Funded Programs Early Detection

Prototype development for the Guided Neuropsychological Evaluation system for the early detection and differential diagnosis of Alzheimer's disease Investigator(s): Andrew Blackwell, PhD Institution(s): Cambridge Cognition

Summary:
Cambridge Cognition Ltd (CCL) develops and markets software based medical devices based upon the world leading CANTAB technology invented at the University of Cambridge. This highly validated technology is already used by many of the world's leading researchers focusing on neurodegenerative diseases, and, in addition, is increasingly used by pharmaceutical companies in the drug development process. A series of independent studies have demonstrated that CANTAB measures of visuospatial associative learning and semantic memory are sensitive in detecting the earliest signs of prodromal Alzheimer's disease (up to 32 months prior to clinical diagnosis) both in memory clinic attendees (Fowler et al., 1995, Fowler et al., 1997; Fowler et al., 2002; Swainson et al., 2001; Blackwell et al., 2004) and in community dwelling cohorts of individuals classified as asymptomatic using current clinical measures (De Jager et al., 2002); De Jager et al., 2005). CCL now intends to take this core technology into mainstream healthcare with a particular focus on improving the early detection and diagnosis of Alzheimer's disease. This is a particularly important and large unmet need which, given the impending registration of disease modifying drugs is now more urgent than ever.

Predicting conversion from MCI to AD via 4-dimensional pattern analysis and classification of ADNI imaging data Investigator(s): Christos Davatzikos, PhD Institution(s): University of Pennsylvania

Summary:
The investigators will apply computer-based image analysis for early detection of structural patterns of brain change that characterize the development of Alzheimer’s diseaes in persons with amnestic mild cognitive impairment and identify patterns that predict which patients are likely to convert from MCI to AD. The project will use data from the Alzheimer\'s Disease Neuroimaging Initiative (ADNI), a $60 million longitudinal study primarily funded by the NIH, the pharmaceutical industry, and by ISOA. The ADNI generates enormous amounts of longitudinal data on AD that is being made publicly available for research through supplemental funds. This proposal therefore represents excellent leverage of ISOA funds.

Proteomic Technologies for the Analysis of the Disease Modifying Effects of IVIg Immunotherapy Investigator(s): Kelvin Lee, PhD Institution(s): Cornell University

Summary:
Significant progress has been made in identifying molecules involved in Alzheimer’s disease. However, there are currently no validated biomarkers for AD that aid in preclinical diagnosis, early diagnosis, or in the monitoring of the effectiveness of drugs in clinical trials or in clinical use. One approach to the identification of biomarkers relies on proteomic analysis of cerebrospinal fluid (CSF). This approach has the potential to account for the multifactorial nature of the disease. There is evidence that univariate tests based on changes in CSF protein expression (for example of tau, phosphoTau, or Aβ42) may have some utility, but none of these offer significant improvement over a detailed clinical examination by an experienced physician. By relying on new statistical methods well-suited to proteomic analysis, the investigators have identified a panel of 23 biomarkers that offer a significant opportunity to improve current diagnostic methods. Current proteomic approaches depend on two-dimensional gel electrophoresis (2DE) as the primary method for detecting these 23 biomarkers. The development of nanobiotechnology-based proteomic methods for the detection of these biomarkers offers significant scientific and practical advantages in terms of sensitivity and specificity. In this study, the investigators will develop nanotechnology based, proteomic methods for the development of a panel of biomarkers that can be used in the early diagnosis of AD. The test will also be used for the monitoring of therapy in a clinical trial of intravenous immunoglobulin (IVIg).

Novel Behavioral Screening Tools for Memory Assessment in Rodents and Humans Investigator(s): Mark A. Gluck, PhD Institution: Rutgers University

Summary:
We propose to develop novel behavioral assessment tools for detecting mild memory impairments (and improvements) that can be used both in mouse models of AD as well as in non-demented elderly and MCI patients. The project is collaborative with the Mayo Clinic, with the transgenic mouse work to be done with Michelle Nicolle at Mayo-Jacksonville, and the parallel human longitudinal MCI->AD conversion studies to be done with Ronald Petersen at Mayo-Rochester. This work will address a high priority need for current AD research: better behavioral paradigms for translational research between rodents and humans. These need to be sensitive to the selective assessment of memory impairments due to dysfunction to the septo-hippocampal memory circuits seen in MCI and early AD. There are three things that make our work unique: (1) our tasks directly translate from rodent to human studies for better pre-clinical to clinical translation of results, (2) our tasks are theoretically motivated by specific neuro-computational theories of the hippocampus in learning and memory (see Gluck & Myers, 2001, MIT Press book, Gateway to Memory: An Introduction to Neural Network Models of Learning and the Hippocampus), and (3) we have already collected and published evidence that our human tasks are highly predictive of very mild hippocampal atrophy seen in non-demented elderly and early MCI which others have shown is predictive of conversion to AD (Myers et al, 2002, 2003). Our tasks are more sensitive at predicting this early mild hippocampal-region atrophy than current standard neuropsychological memory tests Ultimately, this program of research will lead to a novel battery of behavioral tests, standardized across rodents and humans, that researchers can use to evaluate new Alzheimer\'s drugs that target the earliest stages of the disease.

Mindsteams Cognitive Testing for Early Diagnosis and Longitudinal Follow-up of Dementia: A Validation Study Investigator(s): Ely Simon, MD Institution(s): NeuroTrax, LTD