“Looks familiar, but I do not know who she is”:The role of the anterior right temporal lobe in famous face recognition

Processing a famous face involves a cascade of steps including detecting the presence of a face, recognizing it as familiar, accessing semantic/biographical information about the person, and finally, if required, production of the proper name. Decades of neuropsychological and neuroimaging studies have identified a network of occipital and temporal brain regions ostensibly comprising the 'core' system for face processing. Recent research has also begun to elucidate upon an 'extended' network, including anterior temporal and frontal regions. However, there is disagreement about which brain areas are involved in each step, as many aspects of face processing occur automatically in healthy individuals and rarely dissociate in patients. Moreover, some common phenomena are not easily induced in an experimental setting, such as having a sense of familiarity without being able to recall who the person is. Patients with the semantic variant of Primary Progressive Aphasia (svPPA) often recognize a famous face as familiar, even when they cannot specifically recall the proper name or biographical details. In this study, we analyzed data from a large sample of 105 patients with neurodegenerative disorders, including 43 svPPA, to identify the neuroanatomical substrates of three different steps of famous face processing. Using voxel-based morphometry, we correlated whole-brain grey matter volumes with scores on three experimental tasks that targeted familiarity judgment, semantic/biographical information retrieval, and naming. Performance in naming and semantic association significantly correlates with grey matter volume in the left anterior temporal lobe, whereas familiarity judgment with integrity of the right anterior middle temporal gyrus. These findings shed light on the neuroanatomical substrates of key components of overt face processing, addressing issues of functional lateralization, and deepening our understanding of neural substrates of semantic knowledge

Impact des ions zinc et cuivre dans la cascade amyloïde liée à la maladie d'Alzheimer

