Regional and hemispheric susceptibility of the temporal lobe to FTLD-TDP-43-C pathology

Post-mortem studies show that focal anterior temporal lobe (ATL) neurodegeneration is most often caused by frontotemporal lobar degeneration TDP-43 type C pathology. Clinically, patients are inconsistently described with the terms semantic variant primary progressive aphasia (svPPA), semantic dementia (SD), or right temporal variant frontotemporal dementia (FTD) depending on whether the predominant symptoms affect language, semantic knowledge for object or people, or socio-emotional behaviors. The neuroimaging hallmark of these syndromes is ATL atrophy, with various degrees of lateralization. Cases presenting with initial right-sided atrophy are considered to be rarer than left-sided ones, yet estimation of their prevalence is hampered by the paucity of studies on well-characterized, pathology-proven cohorts. Moreover, it is not clear whether left and right variants show a similar distribution of atrophy within the ATL cross-sectionally and longitudinally. Here we study the largest cohort to-date of pathology-proven TDP-43-C cases diagnosed during life as svPPA, SD or right temporal variant FTD. We analyzed clinical, cognitive, and neuroimaging data from 30 cases, a subset of which was followed longitudinally. Guided by recent structural and functional parcellation studies, we constructed four bilateral ATL regions of interest (ROIs). The computation of an atrophy lateralization index allowed the comparison of atrophy patterns between the two hemispheres. This led to an automatic, imaging-based classification of the cases as left-predominant or right-predominant. We then compared the two groups in terms of regional atrophy patterns within the ATL ROIs (cross-sectionally) and atrophy progression (longitudinally). Results showed that 40% of pathology proven cases diagnosed with a temporal variant presented with right-lateralized atrophy. Moreover, the findings of our ATL ROI analysis indicated that, irrespective of atrophy lateralization, atrophy distribution within both ATLs follows a gradient from medial to lateral regions. Finally, in both left and right cases, atrophy appeared to progress to the contralateral ATL, and from the anterior temporal pole to posterior temporal and orbitofrontal regions. Our results indicate that both left and right predominant ATL atrophy is common in TDP-43-C pathology. Moreover, the distribution of damage within the ATL, as well as its temporal extension, are the same regardless of where the atrophy started. As pharmacological interventions become available, the ability to predict the underlying pathology and to track longitudinal changes becomes crucial and, regardless of differences in clinical phenotype, left and right temporal variants of FTD caused by TDP-43-C should be viewed as the same disease. Establishing consistent clinical criteria for focal right temporal degeneration is thus necessary to improve diagnostic accuracy in PPA and FTD. Highlights Anterior temporal lobe (ATL) degeneration is most often caused by FTLD-TDP-43 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 Longitudinally, atrophy spreads similarly in predominantly left and right cases Left and right temporal variants of FTD should be considered the same disease