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AD-Related Dementias Focus
Examine the pathologic phenotype(s) of TDP-43 pathology in asymptomatic persons and those with common dementias.
2027 RFA-NS-20-005: Mechanistic Basis of TDP-43-dependent Pathobiology in Common Dementias (R01) PAR-23-212: Investigating Distinct and Overlapping Mechanisms in TDP-43 Proteinopathies, including in LATE, FTD & other ADRDs (R01 - Clinical Trial Not Allowed) PAR-23-218: Development & Characterization of Experimental models of post-TBI ADRD (R01 - Clinical Trial Not Allowed) RFA-NS-24-003: Assessment of TBI-related ADRD Pathology Related to Cognitive Impairment and Dementia Outcomes (U01 - Clinical Trial Not Allowed) 2.V In Progress DN 2019 ADRD Summit: Emerging Scientific Topics, Focus Area 1: TDP-43 Pathology in Common Dementias, Milestone 3 NINDS Press release: NIH researchers link cases of ALS and FTD to a mutation associated with Huntington’s disease Workshop: LATE 2022 Workshop: Gaps and Opportunities Related to Clinical Detection of Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) Press Release: Abnormal proteins found in the spinal fluid of people with ALS and frontotemporal dementia Workshop: NINDS TBI Classification and Nomenclature Highlight: Abnormal proteins found in the spinal fluid of people with ALS and frontotemporal dementia Workshop: Molecular Mechanisms and Pathobiology of TDP-43 in LATE and Alzheimer's Disease and Its Related Dementias Research on Disease Mechanisms NIH NeuroBioBank The physical biology of neurodegeneration in sporadic Amyotrophic Lateral Sclerosis/Frontotemporal dementia 2020
- At least one study that characterizes TDP-43 dependent pathologic phenotypes in elderly individuals both with and without a clinical diagnosis of a common dementia.
Summary of Key Accomplishments
Epidemiological data suggest that a history of TBI is a significant risk factor for AD/ADRD and that the relative risk may be mediated by injury severity and frequency with increased severity and multiple insults resulting in higher risk. Ongoing NIH-funded studies are currently characterizing the neuropathological features of chronic TBI associated with neurodegeneration and neurocognitive decline. For example, a recent study demonstrated that long term TBI-related brain changes appeared to be subtle and involved non-traditional pathways of neurotoxicity and neurodegeneration.
Another NIH-funded study revealed that brain tissue from individuals who had suffered repetitive head injuries exhibited brain pathologies like those seen in AD/ADRD brains, including markers of immune reaction and tau pathology. Collectively, these findings inform future research on TBI-related dementia including CTE, and two NIH-funded studies are currently developing neuroimaging resources and tools for multi-scale and multi-modality assessment of TBI-related dementia and VCID.
NIH-funded researchers are also working to better understand how the complex interaction between the brain and the structure and function of the gut microbiome impacts cognitive outcomes following TBI. For example, one group of NIH-funded scientists are investigating mechanisms linking alterations in the aged gut microbial community to subsequent AD/ADRD following TBI and testing the hypothesis that restoration of a youthful gut microbiome before or after TBI will improve cognitive outcomes. This builds on a recent study showing that mice fed a diet including probiotics experienced less neuroinflammation and fewer behavioral deficits following TBI.
In FY2024, NIH released a funding opportunity to support and accelerate the development, characterization, and validation of mammalian TBI models that display progressive clinical and pathological characteristics of ADRD following TBI, including CTE.
The key accomplishments summary is current as of June 2024.