Lack of association between acute stroke, post-stroke dementia, race, and ß-amyloid status.

INTRODUCTION: Stroke and Alzheimer disease share risk factors and often co-occur, and both have been reported to have a higher prevalence in African Americans as compared to non-Hispanic whites. However, their interaction has not been established. The objective of this study was to determine if preclinical Alzheimer disease is a risk factor for stroke and post-stroke dementia and whether racial differences moderate this relationship. METHODS: This case-control study was analyzed in 2019 using retrospective data from 2007 to 2013. Participants were adults age 65 and older with and without acute ischemic stroke. Recruitment included word of mouth and referrals in Saint Louis, MO, with stroke participants recruited from acutely hospitalized patients and non-stroke participants from community living older adults who were research volunteers. Our assessment included radiologic reads of infarcts, microbleeds, and white matter hyperintensitites (WMH); a Pittsburgh Compound B PET measure of cortical ß-amyloid binding; quantitative measures of hippocampal and WMH volume; longitudinal Mini Mental State Examination (MMSE) scores; and Clinical Dementia Rating (CDR) 1 year post-stroke. RESULTS: A total of 243 participants were enrolled, 81 of which had a recent ischemic stroke. Participants had a mean age of 75, 57% were women, and 52% were African American. Cortical amyloid did not differ significantly by race, stroke status, or CDR post-stroke. There were racial differences in MMSE scores at baseline (mean 26.8 for African Americans, 27.9 for non-Hispanic whites, p = 0.03), but not longitudinally. African Americans were more likely to have microbleeds (32.8% vs 22.6%, p = 0.04), and within the acute stroke group, African Americans were more likely to have small infarcts (75.6% vs 56.8%, p = 0.049). CONCLUSION: Preclinical Alzheimer disease did not show evidence of being a risk factor for stroke nor predictive of post-stroke dementia. We did not observe racial differences in ß-amyloid levels. However, even after controlling for several vascular risk factors, African Americans with clinical stroke presentations had greater levels of vascular pathology on MRI.

Increased tumor localization and reduced immune response to adenoviral vector formulated with the liposome DDAB/DOPE.

UNLABELLED: We aimed to increase the efficiency of adenoviral vectors by limiting adenoviral spread from the target site and reducing unwanted host immune responses to the vector. We complexed adenoviral vectors with DDAB-DOPE liposomes to form adenovirus-liposomal (AL) complexes. AL complexes were delivered by intratumoral injection in an immunocompetent subcutaneous rat tumor model and the immunogenicity of the AL complexes and the expression efficiency in the tumor and other organs was examined. Animals treated with the AL complexes had significantly lower levels of beta-galactosidase expression in systemic tissues compared to animals treated with the naked adenovirus (NA) (P<0.05). The tumor to non-tumor ratio of beta-galactosidase marker expression was significantly higher for the AL complex treated animals. NA induced significantly higher titers of adenoviral-specific antibodies compared to the AL complexes (P<0.05). The AL complexes provided protection (immunoshielding) to the adenovirus from neutralizing antibody. Forty-seven percent more beta-galactosidase expression was detected following intratumoral injection with AL complexes compared to the NA in animals pre-immunized with adenovirus. CONCLUSIONS: Complexing of adenovirus with liposomes provides a simple method to enhance tumor localization of the vector, decrease the immunogenicity of adenovirus, and provide protection of the virus from pre-existing neutralizing antibodies.

Subcutaneous Administration of a Replication-Competent Adenovirus Expressing HSV-tk to Cotton Rats: Dissemination, Persistence, Shedding, and Pathogenicity.

Since human adenoviruses replicate only in human cells, toxicology studies with adenoviral vectors are hampered by the lack of a permissive nonhuman host. Before a replication-competent adenoviral vector expressing HSV-tk (Ad.OW34) can be used in clinical studies for intratumoral injections in patients with cutaneous lesions of head and neck cancer or intralesional injection for in situ vaccination strategy in advanced metastatic melanoma patients, risks have to be estimated in animal studies. In an attempt to assess potential toxicology, dissemination, persistence and shedding, we injected Ad.OW34 subcutaneously into cotton rats. (Sigmodon hispidus), which are considered a semi-permissive host for human adenoviruses. The animals underwent one or two subcutaneous injection cycles with 2.3 x 10(12) viral particles/kg each or a single course with 6.9 x 10(13) viral particles/kg and were analyzed at defined time points for histopathological changes in the brain, heart, lungs, spleen, liver, kidneys, ovaries, and skin. Additionally, these tissues as well as urine, feces, mouth, and skin swabs were analyzed at multiple time points by real-time quantitative polymerase chain reaction for the presence of vector sequences. The only significant treatment-related histopathologic finding was dermatitis with mild acanthosis at the site of vector injection. All other tissues evaluated were within normal limits or showed changes that were most likely incidental or spontaneous in nature. Vector sequences were detected in the skin at the injection site and to a lesser extent in the liver, spleen, and lungs. In addition, small amounts of vector DNA were detected in the ovaries. The vector sequences were rapidly cleared and the absence of viral sequences in the excreta and swabs of the majority of animals suggest that there was no significant replication of the vector in this host. The administration of Ad.OW34 was also associated with mild hyperamylasemia, lymphocytosis, and granulocytosis; however, we did not observe any clinical signs of illness or death in the experimental animals over the course of the study.