La maladie d'Alzheimer (MA) est une maladie neurodégénérative. Elle représente entre 60-80 % des cas de démence et touche autour de 47 millions de personnes à travers le monde. Deux types de lésions morphologiques de la MA ont été identifiés post mortem : les enchevêtrements neurofibrillaires intra-neuronaux de protéine Tau hyperphosphorylée et les plaques séniles. Les plaques séniles, ou plaques amyloïdes, se forment dans l'espace extracellulaire entre les fentes synaptiques et empêchent les connexions neuronales. Le composant principal de ces plaques est le peptide Amyloïde-ß (Aß) agrégé. Une hypothèse concernant cette maladie propose une mauvaise régulation des ions métalliques, telles que Zn et Cu, et une accumulation de Aß. Cette hypothèse est appelée hypothèse de la cascade amyloïde. Dans cette hypothèse le peptide Aß monomérique, présent aussi dans les cerveaux sains, agrège d'abord en formes oligomériques, puis en fibres, qui vont ensuite constituer les plaques amyloïdes. Il est proposé que le zinc stabilise davantage les fibres et le cuivre les formes oligomériques. Ces formes présentent une grande toxicité liée à la production d'Espèces Réactives de l'Oxygène (ERO), en présence d'un réducteur tel que l'ascorbate. Ces espèces oxydantes sont délétères pour les molécules environnantes. Pour mieux comprendre comment les ions Zn(II) et Cu(II) vont moduler ou induire l'agrégation, leur impact est étudié en comparaison avec le peptide Amyloïde-ß murin (mAß). En effet, les rats et les souris partagent ce peptide et ne développent pas la MA. Le mAß diffère du Aß humain (hAß) par seulement 3 acides aminés sur les 40-42 acides aminés qui constituent la séquence hAß. Pour cette raison, une étude de l'impact de la différence de coordination des ions Zn(II) et Cu(II) au sein des deux peptides sur l'agrégation et la morphologie des agrégats est ici menée. Ceci a pour objectif d'aider une meilleure compréhension de la cascade amyloïde. La deuxième partie de cette thèse se focalise sur la production d'ERO. Jusqu'à récemment, les études étaient focalisées sur les peptides Aß1-n (n=16/28/40/42). Celui ici, en présence des ions cuivre, de dioxygène et d'ascorbate va produire des ERO. Cependant, il est démontré qu'une forte quantité de formes tronquées en position N-terminale du Aß (en particulier Aß4-n et Aß11-n) se trouvent dans les cerveaux post mortem des malades d'Alzheimer. Ces deux peptides présentent un site de coordination pour le Cu(II) de type ATCUN, qui peut donc coordonner fortement les ions Cu(II). Il est donc intéressant d'étudier leur capacité à produire des ERO et/ou capacité à en arrêter la production. Enfin, l'impact du Zn(II) sur la production d'ERO par les complexes AßCu a été évalué, car la concentration en Zn dans les fentes synaptiques est environ 100 fois plus grande que celle en Cu.Alzheimer's disease (AD) is a neurodegenerative disease and it represents the 60-80 % of the dementia cases. It touched around 47 million people worldwide. Two hallmarks of AD were identified in post mortem brain: the intracellular neurofibrillary tangles of hyperphosphorylated Tau protein and the amyloid (or senile) plaques. The amyloid plaques are formed in the extracellular space in the synaptic cleft. These aggregates would prevent the neuronal connections. The major component of the senile plaques is the aggregated Amyloid-ß (Aß) peptide. An hypothesis concerning this disease proposed a metal ions dyshomeostasis and an accumulation of Aß. This hypothesis is called amyloid cascade hypothesis. According to this hypothesis, the monomeric Aß peptide, present also in the healthy brains, aggregates into dimer, trimer... and more generally into oligomers; and then into fibers, which constitute the amyloid plaques. It is considered that zinc ions stabilize the fibers and copper ions the oligomeric forms. These forms present a high toxicity linked to the production of Reactive Oxygen Species (ROS), in the presence of dioxygen and a reducing agent such as ascorbate. These oxidants species are toxic for the surrounding molecules. To better understand how Zn(II) and Cu(II), modulate and/or induce the aggregation of the Aß peptide, their impact was studied and compared to the murine amyloid-ß (mAß) peptide. Indeed, rats and mice share this peptide and do not develop AD. mAß peptide differs from the human (hAß) peptide at 3 only positions on the 40-42 amino acids which constitute the hAß sequence. For this reason, a study of the impact of the different Zn(II) and Cu(II) coordination on the aggregation and on the morphology of aggregates of both peptides was performed. This aims at helping to better describe amyloid cascade hypothesis. The second part of this thesis focuses on ROS production. Until recently, the studies were focused on the peptides Aß1-n (n=16 / 28 / 40 / 42). These peptides in presence of copper ions, O2 and ascorbate produce ROS. However, a high amount of N-truncated Aß peptides, in particular Aß4-n and Aß11-n, was found post mortem in AD brains. These two peptides have an ATCUN coordination site, which strongly coordinates the Cu(II). It is interesting to study their ability to produce or stop ROS production. Finally, the impact of the Zn(II) in the ROS production of AßCu complexes is evaluated. Indeed, the concentration of Zn in the synaptic cleft is around 100 times more than Cu

Effects of zinc and copper ions in the amyloid cascade linked to Alzheimer's disease

