Funded Programs Early Detection

Preclinical development of plasma based AD diagnostic test using a combination of antibody administration and stable isotope labeling kinetics

Summary:
One of the hallmarks of Alzheimer's disease is the presence of amyloid plaques in the brain. One of the main constituents of the plaques is the peptide amyloid beta. Over the last decade, research from animals and humans have pointed to plaques as a leading cause for the progression of Alzheimer's disease and research in humans have shown that amyloid plaques are most likely present in the brain before any clinical signs of Alzheimer's disease (such as memory loss) are present. It has also become clear over the past decade that in order to develop therapeutics that can prevent or slow down the progression of Alzheimer's disease it is important to diagnose as early as possible. Ideally such a diagnostic test would be easy to administer and have high predictive value. In this proposal, C2N Diagnostics will seek to develop a blood based diagnostic test which will assess the level of plaques in the brain and thus allow pre-clinical diagnosis of Alzheimer's disease. This will greatly aid in the clinical trials for amyloid plaque modifying therapeutics and once such drugs get approved this test could be an important screening test to select people that should be on such drugs.

Axonal Density as a Non-Invasive Biomarker for the Early Prediction and Monitoring of Alzheimer\'s Disease: an MRI Pilot Study

Summary:
This study aims to determine whether a new non-invasive neuroimaging biomarker providing information on the tissue integrity of brain white matter is useful for the early diagnose and monitoring of Alzheimer\'s disease (AD). So far, structural MRI measures of brain volumes are used to predict the onset of AD and monitor the progression of the disease. We have recently developed a new MRI method that measures diffusion and is specifically sensitive to microstructural changes in the brain such as demyelination and loss of fibers in the brain white matter. We hypothesize that this method will be a sensitive marker for AD prior to the sensitivity of conventional MRI methods. Therefore, we plan to perform a cross-sectional study in a group consisting of 1) patients with AD, 2) individuals with mild cognitive impairment (MCI) that are likely to convert to AD, and 3) healthy elderly controls in which we will test if our new markers are able to reliably discriminate between those three groups. In addition, we will compare our new MRI method with structural MRI in order to see which method is more sensitive to changes in early AD. The essential innovation in this proposal is the use of diffusion kurtosis imaging (DKI), currently the only clinically available method that provides specific information on the brain white matter integrity such as axonal density and degree of myelination. Our DKI MRI method is a clinically feasible method that requires no contrast or ionizing radiation and takes less than 15 minutes. MRI is currently widely available and our technique is easy to implement, making it an ideal biomarker for early diagnose of Alzheimer\'s disease and testing of new treatments.

Fine-mapping and characterization of genetic biomarkers that facilitate the acceleration of drug discovery for frontotemporal dementias

Summary:
Frontotemporal dementia (FTD) is the fourth most common form of dementia, yet substantial heterogeneity still characterizes its clinical diagnosis. Family history surveys suggest FTD to be significantly heritable. While various genetic mutations have been identified which explain some of the clinical differences between FTD sub-types, much of the clinical variability remains unexplained. Based on our genetic findings in late-onset Alzheimer\'s disease (AD), we propose two hypotheses on the role of complex genetic biomarkers (e.g. poly-T tracts, insertion/deletions, mutations, expansions) in risk and age-of-onset of FTD. The first hypothesis is that a complex genetic polymorphism, displayed as a variable length sequence of T nucleotides in the TOMM40 gene (rs10524523), influences the age-of-onset for FTD. Indeed, our previous work has shown the pivotal role of rs10524523 in modifying the age-of-onset of the related AD pathology. The second hypothesis is that the strong association signal in the TMEM106B gene region, reported using our Duke ADRC FTD cases, is due to a complex variant which can be uniquely tested using evolutionary (phylogenetic) analyses of highly accurate sequencing data of a gene region. Application of this type of analysis to the study of human neurodegenerative diseases is a unique strength of our group. Overall, findings by us and others, indicate a functional and clinical relevance of complex genetic biomarkers that may prove relevant for FTD as well. The proposed study is innovative because no similar work has yet comprehensively investigated genetic biomarkers related to complex variants in TOMM40 and TMEM106B in well-characterized FTD cases. Completion of this work will augment FTD subtyping, potentially providing a means of enriching delay-of-onset clinical trials with subjects most likely to progress to FTD in a given time-frame, and may provide biological basis for the development of effective therapeutic approaches to delay the onset and progression of FTD.

Use of Targeted Multiplex Proteomic Strategies to Identify Cerebral Spinal Fluid-Based Biomarkers in Alzheimer\'s Disease.

Summary:
Although a major goal of the Alzheimer\'s Disease Neuroimaging Initiative (ADNI) project has been the creation of a brain imaging and biomarker database with rapid public access to all raw and processed data, no funds were included in the initial ADNI proposal for exploratory bio-fluid proteomic or metabolomic work. As a result, the ADNI Industry Scientific Advisory Board (ISAB) convened a small group of proteomic/ metabolomic experts to develop an add-on proposal with the intent of characterizing promising bio-fluid biomarker candidates for Alzheimer\'s Disease (AD). The first phase of this project, a plasma-based proteomic proposal, has already been approved and funded by the Biomarkers Consortium and is currently an active project being executed by the Consortium. The present proposal represents a follow-on to the first phase of this project (the plasma-based study) and will seek to qualify a Cerebral Spinal Fluid-based (CSF-based) multiplex panel using the same patient cohort.

Australian Imaging, Biomarkers and Lifestyle study of Ageing (AIBL)

Summary:
The Australian Imaging, Biomarkers and Lifestyle study of Ageing (AIBL) is a multicentre study of 600 healthy elderly persons, 200 individuals with Mild Cognitive Impairment (MCI) and 200 subjects with mild Alzheimer\'s disease (AD). These subjects have undergone neuropsychological assessment and blood collection. A portion of these subjects will also undergo brain imaging to assess brain morphology, using MRI, and brain plaque levels, using PET scan with PiB binding. The study is designed with a baseline and 18 month follow-up time point. Both baseline and 18 month imaging data is available to researchers through the Alzheimer\'s Disease Neuroimaging Initiative (ADNI) website with the support of Alzheimer\'s Association and permit pooling of neuroimaging data and for validation of ADNI findings. Baseline imaging of the AIBL cohort has shown that plaque deposition is almost inevitable with advanced age and that plaque burden is similar at all ages in AD. Preliminary analysis of the 18 month data shows that brain plaque burden changes very slowly. Therefore much longer follow-up than 18 months will be required to fully assess the rate and pattern of plaque deposition and its relationship to brain structural and cognitive changes over time. This grant will permit a 36 month follow-up of brain imaging with clinical assessment in the subcohort of AIBL (287 subjects).