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Mild traumatic brain injury: a risk factor for neurodegeneration

  • Brandon E Gavett1, 2,
  • Robert A Stern1, 2,
  • Robert C Cantu2, 3, 4,
  • Christopher J Nowinski2, 3 and
  • Ann C McKee1, 2, 5, 6Email author
Alzheimer's Research & Therapy20102:18

https://doi.org/10.1186/alzrt42

Published: 25 June 2010

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Archived Comments

  1. Traumatic brain injury and Alzheimer¿s disease

    24 November 2010

    Rovshan Ismailov, University of Pittsburgh

    I agree with Dr. Gavett and colleagues that cohort studies with both detailed and accurate neuropathological assesement of patients diagnosed with head injury are needed. However, we also need more studies that would examine the mechanism of the association between traumatic brain injury and Alzheimer¿s disease.

    Several population based studies favored an association between traumatic brain injury and subsequent Alzheimer¿s disease[1,2]. For instance, a hazard ratio of 2.32 (confidence interval = 1.04 to 5.17) for moderate traumatic brain injury and a hazard ratio of 4.51 (confidence interval = 1.77 to 11.47) for severe head injury was observed in a historical cohort study of 548 World War II veterans[3]. We have reported that the proportion of patients diagnosed with both traumatic brain injury and Alzheimer¿s disease was nearly twice as high as the proportion of patients diagnosed with Alzheimer¿s disease and any other comorbidities (p less than 0.001). In the adjusted (for age, gender, length of stay and primary source of payment) logistic regression analysis, patients diagnosed for traumatic brain injury were 1.82 times more likely to be diagnosed with Alzheimer¿s disease (95% confidence interval 1.28 ¿ 2.58)[4]. A recent meta-analysis of case-control studies confirmed that men diagnosed with traumatic brain injury are at increased risk of developing Alzheimer¿s disease[5]. However, no serious consideration of the mechanism has been provided.

    Obviously, trauma may damage any structure of the brain; however, cerebral vascular wall could be at particular high risk due to the presence of ¿internal¿ forces acting inside the vessel (i.e. shear stress). On the other hand, with the appearance of the ¿hypoperfusion¿ theory as well as findings from numerous population-based studies linking Alzheimer¿s disease to vascular disorders (i.e. hypertension, atherosclerosis etc.), it became evident that the important task for understanding Alzheimer¿s disease is to thoroughly examine hemodynamics and blood rheology. Such approach may also result in finding of successful treatments of Alzheimer¿s disease.

    Thus, the mechanism of the association between traumatic brain injury and Alzheimer¿s disease is complex. For instance, genetic influence (i.e. having apolipoprotein E epsilon4) can worsen prognosis of Alzheimer¿s disease after traumatic brain injury[6,7]. Animal-based experiments observed an increase of amyloid ß peptide following traumatic brain injury[8]. The vascular component of the mechanism of traumatic brain injury-related Alzheimer¿s disease should take into account both direct and indirect trauma to brain vessels, and therefore changes to local hemodynamic and rheological factors[4]. Traumatic compression of the vessel can lead to the appearance of zones with high shear stress (as the result of injury to part of the vessel) and low or zero shear stress (within the zone of boundary layer separation)[9]. We have reported that high shear stress (exceeding the physiological value) may potentially damage the endothelium[9] and increase platelet aggregation[10,11], possibly leading to thrombus formation. On the other hand, trauma may lead to boundary layer separation, resulting in the appearance of a zone with zero shear stress and zero yield velocity[9]. According to current research, this may result in an increase of blood viscosity through increased erythrocyte aggregation and rouleaux formation[4]. As noted above, hyperviscosity may worsen the blood circulation and cause ischemia and local necrosis through deterioration in capillary perfusion[12]. Finally, trauma may lead to the appearance of zones of boundary layer separation, which, in turn, may directly influence the velocity of the movement of the regional brain extravascular fluid[4]. The above consideration of regional brain extravascular fluid dynamics is particularly important in light of the fact that certain waste products such as glutamate or calcium can accumulate there causing degradation of certain cellular components thus playing an important role in the pathogenesis of Alzheimer¿s disease[13,14].

    Rovshan M Ismailov, M.D., M.P.H., Ph.D.

    References

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    [2] Jellinger KA. Head injury and dementia. Curr Opin Neurol 2004; 17(6):719-23.
    [3] Plassman BL, Havlik RJ, Steffens DC et al. Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias. Neurology 2000; 55(8):1158-66.
    [4] Ismailov RM. New insights into the mechanism of Alzheimer's disease: A multidisciplinary approach . edn. Amazon Kindle, 2010.
    [5] Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S, Giora A. Head injury as a risk factor for Alzheimer's disease: the evidence 10 years on; a partial replication. J Neurol Neurosurg Psychiatry 2003; 74(7):857-62.
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    [9] Ismailov RM, Shevchuk NA, Schwerha J, Keller L, Khusanov H. Blunt trauma to large vessels: a mathematical study. Biomed Eng Online 2004; 3(1):14.
    [10] Jen CJ, McIntire LV. Characteristics of shear-induced aggregation in whole blood. J Lab Clin Med 1984; 103(1):115-24.
    [11] Wagner CT, Kroll MH, Chow TW, Hellums JD, Schafer AI. Epinephrine and shear stress synergistically induce platelet aggregation via a mechanism that partially bypasses VWF-GP IB interactions. Biorheology 1996; 33(3):209-29.
    [12] Kwaan HC, Bongu A. The hyperviscosity syndromes. Semin Thromb Hemost 1999; 25(2):199-208.
    [13] Mattson MP. Calcium as sculptor and destroyer of neural circuitry. Exp Gerontol 1992; 27(1):29-49.
    [14] Khachaturian ZS. The role of calcium regulation in brain aging: reexamination of a hypothesis. Aging (Milano) 1989; 1(1):17-34.

    Competing interests

    I declare that I have no significant competing interests

Authors’ Affiliations

(1)
Department of Neurology, Boston University School of Medicine
(2)
Center for the Study of Traumatic Encephalopathy, Boston University
(3)
Sports Legacy Institute
(4)
Department of Neurosurgery, Emerson Hospital, 131 ORNAC Suite 820
(5)
Geriatric Research Education Clinical Center, Edith Nourse Rogers Memorial VA Hospital
(6)
Department of Pathology and Laboratory Medicine, Boston University School of Medicine

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