The goal of this Funding Opportunity Announcement (FOA) is to encourage biomedical, behavioral and social sciences research that will enhance knowledge of mechanisms underlying neuropsychiatric symptoms (NPS) in persons with Alzheimer's disease (AD) or Alzheimer's disease-related dementias (ADRD) so as to enable novel treatment development.

NPS, or Behavioral and Psychological Symptoms of Dementia (BPSD), include aggression, psychosis, anxiety, apathy, depression, agitation, sleep disturbances and wandering,and can be significant challenges to the care and treatment of people with dementia. These NPSsymptoms lead to accelerated declines in both functional abilities and may lead to earlier nursing home placement. Currently, few pharmacological treatments are available. In addition, there is a need to understand behavioral and environmental targets to further refine and develop promising behavioral treatments for these disorders.

The demand for novel treatment approaches highlights the importance of identifying and dealing with the underlying causes of these symptoms among older adults with dementia. There is thus an urgent need to advance the mechanistic understanding of these problems to identify new treatment targets. The National Plan to Address Alzheimer’s Disease specifically calls for the development of better treatments for the behavioral and psychiatric complications due to the disease..

In May, 2017, NIMH and the National Institute on Aging (NIA) held a workshop to assess the current state of research on neuropsychiatric symptoms associated with dementia as well as opportunities and strategies for developing better treatments for NPS NIMH Novel Approaches to Understanding the Mechanisms of the Neuorpsychiatric Symptoms in Alzheimer's and Advancing Therapy Development . The workshop participants agreed that, as a heuristic framework, personal, caregiver, and environmental factors should all be examined as potential targets for treatment development in this area. Particularly crucial to that effort is a better understanding of the neural mechanisms underlying the development of NPS in dementia. If successful, the research to be conducted will clarify both behavioral and biological mechanisms associated with NPS. It may provide clues to novel intervention targets for alleviating some of the burden associated with these symptoms, or may suggest which intervention or prevention strategies might be optimal across the intervention spectrum.

Research Objectives

This FOA is intended to support research designed to identify the neurobiological, behavioral, and social mechanisms underlying NPS in Alzheimer's Disease and Alzheimer's disease related Dementias (AD/ADRD) in order to deepen our understanding of the pathways and contextual factors involved. Research that assesses NPS dimensionally, integrating across multiple levels of analysis and employing cutting-edge methodology from such fields as cognitive and affective neuroscience, neuroimaging, neurophysiology, gene expression and epigenetics, and behavioral intervention research is encouraged. Both basic neuroscience work examining models of NPS and translational approaches to understanding neural circuits involved in the expression of NPS are encouraged.

Research that seeks to clarify mechanism of action of evidence-based treatments or proposes to examine potential biomarkers of treatment response isencouraged and will be accepted if it fits under the mechanistic clinical trials framework. The research supported under this FOA is expected to advance mechanistic understanding of neuropsychiatric syndromes in AD and underlying neurobiology that will advance the field. Suchfindings mayidentify modifiable targets for further intervention development in this area.

Some portion of NPS stem from problems in recognizing and rendering appropriate care for treatable issues in persons with limited cognitive and communicative abilities. Issues, such as medical comorbidities, physical pain/discomfort, hydration, boredom/socialization, etc. can become "unmet needs" that find expression in the form of NPS if not recognized and properly addressed . Research is needed to establish underlying causes for NPS symptoms resulting from these unmet needs in order to develop and implement effective methods for screening and handling such issues across the spectrum of typical care settings.

The use of constructs from NIMH's Research Domain Criteria (RDoC) initiative (http://www.nimh.nih.gov/research-priorities/rdoc/index.shtml), or of RDoC-compatible approaches, in assessing NPS or associated factors, such as emotion processing, other component aspects of mental disorders, and/or related domains of brain function-, is encouraged. RDoC has defined a set of dimensional constructs that may be useful in this research. These constructs are organized according to five domains of brain functioning (negative valence systems, positive valence systems, cognitive systems, arousal/regulatory systems, and systems for social processes). Research on RDoC constructs should employ assessment methods appropriate for each construct of interest and the assessment methods are expected to converge on the construct from at least two levels of analysis. RDoC units of analysis (potential levels of measurement) include genes, molecules, cells, circuits, physiology, behavior, and self-report. Details about RDoC constructs and units of analysis can be found here. Although the structure of the RDoC matrix suggests boundaries among constructs, given the densely integrated and interconnected nature of the brain's circuits, it is understood that the constructs function interactively and that promising empirical approaches to an RDoC-based analysis of NPS and/or associated factors may involve examining intersections among constructs. Applicants may propose to examine dimensional constructs that do not appear in the NIMH RDoC matrices as long as there is strong theoretical support for their relevance to a mechanistic understanding of NPS. Applicants should be able to cite substantial evidence for the validity of such constructs, and to indicate strong theoretical support that the construct maps onto a specific biological system, such as a brain circuit or physiological pathway, thought to be involved in specific aspects of NPS.

