Solange Akselrod Memorial Lectures Date: May 24, 2009 *** Lecture 1: *** Prof. Dan Adam (Technion) Title: Measurement of Cardiac Function - Still a Challenge Abstract: Early detection of remodeling process of the left ventricle (LV), which causes deterioration to heart failure, is critical. Proper treatment at the early stages (of such cardiomyopathy) may allow the LV to return to its normal function and structure. When the treatment is performed at the chronic stages of heart failure, it may cause actually deterioration of the LV function. It is known that efficient function of the left ventricle involves a wringing motion that facilitates ejection and filling. Previous studies reported that various pathologies, even at their early stages, affect the left ventricular global and local rotation. The present study was undertaken to develop myocardial rotation mapping technique of high spatial and temporal resolutions. Rotation maps were derived by processing of apical short-axis cine-echocardiograms in 10 normal human subjects utilizing a novel ultrasound speckle tracking method and high resolution processing. The results show heterogeneity among myocardial layers and at different locations, with larger rotations of the inner layers, and of the posterior wall versus the septum. In order to demonstrate the sensitivity of detection of pathologies at their early stages, rats were injected with Doxorubicin, a chemotherapeutic agent that has been reported to cause heart failure in patients, in order to follow the early stages of cardiomyopathy under controlled manners. Doxorubicin was administered intraperitoneally 5*/wk over four weeks in 8 Wistar rats. Other 2 Wistar rats were used as controls. Out of 8 Doxorubicin rats only 4 survived the full treatment. In these 4 treated rats there was a significant elevation in endocardial rotation (P= 0.006) in apical short axis level after 4-5 weeks of treatment (25.1 +/- 3.7 deg) versus baseline value of rotation (8.0 +/- 2.8 deg). Rotation value was tripled versus baseline value, while ejection fraction remained normal (78.5 +/- 3.5 %). Two rats being treated by Saline maintained normal values of rotation. Thus, echocardiographic mapping of LV rotation is feasible, allowing assessment of myocardial functional heterogeneity that may provide early indication of pathologies and remodeling. With Noa Bachner, Yossi Tsadok, Offir Ertracht, and Ofer Binah *** Lecture 2: *** Prof. Illana Gozes (TAU) Title: ADDRESSING ALZHEIMER'S DISEASE "TANGLES": PRECLINICAL DISCOVERY AND HUMAN EFFICACY OF AL-108 Abstract: AL-108 currently in clinical development for Alzheimer's disease (AD) and cognitive-impairment in schizophrenia is the intranasal formulation of a neuroprotective peptide (termed NAP). We discovered NAP (NAPVSIPQ) by peptide activity scanning of activity-dependent neuroprotective protein (ADNP), a protein essential for neuro-differentiation, brain formation and function. We found that NAP mechanism of action is associated with microtubule stability and reduction in tau pathology. Microtubules are key elements in the cellular cytoskeleton. Tau binds to the microtubule subunit - tubulin and enhances microtubule formation. Dysfunctional brain microtubules are associated with neuronal death and with the accumulation of pathological forms of tau. Recent pre-clinical data associated NAP with protection in several pathologies that involve tauopathies, including the ADNP knock-out mice, the triple transgenic Alzheimer's disease mice and mutant tau transgenic mice. Preliminary results suggest efficacy for intranasal NAP in a model of schizophrenia associated with dysfunctional microtubules. A case study from the NAP discovery and AL-108 development program will be presented to illustrate how discovery research and preclinical data were used toward Phase 2 clinical trials. Allon Therapeutics Inc. (http://www.allontherapeutics.com) recently released results of a Phase IIa clinical trial showing that its drug AL-108 has a positive impact on memory function in patients with amnestic mild cognitive impairment, a precursor to AD. Refs.: JBC 2004;279:28531; CNS Drug Rev. 2005;11:353; J Neuochem 2006;98:973;  CAR 2007;4:507; Pharmacol Ther 2007;114:146; JPET 2007;323:438; & 2008;325:146. Neurobiol of Disease 2009, In press. IG serves as Chief Scientific Officer, Allon Therapeutics. Support: Allon, Adams, Gildor, Elton, A.M.N.