... Considering Approaches to Remedy Research Gaps and Examples of Promising Future Directions...

... The fourth session of the workshop considered forward-looking research ideas to improve traumatic brain injury (TBI) care and outcomes in older adults. Workshop participants (1) explored technologies to predict and prevent falls and to prevent and treat TBI, (2) discussed ... adults in TBI clinical trials, (3) outlined the benefits of aged animal models in TBI research, (4) examined the effects of age on TBI biomarkers, and (5) highlighted examples of drugs for non-TBI indications that may be adopted to clinical trials in TBI....

... animal studies to move the TBI field forward most effectively, including those that (1) study mild TBI, (2) use both sexes, (3) reflect comorbidities and medications common in older adults, (4) ensure that functional outcomes are optimized for age, and (5) include translational outcome measures....

... David Ganz, University of California, Los Angeles, and VA Greater Los Angeles Healthcare System, focused on strategies to prevent TBI in older adults. Falls cause 55 percent of TBI for people aged 65–74 ... and are responsible for 85 percent of TBI in individuals aged 85 years and older (Dams-O’Connor et al., 2013b). Fall prevention efforts commonly target one or more risk factors (e.g., gait, balance, and strength; ... ; function; vision; cognition and mood; orthostatic hypotension; and home safety). The U.S. Preventive Services Task Force recommends exercise for all people age 65 or older at increased risk for falls. Randomized ...

... Ganz highlighted the need for research on strategies to increase adherence to exercise and for research on virtual exercise programs, which are often more accessible and affordable than in-person classes. Improving the design of assistive ... to increase user friendliness and convenience of use may also bolster head impact prevention, Ganz said. Prevention researchers analyzed over 1,000 falls captured by continuous video ... found that the head is more vulnerable to injury upon impact than all other parts of the body, with respective injury probabilities of 40 percent and 11 percent or less. But holding weight-bearing objects including wheelchairs and walkers (with or without wheels) during the fall was associated with ...

... Subdural hematoma is a significant source of TBI in older adults and has a strong association with use of antithrombotic medication, said Ganz. Over the past two decades, there has been a marked rise in the use of ... therapies, and increasing rates of subdural hematoma in older adults (Gaist et al., 2017), which may warrant deescalating antithrombotic therapy in some ... holistic outcomes (e.g., health-related quality of life, functional status) in clinical trials of anticoagulation may help determine which patients stand to benefit from this therapy and inform researchers about the risk–benefit profiles of specific medications, Ganz said....

... USING DIGITAL TECHNOLOGIES TO IMPROVE GERIATRIC TBI PREVENTION, RESEARCH, AND CARE...

... Jeffrey Kaye, Oregon Health & Science University, discussed how smart technologies for post-TBI are designed to prevent deficit progression and facilitate rehabilitation and care, such as gait training via robotic devices, cognitive rehabilitation using virtual reality, telerehabilitation, ... , or to serve as interventions to reduce identified risks (for example, Piau et al., 2020). Home-based assessment technologies measure function and health outcomes related to cognition, mobility, socialization, health behaviors, and other areas. Using varied data streams,...

... prediction models assess risk and inform prevention programs. For example, one program collects data from passive infrared sensors that measure gait speed—as research indicates that ... speed variability decreases in the weeks before a fall—and combines this with responses to a weekly online questionnaire designed to identify functional outcomes in aging (Kaye et al., 2011, 2012)....

... Prediction algorithms use these objective and subjective data to determine fall risk. Technologies to assess balance include smartwatches that recognize falls and digital scales that measure the ... and horizontal axes and center of pressure to detect changes over time. Automobile data ports capture metrics related to cognitive function and dangerous driving that increase the risk of crashes (Seelye et al., 2017). Kaye noted that multiple technologies can be used in concert for ...

... risk, but to support general geriatric health maintenance. Kaye contended that improved measurement of TBI risk factors bolsters prevention efforts and that digital methodologies should be tested in pragmatic trials and embedded in existing studies of aging. Digital measures could become reproducible ... scalable with the establishment of standards and agnosticism from any particular system or device. Such tools move toward individualized predictions, said Kaye, highlighting the need to explore ...

