Tools and resources to understand the vascular pathophysiology of in vivo neuroimaging findings in TBI-related dementia and/or VCID (U24 - Clinical Trials Not Allowed)

RFA-NS-23-002

The purpose of this funding opportunity is to develop and share innovative technologies, methods, protocols, and biomedical materials that further enable the combined analysis of human neuropathology and neuroimaging data aimed at understanding the underlying pathophysiologies of VCID in TBI- and CTE-related dementia and other AD/ADRD diagnoses.

Resources developed are expected to provide tools and techniques to advance and expand community-wide research capacity for performing joint neuropathological and neuroimaging analysis. To accomplish the goal of expanding research capacity in neuropathologically-informed neuroimaging, it is expected that resources developed under this FOA will demonstrate reproducibility and feasibility of use by the broader research community. Applicants are also expected to focus on at least two resource development topics. Resource development topics of interest include, but are not limited to:

• Streamlined approaches that reduce postmortem intervals.
• Methods/sequences/techniques for imaging fresh tissue.
• Innovative fixation techniques that reduce MR signal loss.
• Techniques that enable improved neuropathological analysis of regions demonstrating MR abnormalities.
• Development of analytical MR models to better understand disease processes and neuropathology findings.
• The development of common coordinate systems, or improved co-registration techniques, for co-registration of MR and neuropathology images.
• Development of standardized procedures and/or acquisition techniques to facilitate co-registration across sites. This includes practices that would facilitate the use of machine learning for co-registration.
• Comparisons of various types of techniques, such as fixation techniques or solutions, methods to avoid fixation before MRI, blocking/sectioning techniques, 3D mold types, etc., to demonstrate which lead to the best preservation of the tissue, MR signal, and genetic material.
• Development of atlases to be used in co-registering MR and pathology images.
• Development and discovery of biomedical materials such as new antibodies for staining and processing brain tissue.
• Development of novel MRI sequences suitable to imaging neuropathology in postmortem or ex vivo tissue.

The resource development topics of interest are driven by the need to further understand the pathogenic processes associated with the varied subclinical MR imaging findings, at common field strengths, of presumed vascular origin seen during life of healthy elderly individuals, individuals who exhibit symptoms consistent with AD/ADRD, and individuals with TBI-related dementia, including those with chronic traumatic encephalopathy CTE. Therefore, the topics of interest mentioned above are intended to address the need to understand the following:

• Pathological correlates of white matter hyperintensities
• Diffusion and susceptibility abnormalities in normal-appearing white matter
• Pathologies within and around cortical microinfarcts
• Vascular dysfunction including but not limited to perivascular hemorrhage, vascular structure, and vessel wall abnormalities
• Anti-amyloid therapy-related brain and vascular changes
• Ischemic changes related to cerebral small vessel disease and chronic hypoperfusion
• Evidence of cerebral amyloid angiopathy
• Impaired neurovascular coupling
• Blood-brain barrier leakage

Application budgets are limited to $1.0M in direct costs per year and need to reflect the actual needs of the proposed project.

Not required

March 17, 2023

Carlos C. Faraco, Ph.D., Division of Clinical Research, National Institute of Neurological Disorders and Stroke (NINDS), Telephone: 301-496-9135, Email: carlos.faraco@nih.gov