In this study we have identified 2 distinct clinicopathologic subtypes of right temporal variant FTD, one associated with tau pathology and the other with TDP-43 pathology. These results may advance our knowledge of right temporal variant FTD4,6,7
and FTD in general and could have significant implications for differentiating tau from TDP-43 as the underlying substrate of FTD.
Using atlas-based parcellation, we identified 20 FTD subjects in which the right temporal lobe was the most atrophic region, hence our designation of the cohort as right temporal variant FTD. Similar to other studies, our cohort was characterized by personality change, inappropriate behaviors, episodic memory loss, prosopagnosia, and topographagnosia.3–7
We found personality change and inappropriate behaviors to be the most frequent features of the cohort.4,6
Other features present at any time during the disease course were parkinsonism, compulsive behaviors, craving for sweet foods (sweet tooth), and obsession with puzzles/jigsaws. A few subjects had indiscriminate eating behaviors such as eating soap and dirt, 2 of whom were noted to have persistent hunger. We hypothesize that indiscriminate eating may be occurring secondary to loss of food knowledge and possibly a feeling of persistent hunger. Stereotypical behaviors, previously demonstrated to be associated with striatal atrophy,24
are rare in right temporal variant FTD.
Our 20 right temporal FTD subjects were divided into 2 groups based on clinical diagnosis. Taking into account the significant differences identified in clinical, neuropsychological, and neurobehavioral features between both groups, it is reasonable to suggest two distinct clinico-psychological profiles of right temporal variant FTD. Therefore, at onset, the bvFTD phenotype is best defined by personality change, inappropriate behaviors, positive family history, and relatively poor performance on neurobehavioral testing with better performance on confrontational naming tests. The SMD phenotype is defined by word-finding and comprehension difficulties, prosopagnosia, and topographagnosia,2
absent family history, relatively better performance on neurobehavioral testing, and poor performance on naming tests. As disease progresses, the development of sweet tooth and parkinsonism suggest the bvFTD phenotype, although personality change and inappropriate behaviors will be less helpful to differentiate the 2 phenotypes, as these 2 features will occur later in the SMD subjects.
The results of the VBM analysis shed light on some of these findings. We identified significantly more frontal lobe atrophy, on direct comparison, in the bvFTD group than the SMD group, which concurs with the fact that we found more behavioral dyscontrol in the bvFTD group. Similarly, the presence of sweet tooth, which was common in our bvFTD subjects, has been associated with atrophy of the orbitofrontal cortex,25
and indeed the bvFTD group showed a greater degree of orbitofrontal loss. Conversely, the SMD group showed greater loss in the right fusiform and lateral temporal lobes on direct comparison. We have previously shown that prosopagnosia may be associated with atrophy of the right fusiform and parahippocampal gyri, as well as mesial temporal structures.26
Of these structures, only the fusiform gyrus was involved to a greater degree in the SMD group with prosopagnosia compared to the bvFTD group, suggesting that the fusiform gyrus is the most likely region accounting for prosopagnosia in SMD. Another imaging characteristic differentiating the SMD subjects from the bvFTD subjects, in right temporal FTD, is greater temporal lobe asymmetry in those with SMD compared to lesser temporal lobe asymmetry in those with bvFTD. The bvFTD subjects in this study overlap with those reported in a recent cluster-based study in which we demonstrated that bvFTD subjects can show four distinct patterns of atrophy.27
The majority of the right temporal FTD subjects were indeed classified as showing a predominantly temporal pattern of atrophy, although some were classified as showing a frontotemporal pattern reflecting the additional involvement of the frontal lobes.
The most important finding of this study was the very significant separation of pathologies. All subjects in the bvFTD group with pathologic or genetic confirmation had tau abnormalities, the majority of which were related to mutations in the MAPT
gene. Conversely, all 3 SMD subjects who had pathology were found to have pathology related to TDP-43. More impressive, all 3 subjects in the SMD group with FTLD-TDP shared identical TDP-43 typing: FTLD-TDP type 212
(Sampathu type 113
). These pathologic/genetic differences also shed light on some of the clinical findings. MAPT
mutations were common in the bvFTD group and likely account for the high frequency of parkinsonism observed in the bvFTD group,28
the high frequency of a positive family history,29
and the trend for the bvFTD subjects to have a slightly young age at onset.30
We have also previously found that MAPT
mutations are associated with anteromedial temporal atrophy which concurs with the finding of greater left anteromedial temporal loss in the bvFTD group.14
It should be noted, however, that although MAPT
mutations are associated with right temporal atrophy in this study, we cannot conclude that all subjects with a MAPT
mutation show dominant right temporal lobe atrophy.14
Given the relatively high frequency of MAPT
mutation in our bvFTD group, it is unclear if these results generalize to pure sporadic FTD cohorts. Specifically, it is unclear whether there would be any association between bvFTD and tau in a right temporal variant FTD cohort without MAPT
mutations, although one subject did show sporadic Pick disease. It is actually more likely that SMD with TDP-43 will underlie right temporal variant sporadic FTD. Given that we had such a high proportion of MAPT
mutations in our cohort, and that we only had 3 pathologically confirmed subjects in the SMD cohort, these results will need to be replicated in a larger cohort, with comprehensive genetic analysis and pathologic confirmation. We are not surprised that we did not find any mutations in the progranulin gene since dominant right temporal lobe atrophy is not a feature of progranulin gene mutations.14
The findings from this study have significant implications and further help to decipher the complexity of the FTD field. Differentiating subjects with underlying tau pathology from those with TDP-43 pathology is critical to the field,1
especially in the current era of developing treatment which appears to be focused at the protein level. The findings from this study suggest that subjects with FTD with right temporal lobe atrophy, prominent behavioral features, a positive family history, some frontal lobe atrophy, and modest temporal lobe asymmetry will more likely have underling tau pathology, whereas subjects with prosopagnosia, word-finding and comprehension difficulties, topographagnosia, absent family history, absent frontal lobe atrophy, and marked temporal lobe asymmetry will more likely have TDP-43 pathology. It is therefore important to understand that although predicting pathology is difficult in bvFTD subjects as a whole, it is possible that prediction may be improved if MRI is used to identify those with a pattern of atrophy consistent with right temporal variant FTD. This approach would be similar to the approach used in FTD subjects with left hemisphere atrophy and an aphasia presentation, where those with a nonfluent aphasia and perisylvian atrophy with motor speech impairment associate with tau pathology, while those with a fluent aphasia and left anterior temporal lobe atrophy associate with TDP-43 pathology.1