusiform gyrus activation for concrete words. In turn, significant rTMS effects were found, but only for the retrieval of abstract words. Consistent with previous findings, repetitive stimulation of the right DLPFC had a specific impact on episodic retrieval. Memory retrieval performance was also disrupted when rTMS was applied to the left PARC. Finally, we found a significant positive correlation between the effect sizes of SS right PARC activations for abstract word retrieval and the consequent rTMS interference effects. Taken together these data provide for the first time evidence that also the PARC has a necessary role in episodic retrieval of abstract words. Importantly, from a methodological perspective, our data demonstrate that fMRI-guided rTMS with a SS approach provides a powerful tool to investigate the neural underpinnings of cognitive functions.

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.

Transcranial magnetic stimulation improves naming in Alzheimer disease patients at different stages of cognitive decline.

OBJECTIVE: Word-finding difficulty (anomia) is commonly observed in Alzheimer's dementia (AD). The aim of this study was to assess the effect of repetitive transcranial magnetic stimulation (rTMS) applied to the dorso-lateral prefrontal cortex (dlPFC) on picture naming in 24 probable AD patients with different degrees of cognitive decline. METHODS: High-frequency rTMS was applied to the left and right dlPFC during object and action naming in AD patients. A sham stimulation was used as a control condition. RESULTS: Whilst, as previously reported, stimulation to both the left and the right dlPFC improved action, but not object naming in the mild AD group; an improved naming accuracy for both classes of stimuli was found in the moderate to severe group. CONCLUSIONS: Repetitive transcranial magnetic stimulation applied to the dlPFC improves naming performance also in the advanced stages of AD. Moreover, in the severe group the effect is not specific for action naming, as in the case of the mild AD group. These findings suggest that rTMS can affect the intrinsic ability of the brain to restore or compensate for damaged function and may represent an useful new tool for cognitive rehabilitation.

Education and occupation as proxies for reserve in aMCI converters and AD: FDG-PET evidence.

BACKGROUND: Previous reports have shown that higher education is associated with more severe brain pathology in patients with Alzheimer disease (AD), suggesting that these individuals have a functional reserve provided by education, which masks the clinical expression of a higher degree of neurodegeneration. It is unknown if a similar reserve mechanism exists in patients with amnestic mild cognitive impairment (aMCI). The aim of this study was to assess the impact of education and occupation on brain glucose metabolism (rCMRglc) measured with FDG-PET in aMCI and in a very large sample of subjects with probable AD (pAD). METHODS: A total of 242 patients with pAD, 72 with aMCI, and 144 healthy controls participated in the study. At follow-up, 21 subjects with aMCI progressed to AD. A regression analysis was conducted (SPM2), with education and occupation as independent variables, and rCMRglc as dependent variable, adjusting for demographic data, global cognitive status, and neuropsychological scores. RESULTS: The analysis showed a significant association between higher education/occupation and lower rCMRglc in posterior temporoparietal cortex and precuneus in pAD and aMCI converters, and no correlation in aMCI nonconverters and healthy controls. This means that, when submitted to FDG-PET for diagnostic evaluation, pAD and aMCI converters with higher education/occupation had, for comparable cognitive impairment, a more severe rCMRglc reduction than the ones with lower education/occupation. CONCLUSIONS: This study suggests that education and occupation may be proxies for brain functional reserve, reducing the severity and delaying the clinical expression of Alzheimer disease (AD) pathology. The results in aMCI converters suggest that functional reserve is already at play in the predementia phase of AD.

The logopenic/phonological variant of primary progressive aphasia.

OBJECTIVE: Primary progressive aphasia (PPA) is characterized by isolated decline in language functions. Semantic dementia and progressive nonfluent aphasia are accepted PPA variants. A "logopenic" variant (LPA) has also been proposed, but its cognitive and anatomic profile is less defined. The aim of this study was to establish the cognitive and anatomic features of LPA. METHODS: Six previously unreported LPA cases underwent extensive neuropsychological evaluation and an experimental study of phonological loop functions, including auditory and visual span tasks with digits, letters, and words. For each patient, a voxel-wise, automated analysis of MRI or SPECT data were conducted using SPM2. RESULTS: In LPA, speech rate was slow, with long word-finding pauses. Grammar and articulation were preserved, although phonological paraphasias could be present. Repetition and comprehension were impaired for sentences but preserved for single words, and naming was moderately affected. Investigation of phonological loop functions showed that patients were severely impaired in digit, letter, and word span tasks. Performance did not improve with pointing, was influenced by word length, and did not show the normal phonological similarity effect. Atrophy or decreased blood flow was consistently found in the posterior portion of the left superior and middle temporal gyri and inferior parietal lobule. CONCLUSIONS: Logopenic progressive aphasia (LPA) is a distinctive variant of primary progressive aphasia. Cognitive and neuroimaging data indicate that a deficit in phonological loop functions may be the core mechanism underlying the LPA clinical syndrome. Recent studies suggest that Alzheimer disease may be the most common pathology underlying the LPA clinical syndrome.

Action and object naming in Parkinson's disease without dementia.

The present study aimed to assess the ability in objects and actions naming in Parkinson's disease (PD) patients. Further, we wished to assess the effect of a particular conceptual dimension, i.e. manipulability, on the naming of object and actions. Patients were recruited from the Department of Neurology, University of Brescia. Thirty-two were diagnosed as PD, according to published criteria, and 15 healthy volunteers matched in age and education to patients' sample. All patients underwent a detailed clinical and neurological evaluation. The stimuli used in the action-object picture naming task were taken from the Center for Research in Language-International Picture Naming Project corpus. To assess the effect of manipulability (or the involvement of fine hand movements) the noun-verb stimuli were re-categorized into manipulable and non-manipulable items (i.e. objects which can or cannot be manipulated and actions which do or do not involve fine hand movements). Patients showed a deficit both in action and object naming, compared with controls. In addition, patients with PD but not controls were significantly more impaired in action than in object naming. The current study supports the view that action naming is affected in patients with PD, possibly reflecting the presence of prefrontal dysfunction.