Citations

ABSTRACTBackground: The tau PET ligand 2‐((1E,3E)‐4‐(6‐([11C]methylamino)pyridin‐3‐yl)buta‐1,3‐dienyl)benzo[d]thiazol‐6‐ol ([11C]PBB3) binds to a wide range of tau pathology; however, binding property of PBB3 to non‐tau inclusions remains unknown. To clarify whether [11C]PBB3 binds to α‐synuclein pathology, reactivity of PBB3 was assessed by in vitro fluorescence and autoradiographic labeling of brain sections from α‐synucleinopathies patients.Method: Of 10 pure Lewy body disease and 120 multiple system atrophy (MSA) cases in the Mayo Clinic brain bank, we selected 3 Lewy body disease and 4 MSA cases with a range of α‐synuclein severity based on the quantitative analysis of α‐synuclein burden. PBB3 fluorescence labeling, double or single immunostaining for α‐synuclein and phospho‐tau, Prussian blue staining, and in vitro autoradiography with [11C]PBB3 were performed for these selected samples.Results: PBB3 fluorescence labeled various α‐synuclein lesions including Lewy bodies, Lewy neurites, spheroids, glial cytoplasmic inclusions, and neuronal cytoplasmic inclusions. Meanwhile, autoradiographic labeling with [11C]PBB3 at 10 nM demonstrated no significant binding in Lewy body disease cases. In contrast, significant autoradiographic binding of [11C]PBB3 to the striatopallidal fibers was found in 2 MSA cases, which had high densities of glial cytoplasmic inclusions without tau or iron deposits in this region.Conclusions: Given that the maximum concentration of [11C]PBB3 in human PET scans is approximately 10 nM, the present data imply that α‐synuclein pathology in Lewy body disease is undetectable by [11C]PBB3‐PET, whereas those in a subset of MSA cases with high densities of glial cytoplasmic inclusions could be captured by this radioligand. © 2017 International Parkinson and Movement Disorder Society

Objectives To examine the association between vascular pathology and rate of cognitive decline in older adults independent of Alzheimer's disease ( AD ) pathology. Design Prospective cohort study. Setting Community sample. Participants Individuals from the Einstein Aging Study autopsy series (N = 62). Measurements The Blessed Information‐Memory‐Concentration ( BIMC ) test was used to assess global cognitive status. AD pathology was quantified according to Braak stage (<3 vs ≥ 3). Vascular pathology was quantified using a previously reported macrovascular lesion ( MVL ) score. The association between vascular pathology and antemortem rates of cognitive decline adjusted for level of AD pathology was assessed using linear mixed‐effects models. Results Mean age was 81.8 at enrollment and 89.0 at death. Participants with more than two MVL s had faster cognitive decline than those with no MVL s (difference in annual rate of change in BIMC 0.74 points/yr, P = .03). Braak stage was also associated with cognitive decline (difference 0.57 points/yr, P = .03). The difference in rate of cognitive decline between those with more than two MVL s and those free of vascular lesions persisted after adjustment for AD pathology (difference in rate of change in BIMC 0.68 points/yr, P = .04). The effect of vascular pathology on cognitive decline was not significantly different according to AD pathology. Conclusion Vascular brain pathology is associated with rate of cognitive decline after adjusting for level of AD pathology.

Poly(GP) proteins are a promising pharmacodynamic marker for developing and testing therapeutics for treating C9ORF72 -associated amyotrophic lateral sclerosis.

Abstract Introduction We sought to determine whether a systems biology approach may identify novel late‐onset Alzheimer's disease (LOAD) loci. Methods We performed gene‐wide association analyses and integrated results with human protein‐protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions. Results We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1 , and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H , and APP were differentially expressed in the temporal cortex. Discussion Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.

Abstract Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome‐wide association study (GWAS) for late‐onset AD in Stage 1 sample including whites of European Ancestry, African‐Americans, Japanese, and Israeli‐Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome‐wide significant (GWS) associations in single‐nucleotide polymorphism (SNP)–based tests ( P < 5 × 10 −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1‐AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence ( P < 2.7 × 10 −6 ) for gene‐based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.