Question: With clients who have moderate to severe brain injury, is there a greater risk of Alzheimer's disease or other neurodegenerative conditions than seen in the non-injured population?
Answer: Brain Injury Source, Ask the Doctor
By Nathan D. Zasler, MD, FAAPM&R, FAADEP, DAAPM, CIME
This question is an interesting one which frequently comes up in the context of medicolegal and-to a lesser extent-clinical care. Quite a bit of literature is available now on risk factors for Alzheimer's disease following head trauma. One of the familiar classic references that actually began to examine the neuropathologic basis for senile dementia of Alzheimer's type after severe brain injury was work done by Graham and colleagues from Glasgow, Scotland. Graham et al. found that deposits of beta-amyloid (a type of protein) could be found in as many as 30% of individuals with fatal head/brain injuries. They also noted that this protein was widely distributed and that there was no correlation between its presence and cerebral contusion, intracranial hematoma, axonal injury, ischemic brain injury, brain swelling or the pathology of raised intracranial pressure. Their findings suggested that the deposition of beta-amyloid protein was the consequence of acute phase responses of nerve cells to stress in susceptible individuals.
Further work published by the same group and based on clinical pathologic studies noted that beta-amyloid protein deposition was most likely, but not exclusively, to occur the older the person was at the time of injury. Additionally, and just as interestingly, they found that falls-related injuries tended to be the type associated with this type of post-traumatic neurodegenerative condition.
The fact that there also seems to be a genetic predisposition to development of Alzheimer's-type neurodegenerative conditions following severe traumatic brain injury also is worthy of note. Specifically, a strong association has been found between deposits of beta-amyloid protein in individuals who carry the genotype apolipoprotein E also known as APOE. This also is relevant to an organism's general vulnerability to brain injury, in that animal studies have shown that apolipoprotein E deficiency might impair the ability to recover from TBI.
Three recent studies further edify the role of APOE in outcome after severe TBI. Nicoll et al. (1995) found that approximately one-third of persons dying from acute brain injury not only had excess amounts of amyloid beta protein in their brains but also a frequency that was measurably higher than the rate in the general population for the AOPE-4 allele. Two more recent studies confirm these results. Teasdale et al. (1997) found that possession of the APOE-4 allele contributed to the severity of acquired brain trauma when comparing "carriers" vs. "non-carriers" of the allele in a prospective clinical study. Friedman et al. (1999) in an Israeli study, looked at post-acute outcome in a group of 69 individuals with TBI and found that persons with the APOE-4 allele were more than five times more likely to remain unconscious for more than seven days compared to those who lacked the allele. Only one of the 27 persons with the APOE-4 allele had a good outcome compared to 13 of 42 persons with comparable injuries who reached a good functional recovery.
At Columbia University, studies by Mayeux and colleagues have suggested that there is a ten-fold increase in the risk of Alzheimer's disease in association with apolipoprotein E, epsilon 4 allele and a history of traumatic brain injury compared to a two-fold increase in risk with apolipoprotein-E, epsilon 4 allele alone. Brain injury in the absence of APOE-epsilon 4 allele did not increase risk. Their work also has shown that there appears to be a decreased association between carrying the APOE-epsilon 4 allele and senile dementia of the Alzheimer type (SDAT) in the very old and among African-Americans compared to Caucasians and Hispanics.
APOE-epsilon 4 also has been shown to be associated with chronic traumatic brain injury as a result of boxing. Jordan et al. (1997) at New York Hospital, Cornell University Medical College, noted preliminary findings suggesting that possession of this gene may be associated with increased severity of chronic neurologic deficits in high exposure boxers. These findings raise the question as to whether boxers-amateur and professional-should be screened for APOE and potentially withheld from active participation in boxing if they possess this particular genotype or, at a minimum, warned of the potential "morbidity" of this finding. Just how far should this information and/or screening process go? Should all athletes and/or persons at risk for head trauma/brain injury be made aware of this risk factor?
Older studies certainly have shown that a history of head injury (more accurately, brain injury) is a risk factor for development of Alzheimer's disease, as well as possibly Parkinson's disease, although the latter seems to be more speculative. The work in the last five years clearly shows that severe brain injury is a risk factor for development of senile dementia of the Alzheimer's type; however, there seems to be significant genotypic variables that determine whether some will or will not get this condition following severe traumatic brain injury. Dementia pugilistica or "punch drunk syndrome," which may be seen in boxers after repeated brain injury, certainly is the most well-known example of brain trauma being associated with neurodegenerative disease.
As noted by Jane and Francel (1996) in the textbook Neurotrauma "Frequently patients with Alzheimer's disease and associated head injury have this head injury within five years of the onset of their symptoms." They go on to speculate that brain insult in older individuals may result in different pathological processes than do similar injuries in younger persons, specifically with regard to metabolism of beta-amyloid-the ability for proteolysis (breakdown in protein) of the expressed amyloid-which may be altered with age.
