Not all of the mysteries of life lie in our genetic code. Some can be found buried in our membranes. These shells of fat, sculpted in the central nervous system into the cellular (and subcellular) boundaries of neurons and glia, are themselves complex systems of information. The diversity of neural phospholipids, coupled with their chameleon-like capacity to transmute into bioactive molecules, provides a vast repertoire of immediate response second messengers. The effects of compositional changes on synaptic function have only begun to be appreciated. Here, we mined 29 neurolipidomic datasets for changes in neuronal membrane phospholipid metabolism in Alzheimer's Disease (AD). Three overarching metabolic disturbances were detected. We found that an increase in the hydrolysis of platelet activating factor precursors and ethanolamine-containing plasmalogens, coupled with a failure to regenerate relatively rare alkyl-acyl and alkenyl-acyl structural phospholipids, correlated with disease severity. Accumulation of specific bioactive metabolites [i.e., PC(O-16:0/2:0) and PE(P-16:0/0:0)] was associated with aggravating tau pathology, enhancing vesicular release, and signaling neuronal loss. Finally, depletion of PI(16:0/20:4), PI(16:0/22:6), and PI(18:0/22:6) was implicated in accelerating Aβ42 biogenesis. Our analysis further suggested that converging disruptions in platelet activating factor, plasmalogen, phosphoinositol, phosphoethanolamine (PE), and docosahexaenoic acid metabolism may contribute mechanistically to catastrophic vesicular depletion, impaired receptor trafficking, and morphological dendritic deformation. Together, this analysis supports an emerging hypothesis that aberrant phospholipid metabolism may be one of multiple critical determinants required for Alzheimer disease conversion.

Cognitive decline is sexually dimorphic in Alzheimer's disease (AD). Men show higher incidences of amnestic mild cognitive impairment yet women disproportionally phenoconvert to AD. It is hypothesized that men maintain greater cognitive reserve than women under comparable amyloid-β (Aβ) challenge. One behavioral aspect of cognitive reserve in mice is the capacity to cope with Aβ-associated stereotypies by switching to increasingly effective navigational search strategies in the Morris water maze. To explore inherent sex differences in this paradigm, however, we require an AβPP mouse model wherein behavioral flexibility is impaired earlier in females than males despite equivalent Aβ load. Here, we show that when F1 C57Bl/6×C3H/HeJ TgCRND8 mice are placed on C57Bl/6 background, N5 Tg males and females exhibit equivalent Aβ pathologies at 2, 4, 6, and 8 months of age yet females display learning and memory deficits earlier than males. We further show that this N5 line does not carry the autosomal recessive pde6brd1 mutation that impairs visual acuity and that the estrous cycle is not disrupted on this genetic background. At 5.5 months of age, Tg males, but not females, compensate for Aβ-associated stereotypic behaviors (i.e., hyperactive tight circling) by alternating navigational search strategies and adopting increasingly productive spatial search strategies. Females fail to overcome Aβ-associated stereotypies and do not efficiently switch from systematic to spatial learning strategies. Together, these data identify a novel AβPP mouse model that can be used for preclinical testing of interventions targeting sexual dimorphisms in behavioral indices of cognitive reserve.

With the current push towards using fewer antipsychotics and more non-pharmacological interventions in long-term care, it has become increasingly important for knowledge and best-practice sharing across the province. The “Good Ideas” project began in 2001 in the context of my work as a Royal Ottawa geriatric psychiatry behavioural support outreach nurse to long-term-care facilities in Ottawa. A toolkit was begun as various ideas and tools were found to be useful in the management of behavioural challenges in the care of long term care residents. These non-pharmacological tools can have a significant impact on the management of behavioural challenges. Some were discovered via “out-of-the-box” thinking, some as a result of exploring possibilities on the Web, others were shared with me by colleagues in various roles and settings. I have worked in geriatric psychiatry in various capacities as a nurse at The Royal Ottawa Health Care Group since 1986, and have had the opportunity to accumulate several “good ideas” over time. I found myself carrying various articles, pamphlets, booklets, photos in my workbag and noticed I was being contacted more frequently over time on how to obtain certain items. When these non-pharmacological approaches were implemented, and successful, a common response would be: “what a good idea!” Thus, the name given to the project came to be. Good Ideas has grown over the years as the information has been shared with outreach team members and utilized in their own practice. All contacts are encouraged to share any new “good ideas” they encounter so those too can be added. Originally a hardcopy handout with a list and the resources to outsource items was created and distributed. This evolved into a PowerPoint presentation explaining the usefulness of each tool in specific target behaviours and how to obtain the tool, as well as photos. Later a poster was made and a second version was produced more recently. Currently the project is in the process of being translated to French for our bilingual Ottawa area. The project has circulated among my teammates to be used in education sessions in their long-term-care facilities or as an adjunct to larger full day education sessions on the topic of dementia care. A large colorful hatbox also contains some sample items to add to the hard copies. Good Ideas has been presented at the Regional Geriatric Program Annual Meeting poster presentation Oct 12, 2013, with very positive feedback from participants. Good Ideas is a project in perpetuity, with no stop date planned. It is my hope it will continue to grow long after my retirement date. It promotes the concept of creative thinking about behavioural challenges in dementia care, while supporting that pharmacological intervention should most often be as a last resort.

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