Myelin oligodendrocyte basic protein and prognosis in behavioral-variant frontotemporal dementia

Abstract

Objective: To determine the prognostic utility of tauopathy-associated single nucleotide polymorphisms (SNPs) in sporadic behavioral-variant frontotemporal dementia (bvFTD).

Methods: Eighty-one patients with sporadic bvFTD were genotyped for tauopathy-associated SNPs at rs8070723 (microtubule-associated protein tau [MAPT]) and rs1768208 (myelin-associated oligodendrocyte basic protein [MOBP]). We performed a retrospective case-control study comparing age at onset and disease duration between carriers of ≥1 polymorphism allele and noncarriers for these SNPs. Subanalyses were performed for autopsied subgroups with tauopathy (n = 20) and TDP-43 proteinopathy (n = 12). To identify a potential biological basis for disease duration, neuroimaging measures of white matter integrity were evaluated (n = 37).

Results: Carriers of risk allele (T) in rs1768208 (i.e., MOBP RA+) had a shorter median disease duration (TC/TT = 5.5 years, CC = 9.5 years; p = 0.02). This was also found in the subset of cases with autopsy-confirmed tauopathies (p = 0.04) but not with TDP-43 proteinopathies (p > 0.1). By comparison, polymorphisms at rs8070723 (MAPT) had no effect on disease duration (p > 0.1), although carriers of protective allele (G) in rs8070723 had a younger median age at onset (AG/GG = 54.5 years, AA = 58 years; p < 0.01). MOBP RA+ patients had increased radial diffusivity in the superior corona radiata and midbrain, and reduced fractional anisotropy in the superior corona radiata as well as superior and inferior longitudinal fasciculi compared with noncarriers (p < 0.01).

Conclusions: The rs1768208 risk polymorphism in MOBP may have prognostic value in bvFTD. MOBP RA+ patients have more severe white matter degeneration in bvFTD that may contribute to shorter disease duration. Future studies are needed to help confirm these findings.

Figure 1. Box plots of disease duration for the behavioral-variant frontotemporal dementia cohort

rs1768208 MOBP RA+ carriers of risk allele T (CT/TT) have a shorter median disease duration than noncarriers (CC) in (A) total cohort (p = 0.02) and (B) FTLD-tau subgroup (p = 0.04) but not (C) FTLD-TDP subgroup (p > 0.1). (D) FTLD-TDP and FTLD-tau have a similar disease duration (p > 0.1). FTLD-TDP = frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions; MOBP = myelin-associated oligodendrocyte basic protein; RA = risk allele.

Figure 2. Increased white and gray matter degeneration in direct comparison of patients with behavioral-variant frontotemporal dementia who are rs1768208 risk allele positive (CT/TT) to risk allele negative (CC)

(A) Regions of reduced fractional anisotropy (red). (B) Increased radial diffusivity (green). (C) Reduced gray matter density (blue).