NIH – Center without Walls for PET Ligand Development for Alzheimer’s disease related dementias (ADRDs) (U19 Clinical Trial Optional)

December 17, 2018 by

In 2016, NINDS organized a conference on Alzheimer’s Disease Related Dementias (ADRDs) which focused on  frontotemporal degeneration (FTD), Lewy body dementias (LBD) (including dementia with Lewy bodies (DLB)), Parkinson disease dementia (PDD), vascular cognitive impairment and dementia (VCID), mixed dementias including the associated diagnostic challenges of multiple etiology dementias (MED), and issues related to health disparities. The conference complemented the National Institute on Aging’s “Alzheimer’s Disease Research Summit 2015: Path to Treatment and Prevention.”  Both conferences responded to the National Alzheimer’s Project Act that was signed into law in January 2011. The objective of the ADRD conference was to contribute to the efforts directed at preventing and effectively treating Alzheimer’s disease, including Alzheimer’s disease-related dementias, by 2025.  The Alzheimer’s Disease-Related Dementias Summit solicited input from internationally recognized experts to develop prioritized recommendations to guide scientific research in the next 5 to 10 years. This FOA addresses the following 2016 ADRD milestones: 1) Multiple etiology Dementias – focus area 1, milestone 4 centered on the development of diagnostic biomarkers for multi-etiology dementias; 2) Lewy Body Dementia – focus area 3, milestone 5 centered on the development and validation of diagnostic, prognostic and progression biomarkers; and 3) Frontotemporal Lobar Degeneration focus area 2, milestone 2 centered on the development of FTD biomarkers for diagnosis and disease progression.

Tremendous potential exists for the application of PET imaging for diagnosis and disease progression monitoring in natural history studies and clinical trials of ADRD disorders, but relatively few radioligands are currently available for functional imaging of targets and pathophysiological processes implicated in these brain disorders. Additional challenges exist in identifying PET ligands that provide specificity and selectivity for proteinopathies (tau, synuclein, FUS, TDP43) associated with ADRD disorders.  Hence increasing the availability of PET radiotracers will aid in:  a) understanding the abnormal biological processes that underlie ADRD disorders; b) determining the interaction of a drug or drug candidate with a specified target; c) guiding initial dosing of new therapeutic agents; and d) identifying central biomarkers of the illness, with the potential to predict symptom onset, monitor the progression of the disease, and assess the efficacy of therapeutic compounds.


The purpose of this Funding Opportunity Announcement (FOA) is to support a multi-center, interdisciplinary approach that uses innovative, cutting-edge technologies to identify and validate PET radioligands for ADRD pathways, proteinopathies and pathological processes such as, but not limited to synapse loss or neuroinflammatory responses associated with the human biology of ADRDs. This multi-center, interdisciplinary approach will be established through a Center without Walls, which will incorporate key scientific expertise in research projects and cores, to drive the development of PET radioligands that will facilitate improvements in clinical diagnosis and provide key biomarker tools for patient stratification, target engagement and/or disease progression for ADRD clinical trial design.

Successful development of ADRD PET ligands will be dependent on the availability of well characterized brain tissue, where the post mortem diagnosis, immunohistological characterization of protein load in the brain region to be used and associated clinical and genetic data will be key criteria for brain tissue selection.  Investigators applying to this FOA are encouraged to incorporate collaborations with investigators overseeing brain bank resources in their research plan.  Ideally, material transfer agreements should be in place to access tissue resources prior to application submission.

Utilization of existing resources and clinical infrastructure for ADRD research, where available and appropriate for the study are required to accelerate this discovery effort.  These resources and infrastructure may include but are not limited to the NIH funded natural history studies of Frontotemporal Lobar Degeneration such as the Longitudinal Evaluation of Familial Frontotemporal Dementia (LEFFTDS) the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (AFTFL) cohorts as well as Parkinsonisms, and Lewy Body Dementia cohorts collected under the NINDS Parkinson’s Disease Biomarkers Program (PDBP).

ADRD Proteinopathy Consortium

It is anticipated that advances in structural characterization of ADRD proteinopathies will help to inform PET ligand development for these diseases. To coordinate these efforts a Proteinopathy Consortium will be established by NINDS that includes investigators funded under this FOA and the FOA for Structural Biology of ADRDs Proteinopathies (RFA-NS-18-015).

