Traumatic brain injury and Alzheimer\u2019s:
deficit profile similarities and the impact of
normal ageing

JOSEPH H. HINKEBEIN{ , THOMAS A. MARTIN{ , CHARLES D. CALLAHAN{ and BRICK JOHNSTONE{

Research has suggested that sustaining a traumatic brain injury (TBI) may increase one\u2019s risk of developing Dementia of the Alzheimer\u2019s Type (DAT) later in life. Several neuropathological models have been proposed to explain the association between TBI and DAT and studies using a neuro- psychological deficit profile methodology suggest that the pattern and extent of cognitive decline associated with these conditions are similar. This paper presents a new conceptual model, derived from deficit profile methodology, regarding the relationship between TBI and DAT. This model proposes that, for some individuals, TBI may not lead to true DAT neuropathology, but rather produces a profile of neuropsychological deficits similar to DAT, which increasingly mimics the symptoms of true DAT as the TBI survivor ages. Understanding how TBI may contribute to the development of DAT has important social and medical implications, influencing the direction of prevention efforts and contributing to one\u2019s understanding of DAT.

In recent years, there has been increasing interest in the relationship between a history of traumatic brain injury (TBI) and the later development of Dementia of the Alzheimer\u2019s type (DAT). Although research appears to support such an associ- ation, speculation about its precise nature persists [1\u20133]. The possibility that TBI may increase the risk for DAT has important social and medical implications that underscore the importance of further investigation regarding the relationship between these pathologies. This paper presents a new conceptual model for under- standing these relationships based on neuropsychological deficit profile analysis techniques [4\u20137]. It is hypothesized that TBI produces a profile of neuropsycho- logical deficits similar to DAT, which increasingly mimics the symptoms of true DAT as the person with TBI ages. This paper summarizes the existing literature

Correspondence to: Joseph H. Hinkebein, PhD, ABPP, Department of Health Psychology (DC046.00), University of Missouri, One Hospital Drive, Columbia, MO 65212, USA. e-mail: hinkebeinj@health.missouri.edu

The incidence of TBI in the general population has been estimated 200/100 000 [8]. While young adults (males in particular) are at highest risk for TBI, children and older adults make up the second and third most frequently injured demographic groups [9]. In fact, after the age of 65, the frequency of TBI increases steadily, with equal risk for men and women. Among the elderly, falls are the most frequent cause of TBI, followed by motor vehicle accidents [9]. DAT is the most common cause of dementia among people age 65 and older, with incidence rates of 3.5 per 1000 persons 65\u201369 years of age, rising to 72.8 per 1000 at ages 85\u201389 [10]. Epidemiological research on the incidence of DAT in older persons with a history of TBI remains unclear, although an association has been established [2].

Great strides have been made in the last decade in identifying and understanding the risk factors associated with DAT. Among genetic studies, the presence of the apolipoprotein E allele 4 (ApoE-4) has received the most attention. The association between DAT (late-onset familial and sporadic) and ApoE-4 has been recognized since 1993 [11], although it has been shown that ApoE-4 does not directly cause DAT (the disease can occur in the absence of the allele and there are cases of neuropathologically normal individuals with two copies of the allele) [12]. Environmental and psychosocial risk factors under investigation have included exposure to neurotoxins, brain trauma, lower intelligence, small head size, gender and age [13]. Putative neuroprotective variables include the ApoE-2 genotype, estrogen, higher education level and non-steroidal anti-inflammatory drugs [13].

Accumulating evidence suggests that certain risk factors associated with DAT may also be relevant in recovery from brain trauma. Preliminary evidence suggests that the presence of apoE4 allele may have a negative impact on neurologic recov- ery following TBI, secondary to the accumulation of the protein beta-amyloid [14, 15]. Evidence for a common neuropathological pathway (beta-amyloid protein deposition) supports one of the proposed models for how TBI leads to increased risk for DAT [16]. Specifically, this model suggests that TBI results in greater cerebral deposition of beta-amyloid, which increases the probability that the neuro-degenerative changes associated with DAT (i.e. neurofibrillary tangles and plaques) will occur later in life. There is further evidence suggesting a synergistic interaction between TBI and the presence of the apoE4 allele, which may magnify the probability that an individual will later develop DAT [17, 18].