... INCLUSION OF OLDER ADULTS IN CLINICAL TRIALS AND DATASETS...

... Laurie Ryan, National Institute on Aging, discussed the inclusion of older adults in clinical trials and datasets, noting that the individuals recruited into clinical research studies often do not represent the population most affected by the condition ... interest. Groups underrepresented in clinical research may respond differently to interventions or have higher health and care burdens than the populations included in research. Older adults are underrepresented in clinical research in almost all medical fields, she ... , running the risk that safety concerns and effectiveness outcomes unique to this population will not be detected. Limited empirical guidelines for the treatment and management of TBI in older ...

... Older adults are often affected by exclusion criteria such as upper age limits, comorbid conditions, polypharmacy, and cognitive impairment. Although use of such criteria may be appropriate in early-stage (phase I and...

... medication is developed. Thoughtful selection of exclusion criteria to include the most representative sample possible while maintaining scientific and ethical integrity is crucial, she said....

... Study procedures and logistics influence research participation, explained Ryan, noting that location, time commitment, and requirements for caregiver involvement may pose barriers. She encouraged researchers to collaborate with older adults during the study design phase ... reduce barriers and opportunity costs, using approaches such as participant boards to advise trial design. Ryan shared examples of practices that can increase trial ... and participation by older adults. These include offering home visits, transportation, or remote participation....

... in medical research or are concerned about assignment to the placebo group. Steps to address such factors include networking with community groups and leaders, increasing the proportion of subjects allocated to the experimental treatment, and offering open-label extension after the blinded phase of ... meetings; providing tailored returns of value for the care setting, such as continuing medical education programs or patient education materials; and employing research infrastructure in care settings, such as research coordinators or patient navigators who assist with recruitment and enrollment....

... EFFECT OF AGE AND TIME SINCE INJURY ON TBI BIOMARKERS IN OLDER ADULTS...

... Frederick Korley, University of Michigan, described research on the TBI biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1) using surplus blood from emergency department (ED) blood draws. His group studied a representative sample of ... . The median age of the study population was 69 years. They found that GFAP sensitivity is slightly lower during the first 2 hours after injury and then increases, while UCH-L1 sensitivity is highest during the first 8 hours postinjury and then drops. A small number of patients with coagulopathy ...

... However, the specificity of GFAP showed a marked decline for older adults. Korley explained that reduced specificity reduces the utility of blood tests for ruling out the need for a head ...

... of structural injury typically increase with age, primarily because they are markers of brain cell death that can occur with numerous conditions and is not necessarily specific to TBI. One approach to addressing decreased specificity is to create age-specific cutoffs, thereby increasing diagnostic ... by reducing false positives in older adults. However, biological age and chronological age do not always match, and age-specific cutoffs could lead to underdiagnosis of early disease in healthier patients. Furthermore, cutoffs create multiple patient subgroups that ... pose challenges to conducting reference range studies and raise regulatory considerations. Multiple cutoffs for the same biomarker could complicate clinician interpretation and implementation, leading to ...

... outlined innovative approaches to decreased biomarker specificity in older adults, such as predictive modeling that uses electronic health records and predictive variables independently associated with a biomarker to generate expected values based on a unique patient’s characteristics. ... is acute or chronic can inform TBI diagnosis, said Korley, noting that promising approaches include examining a combination of short half-life and long half-life biomarkers and identifying posttranslational modification of blood proteins....

... Janna Harris, Jackson Laboratory, discussed basic science research on TBI, and the importance of including aged animals in studies. TBI is characterized by its heterogeneity, and modeling in animal subjects offers a high degree ... control over the injury parameters. The vast majority of early-stage research in TBI is performed in rats and mice, which have a typical median lifespan of about 2 years, making them a practical model for aging-related research. Animal models have ... that aging affects cellular and molecular mechanisms—such as the glial cell response, reactive astrocytes, and microglia having longer activation periods—that may be linked with increased neuronal cell death and greater cognitive impairment after TBI (Iboaya ... a TBI are less active in older brains. Despite these insights, studying TBI in older animals is an underrepresented area of basic science research and therapeutic efficacy studies are lacking, said Harris. Historically, the limited studies performed have focused exclusively on male animals, have ... moderate to severe TBI, and have excluded comorbidities and medications that are common in the older adult population....

