Exploring the connection between traumatic brain injury and Alzheimer's disease: A population-based medical record review analysis

Mayo Clinic has been at the forefront of population-based epidemiological research related to both traumatic brain injury (TBI) and Alzheimer's disease and related conditions (ADRC). In May 2015, a Mayo research team was awarded a $795,000 grant by the Department of Defense to study the connection between TBI and ADRC using a population-based medical record review.

TBI causes cognitive and neurobehavioral disorders, including depression and irritability, in some individuals. Given this association, researchers speculate that TBI is also associated with an increased risk of ADRC. ADRC includes Parkinson's disease, Lewy body dementia (LBD), frontotemporal dementia and amyotrophic lateral sclerosis (ALS).

To date, epidemiological studies linking TBI and ADRC have yielded conflicting results. These findings often reflect methodological variations in defining TBI and classifying injury severity and studying clinical cohorts not representative of the broader population.

Additionally, most previous analyses studying the connection between TBI and ADRC also fail to include the least severe injury category, despite the fact that epidemiological data show that this injury category is the most prevalent among both civilian and military populations.

According to Mayo researchers, the most accurate and reliable study design to determine whether the occurrence of TBI increases risk of the development of ADRC is to identify incident TBI events by medical record review within a defined population and classify each by injury severity, identify matched referents within that same population, and follow both cohorts over time to observe incidence rates of ADRC.

Allen W. Brown, M.D., a clinical researcher and director of Brain Rehabilitation at Mayo Clinic's campus in Rochester, Minnesota, is the principal investigator of this research, and Michelle M. Mielke, Ph.D., a translational neuroepidemiologist at Mayo Clinic's campus in Minnesota, is the study's co-principal investigator.

Dr. Brown notes that this study design is unique. "To the best of our knowledge, there are no published reports of a population-based analysis matching TBI cases, identified by medical record review and classified by injury severity into three strata (moderate-severe, mild, concussive), to population-based referents controlled for nonhead trauma. This is particularly important, as nonhead trauma may also increase the risk of ADRC."

Rochester Epidemiology Project

Access to the Rochester Epidemiology Project (REP) offers Mayo researchers a unique capability to study this association. The REP is a medical records linkage system that provides the infrastructure to link the medical records from all sources of care used by the population of Olmsted County, Minnesota.

Olmsted County (2010 census population, 144,248) provides a rare opportunity to investigate the epidemiological connection between TBI and ADRC. Epidemiologic research in Olmsted County is possible because the county is relatively isolated from urban centers, and because local residents receive nearly all of their medical care from a limited number of providers, including Mayo Clinic, Olmsted Medical Center and a few private practitioners.

According to Dr. Brown, access to REP data offers two distinct advantages specific to this study. "By applying the Mayo Classification System for Traumatic Brain Injury Severity, we will have precise information on both severity and number of TBI events. These variables are believed to be important in the subsequent development of ADRC, but never before identified for this purpose by medical record review in a defined population," explains Dr. Brown.

Hypothesis

Mayo researchers hypothesize that individuals in the population with a confirmed TBI will not be at increased risk of developing ADRC compared with age- and sex-matched referents without a TBI, after controlling for nonhead injuries. Mayo researchers also suspect that they are likely to find an increased risk of developing ADRC after TBI in subsets of the cohort with clinical features that have been suspected of increasing this risk, such as multiple injuries or injuries of increased severity. If so, they hope to determine the factors that isolate that group.

Specific aims and research strategy

The Mayo research team has four specific aims:

  • Increase the size of the existing incident cohort of individuals age 30 years and older who experienced TBI between 1985 and 1999 in the population of Olmsted County, Minnesota
  • Classify each TBI event by injury severity and determine the number of TBI events per individual
  • Match, by age and sex, each individual with a confirmed TBI to a population-based referent without a TBI and account for nonhead trauma
  • Longitudinally determine whether TBI, including number of events and severity, is associated with subsequent risk of ADRC after accounting for nonhead trauma

At the conclusion of this study Mayo researchers hope to have identified and confirmed at least 2,235 individuals age 30 and older with any severity of TBI, age- and sex-matched to 2,235 population-based individuals without a TBI. Individuals will be followed from the date of the index TBI event forward until the first clinical diagnosis of an ADRC, the last medical visit in Olmsted County or death. The risk of an ADRC in those with a TBI event will be compared directly with those without a TBI event using Cox proportional hazards models and adjusting for nonhead trauma.

"These Mayo Clinic resources, along with the investigators' expertise and experience in using them to study the epidemiology of TBI and ADRC, make the proposed research novel, unique and highly likely to contribute meaningfully to the field," says Dr. Brown. "We expect this work to benefit both the military and civilian communities, providing new knowledge that will reduce the bias of previous research, and help us more accurately determine the interrelationship between TBI and subsequent development of ADRC."

Definition of TBI based on medical record review

A confirmed event will be defined as a first TBI between Jan. 1, 1985, and Dec. 31, 1999. TBI is defined as a traumatically induced injury that contributes to the physiological disruption of brain function. Evidence in the medical record of physiological disruption includes documentation of any of the following:

  • Loss of consciousness
  • Post-traumatic amnesia
  • Neurological signs of brain injury
  • Evidence of intracerebral, subdural or epidural hematoma, cerebral or hemorrhagic contusion, or brain stem injury
  • Penetrating brain injury
  • Skull fracture
  • Postconcussive signs and symptoms (dizziness, confusion, blurred vision, double vision, headache, nausea or vomiting) that lasted more than 30 minutes and that were not attributable to pre-existing or comorbid conditions

Information from all medical care settings will be included in this proposal (for example, hospital inpatient, hospital outpatient, emergency department, office visit or nursing home).

Individuals who did not seek medical attention specifically for either the event or for sequelae (injuries identified as part of the past medical history) will be excluded since we will not have the information to confirm the TBI and the severity.