Overview

Traumatic brain injury (TBI) has been identified as important risk factor contributing to the later development of dementia. Currently, it is hypothesized that 5-15% of dementia cases are preceded by the occurrence of a TBI (1). Research on the neurological link between TBI and dementia is relatively new, although chronic traumatic encephalopathy (CTE) may be an important foundational connection. An improved understanding of the neuropathology underlying TBI-related dementia is critical for the development of future treatment and prevention strategies.

TBI & Dementia Risk

In the United States, 1.7 million individuals are estimated to sustain a TBI annually (3). While any individual may experience a TBI, populations that are commonly affected include older adults (falls are a primary cause of TBI), athletes, and military personnel (1). TBI may be classified as mild, moderate, or severe, and may occur as a single incident or as a repetitive event (most commonly seen in sports). Connections between moderate and severe forms of TBI are most often linked to dementia at a 2 to 4-fold increased risk, however there is preliminary evidence to support the involvement of mild TBI as well (1,2). Additionally, the history of a TBI at any severity level was shown to predict an earlier age of onset of cognitive impairment in older adults (4).

Evidence suggests that age of TBI occurrence may also influence dementia onset, with a single mild TBI leading to increased dementia risk in older individuals (5). TBI has also been associated with early-onset dementia, or dementia diagnosed before the age of 65, and the increased presence of specific neuropsychiatric symptoms in dementia, including disinhibition (6, 7). Several studies have found that the presence of the apolipoprotein e40 (APOE e4) allele, which has been implicated in both dementia and general cognitive decline, increases the risk of dementia following a TBI, with some research identifying a 10-fold increase in risk (1, 8).

Acute and long-term symptoms of TBI vary based on location and severity of the injury. Chronic traumatic encephalopathy (CTE) is a neurodegenerative syndrome that may follow the occurrence of several TBIs.  While it closely resembles the clinical presentation of Alzheimer’s disease (AD), CTE differs somewhat in its neuropathology.  At the present time, it is unclear how TBI-related dementia cases are similar to CTE. However, researchers propose that an understanding of the neuropathology of CTE may lead to the identification of universal neurological changes following any TBI that leads to dementia and/or AD.

Neurological Changes in TBI

Neuropathological changes following TBI have been studied in animal models and in the presentation of neurodegenerative disease in humans. Studies of animal models have identified the upregulation of proteins that are implicated in human neurodegenerative disease, such as β-amyloid peptides and tau (9, 10). This has been confirmed in studies of humans that have shown the presence of β-amyloid plaques in individuals with a TBI (11). Neurofibrillary tangles (NFTs) were also present, and are a core feature of CTE, although their location in the brain varies from that seen in the more classic presentation of AD (12). In addition to the upregulation of β-amyloid protein precursors, it has been hypothesized that the presence of plaques following a TBI may be due to damaged axons that contribute to amyloid protein accumulation (1, 13).

In addition to the presence of characteristic amyloid plaques and NFTs, TBI is thought to contribute to neurodegenerative disease through other potential pathways, including chronic neuroinflammation. Studies of neuroinflammation following TBI identified the presence of white matter degradation as well as enhanced activation of microglia, which are cells meant to protect the brain but can lead to damage if over-activated or dysregulated (14-16). Additionally, the presence of ongoing brain atrophy (or degeneration) has been implicated in the presence of future cognitive issues, with affected brain areas including the cerebellum, and frontal and temporal lobes (13). Similarly, continued loss of neurons has been seen up to one year following a TBI, and may be linked to neurodegenerative disorders (13).

Treatment Implications

Currently, there is no specific treatment strategy for TBI-related dementia.  While there are guidelines for treating cognitive impairment following a TBI, it is unclear how this may impact the prevention of later dementia development (17).  However, identifying the neuropathology of TBI-related dementia may lead to important treatment implications in the future.  For example, neuroimaging techniques such as serial magnetic resonance imaging (repeated MRIs over time) or molecular imaging (through positron emission topography) have been proposed as useful tools to track neurological changes over time and identify individuals who may be at-risk for later dementia (18).

Dr. Thomas has done neurofeedback with some patients who were in the early stages of cognitive decline, with a strategy following some work as described in his chapter on stopping early dementia with neurotherapy methods (19).  The basic strategy is to increase frontal lobe cerebral blood flow and use neurofeedback to inhibit theta globally in the cortex, following the Dr. Leslie Prichep et al, 2006 study (20) which indicates that those with excessive theta at all QEEG sites have a 90% chance of having cognitive decline 9 years later.