With respect to assessing psychopathology or mental disorder, an RDoC approach encourages taking a dimensional perspective, and concentrating on aspects of behavior and brain function that span a range from intact to gradations of impairment, independent of diagnosis. Thus, in such an approach, recruitment and eligibility of study participants need not be determined on the basis of traditional diagnostic categories, but should instead be based on criteria that result in a sample that is optimized to study the clinical phenomena of interest over their full range of variability. Such an emphasis on understanding the full dimensionality of neurobehavioral functioning generally precludes simple, dichotomous designs comparing patients versus controls. Under this FOA, if an RDoC or other dimensional construct is proposed to serve as the primary variable representing psychopathology (as opposed to using a diagnostic characterization), the study design and sampling plan must be such as to assure that an adequate number of individuals assessed as falling within the more severely impaired ranges of that dimension will be included in the study.

Areas of research interest for this funding opportunity announcement include, but are not limited to:

• Improved understanding of the neurobiological and behavioral mechanisms underlying NPS syndromes in AD and related dementias;
• Assessments of neural circuits involved in apathy or other NPS in AD/ADRD, as compared to other neuropsychiatric diseases;
• Examination of circadian rhythm disruptions as related to the manifestation of agitation and other disruptive behaviors;
• Defining and clarifying specific irregularities of perception, cognition, emotion processing or other basic psychological functions, and their neurobiological correlates that are associated with particular forms of NPS in persons with AD/ADRD;
• Evaluation of differences in the brain circuits or cortical areas recruited during emotional challenge or cognitive task performance in individuals with MCI or AD/ADRD, and whether such differences predict vulnerability to or resilience against onset of NPS;
• Examination of the role of prior psychiatric disorder or other historical factors as influences on the development or expression of NPS syndromes in AD/ADRD;
• Utility of passive sensing technology to more precisely and comprehensively characterize the behavioral patterns, circadian and other neurophysiological fluctuations, environmental exposures, and like factors associated with NPS in persons with AD/ADRD;
• Identification and regulation of clinically relevant brain circuits and/or neurobiological systems that may be targets for treatment development or mechanisms of NPS pathophysiology;
• Development of outcome measures that are clinically meaningful to AD/ADRD patients and caregivers;
• Development of clinically useful biomarkers to predict both NPS onset and or treatment outcome;
• Utility of computational approaches to identify predictive and/or explanatory patterns of factors associated with NPS in available extensive datasets;
• Elucidation, refinement, and implementation of criteria foro distinguishing subjects with NPS syndromes that are not resolvable via appropriate attention to their unmet needs.

Examples of studies that are not responsive to this FOA and will not be reviewed include the following:

• Applications that assess potential NPS mechanisms at only a single level of observation and analysis (i.e., without combining multiple levels/methods such as genetic, cellular, brain circuit, physiological, behavioral, self-report);
• Applications that propose clinical trials of the safety, efficacy, effectiveness, management or implementation of of potential therapies for NPS.

This FOA will support mechanistic clinical trials, defined by the NIH to include studies designed to understand a biological or behavioral process or, the pathophysiology of a disease process, through a manipulation of that process, or to understand the mechanism of action of an intervention (see NOT-OD-15-015).

This funding opportunity announcement will not accept studies whose purpose is to evaluate safety; clinical efficacy, effectiveness, and management; and/or implementation of new interventions. See the NIMH Clinical Trials website (link to https://www.nimh.nih.gov/funding/opportunities-announcements/clinical-trials-foas/index.shtml) for a listing of current NIMH CT FOAs that will support such studies. Also see in particular, the section of that website titled "Limited NIMH Participation on Parent Research Grant FOAs for Clinical Trials" for further details about submission of mechanistic clinical trials to NIMH.

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

• Eligible Agencies of the Federal Government

• U.S. Territory or Possession

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

3. Additional Information on Eligibility

Number of Applications

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

1. Requesting an Application Package

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Letter of Intent

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

[email protected]

All instructions in the SF424 (R&R) Application Guide must be followed.

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• In order to advance the goal of furthering research by widespread data sharing among researchers, investigators funded under this FOA are expected to share those data via the NIMH Data Archive (NDA) either through the RDOC-db interface https://data-archive.nimh.nih.gov/rdocdbor, in the case of mechanistic clinical trial applications, the National Database for Clinical Trials related to Mental Illness (NDCT; http://ndct.nimh.nih.gov/; see NOT-MH-14-015 and NOT-MH-15-012). Applicants should explain what type of data are appropriate and available for sharing in the NDA.

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement .

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Suzana Petanceska, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: [email protected]

Traci Lafferty
National Institute on Aging (NIA)
Telephone: 301-496-8987
Email: [email protected]