Funding Opportunity Number: PAR-25-065
Deadlines: February 5, 2025, March 5, 2025
Description
The goal of this Notice of Funding Opportunity (NOFO) 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, also known as Behavioral and Psychological Symptoms of Dementia (BPSD), include (but are not limited to) 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 symptoms 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 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.
Research Objectives
This NOFO is intended to support research designed to identify the neurobiological, behavioral, and social mechanisms underlying NPS in 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 fields such as cognitive and affective neuroscience, including 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 is encouraged and will be accepted if it fits under the NIH mechanistic clinical trials framework. The research supported under this NOFO is expected to advance mechanistic understanding of neuropsychiatric syndromes in AD/ADRD and underlying neurobiology that will advance the field. Such findings may identify 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, 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. 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 cite substantial evidence for the validity of such constructs and 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 – that is, 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 NOFO, 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 NOFO include, but are not limited to:
- Improved understanding of the neurobiological and behavioral mechanisms underlying NPS syndromes in AD/ADRD.
- 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 NPS onset and/or treatment outcome.
- Utility of computational approaches to identify predictive and/or explanatory patterns of factors associated with NPS in new or in available extensive datasets.
- Elucidation, refinement and implementation of criteria for distinguishing persons with NPS syndromes that are not resolvable via appropriate attention to their unmet needs.