— S. Jacobs & J. L. Thomas

References

  1. Shively, S, Scher, A, Perl, D, & Diaz-Arrastia, R (2012). Dementia resulting from traumatic brain injury: what is the pathology?. Archives of neurology69(10), 1245-1251.
  2. Lee, Y, Hou, S, Lee, C, Hsu, C, Huang, Y, & Su, Y (2013). Increased risk of dementia in patients with mild traumatic brain injury: a nationwide cohort study. PloS one8(5), e62422.
  3. Langlois, J, Rutland-Brown, W, & Thomas, K (2006). Traumatic brain injury in the United States; emergency department visits, hospitalizations, and deaths.
  4. Li, W, Risacher, S, McAllister, T, & Saykin, A (2016). Traumatic brain injury and age at onset of cognitive impairment in older adults. Journal of neurology263(7), 1280-1285.
  5. Johnson, V, & Stewart, W (2015). Traumatic brain injury: age at injury influences dementia risk after TBI. Nature Reviews Neurology11(3), 128.
  6. McMurtray, A, Clark, D, Christine, D, & Mendez, M (2006). Early-onset dementia: frequency and causes compared to late-onset dementia. Dementia and Geriatric Cognitive Disorders21(2), 59-64.
  7. Rao, V, Rosenberg, P, Miles, Q, Patadia, D, Treiber, K, Bertrand, M, Norton, M, Steinberg, M, Tschanz, J, & Lyketsos, C (2010). Neuropsychiatric symptoms in dementia patients with and without a history of traumatic brain injury. The Journal of neuropsychiatry and clinical neurosciences22(2), 166-172.
  8. Mayeux, R, Ottman, R, Maestre, G, Ngai, C, Tang, M, Ginsberg, H, & Shelanski, M. (1995). Synergistic effects of traumatic head injury and apolipoprotein-epsilon4 in patients with Alzheimer’s disease. Neurology45(3), 555-557.
  9. Iwata, A, Chen, X, McIntosh, T, Browne, K, & Smith, D (2002). Long-term accumulation of amyloid-β in axons following brain trauma without persistent upregulation of amyloid precursor protein genes. Journal of Neuropathology & Experimental Neurology61(12), 1056-1068.
  10. Tran, H, LaFerla, F, Holtzman, D, & Brody, D (2011). Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-β accumulation and independently accelerates the development of tau abnormalities. Journal of Neuroscience31(26), 9513-9525.
  11. Johnson, V, Stewart, W, & Smith, D (2012). Widespread tau and amyloid‐beta pathology many years after a single traumatic brain injury in humans. Brain pathology22(2), 142-149.
  12. McKee, A, Cantu, R, Nowinski, C, Hedley-Whyte, E, Gavett, B, Budson, A, Santini, V, Lee, H, Kubilus, C, & Stern, R (2009). Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. Journal of Neuropathology & Experimental Neurology68(7), 709-735.
  13. Smith, D, Chen, X, Iwata, A, & Graham, D (2003). Amyloid β accumulation in axons after traumatic brain injury in humans. Journal of neurosurgery98(5), 1072-1077.
  14. Hanisch, U (2002). Microglia as a source and target of cytokines. Glia40(2), 140-155.
  15. Faden, A, & Loane, D (2015). Chronic neurodegeneration after traumatic brain injury: Alzheimer disease, chronic traumatic encephalopathy, or persistent neuroinflammation?. Neurotherapeutics12(1), 143-150.
  16. Scott, G, Hellyer, P, Ramlackhansingh, A, Brooks, D, Matthews, P, & Sharp, D (2015). Thalamic inflammation after brain trauma is associated with thalamo-cortical white matter damage. Journal of neuroinflammation12(1), 224.
  17. Writer, B, & Schillerstrom, J (2009). Psychopharmacological treatment for cognitive impairment in survivors of traumatic brain injury: a critical review. The Journal of neuropsychiatry and clinical neurosciences21(4), 362-370.
  18. Wilson, L, Stewart, W, Dams-O’Connor, K, Diaz-Arrastia, R, Horton, L, Menon, D, & Polinder, S (2017). The chronic and evolving neurological consequences of traumatic brain injury. The Lancet Neurology16(10), 813-825.
  19. Thomas, J (2011). Brian brightening: Neurotherapy for enhancing cognition in the elderly. In P. Hartman-Stein and A LaRue (Eds) Enhancing cognitive fitness in adults..  NY: Springer, pp 433-444.
  20. Prichep, L, et al., (2006). Prediction of longitudinal cognitive decline in normal elderly with subjective complaints using electrophysiological imaging.  Neurobiology of aging, 27,471-481.