Review
Traumatic brain injury: A risk factor for Alzheimer's disease

https://doi.org/10.1016/j.neubiorev.2012.02.013Get rights and content

Abstract

Traumatic brain injury (TBI) constitutes a major global health and socio-economic problem with neurobehavioral sequelae contributing to long-term disability. It causes brain swelling, axonal injury and hypoxia, disrupts blood brain barrier function and increases inflammatory responses, oxidative stress, neurodegeneration and leads to cognitive impairment. Epidemiological studies show that 30% of patients, who die of TBI, have Aβ plaques which are pathological features of Alzheimer's disease (AD). Thus TBI acts as an important epigenetic risk factor for AD. This review focuses on AD related genes which are expressed during TBI and its relevance to progression of the disease. Such understanding will help to diagnose the risk of TBI patients to develop AD and design therapeutic interventions.

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.

References (95)

  • S. Li et al.

    Transient cognitive deficits are associated with the reversible accumulation of amyloid precursor protein after traumatic brain injury

    Neurosci. Lett.

    (2006)
  • P.C. Liliang et al.

    T proteins in serum predict outcome after severe traumatic brain injury

    J. Surg. Res.

    (2010)
  • G.M. Pasinetti et al.

    Personalized medicine in traumatic brain injury

    Psychiatr. Clin. North Am.

    (2010)
  • J.T. Povlishock

    Pathobiology of traumatically induced axonal injury in animals and man

    Ann. Emerg. Med.

    (1993)
  • S.K. Ray et al.

    Calpain in the pathophysiology of spinal cord injury: neuroprotection with calpain inhibitors

    Brain. Res. Rev.

    (2003)
  • S. Riggio

    Traumatic brain injury and its neurobehavioral sequelae

    Psychiatr. Clin. North Am.

    (2010)
  • K.E. Saatman et al.

    Calpain as therapeutic target in traumatic brain injury

    Neurotherapeutics

    (2010)
  • R. Sandhir et al.

    Age-dependent response of CCAAT/enhancer binding proteins following traumatic injury in mice

    Neurochem. Int.

    (2010)
  • K.E. Schwetye et al.

    Traumatic brain injury reduces soluble extracellular amyloid-β in mice: a methodologically novel combined microdialysis-controlled cortical impact study

    Neurobiol. Dis.

    (2010)
  • B.A. Stoica et al.

    Cell death mechanisms and modulation in traumatic brain injury

    Neurotherapeutics

    (2010)
  • Z. Szabo et al.

    Voluntary exercise may engage proteosome function to benefit the brain after trauma

    Brain Res.

    (2010)
  • G. Tesco et al.

    Depletion of GGA3 stabilizes BACE and enhances β-secretase activity

    Neuron

    (2007)
  • M.K. Thakur et al.

    Estradiol regulates APP mRNA alternative splicing in the mice brain cortex

    Neurosci. Lett.

    (2005)
  • K. Uryu et al.

    Multiple proteins implicated in neurodegenerative disease accumulate in axons after brain trauma in humans

    Exp. Neurol.

    (2007)
  • H. Wang et al.

    An apolipoprotein E-based therapeutic improves outcome and reduces Alzheimer's disease pathology following close head injury: evidence of pharmacogenomic interaction

    Neuroscience

    (2007)
  • Y. Wen et al.

    Increased β-secretase activity and expression in rats following transient cerebral ischemia

    Brain Res.

    (2004)
  • X. Yao et al.

    Ubiquitin and ubiquitin-conjugated protein expression in the rat cerebral cortex and hippocampus following traumatic brain injury (TBI)

    Brain Res.

    (2007)
  • X. Zhang et al.

    Hypoxia-inducible factor 1α (HIF-1α)-mediated hypoxia increases BACE1 expression and-amyloid generation

    J. Biol. Chem.

    (2007)
  • X. Zhang et al.

    Pathological role of hypoxia in Alzheimer's disease

    Exp. Neurol.

    (2010)
  • O. Zohar et al.

    PKC activator therapeutic for mild traumatic brain injury in mice

    Neurobiol. Dis.

    (2011)
  • J.R. Anderson et al.

    Impaired expression of neuroprotective molecules in the HIF-1 α pathway following traumatic brain injury in aged mice

    J. Neurotrauma

    (2009)
  • J.A. Blackman et al.

    Apolipoprotein E and brain injury: implications of children

    Dev. Med. Child Neurol.

    (2005)
  • S. Casas et al.

    Impairment of the ubiquitin-proteasome pathway is a downstream endoplasmic reticulum stress response induced by extracellular human islet amyloid polypeptide and contributes to pancreatic beta-cell apoptosis

    Diabetes

    (2007)
  • V. Conte et al.

    Vitamin E reduces amyloidosis and improves cognitive function in Tg2576 mice following repetitive concussive brain injury

    J. Neurochem.

    (2004)
  • A.F. Cronin

    Traumatic brain injury in children: issues in community function

    Am. J. Occup. Ther.

    (2001)
  • E. Czeiter et al.

    Traumatic axonal injury in the spinal cord evoked by traumatic brain injury

    J. Neurotrauma

    (2008)
  • D.C. David et al.

    Proteosomal degradation of tau protein

    J. Neurochem.

    (2002)
  • J.J. Fins

    Constructing an ethical stereotaxy for severe brain injury: balancing risks, benefits and access

    Nat. Rev. Neurosci.

    (2003)
  • S. Fleminger et al.

    Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication

    J. Neurol. Neurosurg. Psychiatry

    (2003)
  • T. Frugier et al.

    In situ detection of inflammatory mediators in post mortem human tissue after traumatic injury

    J. Neurotrauma

    (2010)
  • J.D. Fryer et al.

    Human apolipoprotein E4 alters the amyloid-β 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model

    J. Neurosci.

    (2005)
  • S.P. Gabbita et al.

    Cleaved-tau: a biomarker of neuronal damage after traumatic brain injury

    J. Neurotrauma

    (2005)
  • B.E. Gavett et al.

    Mild traumatic brain injury: a risk factor for neurodegeneration

    Alzheimer's Res. Ther.

    (2010)
  • P. Ge et al.

    Protein aggregation and proteosome dysfunction after brain ischemia

    Stroke

    (2007)
  • L.K. Glimer et al.

    Age related mitochondrial changes after traumatic brain injury

    J. Neurotrauma

    (2010)
  • S. Gottlieb

    Head injury doubles the risk of Alzheimer's disease

    Br. Med. J.

    (2000)
  • T.W. Groemer et al.

    Amyloid precursor protein is trafficked and secreted via synapric vesicles

    PLoS One

    (2011)
  • Cited by (0)

    View full text