La maladie d'Alzheimer (MA) est une maladie neurodégénérative. Elle représente entre 60-80 % des cas de démence et touche autour de 47 millions de personnes à travers le monde. Deux types de lésions morphologiques de la MA ont été identifiés post mortem : les enchevêtrements neurofibrillaires intra-neuronaux de protéine Tau hyperphosphorylée et les plaques séniles. Les plaques séniles, ou plaques amyloïdes, se forment dans l'espace extracellulaire entre les fentes synaptiques et empêchent les connexions neuronales. Le composant principal de ces plaques est le peptide Amyloïde-ß (Aß) agrégé. Une hypothèse concernant cette maladie propose une mauvaise régulation des ions métalliques, telles que Zn et Cu, et une accumulation de Aß. Cette hypothèse est appelée hypothèse de la cascade amyloïde. Dans cette hypothèse le peptide Aß monomérique, présent aussi dans les cerveaux sains, agrège d'abord en formes oligomériques, puis en fibres, qui vont ensuite constituer les plaques amyloïdes. Il est proposé que le zinc stabilise davantage les fibres et le cuivre les formes oligomériques. Ces formes présentent une grande toxicité liée à la production d'Espèces Réactives de l'Oxygène (ERO), en présence d'un réducteur tel que l'ascorbate. Ces espèces oxydantes sont délétères pour les molécules environnantes. Pour mieux comprendre comment les ions Zn(II) et Cu(II) vont moduler ou induire l'agrégation, leur impact est étudié en comparaison avec le peptide Amyloïde-ß murin (mAß). En effet, les rats et les souris partagent ce peptide et ne développent pas la MA. Le mAß diffère du Aß humain (hAß) par seulement 3 acides aminés sur les 40-42 acides aminés qui constituent la séquence hAß. Pour cette raison, une étude de l'impact de la différence de coordination des ions Zn(II) et Cu(II) au sein des deux peptides sur l'agrégation et la morphologie des agrégats est ici menée. Ceci a pour objectif d'aider une meilleure compréhension de la cascade amyloïde. La deuxième partie de cette thèse se focalise sur la production d'ERO. Jusqu'à récemment, les études étaient focalisées sur les peptides Aß1-n (n=16/28/40/42). Celui ici, en présence des ions cuivre, de dioxygène et d'ascorbate va produire des ERO. Cependant, il est démontré qu'une forte quantité de formes tronquées en position N-terminale du Aß (en particulier Aß4-n et Aß11-n) se trouvent dans les cerveaux post mortem des malades d'Alzheimer. Ces deux peptides présentent un site de coordination pour le Cu(II) de type ATCUN, qui peut donc coordonner fortement les ions Cu(II). Il est donc intéressant d'étudier leur capacité à produire des ERO et/ou capacité à en arrêter la production. Enfin, l'impact du Zn(II) sur la production d'ERO par les complexes AßCu a été évalué, car la concentration en Zn dans les fentes synaptiques est environ 100 fois plus grande que celle en Cu.Alzheimer's disease (AD) is a neurodegenerative disease and it represents the 60-80 % of the dementia cases. It touched around 47 million people worldwide. Two hallmarks of AD were identified in post mortem brain: the intracellular neurofibrillary tangles of hyperphosphorylated Tau protein and the amyloid (or senile) plaques. The amyloid plaques are formed in the extracellular space in the synaptic cleft. These aggregates would prevent the neuronal connections. The major component of the senile plaques is the aggregated Amyloid-ß (Aß) peptide. An hypothesis concerning this disease proposed a metal ions dyshomeostasis and an accumulation of Aß. This hypothesis is called amyloid cascade hypothesis. According to this hypothesis, the monomeric Aß peptide, present also in the healthy brains, aggregates into dimer, trimer... and more generally into oligomers; and then into fibers, which constitute the amyloid plaques. It is considered that zinc ions stabilize the fibers and copper ions the oligomeric forms. These forms present a high toxicity linked to the production of Reactive Oxygen Species (ROS), in the presence of dioxygen and a reducing agent such as ascorbate. These oxidants species are toxic for the surrounding molecules. To better understand how Zn(II) and Cu(II), modulate and/or induce the aggregation of the Aß peptide, their impact was studied and compared to the murine amyloid-ß (mAß) peptide. Indeed, rats and mice share this peptide and do not develop AD. mAß peptide differs from the human (hAß) peptide at 3 only positions on the 40-42 amino acids which constitute the hAß sequence. For this reason, a study of the impact of the different Zn(II) and Cu(II) coordination on the aggregation and on the morphology of aggregates of both peptides was performed. This aims at helping to better describe amyloid cascade hypothesis. The second part of this thesis focuses on ROS production. Until recently, the studies were focused on the peptides Aß1-n (n=16 / 28 / 40 / 42). These peptides in presence of copper ions, O2 and ascorbate produce ROS. However, a high amount of N-truncated Aß peptides, in particular Aß4-n and Aß11-n, was found post mortem in AD brains. These two peptides have an ATCUN coordination site, which strongly coordinates the Cu(II). It is interesting to study their ability to produce or stop ROS production. Finally, the impact of the Zn(II) in the ROS production of AßCu complexes is evaluated. Indeed, the concentration of Zn in the synaptic cleft is around 100 times more than Cu

