Genetic & Neuroanatomic Associations in Sporadic Frontotemporal Lobar Degeneration (I5-1.002)

OBJECTIVE: To evaluate genetic and neuroanatomic associations in frontotemporal lobar degeneration (FTLD) and evaluate if single nucleotide polymorphisms (SNPs) confer risk of specific histopathological subtypes of FTLD. BACKGROUND: FTLD is pathologically heterogeneous and includes either tau (FTLD-tau) or TDP-43 (FTLD-TDP) inclusions. Genome wide association studies (GWAS) have revealed SNPs that are sensitive for FTLD-tau or FTLD-TDP, but the specificity of these SNP associations has not been comparatively evaluated. Neuroimaging studies show distinct atrophy patterns in FTLD-TDP and FTLD-tau mutation carriers, but anatomic associations of SNPs have not been evaluated in sporadic FTLD. We evaluated genetic and neuroanatomic associations using MRI and diffusion tensor imaging (DTI). We also assessed whether certain SNPs confer risk for a specific histopathological subtype of FTLD in an independent autopsy series DESIGN/METHODS: MRI, DTI, and blood DNA were collected in sporadic FTLD (N=92) patients. DNA was genotyped for 21 SNPs that GWAS and other studies have associated with either FTLD-tau or FTLD-TDP. We related MRI and DTI to SNPs using sparse canonical correlation analysis, a multivariate tool to identify associations between two matrices of multimodal data. In an independent autopsy series we related significant SNPs to neuropathological diagnosis of FTLD-tau (N=62) or FTLD-TDP (N=91) obtained using consensus criteria. RESULTS: We observed that rs8070723 (MAPT) was associated with grey matter in temporal cortex; and three SNPs including rs1768208 (MOBP), rs646776 (SORT1) and rs5848 (PGRN) were associated with white matter in the midbrain and superior longitudinal fasciculus (all p<0.001; 1000 permutations). In the autopsy series, rs8070723 (OR=3.4;p<0.0005) and rs1768208 (OR=1.7;p<0.05) conferred significant risk for FTLD-tau relative to FTLD-TDP, and rs646776 (OR=2.0;p<0.05) conferred increased risk for FTLD-TDP relative to FTLD-tau. CONCLUSIONS: We conclude that neuroanatomic and genetic associations contribute to our understanding of sporadic FTLD. Identified brain regions and SNPs may help provide an in vivo screen for the histopathologic basis of FTLD. Study Supported by: NIH: AG043503, T32-AG000255, AG017586, NS044266, AG032953, AG010124; Wyncote Foundation; Alfonso Martin Escudero Foundation Disclosure: Dr. McMillan has nothing to disclose. Dr. Toledo has nothing to disclose. Dr. Avants has nothing to disclose. Dr. Cook has nothing to disclose. Dr. Wood has nothing to disclose. Dr. Suh has nothing to disclose. Dr. Powers has nothing to disclose. Dr. Olm has nothing to disclose. Dr. Elman has nothing to disclose. Dr. McCluskey has nothing to disclose. Dr. Schellenberg has nothing to disclose. Dr. Lee has received personal compensation for activities with Pfizer Inc., Johnson & Johnson, MetLife, and Bristol-Myers Squibb Co. Dr. Lee has received royalty payments from PENN licenses and Eli Lily & Co., Inc. Dr. Lee has received research support from AstraZeneca and Bristol-Myers Squibb Co. Dr. Trojanowksi has received personal compensation for activities with Pfizer Inc., Johnson & Johnson, MetLife, and Bristol-Myers Squibb Co. as a consultant. Dr. Trojanowski has received royalty payments through Penn licenses. Dr. Trojanowksi has received research support from AstraZeneca and Bristol-Myers Squibb Co. Dr. Van Deerlin has nothing to disclose. Dr. Grossman has received personal compensation for activities with Allon Therapeutics.