Purpose

The Alzheimer’s Association is launching a new initiative to stimulate further research and development of new approaches to image molecular changes associated with early neurodegenerative processes in living humans, animal models and cells. The Association’s Request for Applications (RFAs) is aimed at supporting new high-risk exploratory approaches to stimulate new directions of research in molecular imaging. The RFA is designed to enable preliminary pilot research or proof-of-principle studies that can provide data for further research support by other funding agencies.

Background

Tremendous advances have been made in the field of radiological imaging in patients with Alzheimer’s disease. MRI, functional MRI, PET, and SPECT are all showing great promise as diagnostic tools. Nevertheless, the best value for imaging will come from an ability to detect more subtle changes preceding the onset of clinical symptoms. 

The best way to detect those at risk for developing Alzheimer's is to have good imaging or biological markers. Existing markers are not yet fully validated, and some of the markers under investigation are markers of clinical rather than biological phenotype. For example, there is currently no obvious way to measure loss of synapses or dendrites, metabolic changes, alteration in membrane potentials or integrity, protein expression or structural changes at the nanoscale. Finding a way to measure any, or even one, of these parameters represents a huge scientific challenge. The Association’s goal for this RFA is to lay some groundwork, stimulate research and promote novel approaches. 

Potential themes

Based on a "think tank” discussion, the Association puts forth several themes that may be particularly worthy of further research. Grant proposals could address, but are not limited to, the following areas of study: 

1. Blood-brain barrier (BBB) carriers.
Currently, one of the major limitations to brain imaging is finding tracer molecules that easily pass the BBB. This is a complex problem because tracer molecules are often conjugated to carrier molecules that bind targets of interest. Conjugates are often poor candidates for brain penetration. There are ways to temporarily open the BBB, such as using focused ultrasound, or osmotic agents, but these methodologies are not perfect.

2. BBB as an early pathogenic mechanism; endothelial integrity, repair, and function.
Breaches in the BBB can lead to infiltration of immune and other cells and molecules that may trigger inflammatory or adverse reactions in the brain. Measuring BBB integrity is technically challenging, but being able to image when the BBB is not working optimally could yield some useful information.

Vascular dementia is well studied and some vascular change occurs in Alzheimer's, but exactly how the vascular system contributes to Alzheimer's pathology is not clear. What fraction of endothelial cell repair in brain vessels is carried out by local cells, for example? And how do different sized blood vessels in the brain correlate with areas that are most pathologically susceptible? There are also varying degrees of inflammation in the brain in people with Alzheimer's, which may be related to blood vessel pathology and BBB compromise. Amyloid has also been shown to be toxic to endothelial cells, which adds another level of complexity. And it is unclear how endothelial cell function and properties change with age. All these factors may impact blood vessel function. While there are ways to study blood vessels—pulse transit time is used to measure elasticity, for example—the methodologies are relatively unsophisticated. More refined measurement may reveal some relevant relationships.

At a finer scale, transporters in the vessels are key for keeping the brain sated with nutrients, minerals, etc. Are these transporters compromised, and would it be possible to find ways to image transporter function?

3. Algorithm for composite analysis of ADNI data.
The Alzheimer Disease Neuroimaging Initiative (ADNI) is collecting a vast amount of longitudinal data, such as blood and CSF biomarkers, MRI, CSF Aβ and tau, PIB PET, and the data will be open source. However, a composite analysis is needed that takes all the data into account and can come up with sensitive and reliable measures that predict progression to MCI or Alzheimer's.

4. Markers of early diagnosis.
To find out exactly how the disease begins to manifest, it is imperative to look at the very earliest changes that occur in the brain. One approach would be to look at presymptomatic people with autosomal dominant familial Alzheimer’s disease. However, findings from that group may not be relevant to people with sporadic Alzheimer’s. An alternative approach would be to look at groups that are at higher risk for developing the disease, such as those with a family history of sporadic Alzheimer's, cardiovascular disease, ApoE4 genotype, or diabetes. Obtaining longitudinal imaging and biomarker data on those groups prior to the emergence of mild cognitive impairment may help to detect the earliest pathogenic changes. There is a need to push the envelope technologically and use these at-risk groups as a basis for improving current imaging modalities, rather than just repeating other ongoing population studies.

5. Agents to measure soluble beta-amyloid (Aβ) assemblies and other molecules of interest.
Agents that measure Aβ typically do not detect soluble forms of Aβ or do not distinguish between fibrillar and oligomeric soluble forms of the peptide. Finding a compound that fulfills this requirement is a major challenge because agents that do bind soluble forms are likely to bind insoluble Aβ as well. Since most of the Aβ in the brain resides in the insoluble plaques, it is not clear how soluble and insoluble amyloid can be distinguished. It may be possible to develop compounds with the right affinity and kinetics, or to develop compounds that can serve as a scaffold upon which the signal can be amplified further, much like a pro-drug. The pro-drug approach might also work to image other molecules of interest in Alzheimer' pathology, such as the beta- and gamma-secretases and kinases that phosphorylate tau.

6. Non-invasive evaluation of brain membrane potential.
There are indications that amyloid toxicity may lead to an imbalance in neural network activity and in the flow of ions across the cell membrane. Calcium influx may be particularly toxic to the cell, but technically this may be difficult to measure. Measuring changes in the ratio of intra- and extracellular sodium and potassium may be more tractable. In fact, recent advances in whole body imaging, namely increases in the power of the magnetic field, has allowed these measurements, albeit not at very high resolution. Nevertheless, the technique may reveal patterns of functional neuronal alterations in the Alzheimer brain. Other technical hurdles are worth exploring, such as the need for high levels of replacement ions such as rubidium and lithium. 

7. Proteomic, lipidomic, and other metabolomic approaches to broadly profile molecular changes in the brain.  
MR spectroscopy and related approaches could be combined in potentially powerful ways with analyses of postmortem tissues or blood/CSF sampling.

8.  Neural responses to functional challenges.
There is currently no equivalent to a “stress test” for Alzheimer's disease, though there is evidence that people with mild cognitive impairment exhibit differences in fMRI signals during memory tasks. Does the brain respond differently when faced with additional challenges? One possibility is to find ways to objectively measure changes during psychological challenges that might highlight differences between early or presymptomatic patients and controls using conventional and new imaging approaches described above.
 
9. Cellular energetics.
Alzheimer’s disease has been linked to mitochondrial dysfunction and increased oxidative stress in the cells of the brain but it is not clear if changes to the energetics of the cell contribute to the disease. It is also not clear how cellular energetics can be measured. There is a need to find ways of probing cellular metabolism and energetics to explore their relation to disease.

General considerations

Any proposal must have a human connection. Proposals that simply study animal models will not be looked on favorably. Any study that uses animal models must clearly and explicitly demonstrate potential methods of translating and relating findings to the human condition. Ultimately, the goal is to translate the research into strategies to block the earliest presymptomatic processes leading to Alzheimer's.

Because the principle idea is to encourage studies into new technologies and high-risk ventures and translation of this novel technology to human studies, a multidisciplinary approach might be most fruitful. Therefore, the Association strongly encourages submissions from collaborative research teams (e.g., basic scientists and clinical researchers). In addition, while novel and creative ideas are sought, proposals also need to demonstrate feasibility.

The Alzheimer's Association recognizes the need to increase the number of scientists from underrepresented groups in the research enterprise. Researchers from these groups are encouraged to apply.

General requirements

Funding and award period: The Association anticipates funding up to 3 Molecular Imaging awards. Each award is limited to $400,000 (direct and indirect costs) for two to three years. Requests in any given year may not exceed $200,000 (direct and indirect costs). Indirect costs are capped at 10 percent (rent for laboratory/office space is expected to be covered by indirect costs paid to the institution).

Eligibility: Researchers with full-time staff or faculty appointments are encouraged to apply.  Molecular Imaging applications from post-doctoral candidates will not be accepted. 

Deadlines and award dates:  Letters of intent (LOIs) must be received by 5:00 p.m. EASTERN STANDARD TIME, December 1, 2008.  LOIs will not be accepted after this date. No exceptions will be made.

Once the LOI is approved by the Alzheimer’s Association, applications must be received by 5:00 p.m. EASTERN STANDARD TIME, January 8, 2009.  Scientific and technical review will be conducted from February through May 2009.

The second-level review by the Medical and Scientific Advisory Council will be conducted during June 2009. Funding will be awarded by July 2009.

Mechanism of award, reporting requirements and allowable costs:  The mechanism of the award is the individual research grant.  The maximum allowable duration is three years. Annual progress and financial reports are required. Continuation of the grant over the awarded duration is contingent upon the timely receipt of scientific and financial reports. 

Allowable costs under this award:

• It is required that most of the funds awarded under this program be used for direct research support.   

Allowable costs under this award include: 

• Purchase and care of laboratory animals
• Small pieces of laboratory equipment and laboratory supplies
• Computer equipment if used strictly for data collection
• Travel (up to $1,000 per year)
• Salary for the principal investigator, scientific (including post-doctoral fellows) and technical staff (including laboratory technicians and administrative support related directly to the funded project) 

Costs not allowed under this award include:

• Tuition 
• Computer hardware or software for investigators
• Rent for laboratory/office space
• Construction or renovation costs

Budget:  A “budget summary” for the proposed research project is required and must be submitted with the application and within the allowable page limits. However, if the application is to be awarded, a more detailed budget will be required and must be approved prior to the disbursement of funds. Your budget must not exceed the maximum amount of the award ($400,000 for Molecular Imaging).

For more information: E-mail grantsapp@alz.org or call 1.312.335.5747