Background Significant heterogeneity in clinical features of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) cases with the pathogenic C9orf72 expansion (C9P) have been described. To clarify this issue, we compared a large C9P cohort with carefully matched non-expansion (C9N) cases with a known or highly-suspected underlying TDP-43 proteinopathy. Methods A retrospective-cohort study using available cross-sectional and longitudinal clinical and neuropsychological data, MRI voxel-based morphometry (VBM) and neuropathological assessment from 64 C9P cases (ALS=31, FTLD=33) and 79 C9N cases (ALS=36, FTLD=43). Results C9P cases had an earlier age of onset (p=0.047), and in the subset of deceased patients, an earlier age of death (p=0.014) than C9N. C9P had more rapid progression than C9N: C9P ALS cases had a shortened survival (2.6±0.3 years) compared to C9N ALS (3.8±0.4 years; log-rankλ2=4.183,p=0.041), and C9P FTLD showed a significantly greater annualized rate of decline in letter fluency (4.5±1.3words/year) than C9N FTLD (1.4±0.8words/year, p=0.023). VBM revealed greater atrophy in the right fronto-insular, thalamus, cerebellum and bilateral parietal regions for C9P FTLD relative to C9N FTLD, and regression analysis related verbal fluency scores to atrophy in frontal and parietal regions. Neuropathologic analysis found greater neuronal loss in the mid-frontal cortex in C9P FTLD, and mid-frontal cortex TDP-43 inclusion severity correlated with poor letter fluency performance. Conclusions C9P cases may have a shorter survival in ALS and more rapid rate of cognitive decline related to frontal and parietal disease in FTLD. C9orf72 genotyping may provide useful prognostic and diagnostic clinical information for ALS and FTLD patients.

3D-printed bioactive ceramic scaffolds can restore critical mandibular segmental defects to levels similar to native bone after 8 weeks in an adult rabbit, critical sized, mandibular defect model.

Background: Alveolar clefts are traditionally treated with secondary bone grafting, but this is associated with morbidity and graft resorption. Although recombinant human bone morphogenetic protein-2 (rhBMP-2) is under investigation for alveolar cleft repair, safety concerns remain. Dipyridamole is an adenosine receptor indirect agonist with known osteogenic potential. This study compared dipyridamole to rhBMP-2 at alveolar cleft defects delivered using bioceramic scaffolds. Methods: Skeletally immature New Zealand White rabbits underwent unilateral, 3.5 × 3.5-mm alveolar resection adjacent to the growing suture. Five served as negative controls. The remaining defects were reconstructed with three-dimensionally printed bioceramic scaffolds coated with 1000 μm of dipyridamole (n = 6), 10,000 μm of dipyridamole (n = 7), or 0.2 mg/ml of rhBMP-2 (n = 5). At 8 weeks, new bone was quantified. Nondecalcified histologic evaluation was performed, and new bone was evaluated mechanically. Statistical analysis was performed using a generalized linear mixed model and the Wilcoxon rank sum test. Results: Negative controls did not heal, whereas new bone formation bridged all three-dimensionally printed bioceramic treatment groups. The 1000-μm dipyridamole scaffolds regenerated 28.03 ± 7.38 percent, 10,000-μm dipyridamole scaffolds regenerated 36.18 ± 6.83 percent (1000 μm versus 10,000 μm dipyridamole; p = 0.104), and rhBMP-2–coated scaffolds regenerated 37.17 ± 16.69 percent bone (p = 0.124 versus 1000 μm dipyridamole, and p = 0.938 versus 10,000 μm dipyridamole). On histology/electron microscopy, no changes in suture biology were evident for dipyridamole, whereas rhBMP-2 demonstrated early signs of suture fusion. Healing was highly cellular and vascularized across all groups. No statistical differences in mechanical properties were observed between either dipyridamole or rhBMP-2 compared with native bone. Conclusion: Dipyridamole generates new bone without osteolysis and early suture fusion associated with rhBMP-2 in skeletally immature bone defects.