David L. Brody, M.D., Ph.D.

Norman J. Stupp Professor
Neurology

Neurosciences Program

  • 314-362-1381

  • 314-362-1378

  • 314-362-3279

  • 8111

  • Biotechnology Building, Room 201

  • brodyd@neuro.wustl.edu

  • https://neuro.wustl.edu/research/research-labs-2/brody-laboratory/

  • amyloid, , Alzheimer’s disease, Diffusion Tensor Imaging, Traumatic Brain Injury; Chronic traumatic encephalopathy

  • Experimental and Translational Research on Traumatic Brain Injury: Amyloid-beta linkages to Alzheimer`s disease

Research Abstract:

Research in our laboratory and collaborative group is focused traumatic brain injury (TBI), neurodegenerative diseases, and the relationship between TBI and later neurodegeneration. TBI is a major cause of morbidity and mortality in the United States and worldwide (CDC report), and a major risk factor for the development of Alzheimer’s Disease (Plassman et al, Neurology 2000). Repeated concussive TBI’s can lead to a distinct neurodegenerative condition called Chronic Traumatic Encephalopathy (McKee et al, JNEN 2009).
There are three major lines of research in the laboratory. The first is focused on uncovering mechanisms underlying amyloid-beta and tau pathologies following traumatic brain injury. Amyloid-beta is believed to play a central role in the development of Alzheimer ’s disease, the most common cause of late-life dementia. Tau pathology is a hallmark of Chronic Traumatic Encephalopathy, which affects many former athletes in contact sports who have suffered multiple concussions (e.g. football players, boxers). We have developed experimental models of post-traumatic amyloid-beta and tau pathologies using transgenic mice (Tran et al, J. Neurosci 2011). The laboratory uses two models of traumatic brain injury: controlled cortical impact (Brody et al, J. Neurotrauma 2007) and repetitive concussive impact (Shitaka et al, JNEN 2011). Using these models, we are working to test hypotheses regarding the mechanisms underlying injury-related accelerations of amyloid-beta and tau pathologies (Tran et al JNEN 2012). We are also exploring mechanisms underlying genetic risk factors for poor outcomes following TBI such as Apolipoprotein E (Bennett et al, JNEN 2013). From there we hope to develop novel therapeutic strategies to alleviate or prevent these pathologies in mice first, then later in humans. The translational focus of the laboratory is exemplified by our use of microdialysis to elucidate amyloid-beta dynamics following TBI in both mice (Schwetye et al Neurobiol Dis 2010) and human patients (Brody, Magnoni et al Science 2008) in a directly comparable fashion.
The second major line of research is focused on the detection of traumatic axonal injury using advanced MRI methods such as Diffusion Tensor Imaging (DTI), Diffusion Kurtosis Imaging (DKI) and Generalized Q-sampling Imaging (GQI). Again, these methods can be used in both mice and humans in a directly comparable fashion. We have validated DTI in a mouse model of TBI using direct, quantitative comparison of DTI signal abnormalities to histological and electron microscopic “gold-standards.” (Mac Donald et al, Exp Neurol 2007; Mac Donald et al, J Neurosci 2007) DTI appears to be considerably more sensitive to white matter injury than conventional imaging methods, and we have used this method to reveal specific regions of vulnerability to blast-related TBI in studies of US military personnel (Mac Donald et al, N Engl J Med 2011, Mac Donald et al PLoS1 2013). Despite these findings, DTI has substantial limitations, and in ongoing research we are developing and validating more advanced MRI methods using radiological-pathological correlations in post-mortem human brains. This line of research has the potential to revolutionize the way concussion is diagnosed and the extent of injury is assessed, as well as allowing development of in vivo pharmacodynamic biomarkers for therapeutics targeting traumatic axonal injury.
The third major line of research involves purification and characterization of soluble amyloid-beta aggregates (also known as oligomers) from human brain tissue. We have previously shown that quantitative measures of soluble amyloid-beta aggregate concentration in brain lysates can be used to fully differentiate samples from patients with dementia vs. high pathology non-demented controls with no overlap between groups, even though the extent of amyloid-beta plaque pathology was identical between groups. (Esparza et al Annals Neurol 2013). Research from many laboratories around the world has indicated that the soluble amyloid-beta aggregates from human brain may be substantially more toxic than synthetic aggregates or aggregates from other sources. We therefore are engaged in a concerted effort to purify soluble amyloid-beta aggregates from human brain tissue obtained from the well characterized bank of over 1000 brains in the Washington University Knight Alzheimer’s Disease Research Center. With our collaborators, we are performing detailed characterization of the structure and toxicity of these aggregates, and directly compare them with soluble amyloid-beta aggregates derived from animal models of Alzheimer’s disease. This line of investigation has the potential to reveal the root cause of dementia in Alzheimer’s disease, open up major new therapeutic targets and serve to determine which, if any, animal models accurately recapitulate the soluble amyloid-beta aggregates in human brain.

Selected Publications:

CL Mac Donald, AM. Johnson, L Wierzechowski, E Kassner, T Stewart, EC Nelson, NJ Werner, D Zonies, J Oh, R Fang, DL Brody “Prospectively Assessed Clinical Outcomes in Concussive Blast vs. Non-blast Traumatic Brain Injury in Evacuated US Military Personnel.” JAMA Neurology; 71(8):994-1002 (2014). doi: 10.1001/jamaneurol.2014.1114

TJ Esparza, H Zhao, JR Cirrito, NJ Cairns, RJ Bateman, DM Holtzman and D.L. Brody “Amyloid-beta Oligomerization in Alzheimer Dementia vs. High Pathology Controls” Annals of Neurology 2012 doi: 10.1002/ana.23748.

S. Magnoni, T. J. Esparza, V. Conte, M. Carbonara, G. Carrabba, D. M. Holtzman , G. J. Zipfel, N. Stocchetti, and D. L. Brody, “Tau Elevations in the Brain Extracellular Space Correlate with Reduced Amyloid-β Levels and Predict Adverse Clinical Outcomes after Severe Traumatic Brain Injury” Brain 71: 116-29, 2012

H.T. Tran, F.M, LaFerla, D.M. Holtzman, and D.L. Brody, “Controlled Cortical Impact Traumatic Brain Injury in 3xTg-AD Mice Causes Acute Intra-axonal Amyloid-beta Accumulation and Independently Accelerates the Development of Tau Abnormalities.” Journal of Neuroscience 31: 9513-9524, 2011.

C.L. Mac Donald, A.M. Johnson, D Cooper, EC Nelson, N.J. Werner, J.S. Shimony, A.Z. Snyder, M.E. Raichle, J.R. Witherow, R. Fang, S.F. Flaherty, and D.L. Brody, “Detection of Blast-Related Traumatic Brain Injury in US Military Personnel.” New England Journal of Medicine 364 2091-2100 2011.

D.L. Brody, S. Magnoni, K.E. Schwetye, M.L. Spinner, T. J. Esparza, N.Stocchetti, G. J. Zipfel, D. M. Holtzman. “Amyloid-β Dynamics Correlate with Neurological Status in the Injured Human Brain”, Science 321, 1221-1224, 2008.

Last Updated: 8/23/2016 1:37:15 PM

Back To Top

Follow us: