Focal anterior temporal lobe (ATL) degeneration often preferentially affects the left or right hemisphere. While patients with left-predominant ATL (lATL) atrophy show severe anomia and verbal semantic deficits and meet criteria for semantic variant primary progressive aphasia (svPPA) and semantic dementia, patients with early right ATL (rATL) atrophy are more difficult to diagnose as their symptoms are less well understood. Focal rATL atrophy is associated with prominent emotional and behavioral changes, and patients often meet, or go on to meet, criteria for behavioral variant frontotemporal dementia (bvFTD). Uncertainty around early symptoms and absence of an overarching clinicoanatomical framework continue to hinder proper diagnosis and care of patients with rATL disease. Here, we examine a large, well-characterized, longitudinal cohort of patients with rATL-predominant degeneration and propose new criteria and nosology. We identified individuals from our database with a clinical diagnosis of bvFTD or svPPA and a structural MRI (n = 478). Based on neuroimaging criteria, we defined three patient groups: rATL-predominant atrophy with relative sparing of the frontal lobes (n = 46), frontal-predominant atrophy with relative sparing of the rATL (n = 79), and lATL-predominant atrophy with relative sparing of the frontal lobes (n = 75). We compared the clinical, neuropsychological, genetic, and pathological profiles of these groups. In the rATL-predominant group, the earliest symptoms were loss of empathy (27%), person-specific semantic impairment (23%), and complex compulsions and rigid thought process (18%). On testing, this group exhibited greater impairments in Emotional Theory of Mind, recognition of famous people (from names and face), and facial affect naming (despite preserved face perception) than the frontal- and lATL-predominant groups. The clinical symptoms in the first three years of the disease alone were highly sensitive (81%) and specific (84%) differentiating rATL-predominant from frontal-predominant groups. FTLD-TDP (84%) was the most common pathology of the rATL-predominant group. rATL-predominant degeneration is characterized by early loss of empathy and person-specific knowledge, deficits that are caused by progressive decline in semantic memory for concepts of socioemotional relevance. Guided by our results, we outline new diagnostic criteria and propose the name, “semantic behavioral variant frontotemporal dementia” (sbvFTD), which highlights the underlying cognitive mechanism and the predominant symptomatology. These diagnostic criteria will facilitate early identification and care of patients with early, focal rATL degeneration as well as in vivo prediction of FTLD-TDP pathology.

valentinaborghesani@gmail.comThe authors declare no competing financial interests. ABSTRACTThe meaning of words referring to concrete items is thought of as a multidimensional representation that includes both perceptual (e.g., average size, prototypical color) and conceptual (e.g., taxonomic class) dimensions. Are these different dimensions coded in different brain regions? In healthy human subjects, we tested the presence of a mapping between the implied real object size (a perceptual dimension) and the taxonomic categories at different levels of specificity (conceptual dimensions) of a series of words, and the patterns of brain activity recorded with functional magnetic resonance imaging in six areas along the ventral occipito-temporal cortical path. Combining multivariate pattern classification and representational similarity analysis, we found that the real object size implied by a word appears to be primarily encoded in early visual regions, while the taxonomic category and subcategorical cluster in more anterior temporal regions. This anteroposterior gradient of information content indicates that different areas along the ventral stream encode complementary dimensions of the semantic space.

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by semantic memory deficits with relatively preserved motor speech, syntax, and phonology. There is consistent evidence linking focal neurodegeneration of the anterior temporal lobes (ATL) to the semantic deficits observed in svPPA. Less is known about large-scale functional connectivity changes in this syndrome, particularly regarding the interplay between affected and spared language networks that leads to the unique cognitive dissociations typical of svPPA. Using whole-brain, seed-based connectivity on task-free Magnetic Resonance Imaging (MRI) data, we studied connectivity of networks anchored to three left-hemisphere regions crucially involved in svPPA symptomatology: ATL just posterior to the main atrophic area, opercular inferior frontal gyrus, and posterior inferior temporal lobe. First, in 32 healthy controls, these seeds isolated three networks: a ventral semantic network involving anterior middle temporal and angular gyri, a dorsal articulatory-phonological system involving inferior frontal and supramarginal regions, and a third functional connection between posterior inferior temporal and intraparietal regions likely involved in linking visual and linguistic processes. We then compared connectivity strength of these three networks between 16 svPPA patients and the 32 controls. In svPPA, decreased functional connectivity in the ventral semantic network correlated with weak semantic skills, while connectivity of the network seeded from the posterior inferior temporal lobe, though not significantly different between the two groups, correlated with pseudoword reading skills. Increased connectivity between the inferior frontal gyrus and the superior portion of the angular gyrus suggested possible adaptive changes. Our findings have two main implications. First, they support a functional subdivision of the left IPL based on its connectivity to specific language-related regions. Second, the unique neuroanatomical and linguistic profile observed in svPPA provides a compelling model for the functional interplay of these networks, being either up- or down- regulated in response to disease.

Highlights Anterior temporal lobe (ATL) degeneration is most often caused by FTLD-TDP type C pathology. Cases can present with predominantly left (60%) or right (40%) ATL atrophy. Within ATLs, medial regions are more vulnerable than lateral ones. The observed spectrum of clinical phenotypes is driven by atrophy lateralization. Left and right temporal variants of FTD should be considered the same disease.

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A current intense discussion in numerical cognition concerns the relationship between the processing of numerosity and other non-numerical quantities. In particular, it is a matter of debate whether number and other quantities (e.g., size, length) are represented separately in the brain or whether they share a common generalized magnitude representation. We acquired high-resolution functional MRI data while adult subjects engaged in a magnitude comparison task involving either numerosity (i.e., which of the two sets has more elements?) or line length (i.e., which of the two lines is longer?). We compared the activation evoked by the two different types of quantity and observed a common recruitment of a vast portion of occipital and parietal cortices. Using MVPA, we demonstrated that some of the commonly activated regions represented the discrete and continuous quantities via a similar distance-dependent magnitude code. However, we found no effect of distance across the two quantity representations, failing to support the existence of a common, dimension invariant, generalized quantity code. Taken together, these findings indicate that although the processing of number and length is supported by partially overlapping neural resources, representations within these regions do not appear to be based on a common neural code.

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.

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