Genetic and neuroanatomic associations in sporadic frontotemporal lobar degeneration

Neurobiol Aging. 2014 Jun;35(6):1473-82. doi: 10.1016/j.neurobiolaging.2013.11.029. Epub 2013 Dec 2.


Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that are sensitive for tau or TDP-43 pathology in frontotemporal lobar degeneration (FTLD). Neuroimaging analyses have revealed distinct distributions of disease in FTLD patients with genetic mutations. However, genetic influences on neuroanatomic structure in sporadic FTLD have not been assessed. In this report, we use novel multivariate tools, Eigenanatomy, and sparse canonical correlation analysis to identify associations between SNPs and neuroanatomic structure in sporadic FTLD. Magnetic resonance imaging analyses revealed that rs8070723 (MAPT) was associated with gray matter variance in the temporal cortex. Diffusion tensor imaging analyses revealed that rs1768208 (MOBP), rs646776 (near SORT1), and rs5848 (PGRN) were associated with white matter variance in the midbrain and superior longitudinal fasciculus. In an independent autopsy series, we observed that rs8070723 and rs1768208 conferred significant risk of tau pathology relative to TDP-43, and rs646776 conferred increased risk of TDP-43 pathology relative to tau. Identified brain regions and SNPs may help provide an in vivo screen for underlying pathology in FTLD and contribute to our understanding of sporadic FTLD.

Keywords: Biomarkers; Frontotemporal lobar degeneration; Genetics; Neuroimaging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Brain / pathology*
  • DNA-Binding Proteins / genetics*
  • Diffusion Tensor Imaging
  • Female
  • Frontotemporal Lobar Degeneration / genetics*
  • Frontotemporal Lobar Degeneration / pathology*
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Myelin Proteins / genetics
  • Neuroimaging
  • Polymorphism, Single Nucleotide / genetics*
  • Risk
  • tau Proteins / genetics*


  • Adaptor Proteins, Vesicular Transport
  • DNA-Binding Proteins
  • MAPT protein, human
  • MOBP protein, human
  • Myelin Proteins
  • tau Proteins
  • sortilin