The concept of \u2018brain reserve capacity\u2019 [19] has received attention in both the DAT and TBI literature. Brain reserve capacity (BRC) refers to neuronal redun- dancy that may be associated with larger numbers of neurons, greater synaptic density and a larger collection of cognitive resources available for problem solving. In this way, education, intelligence and pre-morbid brain size are all thought to contribute to BRC or cognitive reserve [13]. Thus, as reviewed by Lye and Shores [3], BRC is thought to be neuroprotective, both in recovery from TBI and in postponing age of DAT symptom onset (the so-called \u2018threshold theory\u2019). In exam- ining the link between TBI and DAT, this model would suggest that a history of TBI depletes BRC, thus resulting in a lower threshold and the earlier manifestation of symptoms in those genetically predisposed to DAT.

Related to this model, there is debate as to whether DAT is inevitable with age. In other words, \u2018If we live long enough, will we all be demented?\u2019 [20]. If an affirmative answer to this question is assumed, the brain reserve capacity model

While acknowledging the promising research on the ApoE4 link between TBI and DAT, the authors propose a neuropsychological model that may contribute to the understanding of the association between TBI and DAT, at least for some TBI survivors. It is argued that TBI not only depletes brain reserve capacity, but also creates a characteristic neuropsychological deficit profile that is similar to that seen in DAT. Further, this deficit profile is magnified over time by the normal ageing process (associated with declines in declarative memory, perceptual speed and work- ing memory) [21], which further depletes BRC. Consequently, it is proposed that some persons with TBI, in the absence of true DAT neuropathology, could none- theless develop a geriatric presentation that very much resembles DAT.

Both TBI and DAT result in neuropsychological impairment, typically involving domains such as memory and learning, processing speed and executive skills. The presence of neuropsychological dysfunction is in part determined by comparison of current performance to some estimate of pre-morbid intellectual functioning. Estimation of pre-morbid intellectual functioning is routinely employed to aid interpretation of neuropsychological data [22]. Many methods have been employed to estimate prior level of intellectual functioning including the \u2018best performance method\u2019 [23], \u2018hold/don\u2019t hold\u2019 tests [24], regression methods using demographic data [25] and various reading tests [26]. A recent study evaluating the efficacy of several of these methods found the WRAT-3 reading test to be useful in assessing pre-morbid intellectual functioning in individuals with average-to-below average intellectual ability [22].

Neuropsychological deficit profile analysis was developed as a method to deter- mine an individual\u2019s decline relative to pre-morbid functioning, as opposed to determining an individual\u2019s absolute level of functioning relative to a normative sample. Such profile analysis allows for the determination of the degree to which individuals decline in distinct cognitive domains (e.g. memory, attention, speed of processing, etc.). Subsequently, it can be determined if different brain diseases and injuries are associated with characteristic \u2018profiles\u2019 of cognitive strengths and weak- nesses. In fact, research utilizing this approach has found that distinct deficit profiles are associated with different neurological pathologies, such as TBI [4], DAT [5] and systemic lupus erythematosus [7].

The determination of neuropsychological profiles is based on the assumption that reading abilities remain relatively stable following brain injury and disease. Using reading scores as an estimate of pre-morbid abilities, it is possible to compare concurrent neuropsychological measures (e.g. intelligence, memory, attention, etc.) to reading scores to determine how much an individual has declined in distinct abilities. This method is also advantageous in that it allows for appropriate normative comparisons (i.e. persons of above-average pre-morbid abilities will have test scores compared to above-average reading scores, individuals of low-average pre-morbid