NYU Langone investigators to present new research at 2014 Alzheimer's Association International Conference

(Press-News.org) (New York, NY, July 12, 2014) - Researchers from the Center for Cognitive Neurology (CCN) at NYU Langone Medical Center, NYU School of Medicine, and the Nathan S. Kline Research Institute will present new findings at the 2014 Alzheimer's Association International Conference in Copenhagen, Denmark, July 12 – 17, 2014. The Center for Cognitive Neurology is a multidisciplinary, integrated center devoted to research, clinical care and clinical advances toward the treatment and cure of neurological diseases affecting cognition -- focused on memory, language, attention, auditory, visual and thinking difficulties. The Center is comprised of the Silberstein Alzheimer's Institute which houses the Alzheimer's Disease Center (ADC) and the Pearl I. Barlow Center for Memory Evaluation and Treatment; and basic, translational and clinical research is conducted within more than 20 major NYU centers, programs and laboratories. The focus is on improving the understanding and treatment of diseases and injuries to the nervous system. Neurologists and neuroscientists conduct research in the risks, predictors, prevention, diagnostic tests and potential treatments for Alzheimer's disease (AD), Lewy Body dementia (LBD), vascular dementia, prion disease, mild cognitive impairment, and other related conditions, and have expertise in evaluating, diagnosing and treating individuals with brain conditions that affect memory and/or thinking (cognition). The Center works closely with the NYU Neuroscience Institute, the NYU Parkinson and Movement Disorders Center, the Center for Brain Health, and the Nathan S. Kline Institute for Psychiatric Research. The NYU Alzheimer’s Disease Center is one of 29 Alzheimer's disease research centers in the United States supported by the National Institute on Aging (NIA). As an NIA-supported research facility, the center's goals are to advance current knowledge and understanding of brain aging and Alzheimer's disease, to expand the numbers of scientists working in the field of aging and Alzheimer's research, to work toward better treatment options and care for those living with memory impairment, and most importantly, share these findings with healthcare providers, researchers, and the general public to enhance the care of those affected by Alzheimer’s disease and related dementia. Breaking news from the Alzheimer's Conference. Please call us for either.

Presentations Symposium Name: Non-amyloid Based Therapies, 8:30am-10:00 am S1-02-04 - Sunday, July 13, 2014, 9:30am – 9:50am - Oral Presentation (includes q and a) "Tau Immunotherapies" Author: Sigurdsson, E.M., PhD Tau immunotherapy has great potential for Alzheimer's disease and other tauopathies. Compared to amyloid-β, clearing pathological tau proteins is likely to be effective later in the disease, as the degree of tau pathology correlates better with dementia severity than amyloid-β plaque burden. Both active and passive tau immunizations against various epitopes are effective in mouse models, and one Phase 1 study with a tau immunogen is already underway. Most companies, however, are focused on developing tau antibodies for proof of concept clinical studies. The active approach remains riskier but has excellent future potential, in particular if it can be tailored to the individual's haplotype to maximize beneficial immune response and minimize adverse reactions. The efficacy in the mouse studies can be explained by both extra- and intracellular antibody-mediated clearance of tau aggregates. The importance of each pathway may depend on the properties of the antibodies, the stage of the disease and the experimental model. Some of the positive effects of active tau immunotherapy may also in part be related to favorable T-cell responses, which have not been thoroughly studied in this context. The increased focus in recent years on the tau protein for therapy has renewed interest in it for diagnosis. Beside a few β-sheet dyes that have advanced into clinical trials, antibodies and their derivatives should be considered and are likely to be more specific for pathological tau lesions. We have shown those to reliably enter the brain and identify mice with brain tau pathology in vivo after peripheral injection. The short half-life of the fragments is particularly suitable for imaging. Such targeting may provide valuable information on the tau epitope profile of each patient to tailor therapy for maximal efficacy and safety. Further development of tau antibodies and their derivatives as therapies is likely to advance their use as diagnostic probes as well. Hopefully, these approaches will be shown to be effective in clinical trials in the near future. Better understanding of the mechanisms involved should lead to improved efficacy of such therapies and enhance the accuracy of related diagnostic agents for tauopathies and other protein aggregation diseases.

Monday, July 14, 2014 at 4:00pm - Oral Presentation – Platform Talk "Mitochondria And Death Receptors: Key Targets For Amyloid Toxicity In The Cerebral Vasculature" Silvia Fossati, PhD, Research Assistant Professor of Pathology, NYU School of Medicine, Patrizia Giannoni, Mar Hernandez, Joan Montaner, Jorge Ghiso, Agueda Rostagno Background: The vascular deposition of amyloid, known as Cerebral Amyloid Angiopathy (CAA), is an age-associated condition featured in about 90% of Alzheimer's disease cases. CAA compromises cerebral blood flow and can cause cerebral hemorrhage and cognitive impairment. Very little is known about the mechanisms initiating the amyloid beta (Abeta)-dependent degeneration of cerebral endothelial cells in CAA. Here, we aim to identify the molecular events underlying the apoptotic cascade generated by Abeta in cerebrovascular cells and to pinpoint new targets for drug discovery. Conclusions: Overall, our data suggests a primary contribution of TRAIL death-receptors and mitochondrial dysfunction in Abeta-induced vascular cell death, unveiling new cellular targets for therapeutic intervention.