The overall outcome of the ADRD Proteinopathy Consortium will be a coordinated discovery effort and validation approach to identify protein species and PET ligands relevant to ADRD pathophysiology. An external liaison committee will be identified by the consortium and will be charged with providing expert knowledge support for technical advances in screening and development of PET radioligands.   A face to face meeting will be held annually to integrate structural biology efforts with PET radioligand development for ADRDs.

Center without Walls Program:

  • It is anticipated that an interdisciplinary research approach will enable Centers without Walls to incorporate expertise from multiple disciplines such as structural biology, biochemistry, medicinal chemistry, ADRD model systems, and first-in-human testing of new PET ligands.
  • Center without Walls applications are expected to emphasize novel ideas and approaches, as well as use of state-of-the-art technologies and a team-based approach to achieve stated goals.
  • Synergy must be evident among Center research projects and cores, such that successful completion of the aims could not be accomplished without the Center structure.
  • Research projects and cores must coordinate efforts, such that data from projects and cores inform each other, as well as the overall direction of the Center.  A minimum of two research projects are required.  Each research project will focus on the in vitro and in vivo screening of PET ligands selective for a specific proteinopathy, process or pathway related to ADRD pathogenesis.
  • Proteinopathies of interest include but are not limited to tau, FUS, TDP43, and synuclein, while pathophysiological processes of interest include but are not limited to neuroinflammation and synaptic loss.  Tau ligands must have specificity and selectivity for ADRDs.
  • A Medicinal Chemistry core is required and should provide access to technologies and support the development of reagents required by one or more research projects.  The Medicinal Chemistry core will provide lead compound identification/development and syntheses of chemicals with suitable binding affinity, biodistribution, pharmacokinetics, and physiochemical properties allowing radiochemical synthesis.  The Medicinal Chemistry core will identify any ligand associated toxicology and submit exploratory Investigational New Drug (IND) applications or IND applications required for first-in-human studies.  The Medicinal Chemistry core will provide radiochemical synthesis of new ligands if appropriate.
  • An administrative core is required and should provide overall coordination and support for Center without Walls activities.
  • A clinical core to support first-in-human clinical studies will be required to test and validate the specificity and selectivity of the radioligands developed.  The clinical core should provide an infrastructure that supports rapid access to patient populations relevant to the radioligand under development. The clinical core should also enable pilot human imaging studies with normal controls and pharmacological challenges with analyses of radiometabolites.
  • Collaboration with other institutional or consortium efforts in ADRD research is required.
  • An external scientific liaison committee will be identified in collaboration with NIH staff, within six months of release of the first year notice of grant award.
  • It is anticipated that research in year 1 will focus primarily on the screening of existing compound libraries against ADRD tissue, while research in years 2 to 5 will also include medicinal chemistry efforts around new compound development and first-in-human radioligand testing.

Center without Walls Leadership:

The Center without Walls will be led by a nationally recognized neuroscientist with clinical and/or basic science expertise and active, R01-equivalent, independent funding and excellent scientific productivity. The expertise of the Center without Walls Director may be in areas outside of PET ligand development, if relevant skills can be readily applied to achievement of Center goals. Leadership of the Center without Walls will require coordination with existing government and non-government efforts in ADRD research, as well as the utilization of existing resources and infrastructure to advance the validation of tools and mechanisms developed by the Center.  Success of the Center without Walls will depend upon strong communication, coordination and integration across its components and external collaborations.

Milestone Plans:

Center without Walls projects and medicinal chemistry and clinical cores should be supported by milestone plans.  The milestone plans should include stringent go/no go criteria for advancing a radioligand through first-in-human studies and a timeline for transition from radioligand development to first-in-human studies.  The milestone plans for projects and cores will be used to determine if the development of a ligand will progress or be terminated thereby enabling flexibility in the program to achieve the goals of the overall Center without Walls which should include advancement of PET ligands to first-in-human studies.

The following activities are not allowed under this Center Program, and applications proposing these will be considered non-responsive and will not be reviewed:

  • Projects or Cores that support interventional clinical trials.
  • Natural history studies
  • Animal model development

Applicants are strongly encouraged to consult with NINDS Scientific/Research Staff at the beginning of the planning stage of their application (see Agency contacts, Section VIII).

Projects involving partnerships with industry, small businesses or non-government organizations are encouraged under this FOA. The policy of the NIH is that the results and accomplishments of the activities that it funds and supports should be made available to the public.

Deadline:  February 13, 2019 (letters of intent due 30 days prior to deadline)


Filed Under: Funding Opportunities