P4‐359: PRISM II: AN OPEN‐LABEL STUDY TO ASSESS THE SAFETY, TOLERABILITY, AND EFFECTIVENESS OF DEXTROMETHORPHAN 20 MG/QUINIDINE 10 MG (NUEDEXTA®) IN PSEUDOBULBAR AFFECT (PBA) SECONDARY TO DEMENTIA, STROKE, OR TRAUMATIC BRAIN INJURY (TBI)–EARLY RESULTS OF TRIAL

explanation for the paradoxical findings. Methods: Hyman and colleagues have demonstrated in the mouse taoupathy model that NFT formation does not lead rapidly to cell death (de Calignon, 2011). Rather, NFT-containing neurons appear to be long-lived and able to revert to a normal state (Polydoro, 2013). We have modeled the inferred biology and run simulations using Vensim PLE+, version 6.2Results: The rate of neuronal loss, which in this framework is directly related to the absolute size of the NFT-containing neuron pool, follows a distinctive pattern: an initial increase; a build to a near plateau due to reversion to normal neurons and establishment of an equilibrium between NFT formation and reversion; a decline after the peak, driven by decrease in the size of the pool of NFT-containing neurons due to neuronal death. Importantly, we maintained the same k ATR, representing neurodegenerative stress, over time. Thus this model accounts for an increase in the absolute number of neurons dying per unit time, and associated CSF-ptau, in the initial phases of disease followed by a decline despite constant neurodegenerative stress.The model further predicts that interventions that blocks neuronal loss from the NFT-containing neuron pool (i.e. prevented neurodegeneration) should lead to an acute decrease, rather than preventing an increase, in CSF-ptau. Conclusions: Reductions in CSF-ptau in advanced Alzheimer’s can be accounted for by a biological model in which the number of neurons dying per unit time is related to the size of the pool of long-lived NFT-containing neurons.