Premi E, Formenti A, Gazzina S, Archetti S, Gasparotti R, Padovani A, Borroni B.
Effect of TMEM106B Polymorphism on Functional Network Connectivity in Asymptomatic GRN Mutation Carriers.
JAMA Neurol. 2013 Dec 16;
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In this paper, Premi et al. describe the effect of the TMEM106B risk variant on functional connectivity in progranulin gene (GRN) mutation carriers, more specifically among asymptomatic carriers.
This study provides very valuable information about the early disease processes in frontotemporal dementia. However, such studies are difficult to perform because the frequency of these pathogenic mutations in the general population is very low and the identification of asymptomatic carriers very challenging. In any case, Premi et al. identified 17 asymptomatic individuals with the GRN Thr272fs mutation, and compared them to 14 noncarriers. Although these numbers would in most cases be too small to perform any kind of statistical comparison, the authors used a very clever design to increase the power of the analysis: They used genetic data to confirm that all the individuals come from a common genetic ancestor. This decreased the general heterogeneity of the subjects, and therefore increased the power.
The authors found significantly reduced brain connectivity in the frontoparietal network in the GRN carriers versus the noncarriers. They also found that among the asymptomatic GRN carriers, those with the TMEM106 risk variant had even further losses of brain connectivity in specific brain areas.
I think these findings clearly support the notion that the brain changes and pathology occur much earlier than the clinical symptoms. However, we would all like to know what the expected/estimated age at onset of the GRN carriers is, and that is something this study could not provide. Finally, this study also confirms that the TMEM106B is an important gene in modulating the risk of FTLD.