The empirical observations noted by Jane and Francel may or may not be accurate. Nemetz et al. (1999) recently published a population-based study examining the time of onset of Alzheimer's in persons with and without a history of TBI. They found that TBI reduces the time of onset of Alzheimer's disease among persons at risk for developing the disease. Interestingly, of the greater than 1,200 persons with TBI followed, there was no statistically greater incidence of Alzheimer's noted than in the non-TBI population. Of note, however, was the fact that the median time to Alzheimer's disease onset was approximately eight years earlier. The aforementioned findings imply that environmental risk factors such as the history of traumatic brain injury, in addition to age and even ethnicity, may unmask underlying genotypic risk factors associated with the APOE.
To date, the experimental work in mild to moderate TBI is limited extremely. Data examining APOE-4 allele incidence in mild TBI have not shown a statistically significant difference from non-MTBI controls (Sandel, 1999). Mild and moderate TBI have not been explored adequately as risk factors per se for SDAT. It is this clinician's experience that such injury does not likely increase risk significantly, if at all, for SDAT in these individuals. Part of the reason for this may be related to a threshold effect of injury and the brain's ability to compensate for injury in cases of mild to moderate TBI as compared with severe TBI.
There is still much that we need to learn regarding neurodegenerative conditions following severe brain injury. This is a very furtive area of research and I am sure we will see much more information come to light in the next few years regarding post-traumatic SDAT pathology and etiology, as well as incidence and prevalence. Given the genetic risk factors for this neurodegenerative condition, it only will be a matter of time before we see studies examining the role of gene therapy for treatment of SDAT and/or modulation of APOE-4 allele expression.
Nathan D. Zasler, MD, FAAPM&R, FAADEP, CIME, is an internationally respected specialist in brain injury care and rehabilitation. Dr. Zasler is medical director of the Concussion Care Centre of Virginia, Ltd. and is involved with several brain injury rehabilitation programs in the Richmond, Virginia area including Tree of Life, LLC, a living assistance program for persons with acquired brain injury (ABI). Dr. Zasler has lectured and written extensively on neurologic issues with over 500 lectures and publications including two edited textbooks. Dr. Zasler is a member of numerous editorial boards and is editor-in-chief of the international scientific publication Neurorehabilitation: An Interdisciplinary Journal. He is active in numerous national and international organizations including serving on the Board of Governors of the International Brain Injury Association (IBIA). He is also grant reviewer for several federal agencies and serves on the Advisory Board for the Defense and Veterans Head Injury Program (DVJIP). His main areas of interest include low-level neurologic states after brain injury, post-concussive disorders and neuromedical issues in ABI.
Suggested Readings:
Chen Y, Lomnitski L, Michaelson DM et al.: Motor and cognitive deficits in apolipoprotein E - deficient mice after closed head injury. Neuroscience. 80(4):1225-62, 1997.
Friedman G et al.: Apolipoprotein E-4 genotype predicts a poor outcome in survivors of traumatic injury. Neurology. 52:244-248, 1999.
Graham DI, Gentleman SM, Lynch A et al.: Distribution of beta-amyloid protein in the brain following severe head injury. Neuropathol Appl Neurobiol. 21(1):27-34, 1995.
Graham DI, Gentleman, SM, Nicoll JA et al.: Altered beta-APP metabolism after head injury and its relationship to the etiology of Alzheimer's disease. Acta Neurochir Suppl. 66:96-102, 1996.
Jane J & Francel PC: Age and outcome of head injury. In: Neurotrauma. RJ Narayan, JE Wilberger & JT Povlishock (Eds). New York: McGraw Hill, 1996. Pgs. 793-804.
Jordan CD, Relkin NR, Ravdin LD et al.: Apolipoprotein E Epsilon-4 associated with chronic traumatic brain injury in boxing. JAMA. 278(2):136-40, 1997.
Mayeux R, Ottman R, Maestre G et al: Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer's disease. Neurology. 45:555-557, 1995.
Nemetz PN, Leibson C, Naessen JM et al: Traumatic brain injury and time of onset of Alzheimer's disease: A population-based study. Am J Epidemiol. 149(1):32-40, 1999.
Nicoll JAR et al.: Apolipoprotein E-4 allele is associated with deposition of amyloid beta protein following head injury. Nature Med. 1:135-137, 1995.
Sandel ME. Personal communication, 1999.
Tang MX, Maestre G et al.: Effect of age, ethnicity, and head injury on the association between APOE genotypes and Alzheimer's disease. Ann NY Acad Sci. 16(802):6-15, 1996.
Teasdale GM et al.: Association of apolipoprotein E polymorphism with outcome after head injury. Lancet. 350:1069-1071, 1997.