Symbolic categorization of novel multisensory stimuli in the human brain

When primates (both human and non-human) learn to categorize simple visual or acoustic stimuli by means of non-verbal matching tasks, two types of changes occur in their brain: early sensory cortices increase the precision with which they encode sensory information, and parietal and lateral prefrontal cortices develop a categorical response to the stimuli. Contrary to non-human animals, however, our species mostly constructs categories using linguistic labels. Moreover, we naturally tend to define categories by means of multiple sensory features of the stimuli. Here we trained adult subjects to parse a novel audiovisual stimulus space into 4 orthogonal categories, by associating each category to a specific symbol. We then used multi-voxel pattern analysis (MVPA) to show that during a cross-format category repetition detection task three neural representational changes were detectable. First, visual and acoustic cortices increased both precision and selectivity to their preferred sensory feature, displaying increased sensory segregation. Second, a frontoparietal network developed a multisensory object-specific response. Third, the right hippocampus and, at least to some extent, the left angular gyrus, developed a shared representational code common to symbols and objects. In particular, the right hippocampus displayed the highest level of abstraction and generalization from a format to the other, and also predicted symbolic categorization performance outside the scanner. Taken together, these results indicate that when humans categorize multisensory objects by means of language the set of changes occurring in the brain only partially overlaps with that described by classical models of non-verbal unisensory categorization in primates

Cu(II) binding to various forms of amyloid-β peptides. Are they friends or foes ?

International audienceIn the present micro-review, we describe the Cu(II) binding to several forms of amyloid-β peptides, the peptides involved in Alzheimer's disease. It has indeed been shown that in addition to the " full-length " peptide originating from the precursor protein after cleavage at position 1, several other shorter peptides do exist in large proportion and may be involved in the disease as well. Cu(II) binding to amyloid-β peptides is one of the key interactions that impact both the aggregating properties of the amyloid peptides and the Reactive Oxygen Species (ROS) production, two events linked to the etiology of the disease. Binding sites and affinity are described in correlation with Cu(II) induced ROS formation and Cu(II) altered aggregation, for amyloid peptides starting at position 1, 3, 4, 11 and for the corresponding pyroglutamate forms when they could be obtained (i.e. for peptides cleaved at positions 3 and 11). It appears that the current paradigm which points out a toxic role of the Cu(II) – amyloid-β interaction might well be shifted towards a possible protective role when the peptides considered are the N-terminally truncated ones

Conceptual and Perceptual Dimensions of Word Meaning Are Recovered Rapidly and in Parallel during Reading

International audienceA single word (the noun “elephant”) encapsulates a complex multidimensional meaning, including both perceptual (“big”, “gray”, “trumpeting”) and conceptual (“mammal”, “can be found in India”) features. Opposing theories make different predictions as to whether different features (also conceivable as dimensions of the semantic space) are stored in similar neural regions and recovered with similar temporal dynamics during word reading. In this magnetoencephalography study, we tracked the brain activity of healthy human participants while reading single words varying orthogonally across three semantic dimensions: two perceptual ones (i.e., the average implied real-world size and the average strength of association with a prototypical sound) and a conceptual one (i.e., the semantic category). The results indicate that perceptual and conceptual representations are supported by partially segregated neural networks: Whereas visual and auditory dimensions are encoded in the phase coherence of low-frequency oscillations of occipital and superior temporal regions, respectively, semantic features are encoded in the power of low-frequency oscillations of anterior temporal and inferior parietal areas. However, despite the differences, these representations appear to emerge at the same latency: around 200 msec after stimulus onset. Taken together, these findings suggest that perceptual and conceptual dimensions of the semantic space are recovered automatically, rapidly, and in parallel during word reading