David Okonkwo, M.D., Ph.D.
Epidemiological studies have long implicated traumatic brain injury (TBI) as a major risk factor for future development of Alzheimer’s disease (AD). Because as many as 4 million persons suffer a head injury each year in the U.S., the implications for public health are substantial in addition to the enormous burden on patients and caregivers. Given that TBI is the signature illness of recent military conflicts, there is growing concern for the long-term health of brain-injured warriors and veterans. At present, the pathological hallmarks of AD and related dementias can only be confirmed postmortem on autopsy examination of the brain, although positron emission tomography (PET) imaging techniques have made considerable progress towards an in vivo pathological diagnosis. Nevertheless, efforts to establish a putative link between TBI and increased dementia susceptibility have only recently begun to leverage novel techniques for detecting and characterizing the evolution of abnormal brain pathology in TBI subjects. Such tools have the potential to elucidate the putative mechanisms that predispose some TBI subjects to develop AD later in life. An understanding of these mechanisms, as well as possible genetic and environmental risk factors that promote them, are key to developing novel therapeutic strategies to alter the disease course and delay or prevent the onset of dementia in these TBI survivors.
Key to this strategy is the identification of biomarkers with diagnostic sensitivity and specificity for the as yet unknown pathological processes in TBI survivors that promote the development of AD pathology. Identifying at-risk TBI survivors in prodromal disease phases is critical for realizing therapeutic success, as neurodegeneration is a relatively late but irreversible process in the progression of AD pathology. Thus, there is an urgent, yet unmet demand for definitive, non-invasive biomarkers of trauma-related dementia that would identify individuals at risk, delineate mechanistic targets for therapeutic approaches and monitor response to therapy. This project will deliver a comprehensive neuroimaging biomarker panel for trauma-related dementia to identify TBI survivors at risk for chronic cognitive impairment/neurodegeneration and monitor response to therapy. Included in this biomarker panel are:
- established positron emission tomography (PET) radiotracers targeting hallmark Alzheimer’s disease (AD) pathology, specifically abnormal aggregates of amyloid-beta (Aβ; [11C]PiB) and tau ([18F]AV-1451);
- PET indices of translocator protein 18kDa (TSPO) expression using [11C]PBR-28;
- structural and functional MR measures;
- as well as cerebrospinal fluid and serum biomarkers of Aβ, tau, neuroinflammation, and neuronal injury; and
- cognitive and neuropsychological outcomes.
Okonkwo DO, Puffer RC, Minhas DS, Beers SR, Edelman KL, Sharpless J, Laymon CM, Lopresti BJ, Benso S, Puccio AM, Pathak S, Ikonomovic MD, Mettenberg JM, Schneider W, Mathis CA, Mountz JM. (2019) [18
C]PiB, and [18
F]AV-1451 PET imaging of neurodegeneration in two subjects with a history of repetitive trauma and cognitive decline. Front. Neurol. 10:831
Eisenmenger LB, Huo EJ, Hoffman JM, Minoshima S, Matesan MC, Lewis DH, Lopresti BJ, Mathis CA, Okonkwo DO, Mountz JM. (2016). Advances in PET imaging of degenerative, cerebrovascular, and traumatic cases of dementia. Semin. Nucl. Med. 46:57-87.
From Okonkwo, et al., 2019: Serial transverse brain sections from (A) structural MRI, (B) NeuroReader segmentation, (C) [18F]AV-1451 PET, (D) [11C]PiB PET, and (E) [18F]FDG PET for a subject with a history of repetitive traumatic brain injury and cognitive decline. (A,B) Quantitative analysis of the MRI scan demonstrated normal volumes. (C) The [18F]AV-1451 PET scan is most significant for demonstrating abnormal intensely increased symmetric uptake in the precuneus (FreeSurfer mean [FS] SUVR: 2.97), superior parietal (FS SUVR: 2.86), and lateral occipital regions (FS SUVR: 2.76). There is also abnormally increased uptake in the lateral inferior temporal (FS SUVR: 2.47), entorhinal (FS SUVR: 2.13), lateral orbitofrontal (FS SUVR: 1.78), and superior frontal (FS SUVR: 1.67) regions. (D) The [11C]PiB PET scan demonstrates significant abnormally increased uptake in parietal, temporal and frontal lobes, as in Patient #1, demonstrating a pattern characteristic of AD. Note there is negligible accumulation in the occipital lobes (as compared to the [18F]AV-1451 scan). (E) The [18F]FDG PET scan shows abnormally and relatively symmetric decreased uptake in the posterior temporoparietal regions of the brain, with sparing of the frontal lobes.