Sex and age interact to determine clinicopathologic differences in Alzheimer's disease.

Women reportedly make up two-thirds of Alzheimer's disease (AD) dementia sufferers. Many estimates regarding AD, however, are based on clinical series lacking autopsy confirmation. The Florida Autopsied Multi-Ethnic (FLAME) cohort was queried for AD cases with a total of 1625 identified ranging in age from 53 to 102 years at death. Standard neuropathologic procedures were employed and clinical information was retrospectively collected. Clinicopathologic and genetic data (MAPT and APOE) were stratified by sex. Within the neuropathologically diagnosed AD cohort, the overall number of women and men did not differ. Men were younger at onset of cognitive symptoms, had a shorter disease duration, and more often had atypical (non-amnestic) clinical presentations. The frequency of autopsy-confirmed AD among women and men stratified by age at death revealed an inverse U-shaped curve in men and a U-shaped curve in women, with both curves having inflections at approximately 70 years of age. Regional counts of neurofibrillary tangles differed in women and men, especially when examined by age intervals. Women had overall greater severity of neurofibrillary tangle counts compared to men, especially in the hippocampus. Men were more often classified as hippocampal sparing AD, whereas limbic predominant AD was more common in women. Men and women did not differ in frequency of MAPT haplotype or APOE genotype. Atypical clinical presentations, younger age at onset and shorter disease duration were more frequent in men, suggesting that the lower reported frequency of AD in men may be due to more frequent atypical clinical presentations not recognized as AD. Our data suggest that neuropathologically diagnosed AD cases have the same frequency of women and men, but their clinical presentations and ages at onset tend to differ.

Porin Loss Impacts the Host Inflammatory Response to Outer Membrane Vesicles of Klebsiella pneumoniae.

Antibiotic-resistant strains of Klebsiella pneumoniae often exhibit porin loss. In this study, we investigated how porin loss impacted the composition of secreted outer membrane vesicles as well as their ability to trigger proinflammatory cytokine secretion by macrophages. We hypothesize that porin loss associated with antibiotic resistance will directly impact both the composition of outer membrane vesicles and their interactions with phagocytic cells. Using clonally related clinical isolates of extended-spectrum beta-lactamase (ESBL)-positive Klebsiella pneumoniae with different patterns of porin expression, we demonstrated that altered expression of OmpK35 and OmpK36 results in broad alterations to the protein profile of secreted vesicles. Additionally, the level of OmpA incorporation was elevated in strains lacking a single porin. Porin loss significantly impacted macrophage inflammatory responses to purified vesicles. Outer membrane vesicles lacking both OmpK35 and OmpK36 elicited significantly lower levels of proinflammatory cytokine secretion than vesicles from strains expressing one or both porins. These data demonstrate that antibiotic resistance-associated porin loss has a broad and significant effect on both the composition of outer membrane vesicles and their interactions with phagocytic cells, which may impact bacterial survival and inflammatory reactions in the host.