ATTENTION DEFICITS IN THE TGF344-AD RAT MODEL OF ALZHEIMER’ S DISEASE ARE ASSOCIATED WITH SYMPTOMS OF POSTOPERATIVE DELIRIUM FOLLOWING SEVOFLURANE ANESTHESIA

Abstract Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia worldwide. While memory loss is a hallmark of AD progression, individuals in the early stages of AD often experience challenges in sustaining focus (Perry et al., 1999). This compromised attentional capacity may render them particularly vulnerable to postoperative delirium (POD), a common complication characterized by a state of confusion and inattention following emergence from anesthesia. Currently, the precise relationship between attention deficits in AD and susceptibility to POD is unclear. Developing animal models capable of interrogating this association will be critical for developing targeted interventions to mitigate the risk of POD in vulnerable populations. Aims & Objectives The aim of this study was to characterize the development of sustained attention deficits in adult TgF344-AD rats, a model of AD that recapitulates human AD neuropathology (Cohen et al., 2013), over 18 months using the 5-Choice Serial Reaction Time Task (5CSRTT), a touchscreen task of attention and memory. We hypothesized that attentional deficits would precede memory loss in TgF344- AD rats and contribute to poorer cognitive outcomes following general anesthesia. Methods TgF344-AD rats (N=18) and their wildtype littermates (N=17) were tested twice a week for 18 months on the 5CSRTT to assess progressive changes in sustained attention and working memory. 5CSRTT performance over time and across genotypes was captured by generalized estimating equations. At 18 months, both groups were anesthetized with sevoflurane and placed supine in the testing chamber to recover the righting reflex, a proxy for return of consciousness. Following righting, rats were tested on the 5CSRTT to capture recovery of cognitive function in the hours and days following anesthetic emergence. To test the association between sustained attention and post-anesthetic cognitive recovery, baseline attention scores were correlated with latency to recover attention in the 5CSRTT by linear regression. Results There was a significant interaction between age and genotype on sustained attention performance on the 5CSRTT (p=.0070), with TgF344-AD rats displaying more severe age-related attention deficits than littermate controls. Further, working memory was not significantly impacted by age nor across genotypes, suggesting that deficits in sustained attention precede memory impairments in the TgF344-AD rat model of AD. Compared with age-matched wildtype littermates, 18-month-old TgF344-AD rats show significant delays in recovering attention following sevoflurane anesthesia (p =.0239) and these cognitive deficits persist up to 48 hours following anesthetic exposure. Finally, severity of baseline attentional deficits was significantly correlated with post-anesthetic cognitive recovery latency (p=.0131). Discussion & Conclusion In the prodromal stage of AD, prior to the onset of memory impairments, TgF344-AD rats develop progressive sustained attention deficits. Moreover, a connection between baseline attention deficits and susceptibility to POD-like symptoms following sevoflurane anesthesia was identified. Taken together, these results suggest a significant role for attentional impairments, an early marker of AD neuropathology, in exacerbating the risk of POD. References PERRY, R.J., HODGES, R.H., 1999. Attention and executive deficits in Alzheimer's disease: A critical review, Brain,122, 383–404. COHEN, R. M., REZAI-ZADEH, K., WEITZ, T. M., RENTSENDORJ, A., GATE, D., SPIVAK, I., BHOLAT, Y., VASILEVKO, V., GLABE, C. G., BREUNIG, J. J., RAKIC, P., DAVTYAN, H., AGADJANYAN, M. G., KEPE, V., BARRIO, J. R., BANNYKH, S., SZEKELY, C. A., PECHNICK, R. N. &TOWN, T. 2013. A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric abeta, and frank neuronal loss. J Neurosci, 33, 6245-56.