Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer’s disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562.

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Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline, and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human AD proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy.

Introduction There is a paucity of outcome data for prolonged (>48 hours) closed-suction drains following inflatable penile prosthesis (IPP) placement. Tissue dissection and corporal dilation make scrotal hematomas a potential complication within the first 72 hours following surgery. Maintaining a closed-suction drain represents a method to reduce scrotal hematoma formation and prevent sequela such as infection. However, maintaining a percutaneous tract also represents a feasible pathway for bacterial seeding of a new prosthesis. Given the severe consequences of prosthetic infection, establishing comparable outcomes for delayed drain removal is necessary. Objective To evaluate rates of infection, hematoma and device explantation in a multi-institutional cohort of patients undergoing IPP placement with delayed closed-suction drain removal (48-hour duration or greater) and compare observed outcomes to published outcomes in modern IPP cohorts. Methods Data was collected retrospectively for 209 patients undergoing virgin IPP placement with delayed closed-suction drain removal. Cases were performed by three surgeons at three high-volume centers between 01/01/2020 and 3/31/2022. R for Statistical Computing was used to generate descriptive statistics (Figure 1) and categorical data visualization (Figure 2). No quantitative statistical analysis was performed regarding infection outcomes as the low observed rate would not accommodate robust quantitative analysis. Results Mean drain duration was 66 hours (48 – 312, SD 23). There were 3 device infections (1.4%). Mean patient age was 64.5 years. 84 (40.2%) patients were diabetic, with a mean hemoglobin A1c of 7.2 in these patients. Both penoscrotal and infrapubic approaches were performed (95 versus 114). Reservoir location was either space of Retzius (SOR) or high submuscular (HSM) with the former being more common (164 versus 45). There were 7 (3.3%) post-operative hematomas and 6 patients (2.9%) required device revision for non-infectious causes. Mean follow up interval postoperatively was 170 days (10 – 421 days, SD 78). Conclusions Delayed removal of closed-suction drains after virgin IPP is safe. The outcomes for this study cohort are similar to outcomes reported in other modern virgin IPP series where closed-suction drains were not routinely employed. Prospective studies to further characterize how closed-suction drain placement influences hematoma formation, infection rates, and postoperative pain are necessary to definitively establish the role of delayed drain removal following IPP implantation. Disclosure No

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