4

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 strategies for improving representation of older 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.

Harris identified needs for 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.

TBI PREVENTION STRATEGIES FOR OLDER ADULTS

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 years 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; medications; 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 trials of

exercise—typically two or three in-person classes per week for 12 months—demonstrate a 15 percent relative reduction in total falls (Delbaere et al., 2021; Guirguis-Blake et al., 2024; Tejeda et al., 2024; U.S. Preventive Services Task Force et al., 2024).

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 devices 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 recording of long-term care facility common areas (Komisar et al., 2021, 2022). They 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 a reduced odds of head impact by about one-half, even when the object was released during the fall. Ganz added that integrating existing data sources to improve TBI risk prediction would benefit clinicians at the point of care—enabling prevention efforts to target those at highest risk of TBI.

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 these therapies, and increasing rates of subdural hematoma in older adults (Gaist et al., 2017), which may warrant deescalating antithrombotic therapy in some circumstances. Using 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, and neuromodulation devices (Bonanno et al., 2022). Pre-TBI technologies are designed to identify individuals at risk for TBI by detecting falls, poor driving, or cognitive decline, 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 walking 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 vertical 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 multidomain assessment. He highlighted that passive sensing devices requiring no additional action on the part of the user can facilitate the simultaneous use of multiple data streams, thereby measuring varied functions longitudinally in real-world settings.

Moreover, these technologies carry the potential not only to reduce TBI 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 and 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 methods of using functional data in the clinical community to improve care.

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 of 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 indicated, 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 adults is directly related to the lack of clinical trials that include or target this population, Ryan said.

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

II) studies, Ryan noted that such exclusion is more difficult to justify during phase III clinical trials, which are intended to include the typical patients for whom the 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 to reduce barriers and opportunity costs, using approaches such as participant boards to advise trial design. Ryan shared examples of practices that can increase trial accessibility and participation by older adults. These include offering home visits, transportation, or remote participation.

The use of adaptive study designs can also shorten trials or reduce participant numbers. Individuals may be hesitant to participate in a trial if they lack trust 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 the trial is complete, Ryan identified. Strategies to engage physicians in trial enrollment include direct outreach through in-person 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 people evaluated in EDs for TBI who undergo brain computed tomography (CT) imaging. 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 had positive CT scans but negative biomarker tests. Age caused minimal variance in sensitivity.

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 CT scan. He added that biomarkers

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 accuracy 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 could 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 errors.

Korley 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. Additionally, determining whether biomarker elevation 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.

MODELS OF TBI IN AGED ANIMALS

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 of 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 demonstrated 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 et al., 2019). Moreover, innate neuroprotective genes activated after 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 prioritized 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-related conditions and frailty necessitate larger study cohorts.

Harris identified needs for 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. However, 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 TBI is known to result in cognitive decline it is not fully known whether (1) age-related neurodegeneration is accelerated after TBI, or (2) TBI results in loss of cognitive reserve but does not change the slope of 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 neurodegeneration, 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, and neuroinflammation.

Therapeutics for age-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 brain to better understand the factors contributing to neurodegeneration. In a pharmacoepidemiologic study of older adults with TBI, statin drugs were associated with a 13 percent 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 insurance claim data for 7 million individuals at risk for Alzheimer’s disease that found that sildenafil (i.e., Viagra), a phosphodiesterase-5 inhibitor, demonstrated a 69 percent reduction in dementia risk in nonbrain injured individuals (Kenney et al., 2018).

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

reverses these deficits (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 (e.g., cyclo-oxygenase inhibitors, tumor necrosis factor inhibitors) could potentially also offer benefits 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

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 levels 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 neurodegeneration 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-Arrastia underscored the need for comparative-effectiveness research or methods of conducting pragmatic trials more efficiently than time-intensive randomized clinical trials.

Ryan reiterated the importance of trust in the participation of underrepresented populations in clinical trials. She noted efforts to have the demographics of the workforce supporting clinical trials to be reflective 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, workshop cochairs Kristine Yaffe and David Reuben concluded.

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