The spectrum of cognitive impairment including Alzheimer’s Disease and Related Dementias after liver transplantation

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PROJECT SUMMARY Our highly successful multi-center Functional Assessment in Liver Transplantation (FrAILT) Study, funded by the NIH since 2013, has definitively characterized physical frailty in patients with cirrhosis undergoing liver transplantation (LT) and provided the foundation to codify physical frailty assessment through national guidelines for cirrhosis/LT patient management. As we closed the knowledge gap around physical frailty, we identified a new gap in LT patients—cognitive “frailty”, or more precisely, the manifestation of cognitive impairment. In 2 pilot studies, we found that 30-60% of LT recipients met criteria for cognitive impairment. Yet, currently, the spectrum of post-LT cognitive impairment—from subtle attentional changes to Alzheimer’s Disease and Related Dementias (ADRD)—is not well characterized. As a result, clinicians do not screen for cognitive impairment in the post-LT setting, and LT patients are not referred to specialists for timely diagnosis/management. In this competing renewal, we will leverage our multi-center FrAILT Study to address this unmet need. We hypothesize that LT patients experience premature cognitive syndromes, including ADRD, after LT (relative to the general population), that cognitive impairment impacts post-LT global functional health, and that physical frailty is a major predictor of post-LT cognitive impairment. There is strong scientific premise for these hypotheses, as many risk factors for cirrhosis are linked with cognitive impairment. These include common ADRD comorbidities (e.g., diabetes, hypertension), heavy alcohol use, hepatic encephalopathy, post-LT delirium, and immunosuppression. Physical frailty itself, prevalent in LT patients, shares common pathways with ADRD. The scientific goal of this competing renewal is to deeply characterize the spectrum of cognitive impairment including ADRD in post-LT patients. To accomplish this, we will extend the FrAILT Study at 6 U.S. sites and expand our assessment protocol with neurocognitive screening in ~2,000 post-LT FrAILT patients. Additionally, we will establish new “neuro- hepatology” collaborations with 5 of our sites’ AD Research Centers (ADRC) to conduct deep cognitive profiling—through comprehensive neurocognitive assessments and brain imaging—in 150 post-LT patients who display cognitive impairment. Specifically, we aim to: 1) Characterize the prevalence/incidence of and identify factors associated with post-LT cognitive impairment and evaluate its association with post-LT global functional health; 2) Characterize trajectories of cognitive function in the first year post-LT; 3) conduct deep cognitive profiling to differentiate among the etiologies of dementia. Our established multi-center FrAILT Study is uniquely poised to address this enormous unmet need for deep characterization of cognitive impairment in LT patients who have a high burden of conventional ADRD risks but have traditionally been excluded from ADRD studies. Further, we will develop a novel cohort with rich cognitive data that may yield novel insights into liver- and transplant-related contributors to ADRD in other (general, solid organ transplant) populations.