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28 C Plasma TNF increases after surgery Surgery impaired fear memory is restored with pre-op anti-TNF Generated patent, licensed from Kennedy Inst. for treatment of POCD with anti- TNF Evidence That TNF Plays a Role in POCD In mice Forsberg A et al, Annals of Neurology (2017) 81:4, 572-582 Kazmierski J et al, International Psychogeriatrics (2014), 26:5, 845–855 In humans • Mice subjected to surgery (open tibial fracture) experience a rapid increase in plasma TNF levels (A) - not caused by anesthesia alone (B) • Administration of pre-operative anti-TNF reduces freezing behavior, indicative of contextual fear memory, characteristic of cognitive decline (C) • Surgery in humans triggers TNF release, and is associated with reduced brain activity cognitive decline (1,2) Plasma TNF increases after surgery and correlates with post operative delirium (1) Clark IA, Vissel B. Front Neurosci (2018) 12:257. (2) Alam A et al, EBioMedicine (2018) 37:547-556 Post-op TNF-a (pg/ml) NON-DELIRIOUS (n=72) DELIRIOUS (n=41) OR (95% CI) P value 10.5 (7.65-12.65) 13.4 (10.5-16.7)* 1.12 (1.036-1.210) 0.001 TNF-alpha Pg/ul Preop Postop day 3-4 Time Postop 3 months * 5 4 3 2 1 0 * A 15 10 5 0 Naive 30m 1h 2h 6h 12h TNF a (pg/ml) ND B TNF a (pg/ml) Naive 30m 1h 2h 6h 12h 24h 10 5 0 ND ND ND ND * 80 60 40 20 0 % freezing Naive N + Ab S S + Ab 180 Life Sciences Corp. www.180lifesciences.com Q4 2020