Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors.

Humans express laughter differently depending on the context: polite titters of agreement are very different from explosions of mirth. Using functional MRI, we explored the neural responses during passive listening to authentic amusement laughter and controlled, voluntary laughter. We found greater activity in anterior medial prefrontal cortex (amPFC) to the deliberate, Emitted Laughs, suggesting an obligatory attempt to determine others' mental states when laughter is perceived as less genuine. In contrast, passive perception of authentic Evoked Laughs was associated with greater activity in bilateral superior temporal gyri. An individual differences analysis found that greater accuracy on a post hoc test of authenticity judgments of laughter predicted the magnitude of passive listening responses to laughter in amPFC, as well as several regions in sensorimotor cortex (in line with simulation accounts of emotion perception). These medial prefrontal and sensorimotor sites showed enhanced positive connectivity with cortical and subcortical regions during listening to involuntary laughter, indicating a complex set of interacting systems supporting the automatic emotional evaluation of heard vocalizations.

There is general agreement that, after initial processing in unimodal sensory cortex, the processing pathways for spoken and written language converge to access verbal meaning. However, the existing literature provides conflicting accounts of the cortical location of this convergence. Most aphasic stroke studies localize verbal comprehension to posterior temporal and inferior parietal cortex (Wernicke's area), whereas evidence from focal cortical neurodegenerative syndromes instead implicates anterior temporal cortex. Previous functional imaging studies in normal subjects have failed to reconcile these opposing positions. Using a functional imaging paradigm in normal subjects that used spoken and written narratives and multiple baselines, we demonstrated common activation during implicit comprehension of spoken and written language in inferior and lateral regions of the left anterior temporal cortex and at the junction of temporal, occipital, and parietal cortex. These results indicate that verbal comprehension uses unimodal processing streams that converge in both anterior and posterior heteromodal cortical regions in the left temporal lobe.