February 17, 2022
PA-20-272 - Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional)
This NINDS Notice of Special Interest (NOSI) announces the availability of administrative supplements to support examination of human in-vivo magnetic resonance imaging (MRI) findings of presumed vascular origin (vascular contributions to cognitive impairment and dementia, VCID) as they relate to post-mortem pathology of AD/ADRD. Of interest are brain lesions resulting from dysfunctional vasculature or vascular processes, such as white matter hyperintensities, infarcts (including cortical microinfarcts), and microbleeds, along with cellular, molecular, and in-depth post-mortem imaging and pathological data analysis.
Subclinical brain lesions of presumed vascular origin, such as white matter lesions, brain infarcts, microbleeds, and microinfarcts are frequently observed in AD/ADRD patients, as well as seemingly healthy older adults. They are also known to have downstream consequences including cognitive impairment and dementia, physical disabilities of various types, and clinical stroke. Such lesions are often first identified as incidental imaging findings or as part of a diagnostic work up for unrelated causes, such as headache or mild head trauma. Only recently has it become clear that different AD/ADRD pathologies more frequently than not co-exist in autopsied patients with a history of cognitive impairment and dementia, and that single pathologies are the exception. However, less is known about how imaging findings of presumed vascular origin identified in life relate to pathologies that are seen post-mortem in the cerebral vasculature (both arterial and venous) and in other brain tissues and cellular elements. These imaging findings include ischemic changes related to cerebral small vessel disease and chronic hypoperfusion, evidence of cerebral amyloid angiopathy, vessel and vessel wall abnormalities, impaired neurovascular coupling, blood-brain barrier leakage, abnormalities of diffusion, and cerebrospinal fluid extravasation, and there is a need for studies examining the relationships between these findings and tissue abnormalities and histological changes, including but not limited to the presence of lipofuscin accumulation, iron deposition, vacuole formation, hemosiderin-laden macrophages, and numerous proteinopathies representing different pathological processes and disease states.
The immediate goal of this initiative is to encourage research seeking to understand the pathobiology of the varied brain lesions of presumed vascular origin seen on MR imaging during life of individuals who exhibit symptoms consistent with AD/ADRD and how this compares to healthy, elderly adults. Proposed studies are to be partly focused on post-mortem analyses of pre-mortem imaging data, including correlations with post-mortem imaging and/or pathological data. Projects may utilize existing cohorts with the potential to link prospectively collected pre- and post-mortem data or may focus solely on the collection of post-mortem data (employing electronic health records data or other means to assess pre-mortem health). Histological and molecular analyses are within scope, but advanced MR imaging is of particular interest as the basis for this initiative is the investigation of lesions often found during in-vivo MR at common field strengths. Furthermore, analyses should not be limited to brain tissue and could benefit from the investigation of AD/ADRD-relevant biomarker data obtained during life: e.g., blood, urine, nuclear medicine, or CSF biomarkers of immunological, inflammatory, and vascular processes. Given the focus on MR, questions of interest for this initiative include, but are not limited to:
Pathological correlates of white matter hyperintensities.
Diffusion and susceptibility abnormalities in both normal-appearing and clearly affected white matter.
High- or ultra-high resolution (i.e., MR microscopy) post-mortem imaging of brains with pre-mortem findings of white matter lesions, microbleeds, or microinfarcts, as well as pre-mortem susceptibility or multi-shelled diffusion acquisitions.
Pathological analysis of tissue within and around cortical microinfarcts.
Biomarkers (e.g., immunological, inflammatory, or vascular) that are concomitant with imaging findings of presumed vascular origin, such as white matter lesions, areas of blood brain barrier breakdown, infarcts, and microbleeds.
Analyses relating -omics (e.g., genomic, epigenomic, proteomic, microbiomic) data to AD/ADRD imaging findings.
Applications Not-Responsive to this NOSI:
Projects that do no include analysis of MR data.
Projects proposing unbiased 'omics molecular screens designed to discover new candidate molecules, genes, or pathways are not responsive; however, such approaches may be used to test specific hypotheses about changes that contribute to AD/ADRD disease onset and pathogenesis.
Please note that fixing / embedding media can significantly affect MRI signal, contrast, relaxation rates, and susceptibility. Studies proposing post-mortem MRI should carefully consider the chosen embedding media and how it may affect the proposed MR acquisition.
Applications for this initiative must be submitted using the following opportunity or its subsequent reissued equivalent.
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additions: