This study used the automated technique of VBM to assess patterns of gray matter atrophy in groups of subjects with different MAPT mutations. Remarkably consistent patterns of gray matter atrophy were identified across subjects with the IVS10+16, IVS10+3, N279K, and S305N mutations. All 4 of these groups showed gray matter loss predominantly in the anterior temporal lobes, and particularly involving the medial temporal lobe structures. While subjects with P301L and V337M mutations also showed the most severe loss in the anterior temporal lobes, the loss was focused more on the lateral temporal cortex with relative sparing of the medial temporal lobe. These patterns of atrophy may help differentiate subjects with the P301L or V337M mutations from subjects with the IVS10+16, IVS10+3, N279K, or S305N mutations.
Medial temporal lobe atrophy therefore seems to be a striking feature of the IVS10+16, IVS10+3, N279K, and S305N mutations. Previous studies of individual mutations have found similar results, although no studies have compared multiple mutations. Severe medial temporal lobe atrophy has been observed in a couple of VBM studies that assessed subjects with the IVS10+1621
mutations, and medial temporal lobe atrophy and 18-F-fluoro-deoxyglucose PET hypometabolism have been observed in individual cases of N279K mutation carriers.23
Predominant temporal lobe atrophy has also been reported in subjects with the S305N mutation.24,25
In contrast to the findings in the IVS10+16, IVS10+3, N279K, and S305N mutations, subjects with the P301L and V337M mutations showed gray matter loss predominantly in the lateral temporal lobes. In fact, subjects with the P301L or V337M mutations, when grouped together, showed significantly more involvement of the lateral temporal lobes than the subjects with other MAPT
mutations on direct comparison. A comparison in the opposite direction showed that the subjects with mutations in IVS10+16, IVS10+3, N279K, or S305N showed greater medial temporal lobe atrophy than the P301L or V337M subjects. These results are in keeping with the fact that performance on the test of episodic memory was better on average in the P301L and V337M mutation carriers (average score of 5 vs 2).
The severity and distribution of gray matter loss varied across the different MAPT
mutations. This may in part be due to variability in the time from disease onset to the time of scan across the groups. For example, the V337M group showed a widespread pattern of gray matter loss and had an average time from onset to scan of 20 years, which is longer than any of the other MAPT
mutation groups, suggesting that they may be further along in their disease course than the other groups. However, the P301L subjects also showed widespread loss including the frontal lobes but had a relatively short time from onset to scan of only 4 years, which suggests either that frontal lobe loss is an early feature of P301L mutations or P301L mutations may have a more rapidly progressive disease, and therefore atrophy has spread further through the brain in the same time. Previous studies have typically reported both temporal and frontal atrophy in P301L patients,8,26–28
and others have suggested that P301L subjects are rapidly progressive.8
We also identified severe involvement of the basal ganglia in both the P301L and V337M subjects. Basal ganglia involvement has been previously observed in single P301L cases.27,29
Similarly, the S305N subjects showed gray matter loss in the frontal and parietal lobes but had a short time from onset to scan, although this group only consisted of 2 subjects. Subjects with P301L, V337M, and S305N also performed more poorly on tests of dementia severity (CDR-SB and STMS) than subjects with the other mutations. Therefore, although disease duration could account for the widespread pattern of atrophy observed in the V337M group and even possibly in the P301L group, it seems that S305N may simply be a more severe phenotype given that the disease duration was short (1–3 years). Further investigation with larger numbers of subjects will be needed to determine whether the involvement of the frontal and parietal lobes are mutation specific or consequences of variability in disease duration. Nevertheless, the P301L and V337M groups showed a fundamentally different anatomic pattern of temporal lobe involvement compared with the other mutations which survived in the analysis that corrected for time from onset to scan and therefore could not be a product of simple differences in disease severity. These patterns of atrophy may therefore be useful in distinguishing subjects with the P301L and V337M mutations from those with the IVS10+16, IVS10+3, N279K, or S305N mutations.
The IVS10+16, IVS10+3, N279K, and S305N mutations are all predicted to cause disease by influencing the alternative splicing of tau pre–messenger RNA (mRNA).7,30
They all increase the splicing of exon 10, thus changing the ratio between 3R and 4R tau isoforms and resulting in an increase in 4R tau. Mutation S305N located at the splice site of exon 10 and intronic mutations, IVS10+16 and IVS10+3, are predicted to directly affect a stem-loop RNA structure spanning the splice donor site of intron 10,5,31
whereas mutation N279K has been proposed to increase the inclusion of exon 10 by strengthening a cis-acting polypurine element. The P301L and V337M mutations are also located in exon 10, but in contrast to the other mutations, they do not affect splicing of exon 10 but instead affect the structure and functional properties of the tau protein.7,30
Tau proteins that contain the P301L and V337M mutations are more favorable substrates for phosphorylation32
and hence lead to the aggregation of tau.7,30,33
This dichotomy in function across the mutations seems to correlate with the dichotomy observed in the patterns of temporal lobe atrophy, suggesting a possible relationship between the effect of the mutation on tau and the resultant patterns of atrophy in MAPT
mutation carriers. However, how these different disease mechanisms may influence these anatomic changes is unclear, and further investigation will be needed to investigate whether this relationship generalizes to different mutations.
Although the numbers of subjects in our MAPT
groups were small, we have found evidence that the P301L and V337M mutations have different patterns of atrophy to the IVS10+16, IVS10+3, N279K, and S305N mutations. A feature that is consistent across all these mutations was the fact that all showed the greatest degree of loss in the anterior temporal lobes, which explains the poor performance on tests of memory and naming observed in all the MAPT
mutation groups. We have previously shown that this feature helps to differentiate subjects with mutations in MAPT
from those with mutations in progranulin.9
Indeed, as we have previously published, some of these patients were given an initial diagnosis of mild cognitive impairment or Alzheimer disease9
reflecting the memory impairment. The predominance of IVS10+16, IVS10+3, N279K, and S305N mutation carriers in our previous study explains why we found significant anteromedial temporal lobe atrophy in our group of MAPT
Our results also suggest that there may be a possible association between mutation function and atrophy, with mutations that influence splicing of tau pre-mRNA showing medial temporal volume loss and mutations affecting protein structure showing lateral temporal loss. Future studies will need to expand on these results, particularly with a view to understanding the relationship among disease mechanisms, pathology, and brain atrophy in FTLD.