ReviewTraumatic brain injury: A risk factor for Alzheimer's disease
Highlights
► Traumatic brain injury (TBI) is an important epigenetic risk factor for the development of Alzheimer's disease. ► Aβ plaques which are pathological features of Alzheimer's disease are seen in 30% patients who die of TBI. ► Although many patients survive the initial insult, TBI initiates a chronic disease process. ► As TBI affects many areas of the brain, a multiplicity of neurobehavioral symptoms is common after TBI.
Introduction
National Head Injury Foundation (1988) has defined traumatic brain injury (TBI) as “an insult to the brain caused by an external force that may produce diminished or altered states of consciousness, which results in impaired cognitive abilities or physical functioning”. About 1.4 million people suffer from TBI every year in the United States alone (Zohar et al., 2011). The yearly cost of acute care and rehabilitation for new cases in the United States is between $9 and $10 billion (NIH Consensus Development Panel, 1999). TBI affects all age groups with particular prevalence among children and young adults (Fins, 2003, Kövesdi et al., 2010). It is the leading cause of acquired disability in children (Cronin, 2001). Survivors of TBI suffer from a wide variety of pathologies such as neurological deficits, short and long term brain damage, cognitive, behavioral and emotional impairments, all of which depend on the severity of injury. Neurological deficits in cognition are due to atrophy of hippocampus and damage of white matter tract as evident from functional imaging studies (Atkins et al., 2009).
TBI can be classified as (i) focal damage, which occurs in localized area and causes damage to the underlying brain tissues and vessels, and (ii) diffuse damage, which is not restricted but widespread throughout the brain. Diffuse type mainly involves axonal injury also called diffuse axonal injury (DAI), brain swelling and hypoxia (Hellewell et al., 2010, Laurer et al., 2000). Axonal injury is an almost universal sequel of TBI (Li et al., 2006, Smith, 2000) and a powerful predictor of morbidity and mortality (Czeiter et al., 2008). In axons, it causes an accumulation of proteins, including amyloid precursor protein (APP), which is carried by fast anterograde axonal transport and serves as a sensitive marker of axonal damage. This may result in axonal disconnection leading to loss of axonal function and structure (Chen et al., 2004). TBI is one of the most consistent candidates for initiating the molecular cascades that result in Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (Gavett et al., 2010).
Section snippets
TBI initiates a disease process
Although many patients survive the initial insult, TBI initiates a chronic disease process that may ultimately contribute to their deaths months to years later (Masel and DeWitt, 2010). Cell death after TBI is a major cause of neurological deficits and mortality (Stoica and Faden, 2010, Yu et al., 2008). TBI is a disease process with an initial injury that induces biochemical and cellular changes which in turn contribute to continuing neuronal damage and death over time. This continuing damage
TBI and Alzheimer's disease
TBI is a strong epigenetic risk factor for AD (Fleminger et al., 2003, Magnoni and Brody, 2010, Plassman et al., 2000) which is a neurodegenerative disorder characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles (NFTs) (Slemmer et al., 2011). Senile plaques are formed of aggregates of amyloid beta (Aβ) peptides, whereas NFTs are composed of bundles of pathological fibrils called paired helical filaments (PHFs), which are made up of aberrantly
Neurobehavioral sequelae of TBI
Because TBI affects many areas of the brain, a multiplicity of neurobehavioral symptoms is common after TBI. It includes cognitive impairments, personality changes, aggression, impulsivity, apathy, anxiety, depression, mania and psychosis (Riggio, 2010). Patients often complain of headache or dizziness after head injury (Shawn et al., 2007). Comprehensive mental status testing frequently reveals symptoms of depression or memory dysfunction and requires psychiatric consultation. The two
Conclusions
TBI initiates many different signaling cascades throughout the brain that impact both pathophysiological and neuroprotective processes. Cellular mechanisms that can modulate these processes may play an important role in determining the nature and extent of the damage suffered after TBI and therefore influence overall outcome after injury. Many studies support the hypothesis that the survivors of TBI have a major risk of developing AD. The link between TBI and later development of
Acknowledgements
The authors thank Prof. Rita Christopher, NIMHANS, Bangalore, for critically reading the manuscript and giving useful comments for its improvement. Research work in authors’ laboratory is funded by grants from the Council of Scientific and Industrial Research (CSIR), Department of Science and Technology (DST), Department of Biotechnology (DBT) and Indian Council of Medical research (ICMR), Government of India.
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