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 5 20) and TDP-43 proteinopathy (n 5 12). To identify a potential biological basis for disease duration, neuroimaging measures of white matter integrity were evaluated (n 5 37).Results: Carriers of risk allele (T) in rs1768208 (i.e., MOBP RA1) had a shorter median disease duration (TC/TT 5 5.5 years, CC 5 9.5 years; p 5 0.02). This was also found in the subset of cases with autopsy-confirmed tauopathies (p 5 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 5 54.5 years, AA 5 58 years; p , 0.01). MOBP RA1 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 RA1 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. Neurology ® 2014;83:502-509 GLOSSARY AD 5 Alzheimer disease; ALS 5 amyotrophic lateral sclerosis; bvFTD 5 behavioral-variant frontotemporal dementia; FA 5 fractional anisotropy; FTD 5 frontotemporal dementia; FTLD 5 frontotemporal lobar degeneration; GM 5 gray matter; GMD 5 gray matter density; ILF 5 inferior longitudinal fasciculus; MAPT 5 microtubule-associated protein tau; MOBP 5 myelin-associated oligodendrocyte basic protein; PA 5 protective allele; PSP 5 progressive supranuclear palsy; RA 5 risk allele; RD 5 radial diffusion; SCR 5 superior corona radiata; SLF 5 superior longitudinal fasciculus; SNP 5 single nucleotide polymorphism; STG 5 superior temporal gyrus; TDP-43 5 TAR DNA-binding protein 43; WM 5 white matter.Significant heterogeneity exists in the natural history of behavioral-variant frontotemporal dementia (bvFTD), the most common clinical phenotype in frontotemporal lobar degeneration (FTLD) spectrum pathology. Approximately equal numbers of cases appear to be attributable to the 2 main broad categories of proteinopathies 1,2 : those containing pathologic aggregations of the microtubule-associated protein, tau (i.e., FTLD-tau), 3 and those with inclusions composed of the RNA-b...

Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine

“…Simultaneous evaluation of multiple SNPs from autopsy-confirmed FTLD GWAS [89, 207] finds several SNPs over-expressed in FTLD-Tau or FTLD-TDP in a clinically mixed group of sporadic autopsy-conformed cases [153]. In a study of sporadic bvFTD, the risk allele in FTLD-Tau associated SNP in MOBP was associated with a shorter disease duration and WM loss on DTI in the midbrain and long association fibers [104]. These studies highlight the potential usefulness of SNP genotyping as diagnostic and prognostic markers, although future studies in large populations of FTD patients with known pathology from diverse ethnic backgrounds are needed for confirmation of these associations.…”

Immunoreactivity of myelin‐associated oligodendrocytic basic protein in Lewy bodies

“…1,[4][5][6] However, the localization of MOBP in the human nervous system has not yet been investigated. Recent advances in genome analysis have revealed that mutation in MOBP is a risk factor for Alzheimer's disease (AD) with apolipoprotein E ε4, 7,8 progressive supranuclear palsy (PSP), [9][10][11][12][13] corticobasal degeneration (CBD), 9 amyotrophic lateral sclerosis (ALS) 14 and frontotemporal lobar degeneration (FTLD) 15,16 Furthermore, proteomics analysis has shown that MOBP is a component of cortical Lewy bodies (LBs) in specimens obtained from patients with dementia with LBs (DLB) using laser microdissection. 17 These reports prompted us to investigate whether MOBP is involved in a variety of neurodegenerative diseases.…”

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

“…2b, Table 1 and Supplementary Tables 12–14). SNPs in the MOBP locus have been reported to be associated in a GWAS on progressive supranuclear palsy (PSP) 13 and to act as a modifier for survival in frontotemporal dementia (FTD) 14 . The putative pleiotropic effects of variants in this locus suggest that ALS, FTD and PSP share a neurodegenerative pathway.…”