O3-14-02 - Tuesday, July 15, 2014, 4:00pm to 5:30pm - Oral Presentation "Targeting the Shared Pathological Conformers of both Aß and Hyperphosphylated Tau with a Conformationally Selective Monoclonal Antibody" Author Block Thomas Wisniewski1, Eleanor Drummond2, Krystal Herline2, Yanjie Sun2, Fernando Goni2, 1New York University School of Medicine, New York, New York, United States, 2NYU School of Medicine, New York, New York, United States Background: Currently there is no effective therapy for AD. Immunomodulation stills hold promise but current attempts only address one aspect of the pathology: either amyloid ß (Aß) or the hyperphosphorylated tau (ptau) protein. Furthermore current approaches are not specific for the pathological conformers of either protein. We have developed a novel immunomodulatory approach using a pBri peptide. ABri is a rare form of familial human amyloidosis associated with a missense mutation in a stop codon resulting in the transcription of an intronic sequence, leading to production of a highly amyloidogenic protein with a carboxyl terminus that has no sequence homology to any native human protein. We hypothesized that through conformational mimicry the polymerized Bri peptide (pBri) could induce a conformation selective immune response that will recognize pathological proteins such as oligomeric tau and Aß. We have tested this approach in APP/PS1, 3xTg and TgSwDI AD mouse models and have documented that use of pBri as an immunogen reduces: amyloid plaques, vascular amyloid deposits and neurofibrillary tangles. Using pBri we have developed monoclonal antibodies (mAbs). Currently we are characterizing one such mAb specific for pathological conformers of Aß and tau. Conclusions: We have developed a novel immunization procedure which we have used to produce monoclonal antibodies (mAbs) that recognize multiple pathological proteins, including PrP Res, oligomer A b and ptau. We are characterizing one of these mAbs, TAB1, which gives selective immunolabeling in AD tissue and on Western blots to pathological conformers. We believe that immunotherapy that specifically targets the most toxic, oligomeric forms of Aß and ptau, has a greater chance of success with much less risk of toxicity.

Session Title: Neuroimaging: Imaging Animal Models O4-02-02 - July 16 2014 from 2:15 pm - 3:45 pm – Oral Presentation "Tau Antibody Derivatives as Diagnostic Imaging Agents for Tauopathies" Abstract Authors: Krishnaswamy, S., Lin, Y., Rajamohamedsait, W.J., Rajamohamedsait, H.B., Krishnamurthy, P.K., Pedersen, J.T., Stavenhagen, J.B., Sigurdsson, E.M., Background: Diagnostic imaging agents targeting amyloid-β (Aβ) in Alzheimer's disease (AD) are already in clinical use. Such tau probes are needed to monitor AD progression, the efficacy of tau-targeting therapies, and to identify Aβ negative tauopathies. Antibody-derived ligands are likely to provide excellent specificity for detecting tau lesions, and in particular smaller single chain variable antibody fragments (scFv's) are attractive for in vivo imaging of tau aggregates. Conclusion: Tau scFv's are promising as novel diagnostic markers for AD and related tauopathies, and have therapeutic potential as well.

"Clinical Trials III" Thursday, July 17th, 2014 - 11:30am - 1:00 pm – Oral Presentation "1 Year Global Outcome of a Comprehensive, Individualized, Person Centered Management (CI‐PCM) Program + Memantine in Advanced AD: A Randomized Controlled Trial" Authors: Reisberg, B., Boksay, I., Golomb, J., Agarwal, S., Ghimire, S., Shaker, H., Torossian, C., Xu, J., Kenowsky, S. Background: The worldwide approval of memantine a decade ago, highlighted both treatment possibilities and ongoing treatment needs of persons with moderate to severe AD. Recognizing these needs, we investigated the added value of a Comprehensive, Individualized, Person Centered Management Program (CI‐PCM) in AD persons receiving memantine treatment. Conclusions: At 28 weeks of treatment, a direct comparison of the magnitude of the effect of the CIPCM program on the NYU CIBIC‐Plus global measure indicated a 900% increment over that of memantine treatment alone (2.7 versus 0.3). This absolute effect magnitude of the CI‐PCM vs. memantine alone increases to 3.3 at 52 weeks 11 times the effect of mementine alone at 28 weeks. We conclude that great benefits, perhaps 11 x those of medication, can be achieved with scientific management in persons with advanced AD.

Posters Imaging Pre-Conference: Saturday, July 12, 2014 - 12:45pm – 2:45pm - Poster "Tau Antibody Derivatives as Diagnostic Imaging Agents for Tauopathies" Authors: Krishnaswamy, S., Lin, Y., Rajamohamedsait, W.J., Rajamohamedsait, H.B., Krishnamurthy, P.K., Pedersen, J.T., Stavenhagen, J.B., Sigurdsson, E.M., Background: Diagnostic imaging agents targeting amyloid-β (Aβ) in Alzheimer's disease (AD) are already in clinical use. Such tau probes are needed to monitor AD progression, the efficacy of tau-targeting therapies, and to identify Aβ negative tauopathies. Antibody-derived ligands are likely to provide excellent specificity for detecting tau lesions, and in particular smaller single chain variable antibody fragments (scFv's) are attractive for in vivo imaging of tau aggregates. Methods: Libraries of scFv's were generated from tau antibody hybridomas using phage display technology. Numerous phospho-tau (P-Ser396,404) selective scFv's were identified by ELISA and characterized further by immunoprecipitation, histology and Biacore. Subsequently, the diagnostic imaging utility for tauopathies was assessed for one of the scFv's and compared to its parent antibody using In Vivo Imaging System (IVIS) for proof of concept prior to PET studies. Results: The scFv's showed strong selectivity for phospho-tau vs. non-phospho-tau epitope in ELISA, pulled down tau proteins from AD brains, and bound to pathological tau in AD and Pick's disease brain sections. The potential diagnostic imaging utility of one of these, with the best phospho-tau selectivity on Biacore (1x10-8 M vs. 4x10-3 M for non-phospho-tau), was characterized further by IVIS. Intracarotid or intravenous scFv injection led to a strong IVIS brain signal in transgenic tauopathy mice, that correlated nicely with scFv signal from brain tissue (r=0.97, p END