... Harris said that phenotypes of normal aging may affect study outcomes, and therefore additional steps may be required to identify such phenotypes or to establish baseline values for cognitive measures. Additionally, age- ... conditions and frailty necessitate larger study cohorts....

... animal studies to move the TBI field forward most effectively, including those that (1) study mild TBI, (2) use both sexes, (3) reflect comorbidities and medications common in older adults, (4) ensure that functional outcomes are optimized for age, and (5) include translational outcome measures. ... , she also noted the challenge of generating and using aged animals for these preclinical studies. They are time and resource intensive....

... SELECTED RESEARCH NEEDS AND OPPORTUNITIES FOR THERAPEUTIC DEVELOPMENT...

... Ramon Diaz-Arrastia, University of Pennsylvania, underscored the lack of clinical trials for TBI therapies that include older adults and the lack of clinical trials that focus on the chronic, versus acute, setting. Normal aging is associated with decreasing cognitive performance. While ... cognitive decline from that expected for normal aging. Either model results in crossing the threshold of dementia earlier than someone without injury and would explain the epidemiologic association of increased dementia risk in TBI survivors. Numerous pathologies contribute to trauma-related ... he said. Such age-related pathologies include amyloid aggregation, tau hyperphosphorylation, changes to small brain blood vessels, neuroinflammation, and others. An increasing body of data demonstrates that TBI accelerates certain age-related pathologies, such as axonal degeneration, microvasculopathy, ...

...-related pathologies warrant study in older adults who have had a TBI, he said. For example, studying antiamyloid therapies that reduce amyloid burden and have a moderate effect on phosphorylated tau may be useful for older adults who have had a TBI and meet the criteria of amyloid deposition in the ... to better understand the factors contributing to neurodegeneration. In a pharmacoepidemiologic study of older adults with TBI, statin drugs were associated with a 13 ... reduction in dementia diagnoses (Redelmeier et al., 2019), and more research is needed to determine whether TBI history should be included in recommendations for statin use, he said. He also noted a study of ...

... Diaz-Arrastia’s research indicates that chronic TBI causes deficits in cerebrovascular reactivity, and acute sildenafil administration partially...

... (Kenney at al., 2018). Preclinical studies of glucagon-like peptide-1 (GLP-1) antagonists indicate a neuroprotective effect against age-related and TBI-related neurodegeneration, he said, warranting further research on GLP-1 therapy after TBI (Harej Hrkać et al., 2014). Anti-inflammatory agents ( ... for people with post-TBI neuroinflammation, he said. Diaz-Arrastia underscored that these therapies are already approved for other indications and could therefore be repurposed into clinical trials in TBI....

... Discussion further considered research needs and opportunities, including future directions for biomarker studies and the expansion of clinical trials for interventions addressing TBI among older adults. Korley highlighted the need to ascertain whether TBI biomarker ... are modifiable. The ability to target interventions to patients based on their risk factors, and then see if the intervention caused changes in biomarker levels, would inform care, he says. Diaz-Arrastia remarked on the possibility of tracking ... biomarkers such as neurofilament light chain over time in TBI patients and aging populations to better understand their usefulness. Commenting on the numerous drugs and interventions for other indications that could potentially be repurposed for TBI, Diaz- ... underscored the need for comparative-effectiveness research or methods of conducting pragmatic trials more efficiently than time-intensive randomized clinical trials....

... of the full range of communities being served. Ensuring broad inclusion of older adults in TBI research will be essential to advancing the understanding of TBI among the aging population; establishing accurate diagnostic, prognostic, and care guidance; and improving patient and family outcomes, ... cochairs Kristine Yaffe and David Reuben concluded....